Bioanalytics Core Leslie M Shaw PPMI Annual Investigators Meeting, NYC May 8, 2013 11/16/2011 1
Bioanalytics Core-2013 • Pilot study manuscript accepted for publication in JAMA Neurology • Preparations for analyses of CSF A β 1-42 , t-tau and p- tau 181 in PPMI baseline samples, and baseline, 6 and 12 month longitudinal samples using validated xMAP AlzBio3 immunoassay (all longitudinal samples on same 96 well plate • Aliquot comparisons; compare current lot of immunoassay reagents with that used in 2012 11/16/2011 2
Association of cerebrospinal fluid Ab 1-42 , t-tau, p-tau 181 and alpha-synuclein levels with clinical features of early drug naïve Parkinson’s disease patients; a cross- sectional study By Ju-Hee Kang, David J Irwin, Alice S Chen-Plotkin, Andrew Siderowf, Chelsea Caspell, Christopher S Coffey, Teresa Waligórska, Peggy Taylor, Sarah Pan, Mark Frasier, Kenneth Marek, Karl Kieburtz, Danna Jennings, Tanya Simuni, Caroline M Tanner, Andrew Singleton, Arthur W Toga, Sohini Chowdhury, Brit Mollenhauer, John Q Trojanowski, Leslie M Shaw and the Parkinson’s Progression Marker Initiative 3
Transfer of PPMI CSFs (Initial 102 CSF samples for statistical analysis) 15 Clinical Centers Frozen CSFs 5 F/U CSFs 44 Controls 39 BL HC CSFs 102 CSFs for statistical 120 CSF samples analysis 63 BL PD CSFs 4 BL SWEDD CSFs 76 Patients 9 F/U CSFs 4
Association of cerebrospinal fluid A β 1-42 , t-tau, p-tau 181 and α -synuclein levels with clinical features of early drug naïve Parkinson’s disease patients J-H Kang, DJ Irwin, AS Chen-Plotkin, A Siderowf, C Caspell, CS Coffey, T Waligórska, P Taylor, S Pan, M Frasier, K Marek, K Kieburtz, D Jennings, T Simuni, CM Tanner, A Singleton, AW Toga, S Chowdhury, B Mollenhauer, JQ Trojanowski, LM Shaw and the Parkinson’s Progression Marker Initiative * Objective : Evaluate baseline characteristics and relationship to clinical features of CSF A β 1-42 , t-tau, p-tau 181 and α -SYN in PD patients and matched healthy controls (HC) enrolled in PPMI. Methods : CSF biomarkers were measured by xMAP-Luminex platform and ELISA in HC (N=39) and PD (N=63).
Accessioning and statistical analyses of PPMI CSF biomarker dataset • Simultaneous download of PPMI data for the first 106 study subjects 6/30/2012 by IU and UPenn • Agreed upon a statistical analysis plan • Statistical analyses done at UPenn, SAS script sent to IU for replication • All results in concordance following this process and exchanges of detailed analyses • Data assembly, incorporation into draft manuscript • Manuscript circulated amongst the primary authors and the study site investigator/authors for suggestions, edits, further discussions of the data 6
Statistical Analyses • Software: SAS ver. 9.3 • Group comparison — Mann-Whitney U test (2 groups) — Kruskal-Wallis test with Dunn’s multiple comparison (3 groups) • Association of CSF biomarker levels and clinical variable — Multiple linear or logistic regression model (stepwise selection) with adjustment for confounders (Age, Gender and Education) • Chi-square test for difference in percentage of subjects • Pearson correlation
Demographics of the PPMI subjects HC (N = 39) PD (N = 63) P value Age, years (95% C.I.) 58 ± 13 (54 – 63) 62 ± 10 (59 – 64) 0.2390* Sex, F/M (% of Male) 18/21 (53.8) 24/39 (61.9) 0.4216 # 16.8 ± 2.4 16.4 ± 2.5 Education, years (95% C.I.) 0.1517 * (16.0 – 17.6) (15.8 – 17.0) 61.1 ± 10.0 (58.6 – Age at diagnosis, years - - (95% C.I.) 63.7) Disease duration, median years - 0.4 (0.0 – 2.6) - (range) Number of subjects with CSF 0.1271 # 6 18 Hgb > 200 ng/mL *Mann-Whitney U test; # Chi-square test for HC vs. PD.
