Beruflich Dokumente
Kultur Dokumente
Perspectives
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
1552-5260/$ - see front matter 2011 The Alzheimers Association. All rights reserved.
doi:10.1016/j.jalz.2010.06.007
172
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
Segmentation method
Reference
AN1792
AD
Manual [14]
15
Atorvastatin
ADCLT
AD
Manual [16,17]
18
LEADe
AD
20,21
Donepezil
Memory
impairment study
MCI
Manual [22,23]
24
Tramiprosate
Alphase
AD
Not mentioned
25
Xaliproden
EFC2724
AD
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.
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
Mesial edge
of the
temporal
lobe
Temporal horn
of the lateral
ventricle
27
Slice where
hippocampus is
clearly
distinguished
from the
amygdala
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
Right
4.903
5.264
1.990
2.070
G.B. Frisoni and C.R. Jack / Alzheimers & Dementia 7 (2011) 171e174
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
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
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.
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
174
G.B. Frisoni and C.R. Jack / Alzheimers & Dementia 7 (2011) 171e174
[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]
References
[17]
[1] Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P,
Cummings J, et al. Research criteria for the diagnosis of Alzheimers
disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;
6:734e46.
[2] Morey RA, Petty CM, Xu Y, Hayes JP, Wagner HR II, Lewis DV, et al.
A comparison of automated segmentation and manual tracing for
quantifying hippocampal and amygdala volumes. Neuroimage 2009;
45:855e66.
[3] Chupin M, Hammers A, Liu RSN, Colliot O, Burdett J, Bardinet E,
et al. Automatic segmentation of the hippocampus and the amygdala
driven by hybrid constraints: method and validation. Neuroimage
2009;46:749e61.
[4] Bobinski M, de Leon MJ, Wegiel J, Desanti S, Convit A, Saint
Louis LA, et al. The histological validation of post mortem magnetic
resonance imaging-determined hippocampal volume in Alzheimers
disease. Neuroscience 2000;95:721e5.
[5] Bosscher L, Scheltens P. MRI of the medial temporal lobe for the
diagnosis of alzheimer disease. In: Qizilbash N, Schneider LS,
Chui H, Tarriot P, Brodaty H, Kaye J, et al., eds. Evidence-Based Dementia Practice. Oxford, United Kingdom: Blackwell Science; 2002.
p. II. 4.7.
[6] Geuze E, Vermetten E, Bremner JD. MR-based in vivo hippocampal
volumetrics: 1. Review of methodologies currently employed. Mol
Psychiatry 2005;10:147e59.
[7] Barnes J, Bartlett JW, van de Pol LA, Loy CT, Scahill RI, Frost C, et al.
A meta-analysis of hippocampal atrophy rates in Alzheimers disease.
Neurobiol Aging 2008;30:1711e23.
[8] Colliot O, Chetelat G, Chupin M, Desgranges B, Magnin B, Benali H,
et al. Discrimination between Alzheimer disease, mild cognitive impairment, and normal aging by using automated segmentation of the
hippocampus. Radiology 2008;248:194e201.
[9] Brewer JB, Magda S, Airriess C, Smith ME. Fully-automated
quantification of regional brain volumes for improved detection
of focal atrophy in Alzheimer disease. Am J Neuroradiol 2009;
30:578e80.
[10] Morra JH, Tu Z, Apostolova LG, Green AE, Avedissian C,
Madsen SK, et al. Validation of a fully automated 3D hippocampal
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]