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Cognitive change in Parkinson's disease

Broeders, M.

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Download date: 25 Sep 2018

53

CHAPTER 4

Evolution of mild cognitive

impairment in Parkinson’s disease Mark Broeders, Rob de Bie, Daan C. Velseboer, Johannes D. Speelman, Dino Muslimovic, Ben Schmand Neurology (2013). Vol. 81, pp. 346–352.

Chapter 4

54

ABSTRACT

Objective: We examined the development of Parkinson disease (PD)–mild cognitive impairment (MCI) in patients with newly diagnosed PD over 5 years using recently proposed consensus criteria, and we assessed the reliability of the criteria. Methods: Patients with PD (n = 123) underwent extensive neuropsychological testing at baseline, and after 3 (n = 93) and 5 years (n = 59). Two neuropsychologists independently applied the PD-MCI criteria to examine the interrater and intrarater reliability. Results: At baseline, 35% of patients had PD-MCI. Three years later, 53% of the patients had PD-MCI. At 5-year follow-up, 20 patients who had PD-MCI at an earlier assessment had converted to PD dementia and 50% of the remaining patients without dementia had MCI. The interrater reliability (kappa) was 0.91. The intrarater reliabilities were 0.85 and 0.96. Conclusion: Approximately one-third of patients with newly diagnosed PD fulfill the consensus criteria for PD-MCI; after 5 years, this proportion is approximately 50% of patients without dementia. The criteria have good interrater and intrarater reliability.

Evolution of PD-MCI

55

INTRODUCTION

Mild cognitive impairment (MCI) refers to the stage between normal aging and dementia (Petersen et al., 2001). MCI was originally used to describe prodromal Alzheimer disease (AD). More recently, MCI has become important in studies on Parkinson disease (PD) (Litvan et al., 2011), and is called MCI in PD (PD-MCI) (Litvan et al., 2012). Whereas MCI due to AD is primarily characterized by memory impairment, cognitive deficits of PD-MCI more often concern executive functioning and attention (Ceravolo, Pagni, Tognoni, & Bonuccelli, 2012; Muslimovic, Post, Speelman, & Schmand, 2005).

Previous studies have been hindered by lack of standard criteria for PD-MCI. Some studies used lenient psychometric criteria (Janvin, Larsen, Aarsland, & Hugdahl, 2006), while others applied stringent criteria (Huang et al., 2008). A recent report showed how different criteria influence the outcomes (Dalrymple-Alford et al., 2011). In the same cohort, 14% of the patients were identified with PD-MCI using strict criteria (i.e., 2 scores per cognitive domain at 2 SD below the norm), while as many as 89% had PD-MCI by less rigid criteria (i.e., 1 score per domain at 1 SD below the norm).

Recently, a Movement Disorder Society (MDS) task force proposed consensus criteria for PD-MCI (Litvan et al., 2012). We applied these criteria to examine PD-MCI and its progression to PD dementia (PDD) in a hospital-based cohort of newly diagnosed patients. We previously reported on cognitive decline in this cohort (Broeders et al., 2013; Muslimovic et al., 2005; Muslimovic, Post, Speelman, De Haan, & Schmand, 2009). However, we defined decline by statistical criteria, not by clinical consensus criteria. Here we reanalyzed the data to examine the prevalence of PD-MCI and its development over the course of 5 years. We also examined the reliability of the consensus criteria.

Chapter 4

56

METHODS

Participants

Between 2002 and 2005, 145 consecutive patients with newly diagnosed PD were referred from neurology outpatient clinics in Amsterdam and surrounding areas to this part of the CARPA study (Comorbidity and Aging in Rehabilitation Patients with sequelae of poliomyelitis, osteoarthritis, and PD: the influence on Activities). The inclusion criterion was incident idiopathic PD (Gelb, Oliver, & Gilman, 1999). Patients were excluded if they were older than 85 years, had a history of stroke, had a Mini-Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, 1975) score <24, or had insufficient knowledge of the Dutch language. Eight patients did not have PD, 2 patients did not speak Dutch, 1 patient had been diagnosed with PD 2 years before, and 1 patient withdrew consent. Thus, 133 patients were included. The diagnosis was checked twice during the course of the study by a neurologist (J.S.). Four patients received a revised diagnosis (diffuse Lewy body disease, multiple system atrophy, progressive supranuclear palsy, and dystonic tremor).

The control group (n=70) consisted of friends, family, or spouses of the patients. None had impairments in hearing or visual acuity, history of major psychiatric disorder, head injury with loss of consciousness for more than 1 hour, cerebrovascular disease or other CNS illness, drug or alcohol abuse, or were currently taking psychoactive medication. Controls participated in the neuropsychological evaluation only (see below).

