Establishing Magnetic Resonance Images Orientation for the EADC-ADNI Manual Hippocampal Segmentation Protocol
– SUPPLEMENTARY MATERIAL
Marina Boccardi1, Martina Bocchetta1, Liana G. Apostolova2, Gregory Preboske3, Nicolas Robitaille4, Patrizio Pasqualetti5, D. Louis Collins6, Simon Duchesne4, Clifford R. Jack Jr3, Giovanni B. Frisoni1, for the EADC-ADNI Working Group on The Harmonized Protocol for Hippocampal Volumetry, and for the Alzheimer’s Disease Neuroimaging Initiative*.
Collaborators:
John G. Csernansky7, Mony J. de Leon8, Leyla deToledo-Morrell9, Ronald J. Killiany10, Stéphane Lehéricy11, Nikolai Malykhin12, Johannes Pantel13, Jens C. Pruessner14, Hilkka Soininen15, Craig Watson16.
From:
1LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine) IRCCS – S. Giovanni di Dio – Fatebenefratelli Brescia, Italy (MB, MBocch, GBF);2Mary S. Easton Center for Alzheimer’s Disease Research and Laboratory of NeuroImaging, David Geffen School of Medicine, University of California, Los Angeles (LA);3Department of Diagnostic Radiology, Mayo Clinic and Foundation, Rochester, MN (GP, CJ);4Department of Radiology, Université Laval and Centre de Recherche de l’Institut universitaire de santé mentale de Québec, Quebec City, Canada (NR, SD); 5 AFaR – Associazione Fatebenefratelli per la Ricerca, Rome, Italy; 6McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Canada; 7Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA (JGC);8New York University School of Medicine, Center for Brain Health, New York, NY (MJdL);9Department of Neurological Sciences, Rush University, Chicago, Illinois (LdTM); 10Department of Anatomy and Neurobiology, Boston University School of Medicine (RJK);11Center for NeuroImaging Research - CENIR, ICM - Institut du Cerveau et de la Moelle epiniere; Department of Neuroradiology, Université Pierre et Marie Curie-Paris 6, Inserm U975, CNRS 7225, Groupe Hospitalier Pitié-Salpêtrière, Paris, France (SL);12Department of Biomedical Engineering, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada. (NM); 13Institute of General Practice, University of Frankfurt/Main, Germany (JP);14McGill Centre for Studies in Aging, Department of Psychiatry, McGill University, Montreal, Quebec, Canada (JCP);15Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland (HS); 16Wayne State University School of Medicine, University Health Center, St. Antoine, Detroit, MI (CW).
* Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database ( As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:
This material can be found at
Table S1. Socio-demographic features of the 10 ADNI whose scans were used in the current study.
MTA=Medial Temporal Atrophy (Scheltens et al., JNNP 1992);CTR=healthy controls; MCInc=non converter MCI; MCIc= MCI who subsequently converted to AD; AD=probable Alzheimer’s disease patients.p-values were computed with non-parametric tests (KruskallWallis and Chi-square). 0,1,2,3,4 denote different degrees of MTA, from absent to severe.
MTA scale0 / 1 / 2 / 3 / 4 / p-value
Age, years / 71 (2.8) / 80 (7.8) / 75 (2.8) / 82 (2.1) / 80 (4.2) / 0.219
Gender, female / 2 (100%) / 1 (50%) / 0 (0%) / 0 (0%) / 1 (50%) / 0.212
Education, years / 17 (1.4) / 14 (5.7) / 15 (1.4) / 19 (1.4) / 16 (5.7) / 0.567
ApoE ε4 allele, carriers / 0 (0%) / 0 (0%) / 1 (50%) / 1 (50%) / 1 (50%) / 0.582
Diagnosis, CTR\MCInc\MCIc\AD / 1\1\0\0 / 2\0\0\0 / 1\0\1\0 / 0\1\1\0 / 0\0\1\1 / 0.406
Scanner Manufacturer, Philips\GE\Siemens / 0\1\1 / 0\2\0 / 1\1\0 / 0\1\1 / 0\2\0 / 0.448
Table S2. Crude hippocampal volumes of 10 ADNI subjects obtained through manual segmentation on MRIs oriented along the AC-PC line and long hippocampal axis.
