harmonization of magnetic resonance-based manual hippocampal
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Alzheimer’s & Dementia 7 (2011) 171e174
Perspectives
Harmonization of magnetic resonance-based manual hippocampalsegmentation: A mandatory step for wide clinical use
Giovanni B. Frisonia,*, Clifford R. Jackb
aLENITEM Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, ItalybDepartment of Diagnostic Radiology, Mayo Clinic, Rochester, MN, USA
Abstract Hippocampal atrophy is a marker of disease state and progression in Alzheimer’s disease. The gold
*Corresponding au
13.
E-mail address: gf
1552-5260/$ - see fro
doi:10.1016/j.jalz.201
standard to measure hippocampal volume is through manual segmentation. A number of protocols tomeasure hippocampal volume through manual segmentation have been developed, but the markedheterogeneity of anatomical landmarks has given rise to wide variability of volume estimates.With the aim of fostering the use of hippocampal volume in routine clinical settings, an internationaltask force is currently working on developing a harmonized protocol that will resolve and reduce thepresent heterogeneity. The task force will then validate the harmonized protocol, develop harmonizedprobabilistic hippocampal maps, and develop illustrative and educational material on the use of theharmonized protocol and maps.� 2011 The Alzheimer’s Association. All rights reserved.
Keywords: Alzheimer’s disease; Hippocampal volumetry; MR imaging; Early diagnosis; Clinical trials; Outcome measures
1. Introduction
In the fields of Alzheimer’s disease (AD) care and drugdevelopment, there is an urgent need for the developmentof procedures that would help to estimate hippocampal atro-phy accurately and consistently. In the revised criteria for thediagnosis of AD, an estimate of hippocampal atrophy fromstructural magnetic resonance imaging (MRI) is a key sup-portive marker [1]. In patients with AD, hippocampal atro-phy has been measured in clinical trials of tramiprosate,atorvastatin, AN1792, xaliproden, and donepezil (Table 1).Some of these found evidence of a beneficial drug effecton reduction of hippocampal volume, despite variable clini-cal effects. A notable exception is the AN1792 trial in whichtreated subjects lost more hippocampal volume than non-treated patients, although the loss was not significant. Algo-rithms that automatically segment (delineate) thehippocampus from the surrounding brain tissue on MR brainscans are being actively developed; these will require thegold standard of manual segmentation for validation [2,3].The potential future availability of drugs that alter
thor. Tel.: 39-03-03-50-13-61; Fax: 39-03-03-50-13-
risoni@fatebenefratelli.it
nt matter � 2011 The Alzheimer’s Association. All rights r
0.06.007
progression of cognitive deterioration will make a securediagnosis at the earliest possible stages imperative.
Evidence from imaging-pathological correlations showsthat manual hippocampal segmentation is a valid markerof neurodegenerative changes in AD [4], and several studiesin clinical AD populations from laboratories worldwidehave reported that hippocampal volume in patients were15% to 40% smaller (more atrophied) than controls [5].However, different laboratories use different anatomicallandmarks and measurement procedures. This inconsistencyof approach means that estimates of “normal” hippocampalvolumes may differ by a maximum of 2.5-fold (Table 2) [6].A meta-analysis of rates of atrophy over time showed aneven wider range, with rates varying from 0.32% to 6.8%per year [7]. Without comparability of methods, it is impos-sible to determine whether these differences reflect a neuro-biological heterogeneity or how much of this variance isdetermined by the different protocols.
The most validated procedure to estimate hippocampalatrophy is to calculate hippocampal volumes with manualoutlining using anatomical landmarks by an expert rater onhigh resolution T1-weighted MRI [5]. This manual volume-try is also used as the standard against which automatedsegmentation algorithms [8e12] are assessed; however, inthe absence of an agreed reference protocol for manual
eserved.
