1. Development of a harmonized protocol for hippocampal tracing An EADC-ADNI joint effort 3 rd Meeting, Honolulu, April 13, 2011 Principal Investigators: Giovanni B Frisoni & Clifford R Jack Project Coordinator: Marina Boccardi

2. Housekeeping Information Webinar attendees will be muted to limit surround noise Please write your questions in the “Questions” window. Your question will be forwarded to the speakers.

3. EADC F Barkhof/P ScheltensAmsterdam B Dubois/S LehericiParis N Fox/ J BarnesLondon GB Frisoni Brescia H Hampel/J PantelFrankfurt A SimmonsLondon H SoininenKuopio S TeipelRostock LO WahlundStockholm THE WORKGROUP ADNI CR Jack Jr Rochester, MN M AlbertBaltimore, MD G Barzokis UCLA, CA D Bennet Chicago, IL J Csernansky NorthW U, WA C DeCarli UC Davis, CA M De Leon New York, NY L deToledo-Morrell Chicago, IL J Kaye Portland, OR R Killiany Boston USM, MA PM Thompson LoNI, UCLA, CA M Weiner/S Mueller UCSF/VAMC OTHERS R Camicioli/NV Malykhin Edmonton, AL J O’BrienNewcastle, UK J PruessnerMontreal, QC C Watson Detroit, MI

4. THE WORKGROUP Population-based studies P Sachdev/JJ Maller PATH Through Life Study T Den Heijer Rotterdam Scan Study L Launer Honolulu Asia Aging Study W Jagust SALSA Study Mirjam I. GeerlingsSMART MEDEA Study Advisory board EADC P.I.s B WinbladStockholm Lutz Froelich, Mannheim ADNI P.I. M WeinerUCSF, US Statistical Board S DuchesneQuébec City L CollinsMontreal P PasqualettiRome Clinical Advisor PJ VisserMaastricht Dissemination/Education G WaldemarCopenhagen

5. Funded by Alzheimer’s Association grant n. 174022 Funded in part thanks to an unrestricted grant by Lilly and Wyeth/Pfizer Bartzokis Research support – Janssen; Consultant - Lilly, Pfizer, Novartis; Csernansky Consultant Eli Lilly; Duchesne Research support - Agfa HealthCare Inc.; funding as a partner in the project; Frisoni Consultant Wyeth; Jack Contract – Pfizer; consulting – Élan; Lehericy Consultant - EISAI, Janssen-Cilag DISCLOSURES

6. OUTLINE Preliminary phase Objectives Preliminary phase Latest results from prelim. phase AA-funded project Design Validation Phase 1 Delphi panel

7. DIAGNOSTIC MARKERS IN THE DRAFT REVISED CRITERIA (as of Jan 15th 2011) Alzheimer’s dementia CSF Ab42 - CSF tau/p-tau - Amy PET imaging - FDG PET - Cortical/hippo atrophy MCI due to Alz disease Molecular neuropathology CSF Ab42 CSF tau/p-tau Downstream funct/struct change Amy PET imaging FDG PET Cortical/hippo atrophy Preclinical Alz disease Brain amyloidosis Amy PET imaging CSF Ab42 Synaptic dysfunction/neurodegeneration CSF tau/p-tau FDG PET Cortical/hippo atrophy

8. BACKGROUND Hippocampal volume as an outcome measure in trials of disease modifiers DrugStudyEffectSegment. methodRef TramiprosateAlphase 68% (100 mg) 120% (150 mg) Not mentionedGauthier et al., JNHA 2009 AtorvastatinADCLT “CHV* mm³ -134±174 vs - 583±354 p>.05” Manual protocol Insausti et al., 1998 AJNR; Machulda et al., 2001, Neuroimage Sparks et.a,l CCJM,2008 LEADe “significant at p<.05” MIDAS (semiautomated) Jones et al., Alz&Dem 2008 Feldman et al., Neurology 2010 AN1792 “CHV* % 3.78±2.63 vs 2.86±3.19 p = 0.124” Manual protocol Watson et al., 1992, Neurology Fox N et al., Neurology, 2005 Xaliproden Sanofi- Aventis Trials “significant atrophy” §Not mentionedFrom Vellas B et al. (Review), Lancet Neurol.,2008 Donepezil “CHV* % -6.14±3.49vs - 4.50±2.28 p= 0.07” ε4 carriers only Manual protocol Jack et al., 1989;Radiology Jack et al., 2004; Neurology Jack CR et al., Neurobiol. Aging, 2008 * CHV= Change in hippocampal volume; § referenced link not working

