Alzheimers & Dementia 7 (2011) 171e174

Perspectives

Harmonization of magnetic resonance-based manual hippocampal

segmentation: A mandatory step for wide clinical use
Giovanni B. Frisonia,*, Clifford R. Jackb
a

LENITEM Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
b
Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN, USA

Abstract

Hippocampal atrophy is a marker of disease state and progression in Alzheimers disease. The gold
standard to measure hippocampal volume is through manual segmentation. A number of protocols to
measure hippocampal volume through manual segmentation have been developed, but the marked
heterogeneity 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 international
task force is currently working on developing a harmonized protocol that will resolve and reduce the
present heterogeneity. The task force will then validate the harmonized protocol, develop harmonized
probabilistic hippocampal maps, and develop illustrative and educational material on the use of the
harmonized protocol and maps.
2011 The Alzheimers Association. All rights reserved.

Keywords:

Alzheimers disease; Hippocampal volumetry; MR imaging; Early diagnosis; Clinical trials; Outcome measures

1. Introduction
In the fields of Alzheimers disease (AD) care and drug
development, there is an urgent need for the development
of procedures that would help to estimate hippocampal atrophy accurately and consistently. In the revised criteria for the
diagnosis of AD, an estimate of hippocampal atrophy from
structural magnetic resonance imaging (MRI) is a key supportive marker [1]. In patients with AD, hippocampal atrophy has been measured in clinical trials of tramiprosate,
atorvastatin, AN1792, xaliproden, and donepezil (Table 1).
Some of these found evidence of a beneficial drug effect
on reduction of hippocampal volume, despite variable clinical effects. A notable exception is the AN1792 trial in which
treated subjects lost more hippocampal volume than nontreated patients, although the loss was not significant. Algorithms that automatically segment (delineate) the
hippocampus from the surrounding brain tissue on MR brain
scans are being actively developed; these will require the
gold standard of manual segmentation for validation [2,3].
The potential future availability of drugs that alter

*Corresponding author. Tel.: 39-03-03-50-13-61; Fax: 39-03-03-50-1313.

E-mail address: gfrisoni@fatebenefratelli.it

progression of cognitive deterioration will make a secure

diagnosis at the earliest possible stages imperative.
Evidence from imaging-pathological correlations shows
that manual hippocampal segmentation is a valid marker
of neurodegenerative changes in AD [4], and several studies
in clinical AD populations from laboratories worldwide
have reported that hippocampal volume in patients were
15% to 40% smaller (more atrophied) than controls [5].
However, different laboratories use different anatomical
landmarks and measurement procedures. This inconsistency
of approach means that estimates of normal hippocampal
volumes may differ by a maximum of 2.5-fold (Table 2) [6].
A meta-analysis of rates of atrophy over time showed an
even wider range, with rates varying from 0.32% to 6.8%
per year [7]. Without comparability of methods, it is impossible to determine whether these differences reflect a neurobiological heterogeneity or how much of this variance is
determined by the different protocols.
The most validated procedure to estimate hippocampal
atrophy is to calculate hippocampal volumes with manual
outlining using anatomical landmarks by an expert rater on
high resolution T1-weighted MRI [5]. This manual volumetry is also used as the standard against which automated
segmentation algorithms [8e12] are assessed; however, in
the absence of an agreed reference protocol for manual

1552-5260/$ - see front matter 2011 The Alzheimers Association. All rights reserved.
doi:10.1016/j.jalz.2010.06.007

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G.B. Frisoni and C.R. Jack / Alzheimers & Dementia 7 (2011) 171e174

Table 1
Clinical trials with drugs for Alzheimers disease where hippocampal volume measures were included in the study design
Drug

Trial name

Patients

Effect on hippocampal volume loss

Segmentation method

Reference

AN1792

AD

Manual [14]

15

Atorvastatin

ADCLT

AD

Manual [16,17]

18

LEADe

AD

Semi-automated MIDAS [19]

20,21

Donepezil

Memory
impairment study

MCI

Manual [22,23]

24

Tramiprosate

Alphase

AD

Not mentioned

25

Xaliproden

EFC2724

AD

Change from baseline to follow-up:

Placebo: 22.86% (SD: 3.19)
Treated: 23.78% (SD: 2.63), P 5 .12
Change from baseline to follow-up:
Placebo: 2134 (SD: 174) mm3
Treated: 583 (SD: 354) mm3, P . .05
Significant smaller annualized decrease in
hippocampal volume in treated patients
Change from baseline to follow-up in e4
carriers:
Placebo: 26.14% (SE: 3.49)
Treated: 24.50% (SE: 2.28), P 5 .07
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
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, Alzheimers disease; SD, standard deviation; ADCLT, Alzheimers disease cholesterol-lowering treatment; LEADe, Lipitors effect in
Alzheimers dementia; MCI, mild cognitive impairment; SE, standard error.

