mri, hippocampal atrophy, and cognition: markers for ... · 70th 85th 95th 99th 99 th 95 th 8 5th...
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Using Imaging Markersto Study Drug Effects in AD
Giovanni B FrisoniDeputyDeputy ScientificScientific DirectorDirector
IRCCS Fatebenefratelli IRCCS Fatebenefratelli –– The National Center for The National Center for AlzheimerAlzheimer’’ss DiseaseDisease. Brescia. Bresciawww.centroAlzheimer.org
MRI, hippocampal atrophy, and cognition:markers for enrichment in clinical trials of MCI
Why enriching study groupsin clinical trials of diseasemodifiers in MCI?
How to and consequences: there’s no free lunch
Hippocampal volumetry asenrichment marker
Probable Alzheimer’s Disease(NINCDS-ADRDA)
Mild cognitive impairment
Am
yloi
d/ta
u de
posi
tion
No cognitive symptom
Age
Disease modification in AD
AD non ADpathology
AD non ADpathology
AD non ADpathology
Enriched MCI
Biomarkers in the IWG and NIA-AA diagnostic criteria
Fris
oni H
ampe
lO’B
rien
Ritc
hie
Win
blad
, Lan
cet N
euro
l201
1
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1.0 1.5 2.0
70th 85th 95th 99th
99 th
95 th 8 5th 70 th
1000
2000
3000 4 000
5 000
6000
44 th �
PIB uptake
Hippocampal volume
MCI non converters
MCI converters to dementia
AllMCIs
Distribution of AD markers in MCIs
Lore
nzi e
t al.,
Neu
robi
ol A
ging
201
0
THE PAYOFF OF ENRICHMENT IN MCI CLINICAL TRIALS
Mild
ly a
bnor
mal
bio
mar
ker
Mod
erat
ely
abno
rmal
bio
mar
ker
Sev
erel
y ab
norm
al b
iom
arke
r
Ver
y se
vere
ly a
bnor
mal
bio
mar
ker
(Nat Reviews Neurol 2010)
40:60
� enrolled into clinical trial
� excluded from clinical trial
likely not to have AD
likely to have AD
THE PAYOFF OF ENRICHMENT IN MCI CLINICAL TRIALS
Mod
erat
ely
abno
rmal
bio
mar
ker
Sev
erel
y ab
norm
al b
iom
arke
r
Ver
y se
vere
ly a
bnor
mal
bio
mar
ker
(Nat Reviews Neurol 2010)
40:60
32:32
THE PAYOFF OF ENRICHMENT IN MCI CLINICAL TRIALS
Sev
erel
y ab
norm
al b
iom
arke
r
Ver
y se
vere
ly a
bnor
mal
bio
mar
ker
(Nat Reviews Neurol 2010)
40:60
32:32
25:20
THE PAYOFF OF ENRICHMENT IN MCI CLINICAL TRIALS
Ver
y se
vere
ly a
bnor
mal
bio
mar
ker
(Nat Reviews Neurol 2010)
40:60
32:32
25:20 20:1
5
THE PAYOFF OF ENRICHMENT IN MCI CLINICAL TRIALS (Nat Reviews Neurol 2010)
40:60
32:32
25:20 20:1
5 18:10
0.7
1.0
1.251.33
1.8
72%
0%
35%
55%
68%
“Low hippocampal volume … dichotomized … appears to help enriching recruitment into clinical trials aimed at studying drugs potentially slowing the progress/conversion to AD dementia [and] … might be considered a marker of progression to dementia in subjects with … predementiastage of AD (Dubois 2007), for the purposes of enriching a clinical trial population .”
EMA conclusions
“Collection, handling and measurements of Low hippocampal volume, as measured by MRI should be performed according to Good Clinical Practice and to the specific highest international standards .”
Geuze et al., Mol Psychiatry 2005;10:147-59
Ref. Med borderLat border
Inf borderNorm. 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 choroidalfissure
Notmentioned
The interface of hippocampal tissue and parahippocampal gyruswhite matter
1.990 2.070
There’s more than 40 (very!) different ways to manually segment the hippocampus,
resulting in wildly different volume estimates
2.5-fold difference
The EADC-ADNI Working Group on the Harmonized Protocol for Hippocampal Volumetry
GB Frisoni, M Boccardi, M Bocchetta, R Ganzola, A Redolfi, D Tolomeo, G Corbetta, E Cavedo, M Lanfredi Brescia
B Bartzokis, PM Thompson, L
Apostolova, M Tinley
Los Angeles
CR Jack, G Preboske, C WardRochester
S Duchesne, N RobitailleQuebec City
H Soininen, M Pihlajamäki, Y Liu Kuopio
B Dubois, S Lehericy, C BoutetParis
H Hampel Frankfurt
S Teipel, M GrotheRostock
L-O Wahlund, B WinbaldStockholm
F Barkhof, P Scheltens, W Henneman, M Pronk, F van
Dommelen
Amsterdam
N Fox, J Barnes,
M BlairLondon
A SimmonsLondon
C deCarli, S Hollander
Davis
M Weiner, S Mueller
San Francisco
L deToledo-Morrell, D Bennet, T Stoub
Chicago
JG Csernansky, L Wang, A Christensen Evanston
RJ Killiany, C BauerBoston
M AlbertBaltimore M deLeon
New York
J Kaye, L Silbert, T SwihartPortland
J Pruessner, S Pietrantonio
MontrealR Camicioli, N MalykhinEdmonton
J PantelFrankfurt
C Watson Detroit
J O’Brien, M Firbank, E BurtonNewcastle
P Sachdev, JJ Maller(PATH through life
Study)
M Geerlings, L Gerritsen, M Portegies(SMART-Medea Study)
T denHeijer(Rotterdam Scan Study)
P Pasqualetti,Rome
