J Neurol Res

Journal of Neurology Research, ISSN 1923-2845 print, 1923-2853 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Neurol Res and Elmer Press Inc

Journal website https://www.neurores.org

Original Article

Volume 14, Number 2, December 2024, pages 49-58

Assessing Internal Reproducibility Within a Parkinson’s Disease Cohort by Leveraging an Independent Larger Dataset

Figure 1. Principal component analysis of the discovery cohort (n = 179) based on demographic, motor, and nonmotor characteristics demonstrated two PD subtypes (after imputing missing data and controlling for disease duration). (a) Scatter plot depicting separation of subjects across the first two principal components. (b) Heatmap of clinical characteristics for each cluster identified. The greater red hue indicates greater prevalence, greater blue hue indicates lower prevalence. Traits with a statistically significant difference between clusters, defined as Bonferroni corrected P < 0.05, are indicated with an asterix (*). PD: Parkinson’s disease; RBD: REM-sleep behavior disorder; MAO: monoamine oxidase; PIGD: postural instability and gait disorder; GBA: glucocerebrosidase; LRRK2: leucine-rich repeat kinase 2; H&Y: Hoehn and Yahr scale; PC: principal component.

Figure 2. Principal component analysis of the PPMI cohort (n = 368) based on demographic, motor, and nonmotor characteristics demonstrated three PD subtypes. (a) Scatter plot depicting separation of subjects across the first two principal components. (b) Heatmap of clinical characteristics for each cluster identified, with data scaled using z-scores. The greater red hue indicates more severe impairment or greater number of years; greater blue hue indicates less severe impairment or fewer number of years. Traits with a statistically significant difference between clusters as determined via ANOVA for continuous data and Chi-square for categorical data, defined as Bonferroni corrected P < 0.05, are indicated with an asterix (*). PD: Parkinson’s disease; PPMI: Parkinson’s Progression Markers Initiative; RBD: REM-sleep behavior disorder; UPSIT: University of Pennsylvania Smell Identification Test; MDS-UPDRS: Movement Disorder Society - Unified Parkinson's Disease Rating Scale; MoCA: Montreal Cognitive Assessment; GDS: Geriatric Depression Scale; STAI: State-Trait Anxiety Inventory; SCOPA: Scales for Outcome in Parkinson’s Disease; ESS: Epworth Sleepiness Scale; QUIP: Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease; PC: principal component; ANOVA: analysis of variance; REM: rapid eye movement.

Figure 3. Cluster membership of subjects in Discovery cohort remained largely unchanged after re-clustering based on a limited selection of traits. Pink represents subjects assigned to cluster 1 in both analyses. Blue represents subjects assigned to cluster 2 in both analyses. Purple indicates subjects originally assigned to cluster 1 who were reassigned to cluster 2. Black indicates subjects originally assigned to cluster 2 who were reassigned to cluster 1. PC: principal component.

**Table 1.** Demographic Characteristics for PPMI and Discovery Cohorts at Baseline
	PPMI cohort	Discovery cohort
PPMI: Parkinson’s Progression Markers Initiative; F: female; M: male; SD: standard deviation.
Gender count (%)	M: 242 (66%)/F: 126 (34%)	M: 113 (63%)/F: 66 (37%)
Age at symptom onset (mean ± SD)	61.9 ± 8.8	59.9 ± 9.4
Average current age (mean ± SD)	61.9 ± 8.8	68.7 ± 8.5
Disease duration (mean ± SD)	0.54 ± 0.55 years	8.8 ± 5.1 years
Family history of PD count (%)	Yes: 93 (25%)/no: 275 (75%)	Yes: 105 (59%)/no: 74 (41%)

Table 1. Demographic Characteristics for PPMI and Discovery Cohorts at Baseline

PPMI cohort

Discovery cohort

PPMI: Parkinson’s Progression Markers Initiative; F: female; M: male; SD: standard deviation.