Table 1
Clinical trials with drugs for Alzheimer’s disease where hippocampal volume measures were included in the study design
Drug Trial name Patients Effect on hippocampal volume loss Segmentation method Reference
AN1792 e AD Change from baseline to follow-up:
Placebo: 22.86% (SD: 3.19)
Treated: 23.78% (SD: 2.63), P 5 .12
Manual [14] 15
Atorvastatin ADCLT AD Change from baseline to follow-up:
Placebo: 2134 (SD: 174) mm3
Treated: 583 (SD: 354) mm3, P . .05
Manual [16,17] 18
LEADe AD Significant smaller annualized decrease in
hippocampal volume in treated patients
Semi-automated MIDAS [19] 20,21
Donepezil Memory
impairment study
MCI Change from baseline to follow-up in e4
carriers:
Placebo: 26.14% (SE: 3.49)
Treated: 24.50% (SE: 2.28), P 5 .07
Manual [22,23] 24
Tramiprosate Alphase AD Change from baseline to follow-up:
Placebo: 2419 (SE: 113) mm3
Treated 100 mg: 2135 (SE: 58) mm3,
P 5 .035
Treated: 150 mg: 79.5 (SE: 133) mm3,
P 5 .009
Not mentioned 25
Xaliproden EFC2724 AD Significantly less hippocampal atrophy in
treated patients
Not mentioned 26
NOTE. Some manuscripts fail to provide details on the magnitude and significance of the effect.
Abbreviations: AD, Alzheimer’s disease; SD, standard deviation; ADCLT, Alzheimer’s disease cholesterol-lowering treatment; LEADe, Lipitor’s effect in
Alzheimer’s dementia; MCI, mild cognitive impairment; SE, standard error.
G.B. Frisoni and C.R. Jack / Alzheimer’s & Dementia 7 (2011) 171e174172
volumetry, the comparison of the accuracy of differentautomated methods is virtually impossible.
An international task force has recently been gathered bythe authors of this article with the aim of developing a harmo-nized protocol that will overcome the present heterogeneity(Table 3). The project will run in four phases. Phase I willharmonize existing protocols, phase II will validate theharmonized protocol, phase IIIwill develop harmonized prob-abilistic hippocampal maps, and phase IV will develop anillustrative and educational material on the use of the harmo-
Table 2
Extreme values of normal hippocampal volumes according to studies using differ
Reference
Most anterior
slice
Most posterior
slice
Medial
border
L
b
14 CSF in uncal
recess of
temporal
horn or
alveus
Slice where the
crura of
fornices are
seen in full
profile
Mesial edge
of the
temporal
lobe
T
27 Slice where
hippocampus is
clearly
distinguished
from the
amygdala
One slice anterior
to where the
vertical Sylvian
fissures are no
longer present
Regional outline at
the level of the
choroidal
fissure
N
Adapted from Geuze et al., 2005 [6].
nized protocol and maps. Under the auspices of the Alz-heimer’s Association, the task force had met first in Chicagoin July 2008 to discuss the study design, and recently in Tor-onto in April 2010, wherework to datewas presented and dis-cussed in a hybrid in-person and remote (webinar) workshop.