ADNI Subject / Side / AC-PC / Hippo AxisTracer 1 / Tracer 2 / Tracer 3 / Tracer 1 / Tracer 2 / Tracer 3
1 / R / 2647 / 3066 / 2938 / 2582 / 3364 / 2988
L / 2538 / 2849 / 2843 / 2310 / 3090 / 3085
2 / R / 2476 / 2575 / 2654 / 2476 / 2919 / 2676
L / 2451 / 2540 / 2634 / 2462 / 2782 / 2733
3 / R / 2707 / 3119 / 3076 / 2818 / 3219 / 3296
L / 2630 / 2838 / 2913 / 2675 / 3167 / 3368
4 / R / 3359 / 3746 / 3811 / 3440 / 3902 / 3673
L / 3115 / 3306 / 3547 / 3128 / 3327 / 3585
5 / R / 3336 / 3298 / 3211 / 3184 / 3577 / 3837
L / 3447 / 3204 / 3275 / 3352 / 3509 / 3941
6 / R / 2515 / 2266 / 2901 / 2585 / 2640 / 3019
L / 2451 / 2187 / 2694 / 2477 / 2432 / 2861
7 / R / 2644 / 2734 / 2992 / 2516 / 2862 / 2902
L / 2708 / 2748 / 2882 / 2551 / 2987 / 2939
8 / R / 1887 / 1995 / 2376 / 1946 / 2127 / 2404
L / 2039 / 1949 / 2431 / 1964 / 2171 / 2374
9 / R / 1099 / 1172 / 1052 / 1029 / 1226 / 1201
L / 1326 / 1360 / 1242 / 1254 / 1364 / 1450
10 / R / 1333 / 1453 / 1469 / 1289 / 1558 / 1585
L / 1659 / 1589 / 1822 / 1706 / 1640 / 1952
Absolute inter-rater ICCs were higher (and the confidence intervals narrower) for AC-PC (left: 0.94, 0.79-0.98 CI 95%; right: 0.94, 0.81-0.99) than for hippocampal axes oriented scans (left: 0.87, 0.41-0.97, right: 0.91, 0.53-0.98).
Figure S1.Spatial overlapping among the three tracers in the case with the most favourable similarity coefficient(0.813; subject 3, right hippocampus, segmented on the AC-PC-orientedMRI).An animated figure with these frames is available at
Blue corresponds to Tracer 1, red to Tracer 2, green to Tracer 3. The white region denotes the spatial overlap among all three tracers. Red, green and blue denote regions with no overlapping. Regions where two tracers overlap are indicated in magenta (Tracer 1 and 2), yellow (Tracer 2 and 3) and cyan (Tracer 1 and 3).
This color legend also applies to the following movies available online:
The hippocampal segmentation with the worstsimilarity coefficientfrom the hippocampal axes-oriented segmentations (similarity coefficient=0.717):
The hippocampal segmentation with the worstsimilarity coefficientfrom theAC-PC-oriented traces (similarity coefficient=0.729):
The hippocampal segmentation with the bestsimilarity coefficientfrom the longhippocampal axes-oriented traces(similarity coefficient=0.798):
Table S3. Similarity coefficientsfor each hippocampus segmented on the AC-PC-oriented and long hippocampal axes-oriented planes.
AC-PC / Hippocampal AxesLeft / Right / Left / Right
/ 0.7643 / 0.7676 / 0.7244 / 0.7447
0.7905 / 0.7657 / 0.7773 / 0.7572
0.8048 / 0.8133 / 0.7538 / 0.764
0.8021 / 0.7989 / 0.7985 / 0.7773
0.8105 / 0.8247 / 0.7827 / 0.7758
0.7725 / 0.7561 / 0.7433 / 0.7475
0.8136 / 0.8079 / 0.7832 / 0.7631
0.7293 / 0.7678 / 0.7211 / 0.7638
0.729 / 0.739 / 0.7257 / 0.7177
0.7802 / 0.7732 / 0.7615 / 0.7306
Acknowledgements
The Alzheimer’s Association has provided logistic support for the update meetings of the project in Toronto (April, 2010), Honolulu (July, 2010 and April, 2011),Paris (July, 2011), New Orleans (April, 2012) and Vancouver (July, 2012). Wyeth, part of the Pfizer group, and Lilly have provided unrestricted grants in support of the work reported in this paper. A follow-up project has been funded by the Alzheimer’s Association: “A Harmonized Protocol for Hippocampal Volumetry: an EADC-ADNI Effort”, grant n. IIRG -10-174022.