Gender count (%)

M: 242 (66%)/F: 126 (34%)

M: 113 (63%)/F: 66 (37%)

Age at symptom onset (mean ± SD)

61.9 ± 8.8

59.9 ± 9.4

Average current age (mean ± SD)

61.9 ± 8.8

68.7 ± 8.5

Disease duration (mean ± SD)

0.54 ± 0.55 years

8.8 ± 5.1 years

Family history of PD count (%)

Yes: 93 (25%)/no: 275 (75%)

Yes: 105 (59%)/no: 74 (41%)

**Table 2.** Comparison of Discovery Cohort Clusters
	Cluster 1 (n = 92)	Cluster 2 (n = 87)	Uncorrected P value	Bonferroni corrected P value
Characterization of clinical clusters of the Discovery cohort (n = 179) was based on principal component analysis (PCA) and nonhierarchical k-means clustering analysis. Uncorrected and Bonferoni corrected P values are also shown (traits with P < 0.05 were considered to be significantly different between the two clusters) from Chi-square analysis, unless otherwise specified (^tunpaired t-test, ^WWilcoxon test). ^aVariables that were collected in both the PPMI and Discovery cohorts. The other traits were determined by chart review (MSMD subset) or by interview (NYU subset). Tremor dominant (TD) and Postural Instability and Gait Disorder (PGID) phenotypes were defined based on Movement Disorder Society-Unified Parkinson’s disease rating scale (MDS-UPDRS) score [13]. F: female; M: male; MAOi: monoamine oxidase inhibitor; RBD: REM-sleep behavior disorder; REM: rapid eye movement; SD: standard deviation.
Gender^a count (%)	M: 63 (68%)	M: 50 (57%)	0.158	1
	F: 29 (32%)	F: 37 (43%)
Age at diagnosis^a (year)^t (mean ± SD)	58.5 ± 9.6	61.4 ± 9.0	0.0334	0.735
Disease duration^a (year)^W (mean ± SD)	8.7 ± 5.4	8.9 ± 4.9	0.609	1
+GBA mutation count (%)	13 (14%)	15 (17%)	0.189	1
TD^a count (%)	38 (41%)	22 (25%)	0.252	1
PIGD count (%)	24 (26%)	32 (37%)	0.258	1
Hoehn & Yahr scale (score count)	1:14	1:10	0.444	1
	1.5:18	1.5:8
	2:52	2:44
	2.5:4	2.5:10
	3:3	3:12
	4:1	4:2
	5:0	5:1
Wearing off count (%)	29 (32%)	40 (46%)	0.349	1
Dyskinesias count (%)	23 (25%)	36 (41%)	0.028	0.62
Freezing of gait count (%)	16 (17%)	39 (45%)	0.179	1
Depression^a count (%)	12 (13%)	71 (82%)	< 0.001	< 0.001
Anxiety^a count (%)	7 (7.6%)	73 (84%)	< 0.001	< 0.001
Hallucinations count (%)	6 (6.5%)	21 (24%)	0.302	1
Cognitive impairment^a count (%)	0 (0%)	6 (6.9%)	0.387	1
Orthostatic hypotension^a count (%)	20 (22%)	45 (52%)	0.015	0.33
Constipation^a count (%)	46 (50%)	71 (82%)	0.059	1
Urinary symptoms^a count (%)	39 (42%)	37 (43%)	0.314	1
RBD^a count (%)	32 (35%)	46 (53%)	0.367	1
Aspirin count (%)	18 (19%)	21 (26%)	0.15	1
Dopaminergic agent count (%)	74 (80%)	74 (85%)	0.265	1
MAOi count (%)	22 (24%)	10 (11%)	0.321	1

Table 2. Comparison of Discovery Cohort Clusters

Cluster 1 (n = 92)

Cluster 2 (n = 87)