volumetry, the comparison of the accuracy of different

automated methods is virtually impossible.
An international task force has recently been gathered by
the authors of this article with the aim of developing a harmonized protocol that will overcome the present heterogeneity
(Table 3). The project will run in four phases. Phase I will
harmonize existing protocols, phase II will validate the
harmonized protocol, phase III will develop harmonized probabilistic hippocampal maps, and phase IV will develop an
illustrative and educational material on the use of the harmo-

nized protocol and maps. Under the auspices of the Alzheimers Association, the task force had met first in Chicago
in July 2008 to discuss the study design, and recently in Toronto in April 2010, where work to date was presented and discussed in a hybrid in-person and remote (webinar) workshop.
Twelve most frequently used protocols for manual
hippocampal segmentation were selected from the Alzheimers literature; anatomical landmarks were extracted; hippocampi from two sample brain scans (one representative
AD patient and one healthy control from the Alzheimers

Table 2
Extreme values of normal hippocampal volumes according to studies using different protocols for manual segmentation
Most anterior
slice

Most posterior
slice

Medial
border

Lateral
border

Inferior
border

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

Temporal horn
of the lateral
ventricle

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

Not mentioned

Includes
subicular
complex and
uncal cleft with
the border
separating the
subicular
complex from
the parahippo
campal gyrus
Interface of the
hippocampal
tissue and
parahippocampal
gyrus white
matter

Reference

Adapted from Geuze et al., 2005 [6].

Hippocampal volume (cm3)

Left

Right

4.903

5.264

1.990

2.070

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173

Table 3
The expert working group
EADC centres

ADNI centres

Other centres

Population-based
studies

Statistical working
group

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

A Simmons, London,
United Kingdom

J Csernansky*,
Northwestern
University, IL

PATH through life,

P Sachdev/JJ
Maller

S Duchesne,
Laval
University,
Canada

L-O Wahlund,
Stockholm,
Sweden

M De Leon*,
New York, NY

R Camicioli/N
Malykhin*
University
Alberta, AB,
Canada
C Watson*, WSU,
Detroit, MI

F Barkhof/P
Scheltens,
Amsterdam, The
Netherlands
GB Frisoni,
Brescia, Italy

R Killiany*,
Boston USM,
MA

H Soininen*,
Kuopio, Finland
B Dubois/S
Leherici* Paris,
France
H Hampel/J Pantel*,
University of
Frankfurt, DE
S Teipel, Rostock,
DE

C DeCarli, UC
Davis, CA
CR Jack*, Rochester,
MN

L Collins, MNI, McGill,

Montreal

Advisors
EADC P.I.s: B Winbald
and L Froelich ADNI
P.I.: M Weiner, UCSF, CA
Clinical issues:
PJ Visser, Maastricht,
The Netherlands

Dissemination
and Education:
G Waldemar,
Copenhagen,
Denmark

J OBrien,
Newcastle,
United
Kingdom

G Bartzokis*,
UCLA, CA

Population studies:
L Launer, NIA,
Bethesda, MD
W Jagust,
Berkeley, CA

PM Thompson,
LONI, UCLA,
CA
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.

Disease Neuroimaging Initiative [ADNI] database) were

segmented following all of the 12 protocols and the accuracy of the interpretation of the protocols was checked during interactive webinars with the protocols authors. The
anatomical landmarks certified by the protocols authors
were semantically harmonized; the differences were operationalized into tracing units summarizing all the variability
among protocols; and 3D visual representations of the tracing units were developed. The work done so far has been
presented at the American Academy of Neurology meeting
[13] and the pertinent material can be found at http://www.
hippocampal-protocol.net.
This is a preparatory work for empirical testing of the contribution of each tracing unit to segmentation accuracy and

volumetric differences between patients and controls. The results will be provided to a Delphi panel that will reach consensus on a harmonized protocol. The harmonized protocol
will be validated with neuropathological data and its accuracy will be compared with currently used protocols. Finally,
hippocampal probability maps will be developed. These will
be instrumental to the development of standard operational
procedures for the measurement of hippocampal volume,
an essential feature of any medical test to be used in the clinic.
Social awareness and scientific knowledge of AD have
increased dramatically in the past 20 years. However, therapeutic options are currently limited to symptomatic drugs
and diagnosis is still largely based on individual physician
experience and subjective judgment. Standard operational

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G.B. Frisoni and C.R. Jack / Alzheimers & Dementia 7 (2011) 171e174

procedures for the assessment of disease markers will be the

key to drug discovery and to the development of more effective, technology-assisted care of patients with AD.

[11]

Acknowledgments
Marina Boccardi led the technical group of Rossana Ganzola, Simon Duchesne, Nicolas Robitaille, Alberto Redolfi,
Michela Pievani, and Anna Caroli. Enrica Cavedo helped in
the editorial process of this manuscript. This project was
funded partly from unrestricted grants from Lilly and Wyeth.
The Alzheimers Association has generously taken charge of
organization of workshops. The authors of the protocols
have been key to the work done so far: George Bartzokis,
John G. Csernansky, Mony De Leon, Leyla deToledoMorrell, Ron Killiany, Stephane Lehericy, Nikolai Malykhin, Johannes Pantel, Jens Pruessner, Hilkka Soininen,
and Craig Watson.

[12]
[13]

[14]

[15]

[16]

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