9. Geuze et al., Mol Psychiatry 2005;10:147-59 Ref.Med border Lat border Inf border Norm. hippo vol (cm 3 ) LeftRight Watson et al. Mesial edge of temporal lobe Temp horn of lat ventr Incl subicular complex & uncal cleft w/ border separating subicular complex from parahippo gyrus 4.9035.264 Zipursky et al. Regional outline at choroidal fissure Not mentioned The interface of hippocampal tissue and parahippocampal gyrus white matter 1.9902.070 BACKGROUND The effect of segmentation protocols on hippocampal volume 2 ½ fold

10. OBJECTIVES To survey the most popular protocols for hippocampal segmentation To develop a Harmonized Protocol through expert consensus based on empirical data and experts’ experience To Test the Validity of the Harmonized Protocol

11. DEVELOPMENT OF STANDARDIZED OPERATIONAL PROCEDURES FOR DIAGNOSTIC MARKERS ModalityCollectionMeasurement Hippocampal volume 3D T1 MR ADNI protocol Alzheimer’s Association / EADC-ADNI harmonized protocol (200k US$) Temporo-parietal hypometabolism FDG PET ADNI protocol Head-to-head comparison of TPH metrics (spontaneous – submitted for funding) CSF Ab42 and tau Lumbar puncture Alzheimer’s Association protocol (PI K Blennow) Cortical amyloid deposition Amyloid PET None

12. PRELIMINARY PHASE Operationalization of differences survey and selection of protocols definition of segmentation units (SUs) Quantitative study of SUs intra- and inter-rater reliability of SUs impact of SUs on total hippo volume impact of SUs on difference due to AD

13. B Bartzokis G, et al. Psychiatry Res 1998;82:11-24 C Convit A, et al. Neurobiol Aging 1997;18:131-8 dTMdeToledo-Morrel et al. Neurobiol Aging 2004;25:1197–1203 HHaller JW, et al. Radiology 1997;202:504-10 JJack CR Jr. Epilepsia 1994;35 - Suppl 6:S21-9 KKilliany RJ, et al. Arch Neurol 1993;50:949-54 LLehéricy S, et al. Am J Neuroradiol 1994;15:929-37 MMalykhin NV, et al. Psychiatry Res 2007;155:155-65 PaPantel J, et al. Hippocampus 2000;10:752-8 PrPruessner JC, et al. Cereb Cortex 2000;10:433-42 SSoininen HS, et al. Neurology 1994;44:1660-8 WWatson C, et al. Neurology 1992;42:1743-50 SELECTED PROTOCOLS Boccardi M, Ganzola R, Bocchetta M, Pievani M, Redolfi A, Bartzokis G, Camicioli R, Csernansky JC, de Leon MJ, deToledo-Morrell L, Killiany RJ, Lehéricy S, Pantel J, Pruessner JC, Soininen H, Watson C, Duchesne S, Jack CR Jr, Frisoni GB. Survey of Protocols for the Manual Segmentation of the Hippocampus: Preparatory Steps Towards a Joint EADC-ADNI Harmonized Protocol JAD/Handbooks of Alzheimer's Disease. Accepted with minor revisions – March 2011

14. SEGMENTATION UNITS (SUs): The LEGO blocks concept

15. OPERATIONALIZATION OF DIFFERENCES INTO SEGMENTATION UNITS (SUs) Rendering by Simon Duchesne and Nicolas Robitaille Université Laval and Centre de Recherche Université Laval – Robert Giffard Québec City, Canada