Uncorrected P value

Bonferroni corrected P value

Characterization of clinical clusters of the Discovery cohort (n = 179) was based on principal component analysis (PCA) and nonhierarchical k-means clustering analysis. Uncorrected and Bonferoni corrected P values are also shown (traits with P < 0.05 were considered to be significantly different between the two clusters) from Chi-square analysis, unless otherwise specified (^tunpaired t-test, ^WWilcoxon test). ^aVariables that were collected in both the PPMI and Discovery cohorts. The other traits were determined by chart review (MSMD subset) or by interview (NYU subset). Tremor dominant (TD) and Postural Instability and Gait Disorder (PGID) phenotypes were defined based on Movement Disorder Society-Unified Parkinson’s disease rating scale (MDS-UPDRS) score [13]. F: female; M: male; MAOi: monoamine oxidase inhibitor; RBD: REM-sleep behavior disorder; REM: rapid eye movement; SD: standard deviation.

Gender^a count (%)

M: 63 (68%)

M: 50 (57%)

0.158

F: 29 (32%)

F: 37 (43%)

Age at diagnosis^a (year)^t (mean ± SD)

58.5 ± 9.6

61.4 ± 9.0

0.0334

0.735

Disease duration^a (year)^W (mean ± SD)

8.7 ± 5.4

8.9 ± 4.9

0.609

+GBA mutation count (%)

13 (14%)

15 (17%)

0.189

TD^a count (%)

38 (41%)

22 (25%)

0.252

PIGD count (%)

24 (26%)

32 (37%)

0.258

Hoehn & Yahr scale (score count)

1:14

1:10

0.444

1.5:18

1.5:8

2:52

2:44

2.5:4

2.5:10

3:3

3:12

4:1

4:2

5:0

5:1

Wearing off count (%)

29 (32%)

40 (46%)

0.349

Dyskinesias count (%)

23 (25%)

36 (41%)

0.028

0.62

Freezing of gait count (%)

16 (17%)

39 (45%)

0.179

Depression^a count (%)

12 (13%)

71 (82%)

< 0.001

Anxiety^a count (%)

7 (7.6%)

73 (84%)

< 0.001

Hallucinations count (%)

6 (6.5%)

21 (24%)

0.302

Cognitive impairment^a count (%)

0 (0%)

6 (6.9%)

0.387

Orthostatic hypotension^a count (%)

20 (22%)

45 (52%)

0.015

0.33

Constipation^a count (%)

46 (50%)

71 (82%)

0.059

Urinary symptoms^a count (%)

39 (42%)

37 (43%)

0.314

RBD^a count (%)

32 (35%)

46 (53%)

0.367

Aspirin count (%)

18 (19%)

21 (26%)

0.15

Dopaminergic agent count (%)

74 (80%)

74 (85%)

0.265

MAOi count (%)

22 (24%)

10 (11%)

