Transcript TITOLO TITOLO TITOLO TITOLO TITOLO TITOLO

Development of a harmonized protocol for
hippocampal tracing
An EADC-ADNI joint effort
3rd Meeting, Honolulu, April 13, 2011
Principal Investigators: Giovanni B Frisoni & Clifford R Jack
Project Coordinator: Marina Boccardi
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THE WORKGROUP
EADC
ADNI
F Barkhof/P Scheltens Amsterdam
B Dubois/S Leherici Paris
N Fox/ J Barnes
London
GB Frisoni
Brescia
H Hampel/J Pantel
Frankfurt
A Simmons
London
H Soininen
Kuopio
S Teipel
Rostock
LO Wahlund
Stockholm
CR Jack Jr
Rochester, MN
M Albert
Baltimore, 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’Brien
Newcastle, UK
J Pruessner
Montreal, QC
C Watson
Detroit, MI
THE WORKGROUP
Advisory board
Clinical Advisor
PJ Visser
Maastricht
EADC P.I.s
B Winblad
Stockholm
Lutz Froelich, Mannheim
Dissemination/Education
ADNI P.I.
M Weiner
Statistical Board
UCSF, US
G Waldemar
Copenhagen
S Duchesne Québec City
L Collins
Montreal
P Pasqualetti Rome
Population-based studies
P Sachdev/JJ Maller
T Den Heijer
L Launer
W Jagust
Mirjam I. Geerlings
PATH Through Life Study
Rotterdam Scan Study
Honolulu Asia Aging Study
SALSA Study
SMART MEDEA Study
DISCLOSURES
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
OUTLINE
Preliminary phase
Objectives
Preliminary phase
Latest results from prelim. phase
AA-funded project
Design
Validation Phase 1
Delphi panel
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
Amy PET imaging
Downstream funct/struct change FDG PET
Cortical/hippo atrophy
Preclinical Alz disease
Brain amyloidosis
Amy PET imaging
CSF Ab42
CSF tau/p-tau
Synaptic dysfunction/neurodegeneration FDG PET
Cortical/hippo atrophy
BACKGROUND
Hippocampal volume as an outcome measure
in trials of disease modifiers
Drug
Study
Effect
Segment. method
Tramiprosate
Alphase
68% (100 mg)
120% (150 mg)
Not mentioned
Gauthier et al., JNHA 2009
Atorvastatin
ADCLT
“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)
“CHV* % 3.78±2.63 vs
2.86±3.19
p = 0.124”
Manual protocol
Watson et al., 1992,
Neurology
“significant atrophy” §
Not mentioned
“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
AN1792
Xaliproden
Donepezil
SanofiAventis
Trials
* CHV= Change in hippocampal volume; § referenced link not working
Ref
Jones et al., Alz&Dem 2008
Feldman et al., Neurology
2010
Fox N et al., Neurology,
2005
From Vellas B et al.
(Review), Lancet
Neurol.,2008
Jack CR et al., Neurobiol.
Aging, 2008
BACKGROUND
The effect of segmentation protocols
on hippocampal volume
Ref.
Watson
et al.
Med border
Mesial edge of
temporal lobe
Regional
Zipursky outline at
choroidal
et al.
fissure
Norm. hippo vol
(cm3)
Left
Right
Lat
border
Inf border
Temp horn
of lat ventr
Incl subicular complex & uncal
cleft w/ border separating
subicular complex from
parahippo gyrus
4.903
The interface of hippocampal
tissue and parahippocampal
gyrus white matter
1.990
Not
mentioned
Geuze et al., Mol Psychiatry 2005;10:147-59
5.264
2 ½ fold
2.070
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
DEVELOPMENT OF STANDARDIZED
OPERATIONAL PROCEDURES FOR DIAGNOSTIC
MARKERS
Modality
Collection
Measurement
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
Cortical amyloid
deposition
Amyloid
PET
Hippocampal
volume
Alzheimer’s Association protocol
(PI K Blennow)
None
None
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
SELECTED PROTOCOLS
B
C
dTM
H
J
K
L
M
Pa
Pr
S
W
Bartzokis G, et al.
Convit A, et al.
deToledo-Morrel et al.
Haller JW, et al.
Jack CR Jr.
Killiany RJ, et al.
Lehéricy S, et al.
Malykhin NV, et al.
Pantel J, et al.
Pruessner JC, et al.
Soininen HS, et al.
Watson C, et al.
