aan –toronto, april 11, 2010

AAN –Toronto, April 11, 2010

Development of a harmonized protocol for hippocampal tracing

An EADC-ADNI joint effort

INTRODUCTION

http://eadc.alzheimer-europe.org/introduction.html

Structure:MR hippo volumetry

Alz

he

ime

r

Normal

CS

F t

ota

l ta

u

CSF Abeta42

Biochemistry:CSF tau/Abeta

Function:FDG PET

Amyloid deposits:PET

BACKGROUNDHippocampal volume as a diagnostic marker

Dubois, Feldman et al., Lancet Neurol 2007

Geuze et al., Mol Psychiatry 2005;10:147-59

Ref. Med borderLat border

Inf border

Norm. hippo vol (cm3)

Left Right

Watson et al.

Mesial edge of temporal lobe

Temp horn of lat ventr

Incl subicular complex & uncal cleft w/ border separating subicular complex from parahippo gyrus

4.903 5.264

Zipursky et al.

Regional outline at choroidal fissure

Not mentioned

The interface of hippocampal tissue and parahippocampal gyrus white matter

1.990 2.070

BACKGROUNDThe effect of segmentation protocols

on hippocampal volume

BACKGROUNDHippocampal volume as an outcome measure

in trials of disease modifiersDrug Study Effect Segment. method Ref

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 protocolInsausti et al., 1998 AJNR;

Machulda et al., 2001, Neuroimage

Sparks et .a,l CCJM,2008

LEADe “significant at p<.05”

MIDAS(semiautomated)

Jones et al., Alz&Dem 2008Feldman et al., Neurology 2010

AN1792 “CHV* % 3.78±2.63 vs 2.86±3.19

p = 0.124”

Manual protocolWatson et al., 1992, Neurology

Fox N et al., Neurology, 2005

Xaliproden Sanofi-Aventis Trials

“significant atrophy” § Not mentioned From Vellas B et al. (Review), Lancet Neurol.,2008

Donepezil “CHV* % -6.14±3.49vs -4.50±2.28 p= 0.07”

ε4 carriers only

Manual protocolJack et al., 1989;Radiology

Jack et al., 2004; Neurology

Jack CR et al., Neurobiol. Aging, 2008

* CHV= Change in hippocampal volume; § referenced link not working

BACKGROUNDHippocampal volume (manual segmentation)

as gold standard for automated segmentation algorithms

Morey et al., NeuroImage 2009

To Harmonize Available Protocols for Manual Hippocampal Segmentation

To Test the Validity of the Harmonized Protocol

AIMS

F Barkhof/P Scheltens Amsterdam B Dubois/S Leherici ParisN Fox LondonGB Frisoni BresciaH Hampel/J Pantel FrankfurtA Simmons LondonH Soininen KuopioS Teipel RostockLO Wahlund Stockholm

THE WORKGROUPEADC

CR Jack Jr Rochester, MNG Barzokis UCLA, CAD Bennet Chicago, ILJ Csernansky NorthW U, WAC DeCarli UC Davis, CAM De Leon New York, NYJ Kaye Portland, ORR Killiany Boston USM, MAPM Thompson LoNI, UCLA, CAM Weiner/S Mueller UCSF/VAMC

THE WORKGROUP ADNI

THE WORKGROUPother relevant hippo experts

R Camicioli Univ Alberta, CanadaJ O’Brien NewCastle, UKJ Pruessner McGill, QC, Canada

EADC-ADNI P.I.sB Vellas Toulouse, FranceB Winblad Stockholm, SwedenM Weiner UCSF, US

Population-based studiesM Breteler / T Den Heijer Rotterdam Scan StudyP Sachdev/ JJ Maller PATH through lifeL Launer NIA BethesdaW Jagust Berkeley

THE WORKGROUPAdvisory Boards

Statistical BoardS Duchesne Laval Univ, CanadaL Collins MNI, McGill, MontrealP Pasqualetti AFaR, Rome

Clinical AdvisorPJ Visser Maastricht, The Netherlands

Dissemination/EducationG Waldemar Copenhagen, Denmark

THE WORKGROUPBoards

Marina Boccardi psychologist, PhDRossana Ganzola psychologistEnrica Cavedo psychologistMichela Pievani mathematicianAnna Caroli mathematicianAlberto Redolfi bioinformaticist

THE WORKGROUPPersonnel in Brescia




METHODS


Operationalization of protocols’ differences and extraction of tracing units

Quantification of tracing units’ features

Harmonized protocol

METHODS

Selection criteria

i) Being based on 3D T1 MRI with field strength greater than 1 Tesla

ii) Providing explicit description of landmarks for tracing of hippocampal borders

iii) Being validated on AD/MCI samples, or being widely adopted in the literature about AD.