0.321

**Table 3.** Comparison of Demographic and Clinical Characteristics of the Three Clusters From the PPMI Cohort
	Cluster 1 (n = 71)	Cluster 2 (n = 142)	Cluster 3 (n = 155)	Bonferroni corrected P value
Characterization of clinical clusters of the PPMI cohort (n = 368) was based on principal component analysis (PCA) and nonhierarchical k-means clustering analysis. Uncorrected and Bonferoni corrected P values are also shown (traits with P < 0.05 were considered to be significantly different between the two clusters) from ANOVA analysis, unless otherwise specified (^cChi-square). ^aVariables that were collected in both the PPMI and Discovery cohorts. ^bData that were collected from screening visit instead of baseline visit, due to data availability. Tremor dominant (TD) and Postural Instability and Gait Disorder (PGID) phenotypes were defined based on Movement Disorder Society-Unified Parkinson’s disease rating scale (MDS-UPDRS) score [13]. Depression was defined as Geriatric Depression scale (GDS) score ≥ 10. Anxiety was defined as state-Trait Anxiety Inventory (STAI) score > 40. Cognitive impairment was defined as Montreal Cognitive Assessment (MOCA) score ≤ 25. Orthostatic hypotension, constipation, and urinary symptoms each was defined as Outcomes in Parkinson’s Disease-Autonomic Dysfunction (SCOPA-AUT) subscore > 0. REM behavior disorder was defined as REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) score ≥ 5. Impulse control disorder was defined as MDS-UPDRS subscore > 0. Daytime sleepiness was defined as Epworth Sleepiness Scale > 0. Cognitive impairment was defined as Montreal Cognitive Assessment (MOCA) score ≤ 25. PPMI: Parkinson’s Progression Markers Initiative; F: female; M: male; MAOi: monoamine oxidase inhibitor; RBD: REM-sleep behavior disorder; UPSIT: University of Pennsylvania Smell Identification Test; SD: standard deviation.
Gender^c count^a (%)	M: 37 (52%)	M: 90 (63%)	M: 115 (74%)	0.069
	F: 34 (48%)	F: 52 (37%)	F: 40 (26%)
Family history^c count^a (%)	Y: 20 (28%)	Y: 37 (26%)	Y: 36 (23%)	1
	N: 51 (72%)	N: 105 (74%)	N: 119 (77%)
Age at diagnosis (years) (mean ± SD)	61.1 ± 8.7	57.4 ± 7.6	66.4 ± 7.5	< 0.001
Disease duration (months) (mean ± SD)	5.8 ± 5.9	6.0 ± 6.3	7.2 ± 7.0	1
Motor symptoms (MDS-UPDRS part 3) (mean ± SD)	20.9 ± 7.5	15.0 ± 5.4	26.5 ± 8.0	< 0.001
PIGD (mean ± SD)	1.5 ± 1.4	0.64 ± 0.73	1.4 ± 1.2	1
TD (mean ± SD)	5.2 ± 3.4	4.5 ± 3.0	6.5 ± 3.7	0.008
Hoehn & Yahr^a scale^c (score count)	1:35	1:105	1:18	< 0.001
	2:36	2:37	2:135
			3:2
Depression (GDS)^a (mean ± SD)	5.9 ± 3.0	1.2 ± 1.3	1.7 ± 1.2	< 0.001
Anxiety (STAI)^a (mean ± SD)	90.4 ± 17.7	57.9 ± 12.0	59.6 ± 12.5	< 0.001
Cognitive function (MOCA)^{a, b} (mean ± SD)	27.1 ± 2.6	28.0 ± 1.9	26.5 ± 2.4	0.101
Orthostatic hypotension (SCOPA-AUT)^a (mean ± SD)	0.99 ± 1.2	0.28 ± 0.54	0.41 ± 0.67	< 0.001
Constipation (SCOPA-AUT)^a (mean ± SD)	1.9 ± 1.6	0.47 ± 0.78	1.2 ± 1.1	0.277
Urinary symptoms (SCOPA-AUT)^a (mean ± SD)	6.2 ± 6.6	3.2 ± 2.2	5.0 ± 4.9	1
Impulse control disorder (mean ± SD)	0.77 ± 1.02	0.15 ± 0.36	0.14 ± 0.40	< 0.001
Daytime sleepiness (mean ± SD)	6.8 ± 4.0	5.1 ± 3.2	6.1 ± 3.6	1
RBD (RBDSQ)^a (mean ± SD)	5.3 ± 2.9	3.1 ± 2.0	4.5 ± 2.8	1
Smell function (UPSIT) (mean ± SD)	21.2 ± 8.2	25.2 ± 7.7	20.0 ± 7.9	0.319

Table 3. Comparison of Demographic and Clinical Characteristics of the Three Clusters From the PPMI Cohort

Cluster 1 (n = 71)

Cluster 2 (n = 142)

Cluster 3 (n = 155)