17. Watson 1992 Bartzokis1998 Convit 1997 Jack, 1994; deToledo- Morrell 2004 Killiany 1993 Lehericy 1994 Pruessner 2000 Malykhin 2007 Soininen 1994 Haller 1997 Pantel 2000

18. QUANTITATIVE STUDY OF SUs Computed on 20 subjects, 4 for each degree of MTA scale (Scheltens et al., 1992)

19. QUANTITATIVE STUDY OF SUs

20. Left Right 31 CTR 23 MCI 23 AD Mean volume

21. LEFT HIPPOCAMPUS Controls (n=31)MCI (n=23)AD (n=23)p MCI vs CTR p AD vs CTR p MCI vs AD p AD+MCI vs CTR MinH1467 (204)1122 (263)1023 (251)<0,0005 0,199<0,0005 Alveus/fimbria248 (45)232 (61)200 (48)0,269<0,00050,0550,01 Subiculum243 (72)220 (84)213 (64)0,2790,1180,7540,121 Oblique line196 (67)178 (66)176 (53)0,3380,2620,9360,207 Morphology243 (72)220 (84)213 (64)0,2790,1180,7540,121 Horizontal line234 (72)210 (78)211 (62)0,2430,2210,9570,153 Tail485 (131)383 (99)353 (101)0,003<0,00050,307<0,0005 Crura190 (74)177 (70)146 (69)0,5380,0340,140,101 End Tail296 (120)206 (76)206 (86)0,0030,0040,984<0,0005 MaxHV2443 (291)1957 (348)1788 (342)<0,0005 0,105<0,0005 RIGHT HIPPOCAMPUS Controls (n=31)MCI (n=23)AD (n=23)p MCI vs CTR p AD vs CTR p MCI vs AD p AD+MCI vs CTR MinH1462 (232)1214 (247)1061 (241)<0,0005 0,039<0,0005 Alveus/fimbria255 (47)258 (71)225 (65)0,840,050,1030,35 Subiculum225 (79)208 (89)184 (56)0,4590,0420,2940,109 Oblique line181 (67)167 (71)150 (46)0,4550,0590,3340,122 Morphology225 (79)208 (89)184 (56)0,4590,0420,2940,109 Horizontal line220 (78)203 (83)182 (54)0,4590,0530,3090,117 Tail487 (151)349 (115)349 (131)0,001 0,999<0,0005 Crura187 (75)169 (68)140 (69)0,370,0250,170,058 End Tail301 (120)181 (113)209 (110)<0,00050,0060,394<0,0005 MaxHV2429 (303)2029 (372)1820 (369)<0,0005 0,062<0,0005

23. OUTLINE Preliminary phase Objectives Preliminary phase Latest results from prelim. phase AA-funded project Design Validation Phase 1 Delphi panel

24. AA Funded Project A harmonized protocol for hippocampal volumetry: an EADC-ADNI effort Submitted: Dec 5, 2009 Alzheimer’s Association grant: n. 174022 Duration: Sep 1, 2010 to Aug 31, 2012 More info at www.hippocampal-protocol.net

25. Benchmark Harmonized hippos: 1.5T ADNI scans 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) 5 expert tracers 20 naive tracers The best 5 naive tracers Harmonized Protocol: 1.5T ADNI scans 2 sides x 5 Scheltens’s atrophy scores x 3 time points (0-12°month-24°month) x 3 scanners + retracing for timepoint 1 (SAME on 3T ADNI scans) (total for each rater: 240 hippos – including 40 hippos already traced) GOLD STANDARD Local Protocol : 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) 1 tracer Qualification (10 tracers each SU; 10 whole hippo) Qualification global and local 95% confidence intervals RM-ANOVA: test of rater and rater by center terms RM-ANOVA: test of main effects side, trace- retrace, atrophy, time, scanner, rater Local Protocol : Experimental set (1.5T ADNI): 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) Harmonized Protocol : Experimental set (1.5T ADNI): 2 x each of the 5 Scheltens’s atrophy score x 2 sides (SAME on 3T ADNI scans) (total for each rater: 40 hippos) Harmonized Protocol: 1.5T 3D T1-weighted scans from (Bobinski et al., 2000) pathologically verified set (total for rater: 30 hippos) RM-ANOVA: test of protocol main effect VARIABILITY EVALUATION VALIDATION vs PATHOLOGY Training (tracing 20 hippos on 1.5T ADNI scans with each SU) (SAME on 3T ADNI scans) Delphi panel → harmonized prot