Standard protocol approvals, registrations, and patient consents Written informed consent was obtained from all participants. The institutional review boards of the participating hospitals approved the study.

Neurologic and functional assessment A trained nurse practitioner evaluated physical functioning yearly, except for year 4. Motor impairments were scored with the Unified Parkinson’s Disease Rating Scale (UPDRS) motor section (Fahn & Elton, 1987). Disease stage was rated with the Hoehn & Yahr scale (H&Y) (Hoehn & Yahr, 1967), and functional disability with Barthel Activities of Daily Living (Collin, Wade, Davies, & Horne, 1988), Schwab & England scale (SE-ADL) (Schwab & England, 1969), and Functional Independence Measure (FIM) (van der Putten, Hobart, Freeman, & Thompson, 1999). The Parkinson's Disease Quality of Life questionnaire (PDQL) (de Boer, Wijker, Speelman, & de Haes, 1996) was used to score quality of life. We obtained information on medication with a semi-structured interview. Mood symptoms were measured with the Hospital Anxiety and Depression Scale (HADS) (Zigmond & Snaith, 1983).

Evolution of PD-MCI

57

Neuropsychological assessment All patients who consented underwent neuropsychological testing at baseline and 3- and 5-year follow-up. For assessment of PD-MCI, we used tests that cover 5 cognitive domains (i.e., memory, language, executive functioning, visuospatial skills, and attention) (Litvan et al., 2012). Memory was evaluated using Rey Auditory Verbal Learning Test (Rey, 1964) and Rivermead Behavioral Memory Test logical memory subtest (Wilson, Cockburn, & Baddeley, 1985). Language was assessed with a 30-item Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1983) and Wechsler Adult Intelligence Scale–III (Wechsler, 1997a) Similarities subtest. Executive functioning was studied using the Modified Wisconsin Card Sorting Test (Nelson, 1976) and Controlled Oral Word Association Test (A. Benton, Hamsher, & Sivan, 1983). Visuospatial abilities were examined with clock drawing (Royall, Cordes, & Polk, 1998) and Judgment of Line Orientation (A. L. Benton, Hamsher, Varney, & Spreen, 1983). Attention was investigated using Wechsler Adult Intelligence Test–Revised Digit Symbol Test (Wechsler, 1981) and Trail Making Test part A (Reitan, 1992). Global cognitive functioning was measured with the MMSE and premorbid intelligence with the Dutch version of the National Adult Reading Test (Schmand, Lindeboom, & Harskamp, 1992).

Application of PD-MCI criteria PD-MCI criteria (Litvan et al., 2012) require 1) PD diagnosis, 2) gradual cognitive decline reported by the patient, relatives, or the clinician, 3) deficits at cognitive testing, 4) these deficits do not significantly interfere with functional independence. The cognitive deficits may not be attributable to causes other than PD. The criteria distinguish 2 levels of PD-MCI, which differ in extensiveness of cognitive assessment and level of diagnostic certainty. We used level II guidelines, and distinguished between single- and multi-domain PD-MCI.

We derived subjective cognitive complaints from 2 PDQL questions on memory and concentration. Subjective decline was defined as an answer of frequently (or more often) on at least one of these questions. Information from relatives or other informants or observations by the treating neurologist were lacking. Therefore, we decided that a subject without subjective complaints on the PDQL could still be diagnosed with PD-MCI if he or she scored at least 1.5 SD below the demographically corrected mean on at least 4 tests. We reasoned that cognitive decline of a patient with that amount of abnormal test results would not go unnoticed by his or her relatives or doctor. This strategy was used for all controls, due to absence of information about subjective complaints. Tests with more than one score (e.g., Rey Auditory Verbal Learning Test immediate and delayed recall) were considered abnormal if at least one of the scores was abnormal. Cognitive decline may also be based on results of repeated testing. Thus,

Chapter 4

58

at follow-up a subject could be diagnosed with PD-MCI when there were abnormal score declines for at least 2 tests (see Statistical analyses).

In case of subjective decline, cognitive deficits were defined as impaired performance, i.e., a score at least 1.5 SD below the demographically corrected mean, on at least 2 neuropsychological tests: either 2 tests within 1 domain (single-domain PD-MCI) or at least 1 test in 2 or more domains (multiple-domain PD-MCI).

Functional independence was defined as scores >5 on each of FIM items 14 to 18. These items evaluate cognition-related activities of daily living, independent of motor impairment. They cover language comprehension and expression, social interaction, problem solving, and memory. Lower scores indicate disturbances in these areas.

