PPMI Cognitive-Behavioral Working Group. Daniel Weintraub, MD

Size: px

Start display at page:

Download "PPMI Cognitive-Behavioral Working Group. Daniel Weintraub, MD"

Jocelin Nichols
6 years ago
Views:

1 PPMI Cognitive-Behavioral Working Group Daniel Weintraub, MD PPMI Annual Meeting - May 6-7, 2014

2 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

3 Overview Cognitive and psychiatric battery to remain the same Review of cognitive-behavioral assessments Cognitive categorization process Baseline results Preliminary longitudinal results Manuscripts

4 Study Assessments

5 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)

6 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

7 Cognitive Categorization Process

8 Patient s Perspective

9 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)

10 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

11 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

12 CRF for Recording Cognitive Decline

13 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)

14 Baseline Results

15 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 (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 Positive PD 102 (24%) 10 (5%) a MDS-UPDRS Part III score <.001 Mean (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

16 Cognitive Performance in PD Cognitive Domain Variable Mean (SD) or N (%) Global MOCA score (N=423) 27.1 (2.3) Visuospatial (78%) (21%) <21 4 (1%) Benton Judgment of Line Orientation Score (N=422) 12.8 (2.1) 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) Executive abilities-working memory Mild Impairment 102 (24%) Moderate Impairment 38 (9%) Severe Impairment 13 (3%) Letter Number Sequencing Raw Score (N=422) 10.6 (2.7) Mild Impairment 28 (7%) Moderate Impairment 19 (4%) Severe Impairment 4 (1%) Semantic Fluency Total Score (N=422) 48.7 (11.6) Mild Impairment 61 (14%) 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%) a <1.0 SD below standardized mean score b <1.5 SD below standardized mean score c <2.0 SD below standardized mean score

17 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) < <.001 Gender (male) Education (>12 years) Ethnicity (Hispanic/Latino) N.S. Race (non-white) Family history of PD (no) MDS-UPDRS Part III (greater motor impairment) Hoehn & Yahr stage (stage or above) Duration of disease (longer N.S. duration) TD/Non-TD classification (TD) Side most affected (left)

18 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

19 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)

20 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

21 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 (Min, Max) (0.0, 14.0) (0.0, 15.0) GDS-15 cut-off Not Depressed (<5) 364 (86%) 183 (93%) Depressed ( 5) 59 (14%) 13 (7%) STAI - State score <.001 Mean (Min, Max) (20.0, 76.0) (20.0, 58.0) STAI - Trait score <.001 Mean (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 Negative 410 (97%) 194 (99%) Any positive score 13 (3%) 1 (1%)

22 Predictors of GDS Score in PD Univariate Analysis a Multivariate Analysis b Coefficient p-value Coefficient p-value Age Gender Education Ethnicity Race Family history of PD MoCA score MDS-UPDRS Part III score Hoehn & Yahr stage Duration of disease TD/non-TD classification < <0.001 Side most affected N.S.

23 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

24 Preliminary Longitudinal Results

25 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 (0.287), p= (0.431), p=0.059 F (2, 627)=1926 p=0.15 Education (years) (0.046), p= (0.082), p=0.83 F (2, 643)=0.028, p=0.97 Age (years) (0.014), p< (0.019), p=0.003 F (2, 614)=18.65, p<0.001 GDS score (0.056), p= (0.078), p=0.50 F (2, 621)=0.30, p=0.74 UPDRS motor score (0.159), p= (0.024),p=0.68 F (2, 634)=3.88, p=0.02 UPSIT score (0.016), p< (0.233), p=0.35 F (2, 617)=6.26, p=0.002 PIGD phenotype (0.351), p= (0.478), p=0.86 F (2, 612)=0.38, p=0.69 RBD (% positive) (0.277), p= (0.396), p=0.001 F (2, 621)=6.05, p=0.002

26 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 New QUIP positive 74 c 17.1% 0.0% a ESS New ESS d 31.0% 10.6% 0.03 a Change in ESS score (-3-3.2) 0.0 (-2-1.5) -0.63, 0.53 b New positive psychosis 94 e 14.6% 5.6% 0.17 a NPS expected to improve with therapy GDS GDS remission f 16 g 37.5% 50% 0.10 a Change in GDS score (-1-1) 0.0 (-1-1) -1.13, 0.26 b Change in STAI total score (-5.5-9) -1 ( ) -1.09, 0.27 b Apathy (improvement h ) % (2/42) 3.7% (2/54) 0.65 a Fatigue (improvement i ) % (14/42) 11.1% (6/54) 6.83 (1), Unknown expected effect of therapy

27 Analysis and Publication Plan

28 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

CSF Aβ1-42 predicts cognitive impairment in de novo PD patients

CSF Aβ1-42 predicts cognitive impairment in de novo PD patients Mark Terrelonge MPH *1, Karen Marder MD MPH 1, Daniel Weintraub MD 2, Roy Alcalay MD MS 1 1 Columbia University Department of Neurology 2