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 Keith Hawkins Paolo Barone David Hewitt Melanie Braddabur Jim Leverenz David Burn Irene Litvan Cindy Casacelli Anita McCoy Lama Chahine Susanne Ostrowitzki William Cho Bernard Ravina Thomas Comery Alistair Reith Autilia Cozzolino Irene Richard Johnna Devoto Liana Rosenthal Chris Dodds Holly Shill Jamie Eberling Andrew Siderowf Alberto Espay John Sims Stewart Factor Gretchen Todd Hubert Fernandez Eduardo Tolosa Regan Fong Matt Troyer Douglas Galasko Michael Ward Sandeep Gupta 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) Dementia • Report of cognitive decline • Report of cognitive decline from premorbid status from premorbid status • Impaired cognitive • Impaired cognitive performance performance – At least 2 test scores 1-2 SD – Impairment in at least 2 below the standardized mean cognitive domains – Single or multiple domains • Significant functional • No significant functional impairment resulting from impairment resulting from cognitive decline 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 (7 th %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 PD Healthy p-value Subjects Controls (N = 423) (N = 196) Age 0.33 Mean 61.7 60.8 (Min, Max) (33, 85) (31, 84) Gender 0.77 Male 277 (65%) 126 (64%) Female 146 (35%) 70 (36%) Education 0.30 <13 Years 77 (18%) 29 (15%) 13 Years or more 346 (82%) 167 (85%) Ethnicity 0.62 Hispanic/Latino 9 (2%) 3 (2%) Not Hispanic/Latino 414 (98%) 193 (98%) Race 0.85 White 391 (92%) 182 (93%) Non-white 32 (8%) 14 (7%) Family history <.001 10 (5%) a Positive PD 102 (24%) MDS-UPDRS Part III score <.001 Mean 20.9 1.2 (Min, Max) (4, 51) (0, 13) TD/Non-TD classification NA TD 299 (71%) NA Non-TD 123 (29%) NA Side most affected NA Left 180 (43%) NA Right 233 (55%) NA Symmetric 10 (2%) NA PD duration NA Mean (SD) moths 6.65 (6.50) NA
Cognitive Performance in PD Cognitive Domain Variable Mean (SD) or N (%) Global MOCA score (N=423) 27.1 (2.3) 30 - 26 330 (78%) 21 - 25 89 (21%) <21 4 (1%) Visuospatial Benton Judgment of Line Orientation Score 12.8 (2.1) (N=422) Mild Impairment a 30 (7%) Moderate Impairment b 14 (3%) Severe Impairment c 2 (0%) Memory HVLT Immediate Recall (N=422) 24.4 (5.0) Mild Impairment 131 (31%) Moderate Impairment 73 (17%) Severe Impairment 29 (7%) HVLT Delayed Recall (N=422) 8.4 (2.5) Mild Impairment 139 (33%) Moderate Impairment 70 (17%) Severe Impairment 26 (6%) HVLT Retention (N=422) 0.9 (0.2) Mild Impairment 89 (21%) Moderate Impairment 47 (11%) Severe Impairment 21 (5%) HVLT Discrimination Recognition (N=421) 9.6 (2.6) Mild Impairment 102 (24%) Moderate Impairment 38 (9%) Severe Impairment 13 (3%) Executive abilities-Working memory Letter Number Sequencing Raw Score 10.6 (2.7) (N=422) Mild Impairment 28 (7%) Moderate Impairment 19 (4%) a <1.0 SD below standardized mean score Severe Impairment 4 (1%) b <1.5 SD below standardized mean score Semantic Fluency Total Score (N=422) 48.7 (11.6) Mild Impairment 61 (14%) c <2.0 SD below standardized mean score Moderate Impairment 22 (5%) Severe Impairment 9 (2%) Processing speed-Attention Symbol Digit Modalities Score (N=422) 41.2 (9.7) Mild Impairment 110 (26%) Moderate Impairment 60 (14%) Severe Impairment 27 (6%)
Predictors of MoCA Score in PD Univariate Analysis a Multivariate Analysis b Variable (affected group) Regression p-value Regression p-value Coefficient 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 - - -0.033 0.01 -0.025 0.047 MDS-UPDRS Part III (greater motor impairment) Hoehn & Yahr stage (stage 2 -0.263 0.24 - - or above) -0.026 0.13 - N.S. Duration of disease (longer duration) 0.133 0.59 - - TD/Non-TD classification (TD) Side most affected (left) 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 MDS- UPDRS 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 PD Healthy p-value Subjects Controls (N = 423) (N = 196) GDS-15 score <.001 Mean 2.3 1.3 (Min, Max) (0.0, 14.0) (0.0, 15.0) GDS-15 cut-off 0.008 Not Depressed (<5) 364 (86%) 183 (93%) Depressed (≥5) 59 (14%) 13 (7%) STAI - State score <.001 Mean 33.0 28.0 (Min, Max) (20.0, 76.0) (20.0, 58.0) STAI - Trait score <.001 Mean 32.4 29.1 (Min, Max) (20.0, 63.0) (20.0, 53.0) QUIP disorders Any 1 or more disorders 87 (21%) 36 (18%) 0.51 Gambling 4 (1%) 1 (1%) 0.57 Sex 12 (3%) 5 (3%) 0.84 Buying 11 (3%) 4 (2%) 0.67 Eating 36 (9%) 18 (9%) 0.78 Hobbyism 31 (7%) 19 (10%) 0.31 Punding 21 (5%) 4 (2%) 0.09 MDS-UPDRS Part I Apathy item <.001 Negative 352 (83%) 186 (95%) Any positive score 71 (17%) 9 (5%) MDS-UPDRS Part I Psychosis item 0.047 Negative 410 (97%) 194 (99%) Any positive score 13 (3%) 1 (1%)
Predictors of GDS Score in PD Univariate Analysis a Multivariate Analysis b 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.
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