Biomarker Core ADNI Steering Committee Boston, MA 4/24/2017
Biomarker Core ADNI Steering Committee Boston, MA 4/24/2017 Leslie M Shaw John Q Trojanowski New biomarkers in NIA/ADNI/RARC-approved studies Fluid # Biomarker ADNI study Investigator NFL & Tau diag/prognosis Plasma 3,000+ ADNIGO/2 BL + longitudinal HZetterberg;NMattsson;Kblennow; Sweden sTREM2 CSF 1007 ADNI1/GO/2 BL + longitudinal shared samples MSuares-Calvert,MEwers; DZNE, Germany
sTREM2 levels & AD; IA CSF 1007 ADNI1/GO/2 BL + longitudinal Cruchaga; Wash U Metabolic networks Serum 905 Studies in ADNIGO/2 BL samples RKaddoura-Daouk; Duke Univ, Ab1-42/1-40;ELISA plasma 764 ADNI 1, GO, 2 in BL & longitudinal ISherriff; Araclon Biotech Metabolic networks
serum 833 Studies in ADNI1 BL samples; data uploaded RKaddoura-Daouk; Duke Univ, SNAP25 & neurogranin CSF 612 Longitudinal samples AFagan; Wash University T-& Phos-a-SYN; IA CSF 567 Longitudinal samples, to be uploaded JZhang; University of Wash Vilip 1; YKL-40; IA
402 BL ADNI1; recent publication MSavage;merck/PPSB/FNIH a-Synuclein;xMAP CSF 390 BL ADNI1; several publications JZhang; University of Wash Alzheimers Disease (AD) And Related Dementias (ADRD) Often Show Comorbid Multi-Proteinopathies DISEASE LESIONS COMPONENTS Alzheimers Disease (AD) The most common multi-proteinopathy SPs (100%) NFTs (100%) LBs (-50%)
TDP-43 (-50%) A Tau Alpha-synuclein TDP-43 Frontotemporal Degeneration (FTD) Inclusions Tau (FTLD-Tau), TDP-43 (FTLDTDP), FTLD-FUS Amyotrophic Lateral Sclerosis (ALS) Inclusions TDP-43, FUS, Tau, SOD1 Parkinsons Disease (PD) -/+ Dementia (PDD) & Dementia With Lewy Bodies (DLB) LBs, SPs, NFTs Alpha-synuclein, A, Tau Multiple System Atrophy (MSA) GCIs
Alpha-Synuclein Prion Diseases SPs Prions, Tau, A, Alpha-synuclein Trinucleotide repeat diseases Inclusions Expanded polyglumatine repeats Incidental Alpha-synuclein (Syn) And TDP-43 (TDP) Pathologies Are Rare In PART/NA, But Very Common In AD Such That Only 35% Of AD Patients In Our CNDR Brain Bank Have Pure Plaque And Tangle only AD. PART/Ageing +tdp; 1; 1.64% +syn+tdp; 1; 1.64% AD +tdp; 16.33% primary; +syn+tdp 35.06% ; 21.51% +AD; 16.39%
+syn; 4.92% primary; +tdp 2% 75.41% +tdp+syn 2% +syn; 27.09% TDP-43: Potential Use Useful for diagnosis of AD and related dementias (ADRD) Useful treatment selection for ADRD Useful for formulating prognoses for ADRD Useful for monitoring disease progression for ADRD Useful for monitoring disease modifying therapies when available for ADRD Acknowledgements: Many thanks to Linda K. Kwong, Yan Xu, Dawn M. Riddle and Virginia M.-Y. Lee for all their efforts on TDP-43 antibody production and ELISA development and to John Robinson, Maria Corrada and Claudia Kawas for their efforts on the comorbid pathology studies. These studies were made possible through grants from NIA/NINDS and the Koller Family Foundation as well as the support of the Families of our patients. 5 Why automation of CSF biomarkers? Eliminate as many manual steps as possible Promote best possible precision & accuracy Within-lab
Between-labs using common samples, eg AlzAssn QC program Same study population and pre-analytical protocol, eg, treatment trials Different study populations and pre-analytical protocols, eg, ADNI, BioFINDER Improved lot-to-lot performance clinical laboratory test Enable IVD test approval Can provide both accurate and precise data Use in treatment trials, especially international where local laboratory is essential(eg, China). Between-labs performance: Alz Association QC program KBlennow ADNI3 Aims for Biomarker Core Aim 2: Provide highly standardized A1-42, t-tau and p-tau181 measurements on all ADNI subject CSF samples using the Roche automated immunoassay platform(Cobas e601) and immunoassay reagents. In addition provide immunoassay-independent measurements of A species (A 1-42, A1-40 and A1-38) using a validated reference 2D-UPLC/tandem mass spectrometry method in baseline and longitudinal CSF samples. Continue collaboration with other investigators to achieve harmonization of these measurements across centers and different platforms in support of their use in clinical trials. Change: from manual RUO immunoassay to fully automated immunoassay platform for ADNI 3: Due diligence: started Q4, 2014, in consultation with ADNI Exec Comm & NIA & PPSB/BBWG/DDWG. Selection: in consultation with ADNI PPSB/BBWG/DDWG, chaired by Johan Luthman. Roche Elecsys: validation for Ab1-42 in CSF completed. External QC: Participation in the AlzAssn CSF QC program for Ab1-42 Validation of t-tau and p-tau181: completed FALL, 2016 Analyses of all ADNI CSFs: late FALL, 2016-early WINTER, 2017
