PPMI Cognitive-Behavioral
Working Group
Daniel Weintraub, MD
PPMI Annual Meeting - May 6-7, 2014
Membership
Daniel Weintraub – WG Chair
Tanya Simuni – Steering Committee
Shirley Lasch – IND
Chris Coffey, Chelsea Caspell-Garcia – Statistics Core
Roy Alcalay
Paolo Barone
Melanie Braddabur
David Burn
Cindy Casacelli
Lama Chahine
William Cho
Thomas Comery
Autilia Cozzolino
Johnna Devoto
Chris Dodds
Jamie Eberling
Alberto Espay
Stewart Factor
Hubert Fernandez
Regan Fong
Douglas Galasko
Sandeep Gupta
Keith Hawkins
David Hewitt
Jim Leverenz
Irene Litvan
Anita McCoy
Susanne Ostrowitzki
Bernard Ravina
Alistair Reith
Irene Richard
Liana Rosenthal
Holly Shill
Andrew Siderowf
John Sims
Gretchen Todd
Eduardo Tolosa
Matt Troyer
Michael Ward
Michele York
Overview
• Cognitive and psychiatric battery to remain
the same
• Review of cognitive-behavioral
assessments
• Cognitive categorization process
• Baseline results
• Preliminary longitudinal results
• Manuscripts
Study Assessments
Cognitive Assessments
• Global - Montreal Cognitive Assessment (MoCA)
----------------------------------------------------------------• Memory - Hopkins Verbal Learning Test (HVLT)
• Visuospatial - Benton Judgment of Line Orientation
(JOLO)
• Working memory - Letter-Number Sequencing
(LNS)
• Executive - Semantic fluency (animals, fruits,
vegetables)
• Attention - Symbol-Digit Modalities Test (SDMT)
PPMI Behavioral Assessments
• Geriatric Depression Scale (GDS-15)
• State-Trait Anxiety (STAI)
– State and trait subscales
• Questionnaire for Impulsive-Compulsive
Disorders in Parkinson's Disease (QUIP)
– Screening instrument for ICDs and related
behaviors
Cognitive Categorization
Process
Patient’s Perspective
Addition of Cognitive Diagnosis
• Initially unable to diagnose mild cognitive
impairment (MCI) or dementia in PPMI
• These diagnoses of clinical relevance in PD
– Categorization more clinically meaningful than
change in cognitive test score
• Based on MDS-recommended criteria for
dementia (2007) and MCI (2012)
MDS Criteria for MCI and Dementia
MCI (Level 1)
• Report of cognitive decline
from premorbid status
• Impaired cognitive
performance
– At least 2 test scores 1-2 SD
below the standardized mean
– Single or multiple domains
• No significant functional
impairment resulting from
cognitive decline
Dementia
• Report of cognitive decline
from premorbid status
• Impaired cognitive
performance
– Impairment in at least 2
cognitive domains
• Significant functional
impairment resulting from
cognitive decline
Steps for Determining Annual Cognitive
Diagnosis in PPMI
1. Investigator determines presence of cognitive decline from
pre-PD state based on clinical interview and knowledge of
patient
2. Investigator determines presence of significant functional
impairment due to cognitive deficits interfering with routine
instrumental activities of daily living (IADLs)
3. Subject has neuropsychological testing at study visit
4. Categorization of normal cognition, MCI, or dementia made
centrally based on steps #1, #2 and #3
CRF for Recording Cognitive Decline
Impairment on Cognitive Testing
4 domains and 6 test scores:
Memory (HVLT (# words and recognition discrimination))
Visuospatial (JOLO (correct responses))
Working Memory-Executive (LNS (correct responses) and
semantic fluency (# words))
Attention-Processing Speed (SDMT (correct responses))
MCI – At least 2 test scores >1.5 SD (7th %ile) below
the standardized mean, regardless domain(s)
Baseline Results
“Mild cognitive impairment and neuropsychiatric symptoms in