OPERATIONALIZATIONSelection of segmentation protocols

Plane of tracing: AC-PC line;

Normalization to the Talairach space

Tracing start from the tail of

hippocampus to the hippocampal head

In the following slices, you can find the

hippocampal tracing on consecutive

coronal slices (1.5T) of the control subject and AD patient according to Pruessner's criteria

Areas explicitly excluded

Most anterior slice

Andreas-Retzius gyrus (ARG), the part

of the FG that is adjacent to ARG, crus

of fornix

slice w here one of the follow ing is visible: alveus,

temporal horn of lateral ventricle (uncal recess) or

amygdala

Lateral border Inferior border Medial border

HE

AD temporal horn of

lateral ventricle (uncal recess)

uncal cleft (if visible) CSF of ambient cistern

BO

DY temporal horn of


White matter of the parahippocampal

gyrusCSF of ambient cistern

TA

IL

Discrimination of HT from FG and crus of fornix using arbitrary

borders

adjacent w hite matter atrium of lateral ventricle

Areas explicitly included

CA regions, dentate gyrus, subiculum,

alveus, f imbria, part of the fasciolar gyrus (FG)

BOUNDARIES

Discrimination of HT from ARG using arbitrary borders

Most posterior slice

slice w here an ovoid mass of gray matter started to appear

inferomedially to the trigone of the lateral ventricle

Superior border

temporal horn of lateral ventricle (uncal recess) and alveus

superior excess of the quadrigeminal cistern

OPERATIONALIZATIONProtocols’ features extraction

Tracings carried out on a control and an

AD subject from the ADNI dataset

Tracings sent to the Authors for correction or approval

OPERATIONALIZATIONPrototypical tracings

CTRL

Most posterior slice : slice where an ovoid mass of gray matter (1) started to appear inferomedially of the atrium of lateral ventricle (2)

Sagittalview

2= Atrium of lateral ventricle4= Parahippocampal gyrus5= Gyrus dentatus6= Cornu Ammonis7= Gyrus fasciolaris8= Gyrus of Andreas-Retzius9= Isthmus

The fornix can be excluded by a horizontal line (in fuchsia) from the superior border of the quadrigeminal cistern (3) to the lateral ventricle (2).Part of gyrus fasciolaris (7) and of Andreas-Retzius gyrus (8) can be excluded by a vertical line (in red) from the medial end of the lateral ventricle (2) down to the parahippocampal gyrus (4).

AD

Most posterior slice : slice where an ovoid mass of gray matter (1) started to appear inferomedially of the atrium of lateral ventricle (2)

2= Atrium of lateral ventricle4= Parahippocampal gyrus5= Gyrus dentatus6= Cornu Ammonis7= Gyrus fasciolaris8= Gyrus of Andreas Retzius9= IsthmusSagittal

view

In AD subjects the cerebral structures are atrophic, lateral ventricle (2) and ambient cistern (3) result enlarged. Therefore,the lines used to exclude the gyrus fasciolaris, the Andreas-Retzius gyrus and the fornix do not intersect the hippocampal tail. That being so, is there another way to exclude the gyrus fasciolaris, the Andreas-Retzius gyrus and the fornix in these subjects?


Most anterior slice



of fornix



amygdala


HE

AD temporal horn of



BO

DY temporal horn of




TA

IL


borders





BOUNDARIES





Superior border



For each protocol: features extraction, tracing and author’s certification

AD

CTRL

X 10

OPERATIONALIZATIONAuthors’ check

OPERATIONALIZATIONExtraction of similarities and differences


Most anterior slice

choroid plexis of inferior horn, amygdala

level at w hich the alveus distinguishes the amygdala

from hippocampus


HE

AD inferior horn of the

lateral ventriclew hite matter joining the parahippocampal gyrus

angular bundle

BO

DY

same as head same as head same as head

TA

IL same as head same as head same as head

BOUNDARIES


portion of subiculum, CA f ields

same as head


slice in w hich the fornix appeared as a solid w hite line through the collateral trigone