Clinical characteristics of the PPMI subjects # HC (N = 39) PD (N = 63) p value * H & Y stage 0.03 ± 0.16 1.65 ± 0.51 < 0.0001 UPDRS III motor score 1.6 ± 2.7 22.6 ± 7.6 < 0.0001 Mean tremor score 0.05 ± 0.13 0.53 ± 0.32 < 0.0001 Mean PIGD score 0.01 ± 0.04 0.24 ± 0.26 < 0.0001 UPSIT score 35.1 ± 3.4 21.9 ± 8.1 < 0.0001 Striatal binding ratios PR ¶ /PL/CR/CL PR/PL/CR/CL <0.0001 (Mean values) 1.38/1.39/2.06/2.05 0.62/0.64/1.35/1.34 MoCA (95% C.I.) 28.4 ± 1.0 (28.0 –28.7) 27.2 ± 2.0 (26.7 – 27.7) 0.0054 Semantic fluency 53.8 ± 12.1 49.5 ± 10.6 0.0565 WMSIII-LNS $ test score 12.1 ± 2.8 11.0 ± 2.0 0.0510 SDMT 48.6 ± 11.2 41.9 ± 8.9 0.0051 HVLT-R total recall 9.0 ± 1.6 8.2 ± 1.5 0.0077 HVLT-R delayed recall 9.9 ± 2.3 8.3 ± 2.3 0.0004 #Data were updated based on PPMI database (06.30.2012) *Mann-Whitney U test ¶ PR: Right putamen, PL: Left putamen, CR: Right caudate, CL: Left caudate, N=39 for HC, N=62 for PD
Comparison of CSF Biomarker levels between HC and PD # HC (N = 39) PD (N = 63) P value # 242.8 ± 49.95 228.7 ± 45.63 A β 1-42 (pg/mL) 0.0466 (226.7 – 259.0) * (217.2 – 240.2) 53.9 ± 19.33 46.1 ± 24.71 t-tau (pg/mL) 0.0276 (47.6 – 60.1) (39.8 – 52.3) 24.9 ± 8.45 21.0 ± 7.83 p-tau 181 (pg/mL) 0.0093 (22.2 – 27.6) (19.0 – 23.0) 0.240 ± 0.141 0.215 ± 0.157 t-tau/A β 1-42 ratio 0.0451 (0.195 – 0.286) (0.176 – 0.255) 0.113 ± 0.075 0.099 ± 0.063 p-tau 181 /A β 1-42 ratio 0.1482 (0.089 – 0.138) (0.084 – 0.115) 0.491 ± 0.160 0.543 ± 0.263 p-tau 181 /t-tau ratio 0.6820 (0.439 – 0.543) (0.477 – 0.609) 1264 ± 425.7 1082 ± 611.1 α -syn (pg/mL) 0.0120 (1126 – 1403) (928 – 1235) * Mean ± S.D. (95% confidence interval); # Mann-Whitney U test. #Data were updated based on PPMI database (06.30.2012)
MDS-UPDRS Subsection used to classify Tremor or PIDG-dominant phenotype Mean tremor score (11 items) : UPDRS II – 1) Tremor : UPDRS III – 2, 3) Postural tremor (both upper extremities), 4, 5) Kinetic tremor (both upper extremities), 6-10) Resting tremor (4 extremities and lip/jaw), 11) Rest constancy Mean Postural Instability & Gait Disturbance (PIGD) score (5 items) : UPDRS II – 1) Walking and balance, 2) Freezing : UPDRS III – 3) Gait, 4) Freezing of gait, 5) Postural stability Tremor dominant (TD), or PIGD dominant phenotype - Ratio of tremor/PIGD score ≥ 1.15: Tremor dominant - Ratio of tremor/PIGD score ≤ 0.90: PIGD dominant - 0.90 < Ratio of tremor/PIGD score < 1.15: Intermediate type - If PIGD score is 0, but tremor score > 0: Tremor dominant