27. AA Funded Project: Tracers 26 Tracers: 20 Naïve Tracers for Local + Harmonized Protocol 5 Expert Tracers for Benchmark Images: Martina Bocchetta, Rossana Ganzola, Josephine Barnes, Liana Apostolova, Gregory Preboske 1 Naïve Tracer for Validation versus Pathology: (to be defined)

28. AA Funded Project: Tracers PIValidation tracer Barkhof/ScheltensMargo PronkFelix van Dommelen George BartzokisMat Tinley--- John G. Csernansky Adam Christensen --- Charles DeCarliSarah Hollander --- Leyla DeToledo-Morrell Travis Stoub--- Giovanni FrisoniEnrica Cavedo Mariangela Lanfredi Nick FoxMelanie Blair Mirjam Geerlings Marileen Portegies --- Clifford JackGregory PreboskeChadwick Ward Jeffrey KayeTim Swihart (L. Silbert)--- Ron KillianySarah Greene--- Stephane LehericyClaire Boutet--- Jerome Maller/SachdevJerome Maller--- John O’BrienEmma Burton --- Jens Pruessner Sandra Pietrantonio --- Hilkka SoininenYawu Liu --- Stefan TeipelMichel Grothe ---

29. AA Funded Project: the Tracers’ Kit Forms reporting info about the phase of validation, deadlines, and budget. Please return it filled in and signed. Multitracer and Instruction: please do not share software and link, arrangements taken with Roger Woods http://centroalzheimer.it/public/MB/SOPs/MULTITRACER.rar http://centroalzheimer.it/public/MB/SOPs/MULTITRACER.rar ADNI images: please do not share with anyone else: AC-PC oriented at: http://centroalzheimer.it/public/MB/SOPs/IMG_val1_phase.zip Native images at: http://centroalzheimer.it/public/MB/SOPs/IMG_val1_phase_anal yze.zip

30. FAQs Should I use only Multitracer? Yes, you can use different software/zoom only for visualization Can I take part to both the Delphi and to the Validation? Only if you complete tracings before the Delphi Can I use any software to align images to the long axis of the hippocampus? Yes Am I free to choose image intensity? Yes Should I re-trace images? Images need to be traced ONCE based on local protocol, and ONCE based on the harmonized protocol Can I use different zoom while tracing? No: use only zoom=5 in the coronal, zoom=3 in the sagittal windows Can I use any PC? Yes, provided you always use the same PC throughtout the whole validation phase

31. OUTLINE Preliminary phase Objectives Preliminary phase Latest results from prelim. phase AA-funded project Design Validation Phase 1 Delphi panel

32. AA Funded Project: Delphi Participants PIDelphi Participant Barkhof/ScheltensWouter HennemanGeorge Bartzokis Richard CamicioliR. Camicioli/N. Malykhin John G. Csernansky Lei WangCharles DeCarli Leyla DeToledo-Morrell Nick FoxJosephine Barnes Mirjam Geerlings Lotte Gerritsen Clifford JackC. Jack/G. PreboskeRonald Killiany Jerome MallerP. Sachdev /C. Meslin John O’BrienMichael Firbank Jens Pruessner Hilkka SoininenH. Soininen/M. Pihlajamäki Paul ThompsonLiana ApostolovaCraig Watson Henrike Wolf

33. Delphi panel www.hippocampal-protocol.net One vote (account) for each participating centre is allowed

35. General description Defining Harmonized Landmarks Minimum hippocampal body Alveus/fimbria Medial border Tail Defining Harmonized Segmentation Modalities Rendering Rendering of the shape of the hippocampus based on the selected SUs (i.e., landmarks) Delphi panel