Superior border

inferior horn of the lateral ventricle

same as head

Harmonized language

Reduction of redundancy

Tracing units and subunits


Most anterior slice



of fornix



amygdala


HE

AD temporal horn of



BO

DY temporal horn of




TA

IL


borders





BOUNDARIES





Superior border



axial + coronal + sagittal

Cornu Ammonis, subiculum, vertical digitation alveus and fimbria

Medial border Lateral border

HE

AD

Gyrus ambiensidentified by the

contrast of the WM or CSF

BO

DY

The medial border of the HC w as continued w ith a straight horizontal line (marking the inferior border

of CA and subiculum) across the cortex of the PHG. The cortex below this line w as considered

the PHG, and the cortex above this line w as included as a part of the HC

identified by the contrast of the WM

or CSF

TA

IL





or CSF

WM of parahippocampal gyrus


Superior border

identified by the contrast of the WM or CSF


WM of parahippocampal gyrus (PHG)

Areas explicitly included Plane tracing

identified by the contrast of the WM or CSF, and Thalamus and

caudate nucleus


coronal section in w hich the hippocampus first appeared

adjacent to the trigone of lateral venticle


Most anterior slice

the separation of amygdala and hippocampal head w as

facilitated by sagittal and transverse view s

Inferior border

BOUDARIES

Line outlining the contour of white matter of parahippocampal gyrus [Pa,S]

Orizontal line from the highest medial point of the parahippocampalWM to the cistern [B,H,J¥]

Oblique line with same inclination of parahippocampalWM, connecting the inferior part of the subiculum to the quadrigeminal cistern [K,L,M¥]

45° line connecting the most inferior part of the subiculum medially to the cistern (head and body) [Pr]

vertical line from the CA to the WM of the parahippocampalgyrus [C]

Separation subiculum/enthorinal cortex

Horizontal line from the superior border of the quadrigeminal cistern to the lateral ventricle (tail) [Pr]

Upper border of alveus/fimbria[C,J,L,M,Pr]

Lower border of alveus/fimbria[B,H,K,Pa,S]

Superior border

Where gray matter is visible inferomedially to the trigone of the lateral ventricle [H,M•,Pa•,Pr]

Where the crura of the fornicesare seen in full profile on both sides [J,S]

Where crus of fornix is visible in full profile [C,K,L]

Where inferior and superior colliculiare jointly visualized [B]


AC-PC line [H,K,M,Pa,Pr]Axis of hippocampus [B,C,J,L,S]

Plane of tracing










Superior border







Plane of tracing

OPERATIONALIZATIONExtraction of similarities and differences


Most anterior slice



from hippocampus


HE



angular bundle

BO

DY


TA


BOUNDARIES


portion of subiculum, CA fields

same as head



Superior border


same as head


Most anterior slice



of fornix



amygdala


HE

AD temporal horn of



BO

DY temporal horn of




TA

IL


borders





BOUNDARIES





Superior border



Plane of tracing

Axis of hippocampus [B,C,J,L,S]

AC-PC line [H,K,M,Pa,Pr]


Where inferior and superior colliculi are jointly visualized [B]


Where the crura of the fornices are seen in full profile on both sides [J•,S]


Superior border

Lower border of alveus/fimbria [B,H,K,Pa,S]

Upper border of alveus/fimbria [C,J,L,M,Pr]



vertical line from the CA to the WM of the parahippocampal gyrus [C]


Oblique line with same inclination of parahippocampal WM, connecting the inferior part of the subiculum to the quadrigeminal cistern [K,L,M¥]

Orizontal line from the highest medial point of the parahippocampal WM to the cistern [B,H,J¥]


Operationalization of protocols’ differences


Harmonized protocol

METHODS

Contribution to hippo volume in control and AD

Effect on re-test variability

Contribution to differences between AD and controls

QUANTIFICATION OF TRACING UNITS’ FEATURES

Operationalization of protocols’ differences


Harmonized protocol

METHODS

Participants to a Delphi panel based on:

expertise in hippocampal anatomy

manual tracing scientific production

Assisted decisions based on:

Low variability, highly informative.. ..included in harmonized protocol

High variability, little informative.. ..excluded from harmonized prot

HARMONIZED PROTOCOL

Validation with neuropathological data

Comparison with currently used protocols

Public tracings and probability maps

Standard environment for tracing, learning, and certification

HARMONIZED PROTOCOLValidation & implementation




EARLY RESULTS


Protocols’ features extraction & differences operationalization

Modeling & computations of the operationalized differences

Discussion

EARLY RESULTS

B Bartzokis G, et al. Psychiatry Res 1998;82:11-24

C Convit A, et al. Neurobiol Aging 1997;18:131-8

H Haller JW, et al. Radiology 1997;202:504-10

J Jack CR Jr. Epilepsia 1994;35 - Suppl 6:S21-9

K Killiany RJ, et al. Arch Neurol 1993;50:949-54

L Lehéricy S, et al. Am J Neuroradiol 1994;15:929-37

M Malykhin NV, et al. Psychiatry Res 2007;155:155-65

Pa Pantel J, et al. Hippocampus 2000;10:752-8

Pr Pruessner JC, et al. Cereb Cortex 2000;10:433-42

S Soininen HS, et al. Neurology 1994;44:1660-8

PROTOCOLS’ FEATURES EXTRACTION

http://www.hippocampal-protocol.net


http://www.hippocampal-protocol.net/


Most anterior slice



from hippocampus


HE



angular bundle

BO

DY


TA


BOUNDARIES


portion of subiculum, CA f ields

same as head



Superior border


same as headAreas explicitly

excluded Most anterior slice



of fornix



amygdala


HE

AD temporal horn of



BO

DY temporal horn of




TA

IL


borders





BOUNDARIES





Superior border



axial + coronal + sagittal

Cornu Ammonis, subiculum, vertical digitation alveus and fimbria

Medial border Lateral border

HE

AD

Gyrus ambiensidentified by the

contrast of the WM or CSF

BO

DY





or CSF

TA

IL





or CSF



Superior border



WM of parahippocampal gyrus (PHG)

Areas explicitly included Plane tracing

identified by the contrast of the WM or CSF, and Thalamus and

caudate nucleus


coronal section in w hich the hippocampus first appeared

adjacent to the trigone of lateral venticle


Most anterior slice

the separation of amygdala and hippocampal head w as

facilitated by sagittal and transverse view s

Inferior border

BOUDARIES


Harmonized language

Reduction of redundancy

Tracing units and subunits










Superior border







Plane of tracing










Superior border







Plane of tracing

Plane of tracing






Where the crura of the fornices are seen in full profile on both sides [J,S]


Superior border





vertical line from the CA to the WM of the parahippocampal gyrus [C]





No longer an issue thanks to software for

3D navigation

PROTOCOLS’ FEATURES EXTRACTIONMost anterior slice

H. Haller-Csernansky et al 1997 K. Killiany et al 1993 M. Malykhin et al 2007Pa. Pantel et al 2000Pr. Pruessner et al 2000

B. Bartzokis et al 1998 C. Convit et al 1997 J. Jack 1994L. Lehéricy et al 1994 S. Soininen H et al 1994

Axis of hippocampus AC-PC

PROTOCOLS’ FEATURES EXTRACTIONPlane of tracing

PROTOCOLS’ FEATURES EXTRACTIONMost posterior slice

A. Level where the inferior (1) and superior (2) colliculi are

jointly visualized [B]

B. Slice where the crus of fornix is visible in full profile (3) [C, K,

L]

C. Slice where the crura of fornices on both sides are seen

in full profile (4, 5) [J, S]

D. Slice where an ovoid mass of gray matter (6) appears

inferomedially to the trigone of the lateral ventricle (posterior to

anterior) [H, M, Pa, Pr]

Yellow = Alveus

PROTOCOLS’ FEATURES EXTRACTIONAlveus

Yellow = Fimbria

PROTOCOLS’ FEATURES EXTRACTIONFimbria

PROTOCOLS’ FEATURES EXTRACTIONUpper border

PROTOCOLS’ FEATURES EXTRACTIONMedial borderVertical line [C]

45° line

[Pr]

Line with same inclination WM

[K, L, M]

Horizontal line

[B, H, J]

Morphological details

[Pa, S]

EARLY RESULTS

Protocols’ features extraction & differences operationalization

Modeling & computations of the operationalized differences

Discussion

Plane of tracing






Where the crura of the fornices are seen in full profile on both sides [J,S]


Superior border



Separation subiculum/enthorinal cortexvertical line from the CA to the WM of the parahippocampal gyrus [C]





MODELING & COMPUTATIONS

Modeling by Simon Duchesne and Nicolas Robitaille

Université Laval and Centre de Recherche Université Laval – Robert Giffard

Quebec City, Canada

J Pr M Pa H

B C K L S


DISCUSSION

Features operationalization: 4 tracing units, and subunits

Preliminary info on contribution of units to total hippo volume

3D models may help Delphi panel for developing harmonized protocol

Available: draft paper, and online materialhttp://www.hippocampal-protocol.net

http://www.hippocampal-protocol.net/

April 14: Poster 24 PO3: Ageing and dementia imaging - other

Lilly International

Wyeth International

ACKNOWLEDGEMENTS

aan –toronto, april 11, 2010

Documents

hippocampal tracing

hippocampal volumeref

available protocols

canadaeadcadni p

zipursky et

manual protocolinsausti

neuroimage sparks et

mr hippo volumetrybiochemistry