Continued collaboration: with Kaj Blennow & AlzAssn and IFCC CSF WGs to produce certified reference CSF pools with assigned reference Ab1-42 concentration values, measured with reference 2D-UPLC/tandem mass spectrometry, to provide certified reference materials for validation of Ab1-42 calibrators--promoting harmonization across assay platforms. Review & participate in: studies of pre-analytical factors for CSF collection. Analysis of 2401 ADNI1/GO/2 CSF samples 2401 ADNI pristine CSFs, collected from 9/7/2005 to 7/25/2016 were analyzed in 36 analytical runs at UPenn from 11-17-2016 to 1-20-2017: 402 ADNI1 BASELINE; 819 ADNIGO/2 BASELINE ADNI1: 112 HC, 192 MCI, 98 AD ADNIGO/2: 160 HC, 96 SMC, 277 EMCI, AD 154 LMCI, 132 Analyses of ADNI1/GO/2 CSF Ab1-42, t-tau, p-tau181 using the Roche Elecsys fully automated immunoassay platform Rationale for moving from RUO to full automation Validation of Ab1-42 for precision, accuracy, and clinical performance General statistics for Ab1-42, t-tau, p-tau181, t-tau/Ab1-42, p-tau181/Ab1-42 in the
ADNI1/GO/2 CSF samples Histogram distributions for Ab1-42, t-tau/Ab1-42, p-tau181 Distributions based on FBP amyloid-b PET + or Cutpoint determinations Collaborative study with BioFINDER Concordance with FBP amyloid-b PET Prediction of cognitive decline(CDRsob) Summary Method validation studies at UPenn: Roche Elecsys immunoassay CSF Ab1-42: Analytical studies Short and long-term precision studies Linearity Comparison of Elecsys between UPenn and Roche Comparison with a reference mrm/mass spectrometry method Comparison with the RUO AlzBio3 immunoassay Two sets of non-ADNI CSF samples utilized(250 residual CSF from routine clinic patients; 129 CSFs from the UPenn ADRC) ROC analyses for AD vs HC in 129 CSFs from the UPenn ADRC(62 AD, 67 HC) SUMMARY UPENN/Roche comparison (both use Roche Elecsys,15 CSF pools): PB regressionY = 1.04X - 24.8; Pearsons r = 0.994
Bias at cut-off <10% Slope is within 1.0 0.1 Elecsys, AlzBio3 and LC-MS Abeta(1-42) measurements were performed for 250 samples from data set A and 129 samples from data set B Data set A and B were not pooled as AlzBio3 measurements differed between the two sample sets Correlation between Elecsys and AlzBio3: Spearmans rho 0.86(A)/0.82(B); some non-linearity Elecsys and LC-MS: Spearmans rho 0.95(A)/0.96(B); Linear relationship LC-MS and AlzBio3: Spearmans rho 0.87(A)/0.77(B); some non-linearity details in following ppt. ROC-AUC analysis within the data set B(AD vs HC): equivalent performance of all 3 methods *Toronto 2016 AAIC meeting poster & included in an AAIC symposium talk. Roche Elecsys versus LC/MS for ADNI1 BASELINE CSF Ab1-42 Confirms finding from UPenn Method Comparison study: linear relationship and approximately 1:1 Comparisons between Roche Elecsys & AlzBio3 immunoassays for ADNI1/GO/2 CSFs. Ab 1-42 t-tau
0.09-0.69 0.0086-0.073 ADNIGO/2 Ab1-42 t-tau p-tau181 (pg/mL) (pg/mL) (pg/mL) 594 334 N=127 meanSD 649257 95% CI AD Median
LMCI Median EMCI SMC N=71 NC Median 60.9 49.4 43.7 33.0 Ab1-42 all values 1248 1291 1324 1052
658 793* 562 617 Numbers inside the boxes are the respective median values for BL Ab1-42 in pg/mL placed above the median value horizontal line. *p<0.005 for LMCI ADNIGO+2 vs ADNI1; p=0.11 for NL ADNIGO+2 vs ADNI1; p=0.23 for AD ADNIGO+2 vs ADNI1 t-tau 349 294 218 211 218 334 286 234 Numbers inside the boxes are the respective median values for BL t-tau in pg/mL placed above the median value horizontal line. P=0.81 for NL ADNIGO+2 vs ADNI1; p=0.51 for MCI ADNIGO+2 vs ADNI1; p=0.81 for AD ADNIGO+2 vs ADNI1 p-tau181
