1. Mapping the correlations between CSF Abeta and tau and hippocampal atrophy in 282 ADNI subjects Liana G. Apostolova, Amity E. Green, Kristy S. Hwang, Jonathan H. Morra, Jeffrey L. Cummings, Arthur W. Toga, Clifford R. Jack Jr., John Q. Trojanowski, Leslie M. Shaw, Michael W. Weiner, Paul Thompson

2. Disclosures This work was generously supported by –NIA K23 AG026803 (jointly sponsored by NIA, AFAR, The John A. Hartford Foundation, The Atlantic Philanthropies, The Starr Foundation and an anonymous donor) –UCLA ADRC NIA AG16570 –The Kassel Parkinson’s Disease and the Turken Foundations –The Easton Consortium

3. Background Cerebrospinal fluid (CSF) Abeta and tau are the most established and most promising fluid biomarkers in AD. Low Abeta and increased tau levels have consistently been reported in the CSF of AD subjects as well as those MCI subjects who progress to AD. Frank RA et al., Neurobiol Aging 1998 Thal LJ et al, Alzheimer Dis Assoc Disord, 2006

4. Background cont. AD results in progressive hippocampal volume loss. Hippocampal atrophy is the most established imaging biomarker in AD. Advanced hippocampal atrophy in MCI is suggestive of underlying AD (OR for conversion to AD = 1.75) Jack, 1999 and 2004

5. Objective: To investigate the associations between CSF Abeta and tau levels and hippocampal atrophy in the ADNI cohort at baseline

6. Subjects: Demographic Data NC N=83 MCI N=140 AD N=59 p-value, ANOVA or Chi-Square Age, yr75.6 (5.3)74.0 (7.3)75.7 (7.9)0.16 Gender, M:F41:4291:4934:250.07 Education, yr15.6 (2.9)16.0 (3.0)15.3 (3.2)0.34 MMSE29.1 (1.0)26.9 (1.8)23.4 (1.8)< 0.0001 Comparable to Shaw LM et al, Ann Neurol online pub

7. CSF Biomarker Analysis Multiplex xMAP Luminex platform Innogenetics immunoassay kit-based reagent with the following monoclonal antibodies (Ab) –4D7A3 Ab for Abeta –AT120 Ab for total tau –AT270 Ab for pTau 181p Day-to-day reproducibility showed less then 10% variation Shaw LM et al, Ann Neurol online pub

8. Mean CSF Biomarker Concentrations Comparable to Shaw LM et al, Ann Neurol online pub

9. Check segmentations for accuracy Segment the dataset (1 min) Train the algorithm (15 hours) Ensure tracing accuracy Manually trace the Training Set Automated Hippocampal Segmentation AdaBoost

10. Radial Distance Mapping

11. Mean Hippocampal Volumes

12. 3D Abeta 1-42 correlation maps

13. 3D Tau correlation maps

14. 3D pTau 181p correlation maps

15. Volumetric vs. 3D radial distance associations with CSF biomarkers Left Hippocampus, p-values Right Hippocampus, p-values Abeta 1-42, pg/ml0.023 0.0030.0080.0003 Tau, pg/ml0.0010.0020.0040.003 pTau 181p, pg/ml0.0190.010.0020.0008 Tau/Abeta 1-42 <0.00010.00060.002 pTau 181p /Abeta 1-4 0.0050.0020.0010.0007 Hippocampal volume Hippocampal radial distance

16. Cumulative Distribution Function CSF biomarker association with 3D radial distance

17. Discussion Diagnostic accuracy of premortem CSF biomarkers Biomarker Threshold value ROCSensitivitySpecificityDiagnostic Accuracy Abeta 1-42 192 pg/ml 0.9196.476.987% Tau 93 pg/ml 0.8369.692.381% pTau 181p 23 pg/ml 0.7567.973.170% Tau/Abeta 1-42 0.39 0.9285.784.685% pTau 181p /Abeta 1-42 0.1 0.8691.171.282% Shaw LM et al, Ann Neurol online pub

18. Summary Hippocampal atrophy shows significant correlations with CSF biomarkers in a study sample consisting of NC, MCI and AD 3D hippocampal surface maps show more significant associations with CSF biomarkers relative to hippocampal volumes Abeta, Tau/Abeta 1-42 and pTau 181p /Abeta 1-4 show the strongest correlations with 3D maps of hippocampal atrophy

19. Future Directions Does progressive hippocampal atrophy associate with CSF biomarker changes? Would CSF biomarkers and hippocampal atrophy have an additive value for diagnosing early and presymptomatic AD? Can they be combined to sensitively track disease progression and therapeutic effects?