Two neuropsychologists (M.B., B.S.) independently applied the PD-MCI criteria to each patient's neuropsychological results. In case of disagreement, they independently re-examined the protocols. If these still diverged, they discussed until agreement was reached.

PDD criteria PDD was diagnosed by MDS criteria (Emre et al., 2007). Criteria for probable PDD are a diagnosis of PD before the onset of dementia, MMSE score <26, absence of depression, cognitive deficits severe enough to interfere with daily living, and impairments on at least 2 of the following tests: MMSE serial 7s, pentagon copying, 3-word recall, or clock drawing. We defined impaired daily living as a score ≤5 on one or more of FIM questions 14 to 18. A HADS score <23 indicated the absence of depression. The PDD diagnosis did not require neuropsychological evaluation.

Statistical analyses Raw test scores were standardized and corrected for age, sex, and education based on multiple regression analyses of the control group data. Missing neuropsychological data were imputed as described elsewhere (Broeders et al., 2013).

To identify decline at 3- and 5-year follow-up, we calculated a modified Reliable Change Index (mRCI) for each test (Chelune, Naugle, Lüders, Sedlak, & Awad, 1993), based on the performance of the control group. mRCI is the subject's change score corrected for retest effects (i.e., x2–x1–R) divided by the standard error of the difference between the 2 scores. An mRCI of −1.65 or lower indicates abnormal decline compared to previous performance at p < 0.05 (one-tailed).

Interrater and intrarater reliabilities were calculated using the kappa statistic. Group differences (controls, patients with PD with and without MCI) in clinical and demographic characteristics were analyzed using analyses of variance, χ2, and Kruskal-Wallis tests. We compared cognitive performance of these groups at each measurement

Evolution of PD-MCI

59

by multivariate analyses of covariance on the neuropsychological tests of each cognitive domain with sex, years of education, and age as covariates, and group as independent variable. If a main effect was found, analyses of covariance were performed for each neuropsychological test.

Chapter 4

60

RESULTS

Subjects Seven patients refused neuropsychological assessment, 2 had insufficient knowledge of Dutch to take the tests, and 1 patient had a stroke before assessment. Thus, at baseline 123 patients and 70 controls remained. Three years later, 93 patients and 64 controls participated in the neuropsychological part, and at 5-year follow-up 59 patients and 40 controls participated. The attrition has been extensively described elsewhere (Broeders et al., 2013; Muslimovic et al., 2009) and here in figure 1. Note that we were able to diagnose PDD in patients who were lost to neuropsychological follow-up because clinical data could still be obtained from most of them.

Figure 1. Overview of patients (A) and controls (B) who participated in the present study and those who were lost to follow-up.

At baseline, 43 patients had PD-MCI (35.0% of 123 patients; 95% confidence interval [CI] 26.4%–43.6%); 3 years later, 47 patients (53.4% of 88 patients without PDD; 95% CI 42.8%–64%); and 5 years later, 28 patients (50.0% of 56 patients without PDD; 95% CI 36.6%–64.4%). Demographic and clinical data are shown in table 1.

Evolution of PD-MCI

61

Table 1 Demographic and clinical variables at baseline, 3-year follow-up, and 5-year follow-up for healthy

controls, patients with PD without MCI, and patients with PD with MCI Baseline Year 3 Year 5

HCS N = 70

No MCI N = 80

MCI N = 43

HCS N = 64

No MCI N = 41

MCI N = 47

HCS N = 40

No MCI N = 28

MCI N = 28

Age (yrs) 63.7 (7.3)

65.1 (10.6) 68.2 (8.1) 66.7

(7.4) 65.0 (10.3)

70.3 (8.8)ǂ

66.9 (6.6)

63.8 (7.8)

69.5 (9.6)ǂ

Sex (M/F) 37 / 33 43 / 37 23 / 20 34 / 30 19 / 22

28 / 19 22 / 18 11 / 17 19 / 9

DART-IQ 106 (17) 107 (21) 96 (20)*

ǂ 106 (16)

105 (19)

102 (24)

105 (15) 101 (18) 99 (22)

MMSE 28.3 (1.4)

28.0 (1.9) 27.0 (2.0)*

ǂ 28.1 (1.4)

28.4 (1.3)

27.3 (1.7)*

ǂ 29.1 (1.0)

28.6 (1.3)

27.1 (2.4)*

ǂ Disease duration 18.3

(8.9) 20.0 (13.4) 53.1 (7.1)

56.9 (14.3) 77.8

(7.1) 80.1 (8.7)

LED (mg) 139 (143) 150 (139) 403

(310) 440 (249) 681

(274) 660 (233)

