Transcript Significantly different from HC, p <0.05

The Australian Imaging Biomarkers and Lifestyle
Flagship Study of Ageing
.
AUSTRALIAN ADNI
July 2010 UPDATE
18 month follow-up complete
1111
968
25% of MCI progressed to AD
Large shifts between NMC and SMC
25% AD, 23% MCI, 8% HC lost
Imaging Cohort
The Australian Imaging
Biomarkers and Lifestyle
Flagship Study of Ageing.
24 Non-returners
288
6 Deceased
227
4
Baseline cohort
82 NMC
Clinical follow-up
Imaging follow-up
3
1
6
96 SMC
6
18-month
Imaging cohort
66 NMC
64
90 SMC
53 AD
1
24
4
5
29
39
3
23
3
10
86
17
16
57 MCI
5
73
49
2
12
1
32 MCI
42 AD
Imaging Cohort Baseline
demographics
(n=288)
HC
MCI
AD
178
57
53
Age
73.6 ± 7.6
77.4 ± 7.5*
74.0 ± 8.7
MMSE
28.8 ± 1.2
27.1 ± 2.3*
20.5 ± 4.9*
%ApoE e4
43%
54%
71%*
*Significantly different from HC, p <0.05
Ab burden by clinical classification
*†
Neocortical SUVR
3.5
*
3.0
98%
2.5
67%
31%
2.0
1.5
1.0
HC
MCI
AD
1.42±0.41
1.89±0.62
2.33±0.43
*Significantly different from HC, p <0.05
†Significantly different from AD, p <0.05
Preclinical Alzheimer’s Disease?
Prevalence
of PiB+ve PET
in HC
60
Prevalence (%)
50
40
Prevalence of plaques
in HC
30
(Davies, 1988, n=110)
(Braak, 1996, n=551)
(Sugihara, 1995, n=123)
~15 yrs
Prevalence
of AD
20
(Tobias, 2008)
10
0
30
40
50
60
70
80
Age (years)
90
100
PiB vs Age and ApoE-e4
Ab burden by clinical classification
†
Neocortical SUVR
3.5
†
*
MCI
AD
3.0
2.5
2.0
1.5
1.0
NMC e4- NMC e4+ SMC e4- SMC e4+
1.35±0.36 1.43±0.40 1.25±0.29 1.69±0.51 1.95±0.62 2.34±0.43
(n=39)
(n=29)
(n=38)
(n=35)
(n=55)
(n=31)
†
Significantly different from NMC and SMC e4-, p <0.05
* Significantly different from HC and MCI, p <0.05
Grey matter atrophy vs healthy elderly with no memory complaint
SCI
MCI
AD
Chetelat G, et al. Brain. In Press
GREATER temporal lobe volume (including hippocampus)
in PiB +ve healthy vs PiB –ve healthy
- Brain reserve or compensatory response to damage?
- Better memory performance suggests brain reserve.
3T MRI
VBM 5 toolbox
Manual HV
Chetelat G, et al. Brain. In Press
Increase in Neocortical SUVR
PiB INCREASE OVER 18 Months
0.070
*
†*
0.060
0.050
0.040
0.030
0.020
0.010
0.000
HC
MCI
AD
n=159
(89% retention)
n=39
(68% retention)
n=29
(55% retention)
† Significantly
different from HC (p<0.05)
* Significantly different from baseline (p<0.05)
Increase in Neocortical SUVR
PiB INCREASE OVER 18 Months
*
0.070
0.060
0.050
0.040
0.030
0.020
0.010
0.000
nMC
non-e4
(n=38)
nMC
SMC
e4
non-e4
(n=35)
(n=55)
SMC
e4
MCI
AD
(n=39)
(n=29)
(n=31)
* Significantly different from baseline (p<0.05)
Increase in Neocortical SUVR
PiB increase much greater in baseline PiB+ve
†
0.070
0.060
0.050
0.040
0.030
0.020
0.010
0.000
PiB-
PiB+
PiB-
PiB+
PiB+
(n=115)
(n=44)
(n=12)
(n=27)
(n=28)
HC
MCI
(n=159)
(n=39)