CSF biomarkers according to clinical phenotype in PD patients PIGD-PD TD-PD HC IND-PD p value * Biomarkers (N=14) (N=43) (N =39) (N=6) A β 1-42 (pg/mL) 211.4 ± 45.0 # 236.2 ± 46.8 0.0323 242.8 ± 50.0 215.5 ± 25.0 t-tau (pg/mL) 39.3 ± 28.27 # 50.3 ± 24.01 0.0527 53.9 ± 19.33 31.2 ± 9.97 18.0 ± 6.74 # p-tau 181 (pg/mL) 22.5 ± 8.17 0.0387 24.9 ± 8.45 17.7 ± 4.97 α -syn (pg/mL) a 892.8 ± 542.4 # 1185 ± 649.6 0.0587 1264 ± 425.7 782.6 ± 150.1 α -syn (pg/mL) b 766.3 ± 446.3 # 1122 ± 451.8 0.0286 1267 ± 443.5 775.9 ± 184.8 t-tau/A β 1-42 ratio 0.151 ± 0.072 0.211 ± 0.213 0.225 ± 0.145 0.1089 0.240 ± 0.141 p-tau/A β 1-42 ratio 0.083 ± 0.026 0.093 ± 0.059 0.104 ± 0.068 0.2247 0.113 ± 0.075 p-tau/t-tau ratio 0.588 ± 0.164 0.617 ± 0.398 0.513 ± 0.217 0.7597 0.491 ± 0.160 *PIGD vs. TD; Mann-Whitney U test # P<0.05 versus HC by Kruskal-Wallis test with Dunn’s multiple comparison a α -syn was measured in total subjects, or b subjects with CSF hemoglobin level of < 200 ng/mL 12
Summary of multivariate regression analyses Multivariate regression analysis: lower A β 1-42 (p=0.0383) and p-tau 181 (p=0.0015) are significantly • associated with PD diagnosis, but other biomarkers or their ratios are not. For clinical variables in PD, α -syn (p=0.0081) was significantly associated with the MDS-UPDRS III • motor score and t-tau was marginally associated (p=0.0424). We found that lower levels of CSF A β 1-42 and p-tau 181 were significantly associated with a higher PIGD • risk. Correlation between AD biomarkers and α -synuclein: Total PD HC t-tau p-tau 181 A β 1-42
Association of cerebrospinal fluid A β 1-42 , t-tau, p-tau 181 and α -synuclein levels with clinical features of early drug naïve Parkinson’s disease patients J-H Kang, DJ Irwin, AS Chen-Plotkin, A Siderowf, C Caspell, CS Coffey, T Waligórska, P Taylor, S Pan, M Frasier, K Marek, K Kieburtz, D Jennings, T Simuni, CM Tanner, A Singleton, AW Toga, S Chowdhury, B Mollenhauer, JQ Trojanowski, LM Shaw and the Parkinson’s Progression Marker Initiative * Results : Significantly lower concentrations of all measured CSF biomarkers and t-tau/ A β 1-42 ratio were seen in PD compared to HC, lower α -SYN was associated with a higher risk of PD and decreased CSF p-tau 181 associated with increased UPDRS motor score. Notably, lower CSF A β 1-42 was associated with the postural instability-gait disturbance-dominant phenotype which associates with a more rapid cognitive decline and poor prognosis compared to tremor-dominant patients. There is a significant correlation between α -SYN and t-tau & p-tau in PD and HC subjects. Interpretation : We demonstrate that CSF A β 1-42 , t-tau, p-tau 181 and α -SYN have value for diagnosis and assessment of disease progression in early-stage PD. Further investigations will test the predictive performance of CSF biomarkers for disease progression.
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