UPDRS part III 15.8 (7.8) 19.4 (7.8)ǂ 22.4

(8.9) 27.4 (9.5)ǂ 22.7

(9.1) 26.0 (8.5)ǂ

Tremor 2.2 (1.8) 2.7 (2.0) 1.6 (2.0)

2.8 (3.5) 0.6

(0.8) 0.5 (0.9)

Bradykinesia 5.9 (3.2) 6.8 (3.2) 9.2

(4.3) 9.9 (3.4) 9.1

(3.8) 9.8 (3.4)

Axial symptoms 1.4

(2.0) 2.6 (2.0)ǂ 2.2 (2.5)

3.5 (2.5)ǂ 2.4

(3.2) 3.0 (1.6)ǂ

Scale A 12.2 (5.6) 14.20(5.2)ǂ 16.8

(6.3) 19.7 (7.1) 12.3

(4.2) 14.0 (4.0)

Scale B 1.8 (2.3) 3.1 (2.3)ǂ 2.9 (3.0)

4.7 (2.8)ǂ 2.6

(2.6) 4.3 (1.6)ǂ

HY Stage 1.6 (0.7) 2.1 (0.7)ǂ 2.4

(0.6) 2.7 (0.5)ǂ 2.3

(0.4) 2.6 (0.4)ǂ

Median 1.5 2.0 2.5 2.5 2.5 2.5

HADS 8.5 (6.6) 13.5 (7.5)ǂ 8.0

(5.2) 12.8 (6.8)ǂ 7.9

(5.4) 13.1 (7.8)ǂ

Depression 4.0 (3.6) 6.4 (3.6)ǂ 3.6

(2.9) 6.6 (3.6)ǂ 3.4

(3.0) 6.5 (3.8)ǂ

SE-ADL (%) 91.3 (5.8) 88.1 (7.9)ǂ 86.8

(12.7) 81.5 (13.4)ǂ 88.9

(5.1) 85.0 (7.5)ǂ

BADL 19.7 (0.7) 19.4 (1.5) 19.3

(2.2) 18.6 (2.6)ǂ 19.7

(0.8) 19.7 (0.5)

HCS=Healthy controls, No MCI=PD patients without MCI, MCI=PD patients with MCI, DART=Dutch Adult Reading Test, MMSE=Mini Mental State Examination, LED=Levodopa equivalent dose, UPDRS=Unified Parkinson’s Disease Rating Scale; the motor section, HY=Hoehn and Yahr scale, HADS=Hopsital Anxiety and Depression Rating Scale, SE-ADL=Schwab and England Activities of Daily Living, BADL=Behavioral Assessment of Daily Living, *=<.05 compared to HCS, ǂ=<.05 compared to PD patients without MCI. Patients with PD-MCI had lower MMSE scores than patients without PD-MCI and controls. Patients with PD-MCI also showed more motor symptoms (UPDRS, H&Y stage), mood symptoms (HADS), and functional disability (SE-ADL) than patients without PD-MCI.

Chapter 4

62

Interrater and intrarater agreement We performed 274 neuropsychological evaluations in the PD group. The raters obtained initial agreement on PD-MCI in 262 evaluations (95.6%). The interrater reliability was kappa = 0.91 (p < 0.001; 95% CI 0.87–0.96). The raters independently re-examined 92 randomly selected evaluations of the PD group 2 weeks after their first rating. For rater 1, intrarater reliability was 0.85 (p < 0.001; 95% CI 0.75–0.95), and for rater 2, reliability was 0.96 (p < 0.001; 95% CI 0.90–1.00).

Progression of PD-MCI Progression of PD-MCI is visualized in figure 2. Numbers of patients with single- or multiple-domain PD-MCI and numbers and percentages of impairments for each cognitive domain are shown in figures 3 and 4. At baseline, 43 patients had PD-MCI. Twenty-seven patients with and 4 patients without PD-MCI had complaints on the PDQL. Three years later, 31 of 43 patients with PD-MCI at baseline participated. Six had progressed to PDD; 2 patients previously had single-domain PD-MCI, the others had multiple-domain PD-MCI. Three patients without PD-MCI at baseline progressed to PDD. Twenty-five patients with PD-MCI and 12 patients without PD-MCI had complaints on the PDQL. Of 47 patients with PD-MCI after 3 years, 33 patients participated in the 5-year follow-up. Eight patients developed dementia, of whom 3 had

Figure 2. Progression of PD-MCI in patients with newly diagnosed PD at baseline (n = 123), after 3 years (n = 97), and after 5 years (n = 73)Numbers between brackets for PDD indicate the number of patients who participated in neuropsychological testing.