† Significantly
AD
different from PiB- HC (p<0.0002)
Change in Neocortical SUVR
Healthy Controls: baseline PiB status has
greater influence than ApoE-e4 status on
amyloid increase
0.090
0.080
0.070
0.060
0.050
0.040
0.030
0.020
0.010
0.000
-0.010
PiB-
PiB+
PiB-
PiB+
PiB-
PiB+
PiB-
PiB+
(n=30)
(n=8)
(n=23)
(n=12)
(n=48)
(n=7)
(n=14)
(n=17)
nMC
nMC
(n=38)
non-e4
e4
SMC
non-e4
SMC
(n=35)
(n=55)
(n=31)
e4
AIBL follow-up
MMSE
HC
Decrease in MMSE
0
MCI
AD
†*
†*
-1
-2
-3
-4
-5
† Significantly
different from HC (p<0.007)
* Significantly different from baseline (p<0.03)
AIBL follow-up
Decrease in hippocampal volume
Hippocampal volume
HC
MCI
AD
0.0%
-1.0%
-2.0%
-3.0%
-4.0%
-5.0%
-6.0%
*
†*
†*
† Significantly
different from HC (p<0.05)
* Significantly different from baseline (p<0.003)
AIBL follow-up
Decrease in grey matter volume
Grey matter volume
0.0%
HC
MCI
AD
*
*
†*
-0.5%
-1.0%
-1.5%
-2.0%
-2.5%
* Significantly different from baseline (p<0.002)
Ab burden vs cognition
Baseline
HC
MCI
Neocortical SUVR
r= -0.27 (p = 0.04)
MMSE
r= -0.23 (p = 0.08)
CVLT II delayed recall
AD
Follow-up PiB vs follow-up cognition
by baseline diagnosis
Neocortical SUVR
HC
r= -0.23 (p = 0.004)
MCI
r= -0.36 (p = 0.03)
CVLT II delayed recall
AD
Ab burden vs cognition
Follow up
PiB+ve
only
r= -0.32 (p = 0.02)
Neocortical SUVR
r= -0.40 (p = 0.0071)
MMSE at follow-up
r= -0.46 (p = 0.0017)
CVLT II delayed recall
at follow-up
Change in CVLT II delayed recall
HC at baseline
HC
MCI
AD
Baseline Neocortical SUVR
AIBL
18 months clinical follow-up
HC
MCI
(n=170)
(n=49)
PiB-ve Subjects:
Converters to MCI:
PiB+ve Subjects:
Converters to MCI/AD:
114
2 (2%)
56
4 (7%)
PiB-ve Subjects:
14
Converters to HC:
2 (14%)
Converters to AD:
2 (14%)
PiB+ve Subjects:
35
Converters to HC:
2 (6%)
Converters to AD:
16 (46%)
Prediction of Conversion
MCI to AD at 18 mths
(n=49)
ACCURACY
NPV
Neocortical PiB+ve (SUVR >1.5)
0.66
0.86 (CI 0.56-0.98)
ApoE e4+
0.68
0.85 (CI 0.61-0.96)
CVLT II delayed recall (<0.74)
0.69
0.92 (CI 0.62-0.99)
Hippocampal atrophy (<0.00395)
0.64
0.82 (CI 0.56-0.95)
Plasma Ab42/Ab40 (<0.17)
0.40
0.50 (CI 0.25-0.75)
AIBL PLUS
18 months clinical follow-up
79 MCI
(mean age 73.5 years)
PiB-ve Subjects:
n=27
Converters to non-AD Dementia: 4 (15%)
Converters to AD:
3 (10%)
PiB+ve Subjects:
n=52
Converters to AD:
35 (67%)
Longitudinal PiB PET
5-year follow-up
3.0
AD
Neocortical SUVR
2.5
MCI
HC
2.0
1.5
1.0
HC
0.5
0
20
38
Time (months)
62
Biomarker Discovery
• Plasma Ab measures are not robust.
• Analysis done with RBM and Pfizer has
identified candidate biomarkers with
moderate diagnostic accuracy.
• Plasma ApoE and apoE4 were lower in AD
and inversely correlated with Aβ load in the
PiB-PET subset. ApoE levels were also
significantly lower among ε4 homozygotes.
