1. Development of a harmonized protocol for hippocampal tracing An EADC-ADNI joint effort 5 th Meeting, New Orleans, April 24, 2012 Update as of April 2012 Principal Investigators: Giovanni B Frisoni & Clifford R Jack Project Coordinator: Marina Boccardi AAN – New Orleans

2. HOUSEKEEPING INFORMATION Webinar: -Screen sharing through GotoMeeting -Audio through Première via regular telephone line. Please mute mike through *6 Questions: -Unmute *6 and ask question

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4. OUTLINE - Summary as of to date - Update since last meeting: Delphi panel - Landmarks defined - Segmentation modalities defined - Check for axes - Paper Consensus - Publication policy of project products - Project schedule - Scientific papers schedule

5. SUMMARY AS OF TO DATE

6. BACKGROUND Standardized hippocampal atrophy quantification needed as: - Biomarker for early diagnosis of AD - Surrogate marker tracking disease progression in clinical trials - Validation of automated segmentation algorithms

7. STANDARDIZATION STEPS OF MANUAL HIPPOCAMPAL VOLUMETRY AcquisitionOrientationSegmentation ADNI EADC-ADNI Hippocampal Harmonization Project Funded by Alzheimers Association Co-funded by unrestricted grant from Wyeth and Lilly

8. THE EADC-ADNI WORKING GROUP ON THE Harmonized Protocol for Hippocampal Volumetry GB Frisoni, M Boccardi, M Bocchetta, R Ganzola, A Redolfi, D Tolomeo, G Corbetta, E Cavedo, M Lanfredi Brescia B Bartzokis, PM Thompson, L Apostolova, M Tinley Los Angeles CR Jack, G Preboske, C Ward Rochester S Duchesne, N Robitaille Quebec City H Soininen, MPihlajamäki, Y Liu Kuopio B Dubois, S Lehericy, C Boutet Paris H Hampel Frankfurt S Taipel, M Grothe Rostock L-O Wahlund, B Winbald Stockholm F Barkhof, P Scheltens, W Henneman, M Pronk, F van Dommelen Amsterdam N Fox, J Barnes, M Blair London A Simmons London C deCarli, S Hollander Davis M Weiner, S Mueller San Francisco L deToledo-Morrell, D Bennet, T Stoub Chicago JG Csernansky, L Wang, A Christensen Evanston RJ Killiany, C Bauer Boston M Albert Baltimore M deLeon New York J Kaye, L Silbert, T Swihart Portland J Pruessner, S Pietrantonio Montreal R Camicioli, N Malykhin Edmonton J Pantel Frankfurt C Watson Detroit J OBrien, M Firbank, E Burton Newcastle P Sachdev, JJ Maller (PATH through life Study) M Geerlings, L Gerritsen, M Portegies (SMART-Medea Study) T denHeijer (Rotterdam Scan Study) P Pasqualetti, Rome L Collins Montreal PJ Visser Maastricht L Froelich Mannheim G Waldemar Copenhagen L Launer Bethesda W Jagust Berkeley C Hock, H Wolf, Zurich

9. METHODS Assessment of measurement properties of SUs Break down into segmentation units Bartzokis, 1998 Convit, 1997 Killiany, 1993 Soininen, 1994 Lehericy, 1994 Jack, 1994; deToledo-Morrell, 2004 Haller, 1997 Pruessner, 2000 Malykhin, 2007 Pantel, 2000 Watson, 1992 Survey and operationalization

10. METHODS Assessment of measurement properties of SUs Delphi panel 5 ROUNDS HARMONIZED HIPPOCAMPUS

11. DELPHI PANEL

12. Hippo experts participated to evidence-based Delphi panel P.I. City Delphi Panelist Barkhof/ScheltensAmsterdamWouter Henneman George BartzokisLos AngelesGeorge Bartzokis Richard CamicioliEdmontonNikolai Malykhin John CsernanskyChicagoLei Wang Charles DeCarliSacramentoCharles DeCarli Leyla DeToledo-MorrellChicagoLeyla DeToledo-Morrell Nick FoxLondonJosephine Barnes Mirjam GeerlingsStockholmLotte Gerritsen Clifford JackRochesterClifford Jack/Greg Preboske Ronald KillianyBostonRonald Killiany John OBrienNewcastleMichael Firbank Jens PruessnerMontrealJens Pruessner Hilkka SoininenKuopioH. Soininen/M. Pihlajamäki Paul ThompsonLos AngelesLiana Apostolova Craig WatsonDetroitCraig Watson Christoph HockZurichHenrike Wolf