Evolution of PD-MCI

63

Figure 3. Number and percentage of patients with single domain PD-MCI and multiple domain PD-MCI at baseline (N=43), after three years (N=47) and five years (N=28). single-domain and 5 multiple-domain PD-MCI at the previous assessment. Seventeen patients with PD-MCI and 2 patients without had complaints on the PDQL. In contrast to patients, at baseline 1 (1.4% of 70) control subject fulfilled PD-MCI criteria (not counting the PD diagnosis criterion). After 3 years, 6 controls (9.4% of 64), and after 5 years, 1 control, had PD-MCI (2.5% of 40).

After 1 year, 122 patients participated in the clinical part of the study. Twenty of these patients (17% of 122) were diagnosed with PDD at the end of the study. Although PDD could be diagnosed without neuropsychological examination, the diagnosis did require at least one follow-up since PDD was excluded at baseline. We repeated these analyses with the subset of patients (n = 59) who completed all 3 neuropsychological assessments. At baseline, 16 patients (27.1%) had PD-MCI. Three years later, PD-MCI was diagnosed in 26 patients (44.1%) and PDD in 2 patients (3.4%). After 5 years, 25 patients (42.4%) had PD-MCI and 6 patients (10.2%) had PDD. All patients who progressed to PDD had PD-MCI at an earlier assessment.

Cognitive characteristics of patients with PD-MCI, patients without PD-MCI, and controls An overview of neuropsychological results for each group is shown in table 2. At baseline, with MANCOVAs we found a main effect in each cognitive domain. Subsequent univariate analyses showed that on all tests the patients with PD-MCI scored significantly lower than controls and patients without PD-MCI, except for the Modified Wisconsin CST perseverations where scores did not differ between patients with and MCI obtained lower scores than healthy controls on each memory test and on Substitution.

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64

Figure 4. Percentage of impairments in each cognitive domain (vertical axis) in newly-diagnosed PD patients at baseline (N=123), after three years (N=93), and after five years (N=59). Left panel: patients with single domain PD-MCI; right panel: patients with multiple domain PD-MCI.

Three years later, we again found a main effect for each cognitive domain. Post-hoc analyses showed that on each test, PD patients with PD-MCI scored lower than healthy controls and patients without PD-MCI. All differences were statistically significant, except for the differences between patients with and without PD-MCI on the BNT. PD patients without PD-MCI scored lower than healthy controls on every test, but these differences were significant for Substitution only.

At 5-year follow-up, main effects were seen again for each domain. PD patients with PD-MCI scored lower than the controls and patients without PD-MCI; however, the differences between patients with PD-MCI and controls did not reach statistical significance for Judgment Of Line Orientation. Also, the differences between the three groups did not reach statistical significance for the Boston Naming Test, although we did observe a trend for the difference between patients with and without PD-MCI (p=0.057). Patients without PD-MCI obtained lower scores than controls on each test, but only the difference on Substitution was significant.

Analysis of loss to follow-up Attrition is common in longitudinal cohort studies. This may result in selection bias, for instance, when the more severely impaired persons do not participate in the follow-up. The neuropsychological part of our study had a rather high attrition rate. Therefore, the true proportion of patients who suffer from PD-MCI may actually be larger than what we reported. The clinical part of our study had less attrition, so that we have some information about part of the patients who were lost to follow-up. To examine attrition more in detail, for each neuropsychological follow-up, we compared demographic and clinical variables at a previous time-point of participants who continued and those who were lost to follow-up. First, we compared baseline data

Evolution of PD-MCI

65

from patients without PD-MCI (N=41) and patients with PD-MCI (N=47) after three years with those who were lost to follow-up (N=25). Patients who were lost to follow-up and those who had PD-MCI at the three-year follow-up were significantly older and had lower MMSE scores at baseline than patients who remained without PD-MCI (see table 3). Patients with PD-MCI at three-year follow-up showed more baseline axial problems compared to patients without PD-MCI; the same trend was visible in those who were lost to follow-up.

A second set of similar analyses was conducted to compare three-year follow-up demographic and clinical data between patients with PD-MCI (N=28) and patients without PD-MCI (N=28) at five-year follow-up with patients who were lost to five-year follow-up (N=24). Demographic and clinical variables are shown in table 4. Compared to patients without PD-MCI after five years, patients who were lost to follow-up and those with PD-MCI were significantly older. Patients lost to follow-up also had higher UPDRS and HY scores, more axial symptoms, more motor impairments that are partially responsive or unresponsive to L-dopa (Levy Scale B), and higher scores on disability scales than patients without PD-MCI. Patients with PD-MCI did show more mood symptoms (HADS) than those without PD-MCI.