36. In these pages you will find the information that will help you to decide how a harmonized protocol for hippocampal segmentation should be defined. You will be provided with information about terms and concepts, and with quantitative information. Based on your experience, and helped by this information, you can express your choices about the features that should characterize a harmonized protocol for hippocampal segmentation. Step by step, you can also obtain a rendering of the hippocampus obtained based on your choices.You can practice, go back and forward in the pages, and change your choices, until you have clicked the final “submit” button. The questionnaire is composed of two parts. First part: Definition of Landmarks The first part of the questionnaire relates to the operationalized differences among segmentation protocols, i.e., about the “Segmentation Units” (SUs) (see Figure below). You can include or exclude each SU from your choice for a harmonized protocol, deciding with the help of the information provided on the menu on the left side. Inclusion or exclusion of SUs is equivalent to defining landmarks. In fact, SUs are defined based on the variability of landmarks definition that we have extracted from the available literature (see MS circulated, currently submitted to JAD, and the Protocol for the Tracing of SUs) Second part: Segmentation Modalities In the second part, you are asked to express your opinion about other issues, related to segmentation modalities rather than to the definition of landmarks. ABOUT THE QUESTIONNAIRE About the Questionnaire Inclusion of Segmentation Units in the Harmonized Protocol Minimum hippocampus Alveus/fimbria Medial border Tail Definition of tracing modalities Disambiguating Hippocampus/Amygdala Disambiguating Hippoc/Vestigial Tissue Internal liquor “Islands” of tissue Tracing of not visible structure See how the SUs compose the maximum hippocampus

37. Minimum Hippocampus (MinH) See the hippocampus built so far MinH is the portion of hippocampus segmented by all of the examined protocols It is defined by the most restrictive criteria for the tracing of superior, medial, lateral and caudal boundaries, across available protocols. It includes the head and part of the body of the hippocampus MinH compounds the 60% of the Maximun Hippocampal Volume, as computed by summing up the volume of all (most inclusive) SUs. Intra rater re-test reliability for MinH is 0.992 Inter rater re-test reliability for MinH is 0.974 MinH conveys 28.5% of the volume difference due to AD. Its global impact on the total volume difference due to AD is of 67% (this measure is of course influenced by the size of the Unit). Here you can find all values about SUs (PDF) (*) All protocols ionclude MinH No need to choose Back Save Next Main menu

38. Alveus/Fimbria (A/F) A/F is the hippocampal white matter covering the dorso-lateral tissue of the hippocampus. The SU relates to how it can be detected and segmented on magnetic resonance images. It is either included or excluded by the available tracing criteria. Main menu A/F compounds the 10.5% of the Maximun Hippocampal Volume, as computed by summing up the volume of all (most inclusive) SUs. Intra rater re-test reliability for A/F is 0.863 Inter rater re-test reliability for A/F is 0.885 Nonetheless, the tracing of the MinH and A/F as a unique structure (as it happens in ordinary tracing) has an intra-rater reliability of 0.993, and an inter-rater of 0.973. A/F alone conveys 15.5% of the volume difference due to AD. Its global impact on the total volume difference due to AD is of 6% (this measure is of course influenced by the size of the Unit). Here you can find all values about SUs (PDF) (*) Would you include A/F in a harmonized protocol? YESNO? See the hippocampus built so far Back Save Next

39. Subiculum The subiculum relates to the less restrictive criteria for tracing the medial border, at the level of the hippocampal body, where the entorhinal cortex must be separated from the hippocampus. The SU “Subiculum” DOES NOT correspond to the anatomical subiculum. The three SUs “Subiculum” are PARTIALLY OVERLAPPING (3 and 2 both include 1). 1 2 3 1 - Oblique line with same inclination of parahippocampal WM, connecting the inferior part of the subiculum to the quadrigeminal cistern; 2 - Horizontal line from the highest medial point of the parahippocampal WM to the cistern; 3 – Morphology line outlining the contour of white matter of parahippocampal gyrus and of visible gray matter boundaries. Subiculum 2 - Horizontal Subiculum 3 - Morphology Subiculum 1 - Oblique Back Save Next Main menu