13. L Apostolova Los Angeles J Barnes London G Bartzokis Los Angeles C deCarli Sacramento L deToledo- Morrell Chicago M Firbank Newcastle L Gerritsen Stockholm W Henneman Amsterdam CR Jack Rochester R Killiany Boston N Malykhin Edmonton J Pruessner Montreal H Soininen Kuopio L Wang Chicago C Watson Detroit H Wolf Zurich

14. Delphi panel results RoundMedianAgreeNeutralDisagreeP N (%) (Binomial) Landmarks Inclusion of alveus/fimbriaII913 (81%)0 (0%)3 (19%)0.021 Segmentation of subiculum (morphology - I choice)III7.511 (69%)4 (25%)1 (6%)0.006 Segmentation of subiculum (horizontal - II choice)III-13 (81%)0 (0%)3 (19%)0.021 Inclusion of tail endIII912 (75%)2 (12.5%) 0.013 Harmonized HippocampusII814 (88%)1 (6%) 0.001 Segmentation Modality Disambiguating amygdala with 3D navigationII816 (100%)0 (0%) <0.0005 Inclusion of vestigial tissueIII-10 (63%)0 (0%)6 (37%)n.s. CSF poolsIII814 (88%)0 (0%)2 (12%)0.004 Not visible structures (final definition)III816 (100%)0 (0%) <0.0005 Separating Alveus/Fimbria from fornixIV812 (82%)0 (0%)1 (8%)0.003 AC-PC Image orientationV8.511 (79%)2 (14%)1 (7%)0.006

15. LANDMARKS

16. Delphi consensus - LANDMARKS Alveus/Fimbria: The hyperintense tissue located on the dorso- lateral aspect of the hippocampal head and body. Significant agreement on Round II p=0.021

17. Delphi consensus - LANDMARKS Subiculum-Morphology: A line following the visible contour of the medial border of the hippocampus, and relying on the morphological details. Significant agreement on Morphology as first choice criterion on Round III P=0.006

18. Delphi consensus - LANDMARKS Subiculum- Horizontal: A horizontal line connecting the highest point of the parahippocampal WM medially, to the ambient cistern. Significant agreement on Horizontal as second choice criterion on Round III p=0.021 ObliqueHorizontal Line as second choice

19. Delphi consensus - LANDMARKS Tail: all hippocampal tissue visible from the joint visualization of the superior and inferior colliculi, to the most caudal slice where GM mass is visible inferomedially to the trigone of the lateral ventricle. Significant agreement on Round III p=0.013

20. Delphi consensus - LANDMARKS Harmonized Hippocampus: Global definition of hippocampus, including all SUs Significant agreement on Round II p=0.001

21. Delphi consensus - LANDMARKS Covers 100% of hippocampus proper Captures 100% of AD-related atrophy Intra-rater (BS-Mayo-LONI-Mainz): 0.98 Inter-rater (BS-Mayo-LONI-Mainz): 0.94

22. Delphi Landmark Consensus movie "Movie 1

23. SEGMENTATION MODALITIES

24. Delphi consensus – Discrimination Amy/Hippo Significant agreement for discrimination based on 3D navigation Round II p<0.0005 Not possiblePossible

25. Delphi consensus – Vestigial Disagreement for discrimination based on 3D navigation in round III Includeexclude vestigial

26. Delphi consensus – CSF pools

27. The CSF located internal to the hippocampus, also in unexpected regions, must be excluded from the segmentation when the tracer is sufficiently sure that the hypointense voxels correspond to CSF, and not to partial volume effect. Delphi consensus – CSF pools disagreeagree with definition Round IIIp=0.004

28. Delphi consensus – hardly visible structures

29. …a priori knowledge of hippocampal morphology must be used to carry out additional checks to ascertain whether hippocampal tissue can be detected in atrophic patients. Round III p<0.0005

30. Delphi consensus – separate Fimbria/Fornix

31. Include the WM as alveus/fimbria whenever it appears attached to the hippocampal GM. Exclude the above WM as fornix. this part diverges from the plane parallel to the parahippocampal WM, taking a different angle, and is clearly detached from hippocampal GM Delphi consensus – separate Fimbria/Fornix Round IV p=0.003

32. Delphi consensus – image orientation Methodological problem: data fed to Delphi were collected on the AC-PC axis. Shift to hippo axis may represent an inconsistency. We compared the topographic and volumetric stability (TRTR and IRR of master tracers) of segmentation on hippo and AC-PC axes.