Psychiatry Res 1998;82:11-24
Neurobiol Aging 1997;18:131-8
Neurobiol Aging 2004;25:1197–1203
Radiology 1997;202:504-10
Epilepsia 1994;35 - Suppl 6:S21-9
Arch Neurol 1993;50:949-54
Am J Neuroradiol 1994;15:929-37
Psychiatry Res 2007;155:155-65
Hippocampus 2000;10:752-8
Cereb Cortex 2000;10:433-42
Neurology 1994;44:1660-8
Neurology 1992;42:1743-50
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
SEGMENTATION UNITS (SUs):
The LEGO blocks concept
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
Bartzokis1998
Jack, 1994;
deToledoMorrell 2004
Convit 1997
Killiany 1993
Soininen 1994
Lehericy
1994
Haller 1997
Pruessner 2000
Malykhin 2007
Watson 1992
Pantel 2000
QUANTITATIVE STUDY OF SUs
Intra-rater
0.992
Inter-rater
0.974
Alveus/fimbria
0.863
0.885
MinHB+Alveus/fimbria
0.993
0.973
Oblique line
0.964
0.907
Morphology
0.981
0.937
Horizontal line
0.980
0.932
Crus/crura
0.998
0.937
Most caudal
0.988
0.905
MinHB
Subiculum
Tail
Computed on 20 subjects, 4 for each degree of MTA
scale (Scheltens et al., 1992)
QUANTITATIVE STUDY OF SUs
Controls
MCI
AD
n=31
n=23
n=23
MCI
vs CTR
AD
vs CTR
MCI
vs AD
AD+MCI
vs CTR
Age, years
75.7 (5.2)
76.1 (5.6)
76.3 (5.6)
0.82
0.70
0.90
0.72
Gender, F
15 (48%)
11 (48%)
11 (48%)
0.99
0.99
0.99
0.96
Educ, yrs
16.0 (3.0)
15.6 (3.4)
15.2 (3.4)
0.73
0.79
0.70
0.51
243 (25)
134 (23)
136 (26)
<0.001
<0.001
0.76
<0.001
CSF Aβ, pg/ml
Significance
BARTZOKIS_L
2400,00
CONVIT_L
2400,00
Left
HALLER_L
JACK_deTOLEDO
_MORRELL_L
2200,00
KILLIANY_L
2200,00
CONVIT_R
Right
HALLER_R
JACK_deTOLEDO
_MORRELL_R
KILLIANY_R
LEHERICY_L
LEHERICY_R
PRUESSNER_MAL
YKHIN_L
PRUESSNER_MAL
YKHIN_R
PANTEL_L
2000,00
Media
Mean
Mediavolume
2000,00
BARTZOKIS_R
1800,00
SOININEN_L
SOININEN_R
WATSON_L
WATSON_R
31 CTR
23 MCI
23 AD
1800,00
1600,00
1600,00
1400,00
1400,00
1200,00
PANTEL_R
1200,00
CTRL
MCI
AD
CTRL
MCI
AD
LEFT HIPPOCAMPUS
Controls (n=31)
MinH
MCI (n=23)
AD (n=23)
p
MCI vs
CTR
p
AD vs CTR
p
MCI vs AD
p
AD+MCI vs
CTR
1467 (204)
1122 (263)
1023 (251)
<0,0005
<0,0005
0,199
<0,0005
Alveus/fimbria
248 (45)
232 (61)
200 (48)
0,269
<0,0005
0,055
0,01
Subiculum
243 (72)
220 (84)
213 (64)
0,279
0,118
0,754
0,121
Oblique line
196 (67)
178 (66)
176 (53)
0,338
0,262
0,936
0,207
Morphology
243 (72)
220 (84)
213 (64)
0,279
0,118
0,754
0,121
Horizontal line
234 (72)
210 (78)
211 (62)
0,243
0,221
0,957
0,153
Tail
485 (131)
383 (99)
353 (101)
0,003
<0,0005
0,307
<0,0005
Crura
190 (74)
177 (70)
146 (69)
0,538
0,034
0,14
0,101
End Tail
296 (120)
206 (76)
206 (86)
0,003
0,004
0,984
<0,0005
MaxHV
2443 (291)
1957 (348)
1788 (342)
<0,0005
<0,0005
0,105
<0,0005
p
AD vs CTR
p
MCI vs AD
p
AD+MCI
vs CTR
RIGHT HIPPOCAMPUS
Controls (n=31)
MinH
MCI (n=23)
AD (n=23)
p
MCI vs
CTR
1462 (232)
1214 (247)
1061 (241)
<0,0005
<0,0005
0,039
<0,0005
Alveus/fimbria
255 (47)
258 (71)
225 (65)
0,84
0,05
0,103
0,35
Subiculum
225 (79)
208 (89)
184 (56)
0,459
0,042
0,294
0,109
Oblique line
181 (67)
167 (71)
150 (46)
0,455
0,059
0,334
0,122
Morphology
225 (79)
208 (89)
184 (56)
0,459
0,042
0,294
0,109
Horizontal line
220 (78)
203 (83)
182 (54)
0,459
0,053
0,309
0,117
Tail
487 (151)
349 (115)
349 (131)
0,001
0,001
0,999
<0,0005
Crura
187 (75)
169 (68)
140 (69)
0,37
0,025
0,17
0,058
End Tail
301 (120)
181 (113)
209 (110)
<0,0005
0,006
0,394
<0,0005
MaxHV
2429 (303)
2029 (372)
1820 (369)
<0,0005
<0,0005
0,062
<0,0005
Controls
(n=31)
1467 (204)
% of
total
hippo
60%
Alveus/fimbria
248 (45)
Subiculum
LEFT HIPPOCAMPUS
MCI (n=23)
AD (n=23)
1122 (263)
1023 (251)
% diff
MCI vs
CTR
23,5%
10%
232 (61)
200 (48)
6,5%
3%
19%
7%
243 (72)
10%
220 (84)
213 (64)
9,5%
5%
12%
4,5%
Oblique line
196 (67)
8%
178 (66)
176 (53)
9%
3,5%
10%
3%
Morphology
243 (72)
10%
220 (84)
213 (64)
9,5%
5%
12%
4,5%
Horizontal line
234 (72)
9%
210 (78)
211 (62)
10%
5%
10%
3,5%
Tail
485 (131)
20%
383 (99)
353 (101)
21%
21%
27%
20,5%
Crura
190 (74)
8%
177 (70)
146 (69)
6,5%
2,5%
23%
6,5%
End Tail
296 (120)
12%
206 (76)
206 (86)
30%
18,5%
30%
14%
MaxHV
2443 (291)
100%
1957 (348)
1788 (342)
20%
100%
27%
100%
% MCI vs
CTR
(impact)
62%
% diff
AD vs
CTR
27%
% AD vs
CTR (impact)
MinH
Controls
(n=31)
1462 (232)
% of
total
hippo
60%
Alveus/fimbria
255 (47)
Subiculum
RIGHT HIPPOCAMPUS
MCI (n=23)