We hypothesized that our frequency estimation of PD-MCI is biased as a result of attrition. The results shown support this hypothesis. Patients who did not partake in follow-up examinations were older and showed significantly more clinical symptoms than patients without PD-MCI at previous assessments. Furthermore, clinical status of patients who were lost to neuropsychological follow-up was highly similar to clinical status of patients who were eventually identified with PD-MCI.

Sensitivity analysis of PD-MCI frequency estimates After three years, 88 non-demented patients participated in the neuropsychological follow-up and 9 patients had PDD. Thus, information of 26 patients is lacking. If we assume that none of these 26 patients had PD-MCI after three years, then the percentage of patients with PD-MCI at the three year follow-up would be 41.2% (47 of 114 non-demented PD patients). This is the theoretically lower bound of the frequency estimate at three years after PD diagnosis. In contrast, if all 26 patients would have PD-MCI after three years, the percentage would change to 64.0% (73 of 114 non-demented PD patients). This is the upper bound of the estimate. At five year follow-up, neuropsychological data were collected from 56 non-demented patients and an additional 17 patients were diagnosed with PDD. Thus, of the 97 patients from whom we had information at the three year follow-up, 24 were lost to follow-up after five years. If we assume that none of those 24 patients had PD-MCI after five years, the proportion of patients with PD-MCI at the five year follow-up would be

Chapter 4

66

Ta

ble

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raw

sco

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stan

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dev

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MC

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p <

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01

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32.8

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46.9

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45.8

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10.4

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19.8

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10.9

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18.9

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12.9

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14.7

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uage

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= 8.

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< 0

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< 0

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= 8.

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< 0

.001

BNT

**

55.5

(3.2

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51.7

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55.5

(2.9

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52.7

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53.5

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mila

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20.2

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; p <

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; p <

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M

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Evolution of PD-MCI

67

35.0% (lower bound of the estimate; 28 of 80 non-demented PD patients). However, if all 24 patients had PD-MCI, the proportion would increase to 65% (upper bound; 52 of 80 non-demented PD patients).

Given the results shown above, i.e. worse clinical status in patients who were lost to follow-up than those who continued to participate, the true proportion of patients with PD-MCI after three years is most likely higher than what we reported. We expect it to be between 53.4% (as shown in the manuscript) and 64.0%. After five years, the true proportion of patients with PD-MCI probably lies between 50.0% (as shown in the manuscript) and 65.0%.

Table 3. Baseline demographic and clinical variables for patients without PD-MCI at year 3 (N=41), patients with PD-MCI at year 3 (N=47), and patients who were lost to follow-up (N=25) at year 3. Mean and SD.

PD – no MCI N=41

PD – MCI N=47

Lost to follow-up N=25

Age (years) 61.9 (10.4) 67.21 (8.8)* 67.0 (12.0)*

MMSE 28.3 (1.7) 27.4 (1.7)* 27.3 (2.7)*

LED (mg) 129.3 (132.1) 175.3 (150.4) 101.2 (128.2)

UPDRS part III 16.3 (7.7) 16.9 (7.8) 16.6 (8.7)

Tremor 2.3 (2.0) 2.4 (2.1) 2.3 (1.5)

Bradykinesia 6.3 (3.0) 6.1 (3.2) 5.6 (3.3)

Axial symptoms 1.2 (1.8) 1.9 (1.9)* 1.8 (2.4)

Scale A 12.8 (5.6) 12.7 (5.5) 12.4 (5.6)

Scale B 1.8 (2.2) 2.4 (2.1) 2.2 (2.9)

HY Stage 1.6 (0.6) 1.8 (0.7) 1.8 (0.8)

HADS 9.9 (6.3) 10.8 (8.4) 9.0 (6.6)

Depression 4.4 (3.1) 5.0 (4.1) 4.5 (3.9)

SE-ADL (%) 89.3 (5.2) 90.9 (6.9) 90.8 (9.5)

BADL 19.7 (0.7) 19.6 (1.4) 19.4 (1.0)

PD - No MCI=PD patients without MCI, PD - MCI=PD patients with PD-MCI, MMSE=Mini Mental State Examination, LED=Levodopa equivalent dose, UPDRS=Unified Parkinson’s Disease Rating Scale; the motor section, Scale A=Motor impairments that are responsive to levodopa, Scale B=Motor symptoms that are partially responsive or unresponsive to levodopa, HY=Hoehn and Yahr scale, HADS=Hopsital Anxiety and Depression Rating Scale, SE-ADL=Schwab and England Activities of Daily Living, BADL=Behavioral Assessment of Daily Living, *=<.05 compared to PD patients without PD-MCI.