• GWAS of PiB cohort performed in
collaboration with Harvard – results still
awaited.
Peripheral Blood Biomarkers
Simon Laws, et al – poster ICAD 2010
AD vs Healthy Elderly
Healthy Elderly
PiB+ vs PiB–
@ 70% specificity,
sensitivity is 76%
Apolipoprotein E
16
n=1086
ANOVA , F = 12.235, P < 0.001
15.5
Plasma ApoE Level (mg/dl)
* Tukey HSD, P < 0.001 vs. HC and SMC, P = 0.014 vs. MCI
15
14.5
*
14
13.5
0
~
13~
n = 367
HC
n = 387
n = 125
n = 207
SMC
MCI
AD
Clinical Classification
ApoE levels within Clinical groups
Physical Activity
• Both total physical activity and higher intensity physical activity
is associated with;
– Lower insulin (Regensteiner, 1991)
– Lower triglycerides (Lehtonen, 2009)
– Higher levels of HDL (Lehtonen, 2009)
• Higher levels of intense physical activity is associated with better
performance in assessments targeting;
– Working memory
– Attention
– Verbal & Spatial Learning and Recall
– Executive Functioning
The Australian Imaging, Biomarkers and Lifestyle Study of ageing
(AIBL): methodology and baseline characteristics of 1112 individuals
recruited for a longitudinal study of Alzheimer’s disease.
Ellis KA, et al.
International Psychogeriatrics. 2009;21:672-687.
Amyloid Imaging Results from the Australian Imaging,
Biomarkers and Lifestyle Study of Ageing (AIBL).
Rowe CC, et al.
Neurobiology of Aging - 2010 ADNI special edition.
Online: 15-MAY-2010 DOI information:10.1016/j.neurobiolaging. 2010.04.007
Baseline MRI, PiB scans and corresponding clinical data on 237
participants are available from
www.loni.ucla.edu/ADNI/Data/
(go to Current Project drop down menu and select AIBL)
or from http://aibl.csiro.au/adni/
Financial Supporters
•
•
•
•
•
Australian Government through CSIRO
Pfizer
Alzheimer’s Association
Alzheimer’s Drug Discovery Foundation
An anonymous Foundation
Acknowledgements
AIBL study
team
Osca Acosta
David Ames
Jennifer Ames
Manoj Agarwal
David Baxendale
Kiara Bechta-Metti
Justin Bedo
Carlita Bevage
Lindsay Bevege
Pierrick Bourgeat
Belinda Brown
Ashley Bush
Tiffany Cowie
Kathleen Crowley
Andrew Currie
David Darby
Daniela De Fazio
James Doecke
Denise El- Sheikh
Kathryn Ellis
Kerryn Dickinson
Noel Faux
Jonathan Foster
Jurgen Fripp
Christopher Fowler
Veer Gupta
Gareth Jones
Jane Khoo
Asawari Killedar
Neil Killeen
Tae Wan Kim
Adam Kowalczyk
Eleftheria Kotsopoulos
Gobhathai Kunarak
Rebecca Lachovitski
Simon Laws
Nat Lenzo
Qiao-Xin Li
Xiao Liang
Kathleen Lucas
James Lui
Georgia Martins
Ralph Martins
Paul Maruff
Colin Masters
Andrew Milner
Claire Montague
Lynette Moore
Audrey Muir
Christopher O’Halloran
Graeme O'Keefe
Anita Panayiotou
Athena Paton
Jacqui Paton
Jeremiah Peiffer
Svetlana Pejoska
Kelly Pertile
Kerryn Pike
Lorien Porter
Roger Price
Parnesh Raniga
Alan Rembach
Miroslava Rimajova
Elizabeth Ronsisvalle
Rebecca Rumble
Mark Rodrigues
Christopher Rowe
Olivier Salvado
Jack Sach
Greg Savage
Cassandra Szoeke
Kevin Taddei
Tania Taddei
Brett Trounson
Marinos Tsikkos
Victor Villemagne
Stacey Walker
Vanessa Ward
Bill Wilson
Michael Woodward
Olga Yastrubetskaya