AD (n=23)
% MCI vs
CTR
(impact)
71%
% diff
AD vs
CTR
30%
% AD vs
CTR (impact)
68%
1214 (247)
1061 (241)
% diff
MCI vs
CTR
17%
11%
258 (71)
225 (65)
-1%
-0,5%
12%
5%
225 (79)
9%
208 (89)
184 (56)
8%
4%
18%
6,5%
Oblique line
181 (67)
8%
167 (71)
150 (46)
8%
3,5%
17%
5%
Morphology
225 (79)
9%
208 (89)
184 (56)
8%
4%
18%
6,5%
Horizontal line
220 (78)
9%
203 (83)
182 (54)
7,5%
4%
17%
6%
Tail
487 (151)
20%
349 (115)
349 (131)
28,5%
34,5%
28,5%
22,5%
Crura
187 (75)
8%
169 (68)
140 (69)
10%
4,5%
25%
7,5%
End Tail
301 (120)
12%
181 (113)
209 (110)
40%
30%
31%
15%
MaxHV
2429 (303)
100%
2029 (372)
1820 (369)
16,5%
100%
25%
100%
MinH
66%
OUTLINE
Preliminary phase
Objectives
Preliminary phase
Latest results from prelim. phase
AA-funded project
Design
Validation Phase 1
Delphi panel
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
Delphi panel → harmonized prot
VARIABILITY
EVALUATION
GOLD STANDARD
5 expert tracers
1 tracer
20 naive tracers
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)
VALIDATION vs
PATHOLOGY
Training
(tracing 20 hippos on 1.5T ADNI
scans with each SU)
(SAME on 3T ADNI scans)
Local Protocol:
1.5T 3D T1-weighted scans
from (Bobinski et al., 2000)
pathologically verified set
(total for rater: 30 hippos)
Benchmark Harmonized hippos:
Qualification
(10 tracers each SU;
10 whole hippo)
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)
RM-ANOVA: test
of rater and rater by
center terms
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)
Qualification
Harmonized Protocol:
global and local
95% confidence
intervals
1.5T 3D T1-weighted scans
from (Bobinski et al., 2000)
pathologically verified set
(total for rater: 30 hippos)
Harmonized Protocol:
The best 5
naive tracers
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)
RM-ANOVA: test
of protocol main
effect
RM-ANOVA: test of
main effects side, traceretrace, atrophy, time,
scanner, rater
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)
AA Funded Project: Tracers
PI
Validation tracer
Barkhof/Scheltens
George Bartzokis
John G. Csernansky
Charles DeCarli
Leyla DeToledo-Morrell
Giovanni Frisoni
Nick Fox
Mirjam Geerlings
Clifford Jack
Jeffrey Kaye
Ron Killiany
Stephane Lehericy
Jerome Maller/Sachdev
John O’Brien
Jens Pruessner
Hilkka Soininen
Stefan Teipel
Margo Pronk
Mat Tinley
Adam Christensen
Sarah Hollander
Travis Stoub
Enrica Cavedo
Melanie Blair
Marileen Portegies
Gregory Preboske
Tim Swihart (L. Silbert)
Sarah Greene
Claire Boutet
Jerome Maller
Emma Burton
Sandra Pietrantonio
Yawu Liu
Michel Grothe
Felix van Dommelen
--------Mariangela Lanfredi
--Chadwick Ward
-----------------
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
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
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
OUTLINE
Preliminary phase
Objectives
Preliminary phase
Latest results from prelim. phase
AA-funded project
Design
Validation Phase 1
Delphi panel
AA Funded Project: Delphi Participants
PI
Delphi Participant
Barkhof/Scheltens
George Bartzokis
Richard Camicioli
John G. Csernansky
Charles DeCarli
Leyla DeToledo-Morrell
Nick Fox
Mirjam Geerlings
Clifford Jack
Ronald Killiany
Jerome Maller
John O’Brien
Jens Pruessner
Hilkka Soininen
Paul Thompson
Craig Watson
Wouter Henneman
George Bartzokis
R. Camicioli/N. Malykhin
Lei Wang
Charles DeCarli
Leyla DeToledo-Morrell
Josephine Barnes
Lotte Gerritsen
C. Jack/G. Preboske
Ronald Killiany
P. Sachdev /C. Meslin
Michael Firbank
Jens Pruessner
H. Soininen/M. Pihlajamäki
Liana Apostolova
Craig Watson
Henrike Wolf
Delphi panel
One vote (account) for each participating centre is
allowed
www.hippocampal-protocol.net
Delphi panel
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)
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
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.
See how the SUs compose the maximum hippocampus
Minimum Hippocampus (MinH)
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
All protocols ionclude
MinH
No need to choose
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).
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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.
Would you include A/F
in a harmonized