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Table 4. Demographic and clinical variables at three-year follow-up for patients without PD-MCI at five

year follow-up (N=28), patients with PD-MCI at five year follow-up (N=28), and patients who were lost to follow-up (N=24) at year 5. Mean and SD.

PD – no MCI N=28

PD – MCI N=28

Lost to follow-up N=24

Age (years) 61.7 (7.8) 67.3 (9.5)* 73.0 (9.3)*

MMSE 28.5 (1.4) 27.7 (1.9) 27.6 (1.4)

LED (mg) 261.2 (263.7) 428.3 (259.1) 490.3 (322.0)

UPDRS part III 20.9 (8.1) 24.4 (8.0) 28.3 (10.6)*

Tremor 1.7 (2.3) 2.2 (2.5) 2.9 (4.0)

Bradykinesia 8.6 (4.3) 9.3 (3.0) 10.5 (4.1)

Axial symptoms 2.0 (2.1) 2.5 (1.7) 3.8 (3.4)*

Scale A 15.9 (6.3) 17.9 (6.3) 20.2 (7.4)

Scale B 2.6 (2.4) 3.6 (2.0) 5.0 (3.6)*

HY Stage 2.3 (0.5) 2.5 (0.4) 2.8 (0.7)*

HADS 8.2 (5.3) 12.9 (6.2)* 10.5 (8.1)

Depression 3.6 (2.8) 6.0 (3.2)* 5.9 (4.8)

SE-ADL (%) 88.2 (7.7) 86.8 (4.8) 78.3 (20.4)*

BADL 19.7 (0.7) 19.6 (0.6) 17.7 (4.1)*

PD - No MCI=PD patients without MCI, PD - MCI=PD patients with PD-MCI, MMSE=Mini Mental State Examination, LED=Levodopa equivalent dose, UPDRS=Unified Parkinson’s Disease Rating Scale; the motor section, Scale A=Motor impairments that are responsive to levodopa, Scale B=Motor symptoms that are partially responsive or unresponsive to levodopa, HY=Hoehn and Yahr scale, HADS=Hopsital Anxiety and Depression Rating Scale, SE-ADL=Schwab and England Activities of Daily Living, BADL=Behavioral Assessment of Daily Living, *=<.05 compared to PD patients without PD-MCI.

Evolution of PD-MCI

69

DISCUSSION

We applied the new PD-MCI criteria to examine the prevalence of MCI and its development over the course of 5 years. In our cohort of newly diagnosed patients, about one-third fulfilled the criteria for PD-MCI at the time of diagnosis. After 3 and 5 years, the proportion increased to approximately 50%. All but 3 patients, who progressed to PDD, had been identified with PD-MCI at a previous assessment. Interrater and intrarater reliabilities for the criteria were good to excellent. Moreover, our experience is that the criteria are easy to apply, which adds to their usefulness in clinical practice.

The prevalence of 35% PD-MCI at baseline is largely in accordance with previous studies on cognitive impairments in newly diagnosed patients (Foltynie, Brayne, Robbins, & Barker, 2004), even though criteria and study samples differed. In a recent study (Dalrymple-Alford et al., 2011), the authors proposed criteria that provided the best balance between sensitivity and specificity for PD-MCI, viz 2 test scores below −1.5 SD within a single domain or 1 score below −1.5 SD in multiple domains. With these criteria, 30%–37% of their patients had PD-MCI, which is in line with our result. In our previous report (Muslimovic et al., 2005), we used a stricter criterion, which led to only 24% of patients being diagnosed with cognitive impairments. This discrepancy may reflect the cautious approach we adopted in our previous report. Another study reported an even lower percentage of PD-MCI (14.8%) in an otherwise similar cohort, but with slightly modified criteria (Poletti et al., 2012). This study ignored subjective complaints, used a fixed cutoff (−1.5 SD), and divided cognitive tests into domains in a different way than proposed by the consensus criteria. These methodological differences might explain the low percentage.

In contrast to previous findings, the majority of patients in our study had multiple-domain PD-MCI at baseline and after 3 years. However, previous studies often used fewer tests per domain (Janvin et al., 2006). Employing multiple tests in a domain, or using tests that are more sensitive to cognitive disorders, increases the chance of finding impairments. More in line with previous neuropsychological reports (Janvin et al., 2006), is the great diversity of cognitive impairments in our patients with multiple-domain PD-MCI, whereas cognitive impairment in patients with single-domain PD-MCI was mostly restricted to the attention domain. These subtypes of PD-MCI have been associated with different metabolic and pathologic abnormalities (Dalrymple-Alford et al., 2011; Lee et al., 2010; Lyoo, Jeong, Ryu, Rinne, & Lee, 2010). For instance, there are neuroanatomic differences, such as decreased gray matter density in the bilateral precuneus, left primary motor, and right parietal areas, in patients with amnestic PD-MCI compared to amnestic MCI in persons without PD (Lee et al., 2010). Furthermore, a PET study identified widespread cortical hypometabolism in patients with multiple-domain PD-MCI compared to patients with single-domain PD-MCI, which may be

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caused by emerging PDD pathology (Lyoo et al., 2010). However, these studies suffer from the methodological difficulties we described before, i.e., differences in PD-MCI criteria. It would be informative to replicate these findings using the new consensus criteria.