40. Subiculum (medial border of the hippocampal body) Main menu Subiculum 1 – “Oblique line” is defined by a medial border consisting in an oblique line with same inclination of parahippocampal WM, connecting the inferior part of the subiculum to the quadrigeminal cistern. The Subiculum “Oblique line” is entirely included in the other two criteria for segmenting the medial boundary (Horizontal and Morphology lines). Thus you can either include this, and choose also a most inclusive criterion for the medial border, or exclude this and choose a more inclusive criterion, obtaining the same result) The Subiculum “Oblique line” compounds the 8% of the Maximun Hippocampal Volume, as computed by summing up the volume of all (most inclusive) SUs. Intra rater re-test reliability for “Oblique line” is 0.964 Inter rater re-test reliability for “Oblique line” is 0.907 It conveys 13.5% of the volume difference due to AD Its global impact on the total volume difference due to AD is of 4% (this measure is of course influenced by the size of the Unit). Would you include “oblique line” in a harmonized protocol? YESNO? 1 See the hippocampus built so far Back Save Next

41. Subiculum (medial border of the hippocampal body) Subiculum 2 – “Horizontal line” is defined by a medial border consisting in a horizontal line drawn from the highest medial point of the parahippocampal WM to the cistern. The Subiculum “Horizontal line” includes the tissue that would be segmented with the “Oblique line”, but it is alternative to the criterion “Morphology” for segmenting the medial boundary. Would you include “Horizontal line” in a harmonized protocol? YESNO? 2 Subiculum 2 – “Horizontal line” compounds the 9% of the Maximun Hippocampal Volume, as computed by summing up the volume of all (most inclusive) SUs: Intra rater re-test reliability for Subiculum 2 is 0.980 Inter rater re-test reliability for Subiculum 2 is 0.932 It conveys 13.5% of the volume difference due to AD Its global impact on the total volume difference due to AD is of 5% (this measure is of course influenced by the size of the Unit). Here you can find all values about SUs (PDF) (*) Main menu See the hippocampus built so far Back Save Next

42. Subiculum (medial border of the hippocampal body) Would you include “Morphology line” in a harmonized protocol? YESNO? 3 Subiculum 3 – “Morphology” is defined by a line outlining the contour of the white matter of the parahippocampal gyrus and of the visible gray matter boundaries on the medial aspect of the hippocampal body. Subiculum 3 – “Morphology” compounds the 9.5% of the Maximun Hippocampal Volume, as computed by summing up the volume of all (most inclusive) SUs: Intra rater re-test reliability for Subiculum 3 is 0.981 Inter rater re-test reliability for Subiculum 3 is 0.937 It conveys 15% of the volume difference due to AD Its global impact on the total volume difference due to AD is of 5.5%(this measure is of course influenced by the size of the Unit). Subiculum 3 - “Morphology” includes the tissue that would be segmented with the “Oblique line”, but it is alternative to the criterion “Horizontal” for segmenting the medial boundary. If you selected “Horizontal”, and you select “Morphology” in this window, the criterion “Morphology” will finally be selected. Main menu See the hippocampus built so far Back Save Next

43. Tail 2121 The tail consists of the SUs representing the less restrictive criteria for segmenting the most caudal tissue of the hippocampus. The two SUs are NOT OVERLAPPING: Tail 1 – “Crura” includes the slices from the colliculi level to the crus/crura level; Tail 2 – “Tail End” includes the most caudal slices where hippocampal tissue can be seen, beyond the crura level. Here you can find all values about SUs (PDF) (*) Tail – End Tail – Crura Main menu See the hippocampus built so far Back Save Next