Twelve most frequently used protocols for manualhippocampal segmentation were selected from the Alz-heimer’s literature; anatomical landmarkswere extracted; hip-pocampi from two sample brain scans (one representativeAD patient and one healthy control from the Alzheimer’s
ent protocols for manual segmentation
ateral
order
Inferior
border
Hippocampal volume (cm3)
Left Right
emporal horn
of the lateral
ventricle
Includes
subicular
complex and
uncal cleft with
the border
separating the
subicular
complex from
the parahippo
campal gyrus
4.903 5.264
ot mentioned Interface of the
hippocampal
tissue and
parahip-
pocampal
gyrus white
matter
1.990 2.070
Table 3
The expert working group
EADC centres ADNI centres Other centres
Population-based
studies
Statistical working
group Advisors
N Fox, London,
United Kingdom
M Albert, Johns
Hopkins
University,
Baltimore, MD
J Pruessner*,
McGill
University,
QC, Canada
Rotterdam Scan
Study, M B
reteler/T den
Heijer
P Pasqualetti,
AFAR, Roma
EADC P.I.s: B Winbald
and L Froelich ADNI
P.I.:MWeiner,UCSF,CA
Clinical issues:
PJ Visser, Maastricht,
The Netherlands
A Simmons, London,
United Kingdom
J Csernansky*,
Northwestern
University, IL
R Camicioli/N
Malykhin*
University
Alberta, AB,
Canada
PATH through life,
P Sachdev/JJ
Maller
S Duchesne,
Laval
University,
Canada
L-O Wahlund,
Stockholm,
Sweden
M De Leon*,
New York, NY
C Watson*, WSU,
Detroit, MI
L Collins, MNI, McGill,
Montreal
Dissemination
and Education:
G Waldemar,
Copenhagen,
Denmark
F Barkhof/P
Scheltens,
Amsterdam, The
Netherlands
R Killiany*,
Boston USM,
MA
J O’Brien,
Newcastle,
United
Kingdom
GB Frisoni,
Brescia, Italy
G Bartzokis*,
UCLA, CA
Population studies:
L Launer, NIA,
Bethesda, MD
W Jagust,
Berkeley, CA
H Soininen*,
Kuopio, Finland
C DeCarli, UC
Davis, CA
B Dubois/S
Leherici* Paris,
France
CR Jack*, Rochester,
MN
H Hampel/J Pantel*,
University of
Frankfurt, DE
PM Thompson,
LONI, UCLA,
CA
S Teipel, Rostock,
DE
L deToledo-Morrell*,
Rush UMC,
Chicago, IL
J Kaye, Portland,
OR
M Weiner/S
Mueller, UCSF, CA
D Bennett, Rush
ADC, Chicago, IL
*The authors of segmentation protocols that will contribute to the harmonized protocol.
G.B. Frisoni and C.R. Jack / Alzheimer’s & Dementia 7 (2011) 171e174 173
Disease Neuroimaging Initiative [ADNI] database) weresegmented following all of the 12 protocols and the accu-racy of the interpretation of the protocols was checked dur-ing interactive webinars with the protocols’ authors. Theanatomical landmarks certified by the protocols’ authorswere semantically harmonized; the differences were opera-tionalized into tracing units summarizing all the variabilityamong protocols; and 3D visual representations of the trac-ing units were developed. The work done so far has beenpresented at the American Academy of Neurology meeting[13] and the pertinent material can be found at http://www.hippocampal-protocol.net.
This is a preparatorywork for empirical testing of the con-tribution of each tracing unit to segmentation accuracy and
volumetric differences between patients and controls. The re-sults will be provided to a Delphi panel that will reach con-sensus on a harmonized protocol. The harmonized protocolwill be validated with neuropathological data and its accu-racy will be compared with currently used protocols. Finally,hippocampal probability maps will be developed. These willbe instrumental to the development of standard operationalprocedures for the measurement of hippocampal volume,an essential feature of anymedical test to be used in the clinic.
Social awareness and scientific knowledge of AD haveincreased dramatically in the past 20 years. However, thera-peutic options are currently limited to symptomatic drugsand diagnosis is still largely based on individual physicianexperience and subjective judgment. Standard operational
G.B. Frisoni and C.R. Jack / Alzheimer’s & Dementia 7 (2011) 171e174174
procedures for the assessment of disease markers will be thekey to drug discovery and to the development of more effec-tive, technology-assisted care of patients with AD.
Acknowledgments
Marina Boccardi led the technical group of Rossana Gan-zola, Simon Duchesne, Nicolas Robitaille, Alberto Redolfi,Michela Pievani, and Anna Caroli. Enrica Cavedo helped inthe editorial process of this manuscript. This project wasfunded partly from unrestricted grants from Lilly andWyeth.The Alzheimer’s Association has generously taken charge oforganization of workshops. The authors of the protocolshave been key to the work done so far: George Bartzokis,John G. Csernansky, Mony De Leon, Leyla deToledo-Morrell, Ron Killiany, Stephane Lehericy, Nikolai Maly-khin, Johannes Pantel, Jens Pruessner, Hilkka Soininen,and Craig Watson.
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