34.0 28.4 19.9 19.3 19.3 33.2 27.6 20.7 Numbers inside the boxes are the respective median values for p-tau 181 in pg/mL placed above the median value horizontal line. *p=0.71 for ADNIGO+2 vs ADNI1; p=0.43 for MCI ADNIGO+2 vs ADNI1; p=0.88 for AD ADNIGO+2 vs ADNI1. Frequency distribution plots: upper are mixture model plots, lower are FBP+ and FBP- for ADNI SMC/EMCI/LMCI/AD Ab1-42 tau/Ab1-42 ptau181/Ab1-42 ROC Curves for SMC+EMCI+LMCI+AD CSF biomarkers using FBP PET+/- as the clinical endpoint* AUC values: p-tau/Ab1-42 t-tau/Ab1-42 Ab1-42 p-tau181 t-tau
Cutpoint values: p-tau/Ab1-42 0.021 t-tau/Ab1-42 0.222 Ab1-42 980 pg/mL p-tau181 21.8 pg/mL t-tau 245 pg/mL *SUVR of 1.1 used: Landau and Jagust Cutpoint assessments for CSF Ab1-42, t-tau & p-tau181 in ADNI ROC with FBP PET as the endpoint: Ab1-42, 980 pg/mL t-tau, 245 pg/mL p-tau181, 21.8 pg/mL t-tau/Ab1-42, 0.22 p-tau181/Ab1-42, 0.021 Disease-independent mixture modeling Ab1-42, 1016 pg/mL t-tau/Ab1-42, 0.19 t-tau, NA p-tau181/Ab1-42, 0.018 p-tau181, NA Prediction from BioFINDER study based on pre-analytic differences Ab1-42, 880 pg/mL
t-tau, 270 pg/mL p-tau181, 24 pg/mL t-tau/Ab1-42, 0.33 p-tau181/Ab1-42, 0.028 Concordance plots for FBP vs CSF Ab1-42 in ADNIGO/2 SMC, EMCI, LMCI & AD participants at BASELINE Concordance plots for FBP vs CSF tau/Ab1-42 in ADNIGO/2 SMC, EMCI, LMCI & AD participants at BASELINE Concordance plots for FBP vs CSF ptau/Ab1-42 in ADNIGO/2 participants at BASELINE Prediction of cognitive decline(CDRsob) in ADNIGO/ 2 LMCI subjects Ab1-42 t-tau/Ab1-42 riskTAA2i Vertical red arrow points to regression line for CDRsob values associated with Ab1-42 values below cutpoint value, t-tau/Ab1-42 values above cutpoint value, and logistic regression model(includes Ab1-42, t-tau and APOE e4 allele # as covariates) values above cutpoint value. Summary Roche Elecsys immunoassays for Abeta1-42, t-tau and p-tau181 completed for 2401 ADNI1/GO/2 CSFs, and uploaded on the ADNI/LONI website, March 2017 Precision and accuracy validations completed according to CLSI EP05 General stats, Frequency distributions, mixture modeling & ROC with FBP PET as endpt described
The t-tau/Ab1-42 and p-tau181/Ab1-42 ratios outperformed Ab1-42 alone for clinical utilities based on: Comparisons to FBP PET in ROC analyses Concordance with FBP PET Disease-independent mixture modeling This observation is consistent with the BioFINDER study(using Roche platform/flutemetmol PET) as well as multiple other studies that used other immunoassay platforms and clinical endpoints: Seeburger, 2015(OPTIMA study, N=227, autopsy-based diagnosis); Fagan, 2011(HASD, PIB PET based endpoint, N=103); Palmqvist, 2015(BioFINDER, Flutemetamol PET, N=366) Mechanism possibilities: normalization of variance; tau abnormality adds to predictive performance, further studies needed Cutpoint assessments: ROC with FBP as endpoint; disease independent mixture modeling; extrapolation from BioFINDER study based on pre-analytical differences Prediction performance of BASELINE CSF AD biomarkers for cognitive decline documentation Continue ongoing work with ADNI and other studies toward goal of defining universal cutpoints for Ab1-42, t-tau and p-tau181. Continue to work with colleagues on pre-analytical and other factors to help minimize and control these sources of variability Implement in ADNI3 Collaboration on multimodal studies that include CSF, imaging, genetic, clinical parameters Biomarker Research Lab Magdalena Korecka Michal Figurski Magdalena Brylska Teresa Waligorska Leona Fields
Jacob Alexander Ju Hee Kang CNDR/ADRC John Trojanowski Virginia M-Y Lee Steve Arnold Murray Grossman Jon Toledo Alice Chen-Plotkin ACKNOWLEDGEMENTS William Hu Anne Fagan Hugo Vanderstichele Kaj Blennow Henrik Zetterberg Chris Clark* Manu Vandijck John Lawson Udo Eichenlaub Tobias Bittner The Roche team Robert Dean Holly Soares Adam Simon Eric Siemers Piotr Lewczuk William Potter Rand Jenkins
Erin Chambers *Deceased MJ Fox Fdn for PD research Supported by the NIH/NIA & families of our patients ADNI investigators include: (complete listing available at www.loni.usc.edu\ADNI\ Collaboration\ADNI_Manuscript_Citations.pdf
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