33. Liana Apostolova Gregory Preboske Martina Bocchetta Design of axis check segmented (based on Harmonized Prot) 10 ADNI subjects (R+L) on hippo axison AC-PC axis Volume agreement within and between tracers and Dices coefficients for spatial overlapping were computed.

34. Image orientation better overlapping of segmentation in AC-PC Dices coefficients for spatial overlapping agreement between MB and GP.

35. Image orientation: visualization of tracings shows better overlapping in AC-PC "Movie 2" "Movie 2" Maximum Dice for AC-PC (0.8908) computed between Tracer 2 and Tracer 3, and corresponding to Subject 3, Right hippo.

36. The Delphi panel agreed to keep AC-PC, in consideration of the methodological problem and the new evidence: Median 8.5 Binomial p=0.006 Delphi panel V: agreement for AC-PC disagreementagreement Round V p=0.006

37. PUBLICATION POLICY

38. Publication policy http://www.hippocampal-protocol.net/SOPs/LINK_PAGE/Publication_Policy_V3-2.pdf Latest release: March 28 Steering Committee Applicability Availability of deliverables Authorships Acknowledgements Revisions

39. Availability of deliverables The Harmonized Protocol (i.e. the text description and illustrative material), the digital master tracer masks, and digital training sets (masks developed by the 5 best naïve tracers) will be available only to beta-test users in the period (about 1 year) between the end of the Delphi Panel and the publication of the full validation results (i.e. the analysis of the whole set of hippocampal tracings by all naïve tracers). To qualify as beta-testers, users will submit proposals to the SC; if accepted, beta-testers will be granted access to deliverables under conditions dictated by a written cooperation agreement that will be signed by the user and the Chair of the SC. Assuming mutual benefit, the cooperation agreement will include provisions related to scientific publications, donations, and feedback that beta users will provide on their exploitation of the Harmonized Protocol.

40. PROJECT SCHEDULE

41. FUTURE STEPS 1. Develop a qualification environment and qualification thresholds for naïve tracers and automated algorithms (by June 2012) "Movie 3 Prototype of qualification environment and thresholds

42. FUTURE STEPS 2. Validate on: - 1800 ADNI hippocampi segmented by 20 human tracers - 20x2 (R&L) hippocampi with volume on pathology, neuronal density, and ex vivo MR (by January 2013) Variability Sources Examination: Effects of: rater, trace-retrace, side, atrophy, time/progression, scanner, strength field

43. GANTT

44. PAPERS SCHEDULE

45. Papers describing the project 1. Survey of protocols (preliminary phase; published, JAD 2011) 2. Operationalization (preliminary phase; submitted to Alzheimers & Dementia, MS n. ADJ-D-12-00094) 3. Orientation check (Brescia Team, in progress) 4. Delphi consensus (Brescia Team, in progress) 5. Master tracers practice and reliability (Brescia Team, in progress) 6. Development of certification platform (Duchesne & coll) 7. Validation data and Protocol definition (Brescia Team) 8. Validation vs pathology (TBD)

46. AAN - Session S04: Aging and Dementia: Therapeutic Interventions Delphi Consensus on Landmarks for the Manual Segmentation of the Hippocampus on MRI: Preliminary Results from the EADCADNI Harmonized Protocol Working Group platform presentation number S04.003 Tuesday, April 24, 2012 at 1:30 pm Results will be presented at

47. Results will be highlighted at www.hippocampal-protocol.net More info about the project at Geriatric Neurology Section Highlights in the Field Wednesday, April 25th from 5:30-6:30 p.m. Room 356/357 (Drs. Ringman and Apostolova)

48. Acknowledgements Maria Carrillo, Meredith McNeil Alzheimers Association, Chicago IL All partners!