Bonferroni corrected P value

Characterization of clinical clusters of the PPMI cohort (n = 368) was based on principal component analysis (PCA) and nonhierarchical k-means clustering analysis. Uncorrected and Bonferoni corrected P values are also shown (traits with P < 0.05 were considered to be significantly different between the two clusters) from ANOVA analysis, unless otherwise specified (^cChi-square). ^aVariables that were collected in both the PPMI and Discovery cohorts. ^bData that were collected from screening visit instead of baseline visit, due to data availability. Tremor dominant (TD) and Postural Instability and Gait Disorder (PGID) phenotypes were defined based on Movement Disorder Society-Unified Parkinson’s disease rating scale (MDS-UPDRS) score [13]. Depression was defined as Geriatric Depression scale (GDS) score ≥ 10. Anxiety was defined as state-Trait Anxiety Inventory (STAI) score > 40. Cognitive impairment was defined as Montreal Cognitive Assessment (MOCA) score ≤ 25. Orthostatic hypotension, constipation, and urinary symptoms each was defined as Outcomes in Parkinson’s Disease-Autonomic Dysfunction (SCOPA-AUT) subscore > 0. REM behavior disorder was defined as REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) score ≥ 5. Impulse control disorder was defined as MDS-UPDRS subscore > 0. Daytime sleepiness was defined as Epworth Sleepiness Scale > 0. Cognitive impairment was defined as Montreal Cognitive Assessment (MOCA) score ≤ 25. PPMI: Parkinson’s Progression Markers Initiative; F: female; M: male; MAOi: monoamine oxidase inhibitor; RBD: REM-sleep behavior disorder; UPSIT: University of Pennsylvania Smell Identification Test; SD: standard deviation.

Gender^c count^a (%)

M: 37 (52%)

M: 90 (63%)

M: 115 (74%)

0.069

F: 34 (48%)

F: 52 (37%)

F: 40 (26%)

Family history^c count^a (%)

Y: 20 (28%)

Y: 37 (26%)

Y: 36 (23%)

N: 51 (72%)

N: 105 (74%)

N: 119 (77%)

Age at diagnosis (years) (mean ± SD)

61.1 ± 8.7

57.4 ± 7.6

66.4 ± 7.5

< 0.001

Disease duration (months) (mean ± SD)

5.8 ± 5.9

6.0 ± 6.3

7.2 ± 7.0

Motor symptoms (MDS-UPDRS part 3) (mean ± SD)

20.9 ± 7.5

15.0 ± 5.4

26.5 ± 8.0

< 0.001

PIGD (mean ± SD)

1.5 ± 1.4

0.64 ± 0.73

1.4 ± 1.2

TD (mean ± SD)

5.2 ± 3.4

4.5 ± 3.0

6.5 ± 3.7

0.008

Hoehn & Yahr^a scale^c (score count)

1:35

1:105

1:18

< 0.001

2:36

2:37

2:135

3:2

Depression (GDS)^a (mean ± SD)

5.9 ± 3.0

1.2 ± 1.3

1.7 ± 1.2

< 0.001

Anxiety (STAI)^a (mean ± SD)

90.4 ± 17.7

57.9 ± 12.0

59.6 ± 12.5

< 0.001

Cognitive function (MOCA)^{a, b} (mean ± SD)

27.1 ± 2.6

28.0 ± 1.9

26.5 ± 2.4

0.101

Orthostatic hypotension (SCOPA-AUT)^a (mean ± SD)

0.99 ± 1.2

0.28 ± 0.54

0.41 ± 0.67

< 0.001

Constipation (SCOPA-AUT)^a (mean ± SD)

1.9 ± 1.6

0.47 ± 0.78

1.2 ± 1.1

0.277

Urinary symptoms (SCOPA-AUT)^a (mean ± SD)

6.2 ± 6.6

3.2 ± 2.2

5.0 ± 4.9

Impulse control disorder (mean ± SD)

0.77 ± 1.02

0.15 ± 0.36

0.14 ± 0.40

< 0.001

Daytime sleepiness (mean ± SD)

6.8 ± 4.0

5.1 ± 3.2

6.1 ± 3.6

RBD (RBDSQ)^a (mean ± SD)

5.3 ± 2.9

3.1 ± 2.0

4.5 ± 2.8

Smell function (UPSIT) (mean ± SD)

21.2 ± 8.2

25.2 ± 7.7

20.0 ± 7.9

0.319