44. Tail 1 Tail 1 – “Crura” includes the slices from the colliculi level to the crus/crura level. For the segmentation of the Tail, you can include only this SU, or both this SU and Tail End. Tail 1 - “Crura” compounds the 8% of the Maximun Hippocampal Volume, as computed by summing up the volume of all (most inclusive) SUs: Intra rater re-test reliability for Tail 1 is 0.998 Inter rater re-test reliability for Tail 1 is 0.937 It conveys 24% of the volume difference due to AD Its global impact on the total volume difference due to AD is of 7% (this measure is of course influenced by the size of the Unit). Here you can find all values about SUs (PDF) (*) Would you include Tail - “Crura” in a harmonized protocol? YESNO? Main menu See the hippocampus built so far Back Save Next

45. Tail 2 If you did not include Tail 1 – “Crura”, you can not include “Tail End” in a protocol for hippocampal segmentation. Any issue relating to the separation of caudal hippocampal tissue from vestigial hippocampal gray matter will be considered on a later stage. Therefore, we invite you to answer about the inclusion of this SU independently on the need to separate it from vestigial gray matter. Tail 2 – “Tail End” includes the most caudal slices where hippocampal tissue can be seen, beyond the crura level. Tail 2 compounds the 12% of the Maximun Hippocampal Volume, as computed by summing up the volume of all (most inclusive) SUs: Intra rater re-test reliability for Tail 2 is 0.988 Inter rater re-test reliability for Tail 2 is 0.905 It conveys 30.5% of the volume difference due to AD Its global impact on the total volume difference due to AD is of 14.5% (this measure is of course influenced by the size of the Unit). Would you include “Tail End” in a harmonized protocol? YESNO? Main menu See the hippocampus built so far Back Save Next

46. Answer C Answer A Answer B

47. General description Inclusion of SUs in the Harmonized Protocol Minimum hippocampal body Alveus/fimbria Medial border Tail Definition of tracing modalities Delphi panel

49. Disambiguating Hippocampus/Vestigial Tissue Main menu Thanks to software for 3D navigation, the vestigial gray matter on the hippocampal tail, as defined by Duvernoy, can be seen, dorsomedially, as a gray scythe, separated from the hippocampus by a thin white matter layer. Exclusion of this tissue based on 3D visualization amounts to about 1% of the total hippocampal volume. Attempts have been made to exclude this tissue Pruessner JC, et al. (2000), Malykhin, N, et al. (2007). Unfortunately, arbitrary lines provide an easy solution, but often fail in excluding the vestigial tissue from atrophic AD subjects.

50. CSF pools Main menu The presence of isolated holes was more frequent in patients with memory disorders than in controls and this presence increased with age [Maller et al., 2010]. However there were some heterogeneous results. Poor correlation was found between isolated holes and age or atrophy, while the perihippocampal fissures (open holes) were strongly related with rate of atrophy and age in other reports [Li et al., 2006]. Back Save Next Would you exclude internal liquor from hippocampal segmentation? NO YES when connected to external liquor (case left) YES always, also when not connected to external liquor, by tracing isolated holes (cases left and right) other

51. Tracing of not visible structures Main menu In some cases it is difficult to discriminate structures that there should exist, like the subiculum, in very atrophic AD subjects. How would you trace in these cases? Back Save Next Trace only what is unequivocally seen from the available scan after attempts to adjust contrast in order to detect any scantly visible tissue (upper line)YESNO? Trace a very thin portion located in the target position, in order to complete the anatomical structure (lower line) YESNO?

52. Answer A Answer B Answer C Answer D Answer E Answer F Answer G

53. Publications – Full Papers Frisoni GB, Jack CR. Harmonization of magnetic resonance-based manual hippocampal segmentation: A mandatory step for wide clinical use. Alzheimer’s & Dementia, Volume 7, Issue 2, Pages 171-174, March 2011. Boccardi M, Ganzola R, Bocchetta M, Pievani M, Redolfi A, Bartzokis G, Camicioli R, Csernansky J, de Leone MJ, deToledo-Morrell L, Killiany RJ, Lehéricy S, Pantel J, Pruessner JC, Soininen H, Watson C, Duchesne S, Jack CR Jr, Frisoni GB. Survey of Protocols for the Manual Segmentation of the Hippocampus: Preparatory Steps Towards a Joint EADC-ADNI Harmonized Protocol. JAD/Handbooks of Alzheimer's Disease. Accepted with minor revisions, March 2011.