Longitudinal studies on PDD reported incidence rates of 15%–35% within 5 years after study onset (de Lau, Schipper, Hofman, Koudstaal, & Breteler, 2005; Hobson & Meara, 2004; Reid, Hely, Morris, Loy, & Halliday, 2011). So far, only one study has examined the prognostic value of PD-MCI (Janvin et al., 2006). In that study, 62% of patients with PD with MCI developed dementia within 4 years. In our study, approximately 17% developed PDD, and only 26% (11 of 43) of patients with PD-MCI at baseline progressed to dementia within 5 years. There are several explanations for this discrepancy. First, our subjects were relatively young and had short disease duration. Younger age is associated with longer survival without dementia (de Lau et al., 2005). Also, our cohort had mild disease severity compared to other studies (Hobson & Meara, 2004). Second, we used PDD criteria proposed by the MDS instead of DSM-III-R criteria. Furthermore, some studies based the PDD diagnosis exclusively on cognitive performance, without taking impaired daily living into account (de Lau et al., 2005). Third, while some studies similar to ours followed newly diagnosed patients (Foltynie et al., 2004), others examined the prevalence of PDD in cohorts with patients at various disease stages (de Lau et al., 2005; Hobson & Meara, 2004). Longer disease duration could be a contributing factor to PDD. Nonetheless, almost all our patients who progressed to PDD had been identified with PD-MCI at a previous assessment (baseline or 3-year follow-up). Thus, the concept of PD-MCI has, at least to some extent, prognostic value. Longer follow-up durations are necessary to establish the prognosis more thoroughly.

Our sample size was too small, and the follow-up interval too brief, to precisely estimate sensitivity (proportion of patients with PDD who have earlier been diagnosed with PD-MCI), specificity (proportion of patients who do not progress to PDD and who remain without PD-MCI), and predictive value of the consensus criteria. Specificity will probably be low because some patients may deteriorate only very slowly. To reliably estimate the positive predictive value of the PD-MCI criteria, low specificity rates need to be determined with high precision. Consequently, a proper validation of the PD-MCI criteria needs a study with a substantial sample size, for example more than 500 patients at baseline, and a long follow-up duration of, say, 8–10 years with regular examinations, for instance each year (Carley, Dosman, Jones, & Harrison, 2005).

Our study has limitations. First, we did not assess subjective cognitive complaints, or observation of cognitive decline by a relative, caregiver, or clinician, in a systematic way. We used questions on subjective complaints from a quality of life scale and applied more stringent psychometric criteria for patients without subjective

Evolution of PD-MCI

71

complaints, but this may not have been sensitive enough. Our criterion for cognitive decline in absence of subjective complaints was impaired performance on at least 4 tests. We believe this is acceptable as a second-best choice, but future studies should include a cognitive complaints interview and collect information from clinicians and caregivers. Second, the neuropsychological part has a high attrition rate. This led to selection bias. Patients who were lost to follow-up had greater disease severity and more cognitive impairment than those who continued to participate. Thus, the actual percentage of PD-MCI is somewhat higher than reported here. Third, our PD sample was hospital-based, possibly including many patients with relatively severe or complicated disease. However, ours is not very different from population-based samples (Foltynie et al., 2004).

Study funding Supported by the Prinses Beatrix fonds (grant PGO01-0138 to B.S.) and the Michael J. Fox Foundation (grant to B.S.). It is part of the CARPA project, sponsored by ZonMW.

Disclosure M. Broeders reports no disclosures. R. de Bie received an unrestricted fellowship grant from Medtronic (Minneapolis, MN). D. Velseboer, J. Speelman, D. Muslimovic, and B. Schmand report no disclosures. Go to Neurology.org for full disclosures.

Acknowledgement The authors thank Annick Gorissen, Dorien Standaar, Miranda Postma, Stefanie de Vries, and Nadine Fleitour, AMC research nurses, for their help in collecting the data; the participating hospitals for help with patient inclusion; and the patients and controls who participated in this study.