early, untreated Parkinson disease: results from the PPMI Study”
Enrolled Subjects
Variable
Age
Mean
(Min, Max)
Gender
Male
Female
Education
<13 Years
13 Years or more
Ethnicity
Hispanic/Latino
Not Hispanic/Latino
Race
White
Non-white
Family history
Positive PD
MDS-UPDRS Part III score
Mean
(Min, Max)
TD/Non-TD classification
TD
Non-TD
Side most affected
Left
Right
Symmetric
PD duration
Mean (SD) moths
PD
Subjects
(N = 423)
Healthy
Controls
(N = 196)
61.7
(33, 85)
60.8
(31, 84)
277 (65%)
146 (35%)
126 (64%)
70 (36%)
77 (18%)
346 (82%)
29 (15%)
167 (85%)
9 (2%)
414 (98%)
3 (2%)
193 (98%)
391 (92%)
32 (8%)
182 (93%)
14 (7%)
p-value
0.33
0.77
0.30
0.62
0.85
<.001
102 (24%)
10
(5%)a
<.001
20.9
(4, 51)
1.2
(0, 13)
299 (71%)
123 (29%)
NA
NA
180 (43%)
233 (55%)
10 (2%)
NA
NA
NA
6.65 (6.50)
NA
NA
NA
NA
Cognitive Performance in PD
Cognitive Domain
Variable
Global
MOCA score (N=423)
30 - 26
21 - 25
<21
Benton Judgment of Line Orientation Score
(N=422)
27.1 (2.3)
330 (78%)
89 (21%)
4 (1%)
12.8 (2.1)
Mild Impairmenta
Moderate Impairmentb
Severe Impairmentc
HVLT Immediate Recall (N=422)
Mild Impairment
Moderate Impairment
Severe Impairment
HVLT Delayed Recall (N=422)
Mild Impairment
Moderate Impairment
Severe Impairment
HVLT Retention (N=422)
Mild Impairment
Moderate Impairment
Severe Impairment
HVLT Discrimination Recognition (N=421)
30 (7%)
14 (3%)
2 (0%)
24.4 (5.0)
131 (31%)
73 (17%)
29 (7%)
8.4 (2.5)
139 (33%)
70 (17%)
26 (6%)
0.9 (0.2)
89 (21%)
47 (11%)
21 (5%)
9.6 (2.6)
Mild Impairment
Moderate Impairment
Severe Impairment
Letter Number Sequencing Raw Score
(N=422)
102 (24%)
38 (9%)
13 (3%)
10.6 (2.7)
Mild Impairment
Moderate Impairment
Severe Impairment
Semantic Fluency Total Score (N=422)
Mild Impairment
Moderate Impairment
Severe Impairment
Symbol Digit Modalities Score (N=422)
28 (7%)
19 (4%)
4 (1%)
48.7 (11.6)
61 (14%)
22 (5%)
9 (2%)
41.2 (9.7)
Visuospatial
Memory
Executive abilities-Working memory
Processing speed-Attention
Mild Impairment
Moderate Impairment
Severe Impairment
Mean (SD) or N (%)
110 (26%)
60 (14%)
27 (6%)
a<1.0
SD below standardized mean score
SD below standardized mean score
c<2.0 SD below standardized mean score
b<1.5
Predictors of MoCA Score in PD
Univariate Analysisa
Variable (affected group)
Regression
p-value
Coefficient
Multivariate Analysisb
Regression
p-value
Coefficient
Age (older age)
-0.047
<.001
-0.043
<.001
Gender (male)
0.635
0.007
0.590
0.01
Education (>12 years)
-0.108
0.71
-
-
Ethnicity (Hispanic/Latino)
1.043
0.18
-
N.S.
Race (non-white)
-1.090
0.01
-1.327
0.001
Family history of PD (no)
-0.042
0.87
-
-
MDS-UPDRS Part III (greater
motor impairment)
Hoehn & Yahr stage (stage 2
or above)
Duration of disease (longer
duration)
TD/Non-TD classification
(TD)
Side most affected (left)
-0.033
0.01
-0.025
0.047
-0.263
0.24
-
-
-0.026
0.13
-
N.S.
0.133
0.59
-
-
0.045
0.83
-
-
Cognitive Categorization - I
• Using MoCA cut-off score of <26, 22.0% of the
subjects met criteria for cognitive impairment
• Based on the detailed cognitive tests, 8.9% met
criteria for MCI
– 51.4% were impaired on 2 tests, 37.8% on 3 tests, and
10.8% on 4 tests
– Nearly all (89.2%) MCI patients had impairment on at
least one memory test
• Given only four cognitive domains covered, and
two only had single test, not possible to calculate
frequency of amnestic versus non-amnestic or
single- versus multiple-domain MCI
Cognitive Categorization - II
• Investigators recorded cognitive decline in
only 5 participants!