54. Publications – Congress Presentations AAN 2010 (Toronto, April 10-17): Frisoni GB, Boccardi M, Ganzola R, Duchesne S, Robitaille N, Redolfi A, Bartzokis GB, Csernansky J, de Leon MJ, Killiany RJ, Lehericy S, Malykhin NV, Pantel J, Pruessner JC, Soininen H, Jack C. Survey of Protocols for Manual Hippocampal Volumetry: Preparatory Steps for an EADC-ADNI Harmonized Protocol.Neurology, Volume 74, Issue 9, Pages A215-A215, Suppl. 2, March 2 2010.Presented as a poster. AIC 2010 (Honolulu, July 10): Boccardi M, Ganzola R, Duchesne S, Redolfi A, Bartzokis G, Csernansky J, deLeon MJ, Killiany RJ, Lehéricy S, Malykhin N, Pantel J, Pruessner JC, Soininen H, Jack C, Frisoni GB. Survey of segmentation protocols for hippocampal manual volumetry: preparatory phase for an EADC-ADNI harmonization protocol. Alzheimer’s & Dementia, IC-03-02, Volume 6, Issue 4, Suppl 1, S58-59, July 2010. Presented as an oral communication.

55. ICAD 2010 (Honolulu, July 10-15): Boccardi M, Ganzola R, Duchesne S, Redolfi A, Bartzokis G, Csernansky J, deLeon MJ, Killiany RJ, Lehéricy S, Malykhin N, Pantel J, Pruessner JC, Soininen H, Jack C, Frisoni GB. Survey of segmentation protocols for hippocampal manual volumetry: preparatory phase for an EADC-ADNI harmonization protocol. Alzheimer’s & Dementia, IC-03-02, Volume 6, Issue 4, Suppl 1, S58-59, July 2010. Presented as a hot poster. CTAD 2010 (Toulouse, November 3-5): Boccardi M, Ganzola R, Robitaille N, Bocchetta M, Redolfi A, Bartzokis G, Camicioli R, Csernansky JG, de Leon MJ, deToledo-Morrell L, Killiany RJ, Lehéricy S, Pantel J, Pruessner JC, Soininen H, Watson C, Duchesne S, Jack C, Frisoni GB. Survey of segmentation protocols for manual hippocampal volumetry: preparatory phase for an EADC-ADNI harmonization effort. The Journal of Nutrition, Health & Aging, Volume 14, Suppl 2, S12, 2010. Presented as a poster. Publications – Congress Presentations

56. AD/PD Congress 2011 (Barcelona, March): Boccardi M, Bocchetta M, Ganzola R, Redolfi A, Robitaille N, Bartzokis G, Csernansky J, deLeon MJ, deToledo-Morrell L, Killiany RJ, Lehéricy S, Malykhin N, Pantel J, Pruessner JC, Soininen H, Watson, CR, Duchesne S, Jack C, Frisoni GB. Survey of protocols for hippocampal manual volumetry: preparatory step for an EADC-ADNI harmonization protocol. Neurodegenerative Disease (Alzheimer’s and Parkinson’s Diseases: Advances, Concepts and New Challenges), Volume 8, Suppl 1, Page 1, March 2011. Presented as a poster.

57. AAN 2011 Poster 006, Future of Neuroscience Conference, Implications of the ADNI for Treatment, April 15 2011

58. Acknowledgements Mike & Barbara Urbut, Stuart & Amy Savitz, Harriet K. Burnstein, Chicago, IL Martina Bocchetta, Rossana Ganzola, Alberto Redolfi, Daniele Tolomeo, Gabriele Corbetta IRCCS FBF, Brescia, Italy Nicolas Robitaille, Simon Duchesne, Univ Laval, Quebec City, CAN Maria Carrillo, Meredith McNeil Alzheimer’s Association, Chicago IL All partners!