L CollinsMontreal
PJ VisserMaastricht
L Froelich Mannhei
m
G Waldemar Copenhagen
L Launer Bethesda W Jagust
Berkeley
C Hock, H Wolf,Zurich
Frisoni & Jack, Alzh Dement 2011; Boccardi et al., JAD 2011; Boccardi et al., Alzh Dement submitted
Standardization of manual hippocampal volumetry
Acquisition Orientation Segmen-tation
ADNI
EADC-ADNI Hippocampal Harmonization Project
Funded by Alzheimer’s Association Co-funded by unrestricted grant from Wyeth and
Lilly
Extraction of largest possible common units(“LEGO blocks” or Segmentation Units)
Boccardi et al., JAD 2011
METHODS
Assessment of measurement
properties of SUs
Break down into segmentation
units
Bar
tzok
is, 1
998
Con
vit,
1997
Kill
iany
, 199
3S
oini
nen,
199
4Le
heric
y, 1
994
Jack
, 199
4;de
Tol
edo-
Mor
rell,
200
4H
alle
r, 1
997
Pru
essn
er, 2
000
Mal
ykhi
n, 2
007
Pan
tel,
2000
Wat
son,
199
2
Survey and operationalization
Boc
card
i et a
l., J
AD
201
1; B
occa
rdi e
t al.,
Alz
h D
emen
t sub
mitt
ed
METHODS
Assessment of measurement
properties of SUsDelphi panel
Answers are summarized and
anonymized
Disagreement issues are extracted
Disagreement issues are submitted to the
panel
Panel answers
Initial set of questions
5 ROUNDS
Covers 100% of hippo properCaptures 100% of AD atrophyVery high IRR & TRTR: <.96
Boccardi et al., JAD 2011; Boccardi et al., in preparation
1) test-retest variability
2) impact on total hippo volume
3) informativenessfor differences between AD and controls
How is the Harmonized Protocol Working?Agreement among L Apostolova (UCLA), M Bocchetta (IRCCS FBF), and
G Preboske (Mayo)
FUTURE STEPS
1. Develop reference probabilistic masks (ongoing)- 5 “master tracers”
2. Develop a qualification procedure, environment, and thresholds for
- naïve tracers - automated algorithms
3. Validate on:- 1800 ADNI hippocampi segmented by 20 human
tracers- MR-pathological datasets (volume on pathology,
neuronal density, volume on ex vivo MR)
4. Segmentation protocol and benchmark masks:- available to beta-testers based on ad hoc agreements
until the end of validation process (summer 2013), - no restrictions afterwards
CONCLUSIONS
Enrichment of clinical trials of diseasemodifiers in MCI is critical to detectsignal of efficacy
There is no magic enrichment recipe: a matter of earn/pay balance
Hippocampal volumetry isconceptually mature for enrichmentpurposes
Operational procedures might be refined with the harmonized manualsegmentation protocol as benchmark
G BartzokisLos Angeles
M deLeonNew York
L deToledo-MorrellChicago
J CsernanskyChicago
CR JackRochester
R KillianyBoston
S LehericyParis
N MalykhinEdmonton
J PantelFrankfurt
J PruessnerMontreal
H SoininenKuopio
C WatsonDetroit
DELPHI PANELISTS
L ApostolovaLos Angeles
J BarnesLondon
G BartzokisLos Angeles
C deCarli Sacramento
L deToledo-Morrell Chicago
M FirbankNewcastle
L GerritsenStockholm
W HennemanAmsterdam
CR JackRochester
R KillianyBoston
N Malykhin Edmonton
J PruessnerMontreal
H SoininenKuopio
L WangChicago
C WatsonDetroit
H WolfZurich
AUTHORS OF ORIGINAL SEGMENTATION PROTOCOLS
L ApostolovaLos Angeles
M BocchettaBrescia
R GanzolaBrescia
G PreboskeRochester
D WolfMainz
MASTER TRACERS
COWORKERS AT THE LAB OF NEUROIMAGINGThe National Centre for Alzheimer’s Disease, Brescia
Hippo Harmo TeamM Boccardi, M Bocchetta, E Cavedo
A Redolfi, G Corbetta, D Tolomeo
EnrichmentM Lorenzi
Aphasia Apraxia Agnosia
Spared SM and visual functions
Encoding semantic memories
Smell discrim.
Encoding episodic &
spatial memories
AMYLOID PLAQUES
Braak & Braak , Acta Neuropath 1991
Tha
l et a
l., N
euro
logy
200
2
?
TANGLES
Atrophy is an intermediate phenotype between neurodegeneration and clinical symptoms
SYMPTOMSNEURODEGE-
NERATION ATROPHY
Frisoni et al., J Neurol 2009
Courtesy of P. Giannakopoulos
Frisoni et al., J Neurol 2009
HIPPOCAMPAL MAPPINGThe method 2
CA1
Fimbria
Subiculum
CA1
CA2-3
Presubiculum
Subiculum
R L
Frisoni et al. Neuroimage 2006
31
Atrophy in AD maps onto areas known to be affected by tau pathology and is specific to AD
L’atrophie dans la MA mappe sur les régions atteint es par le dépot de tau et elle est spécifique à la MA
Alzheimer’s pattern
Frisoni et al., Brain 2007
CA1 CA2-3Aging pattern
Frisoni et al., Brain 2007
Lewy body pattern
Sabattoli et al., NeuroImage 2008
Antisocial dis. pattern
Boccardi et al., Hum Brain Mapp 2010
Correlation of brain atrophy with rate of MMSE decline in 29 AD patients ( r= 0.80, p < 0.001).
Fox
et a
l., N
euro
logy
1999
;52:
1687