• Using this variable and applying MDS Task
Force recommended criteria yielded MCI rate
of only 0.4% (1/240)
• Then substituting non-zero score on the MDSUPDRS Part I cognitive impairment item for
cognitive decline, frequency of MCI increased
slightly to 4.1% (17/415)
MoCA – Test Categorization Agreement
• Agreement between MoCA and cognitive test
categorization of impairment is low (kappa
=0.092)
• Of 89 subjects with MoCA score <26, only
14.6% had MCI based on cognitive tests
• Of 37 subjects who met cognitive test criteria
for MCI, only 35.1% scored <26 on the MoCA
Psychiatric Symptoms in PD Patients
and Controls
Enrolled Subjects
Variable
GDS-15 score
Mean
(Min, Max)
GDS-15 cut-off
Not Depressed (<5)
Depressed (≥5)
STAI - State score
Mean
(Min, Max)
STAI - Trait score
Mean
(Min, Max)
QUIP disorders
Any 1 or more disorders
Gambling
Sex
Buying
Eating
Hobbyism
Punding
MDS-UPDRS Part I Apathy item
Negative
Any positive score
MDS-UPDRS Part I Psychosis item
Negative
Any positive score
PD
Subjects
(N = 423)
Healthy
Controls
(N = 196)
2.3
(0.0, 14.0)
1.3
(0.0, 15.0)
p-value
<.001
0.008
364 (86%)
59 (14%)
183 (93%)
13 (7%)
33.0
(20.0, 76.0)
28.0
(20.0, 58.0)
32.4
(20.0, 63.0)
29.1
(20.0, 53.0)
87 (21%)
4 (1%)
12 (3%)
11 (3%)
36 (9%)
31 (7%)
21 (5%)
36 (18%)
1 (1%)
5 (3%)
4 (2%)
18 (9%)
19 (10%)
4 (2%)
352 (83%)
71 (17%)
186 (95%)
9 (5%)
<.001
<.001
0.51
0.57
0.84
0.67
0.78
0.31
0.09
<.001
0.047
410 (97%)
13 (3%)
194 (99%)
1 (1%)
Predictors of GDS Score in PD
Univariate Analysisa
Multivariate Analysisb
Coefficient
p-value
Coefficient
p-value
Age
-0.016
0.20
-
-
Gender
0.164
0.51
-
-
Education
-0.350
0.26
-
-
Ethnicity
0.558
0.50
-
-
Race
0.765
0.09
0.913
0.040
Family history of PD
0.018
0.95
-
-
MoCA score
-0.004
0.94
-
-
MDS-UPDRS Part III score
0.025
0.06
0.029
0.03
Hoehn & Yahr stage
0.165
0.49
-
-
Duration of disease
-0.001
0.97
-
-
TD/non-TD classification
0.919
<0.001
0.970
<0.001
Side most affected
-0.295
0.18
-
N.S.
Conclusions About De Novo PD
• 20% of PD patients screening positive for MCI and
close to 10% meet cognitive test-based criteria
• Multiple NPS (e.g., depression, anxiety and apathy)
more common in untreated PD patients compared
with general population
• Rates of NPS associated with DRT (e.g., psychosis
and ICDs) either low or similar to controls
• Statistically significant findings despite potential
self-exclusion of patients with significant cognitive
impairment or NPS given rigors of PPMI, relatively
young age, and highly educated population
Preliminary Longitudinal Results
Predictors of MoCA Decline Over 2
Years in PD Patients
Change in MoCA score over time
Baseline values
Month 12
Month 24
Entire time period
Gender
-0.288 (0.287), p=0.33
-0.817 (0.431), p=0.059
F (2, 627)=1926 p=0.15
Education (years)
-0.006 (0.046), p=0.90
-0.018 (0.082), p=0.83
F (2, 643)=0.028, p=0.97
Age (years)
-0.081 (0.014), p<0.001
-0.056 (0.019), p=0.003
F (2, 614)=18.65, p<0.001
GDS score
0.009 (0.056), p=0.87
-0.053 (0.078), p=0.50
F (2, 621)=0.30, p=0.74
UPDRS motor score
-0.044 (0.159), p=0.006
-0.010 (0.024),p=0.68
F (2, 634)=3.88, p=0.02
UPSIT score
0.0577 (0.016), p<0.001
0.216 (0.233), p=0.35
F (2, 617)=6.26, p=0.002
PIGD phenotype
-0.268 (0.351), p=0.45
0.0819 (0.478), p=0.86
F (2, 612)=0.38, p=0.69
RBD (% positive)
-0.370 (0.277), p=0.18
-1.370 (0.396), p=0.001
F (2, 621)=6.05, p=0.002
Impact of Initiating PD
Therapy on Non-Motor Symptoms
N
Treated (n=42)
Untreated (n=54)
Chi-square (df), or Mann-
Whitney U test; p value
NPS expected to worsen with therapy
74c
17.1%
0.0%
0.009a
New ESS ≥10
76d
31.0%
10.6%
0.03a
Change in ESS score
96
0.5 (-3 - 3.2)
0.0 (-2 -1.5)
-0.63, 0.53b
New positive psychosis
94e
14.6%
5.6%
0.17a
New QUIP positive
ESS
NPS expected to improve with therapy
GDS
GDS remissionf
16g
37.5%
50%
0.10a
Change in GDS score
96
0.0 (-1 - 1)
0.0 (-1 - 1)
-1.13, 0.26b
Change in STAI total score
96
2.5 (-5.5 - 9)
-1 (-13 – 6.5)
-1.09, 0.27b
Apathy (improvementh)
96
4.7% (2/42)
3.7% (2/54)
0.65a
Fatigue (improvementi)
96
33.3% (14/42)
11.1% (6/54)
6.83 (1), 0.009
Unknown expected effect of therapy
Analysis and Publication Plan
Cognitive-Behavioral Papers
• Complete cognitive categorization process
• Baseline clinical manuscript
– Ready for submission
• Baseline biomarker manuscript
– Awaiting complete biomarker dataset
• Future manuscripts to be at initiative of
individual investigators