protocol?
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
YES
NO
?
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).
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Subiculum
1
2
3
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.
Subiculum 1 - Oblique
The SU “Subiculum” DOES NOT
correspond to the anatomical subiculum.
The three SUs “Subiculum” are
PARTIALLY OVERLAPPING (3 and 2 both
include 1).
Subiculum 2 - Horizontal
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.
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Subiculum 3 - Morphology
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Subiculum (medial border of the hippocampal body)
1
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)
Would you include
“oblique line” in a
harmonized protocol?
YES
NO
?
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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).
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Subiculum (medial border of the hippocampal body)
2
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.
Would you include
“Horizontal line” in a
harmonized protocol?
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.
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) (*)
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?
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See the hippocampus built so far
Subiculum (medial border of the hippocampal body)
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” 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.
Would you include
“Morphology line” in a
harmonized protocol?
YES
NO
?
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).
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Tail
2
1
Tail – End
The tail consists of the SUs representing the less restrictive
criteria for segmenting the most caudal tissue of the
hippocampus.
Tail – Crura
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.
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See the hippocampus built so far
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:
Would you include Tail
- “Crura” in a
harmonized protocol?
YES
NO
?
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).
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Tail
2
Tail 2 – “Tail End” includes the most
caudal slices where hippocampal tissue
can be seen, beyond the crura level.
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.
Would you include “Tail
End” in a harmonized
protocol?
YES
NO
?
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
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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).
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Answer A
Answer B
Answer C
Delphi panel
General description
Inclusion of SUs in the Harmonized Protocol
Minimum hippocampal body
Alveus/fimbria
Medial border
Tail
Definition of tracing modalities
Disambiguating Hippocampus/Vestigial Tissue
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.
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CSF pools
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].
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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
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Tracing of not visible structures
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?
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)
YES
NO
?
Trace a very thin portion located in the target position, in
order to complete the anatomical structure (lower line)
YES
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NO
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?
Answer A
Answer B
Answer C
Answer D
Answer E
Answer F
Answer G
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.
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.
Publications – Congress Presentations
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
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.
AAN 2011
Poster 006, Future of Neuroscience Conference,
Implications of the ADNI for Treatment, April 15 2011
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!