NR and SD have received funding support from the Ministère du Développement Économique, de l’Innovation et de l’Exportation du Québec.
EADC-ADNI centres and PIs taking part to the project are listed in the official project web-site (
EADC-ADNI Working Group on The Harmonized Protocol for Hippocampal Volumetry.
The project PI is Giovanni B Frisoni, IRCCS Fatebenefratelli, Brescia, Italy; the co-PI is Clifford R. Jack, Mayo Clinic, Rochester, MN; the Statistical Working Group is led by Simon Duchesne, Laval University, Quebec City, Canada; project Coordinator is Marina Boccardi, IRCCS Fatebenefratelli, Brescia, Italy. EADC Centres (local P.I.) are: IRCCS Fatebenefratelli, Brescia, Italy (GB Frisoni); University of Kuopio and Kuopio University Hospital, Kuopio, Finland (H Soininen); Höpital Salpètriere, Paris, France (B Dubois and S Lehericy); University of Frankfurt, Frankfurt, Germany (H Hampel); University Rostock, Rostock, Germany (S Teipel); Karolinska institutet, Stockholm, Sweden (L-O Wahlund); Department of Psychiatry Research, Zurich, Switzerland (C Hock); Alzheimer Centre, Vrije Univ Medical Centre, Amsterdam, The Netherlands (F Barkhof and P Scheltens); Dementia Research Group Institute of Neurology, London, United Kingdom (N Fox); NEUROMED, Centre for Neuroimaging Sciences, London, United Kingdom (A Simmons). ADNI Centres are: Mayo Clinic, Rochester, MN (CR Jack); University of California Davis, CA (C DeCarli); University of California, Los Angeles (UCLA), CA (G Bartzokis); University of California San Francisco (UCSF), CA (M Weiner and S Mueller); Laboratory of NeuroImaging (LoNI), University of California, Los Angeles (UCLA), CA (PM Thompson and LG Apostolova); Rush University Medical Center, Chicago, IL (L deToledo-Morrell); Rush Alzheimer's Disease Center, Chicago, IL (D Bennet); Nortwestern University, IL (J Csernansky); Boston University School of Medicine, MA (R Killiany); John Hopkins University, Baltimore, MD (M Albert); Center for Brain Health, New York, NY (M De Leon); Oregon Health&Science University, Portland, OR (J Kaye). Other Centres are: McGillUniversity, Montreal, Quebec, Canada (J Pruessner); University of Alberta, Edmonton, AB, Canada (R Camicioli and N Malykhin); Department of Psychiatry, Psychosomatic, Medicine & Psychotherapy, Johann, Wolfgang Goethe-University, Frankfurt, Germany (J Pantel); Wayne State University (WSU), Detroit, MI (C Watson); Institute for Ageing and Health, Wolfson Research Centre, Newcastle GeneralHospital, Newcastle, United Kingdom (J O'Brien). Population based Studies: PATH through life, Australia (P Sachdev and JJ Maller); SMART-Medea Study, The Netherlands (MI Geerlings); Rotterdam Scan Study, The Netherlands (T denHeijer). Statistical Working Group: AFAR (Fatebenefratelli Association for Biomedical Research) San Giovanni Calibita - Fatebenefratelli Hospital - Rome, Italy (P Pasqualetti); Laval University, Quebec City, Canada (S Duchesne); MNI, McGill University, Montreal, Canada (L Collins). Advisors: Clinical issues: PJ Visser, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands; EADC PIs: B Winbald, Karolinska Institute, Sweden and L Froelich, Central Institute of Mental Health, Mannheim, Germany; Dissemination & Education: G Waldemar, Copenhagen University Hospital, Copenhagen, Denmark; ADNI PI: M Weiner, University of California San Francisco (UCSF), CA; Population Studies: L Launer, National Institute on Aging (NIA), Bethesda and W Jagust, University of California, Berkeley, CA.