Transcript Philadelphia April 2014 Total Number of FDG Scans by Group Number of FDG Scans Normal SMC EMCI LMCI AD Total Total.

Philadelphia
April 2014
Total Number of FDG Scans by Group
Number
of FDG
Scans
Normal
SMC
EMCI
LMCI
AD
Total
1
119
104
165
158
138
684
2
133
0
141
74
25
373
3
6
0
1
18
17
42
4
13
0
0
16
58
87
5
33
0
0
41
0
74
6
15
0
0
49
0
64
7
19
0
0
29
0
48
8
5
0
0
26
0
31
9
0
0
0
1
0
1
343
104
307
412
238
1404
Total
Total Number of Florbetapir Scans by
Group
Number of
Florbetapir
Scans
Normal
SMC
EMCI
LMCI
AD
Total
1
138
74
160
167
125
664
2
135
0
145
91
13
384
Total
273
74
305
258
138
1048
The last ADNI Subject will have his second scan by December 2015
By the end of 2014 there will be ~800 subjects with 2 scans
There are currently 5 subjects with 3 scans
By December 2014 there will be ~100 third scans
Early AV45 Images are Visually Similar to
FDG-PET Using 3D-SSP Analysis
Surface-projected z-scores (compared to 22 normal subjects)
45 sec-6 min post-injection
Pons-normalized
Norman Foster, Angela Wang University of Utah
Regional ROI Z-score values are Similar in
Early Phase AV45 and FDG Scans
Regional ZScores
Differences in Early AV45 and FDG
SMC
EMCI
SMC
EMCI
2
0
−2
−4
Z Scores
Scan Type
LMCI
eAV45
AD
AD
LMCI
FDG
2
0
−2
−4
FRT
MFRT
PRT
MPRT
TMP
MTMP
ACING
PCING
FRT
MFRT
PRT
MPRT
TMP
MTMP
ACING
PCING
ROI
Z-scores by cortical regions and Diagnosis for Early
Florbetapir Frames and FDG
Norman Foster, Angela Wang University of Utah
Subject frequency
Florbetapir status by diagnosis
27% florbetapir+
Normal
N=266
27% florbetapir+
SMC
N=74
45% florbetapir+
Early MCI
N=302
63% florbetapir+
Late MCI
N=219
85% florbetapir+
AD
N=187
Baseline florbetapir cortical SUVR
Total N=1048
Florbetapir by APOE4 status
Subject frequency
APOE4-
APOE4+
21% florbetapir+
46% florbetapir+
Normal
N=265
15% florbetapir+
55% florbetapir+
SMC
N=72
30% florbetapir+
66% florbetapir+
Early MCI
N=299
39% florbetapir+
87% florbetapir+
Late MCI
N=219
58% florbetapir+
98% florbetapir+
Baseline florbetapir cortical SUVR
Baseline florbetapir cortical SUVR
AD
N=184
Total
N=1039
Florbetapir change
Normal
N=135
EMCI
N=144
AD
N=35
LMCI
N=70
Florbetapir not increasing
N=156
3/88 (3%) converters
Florbetapir cortical SUVR
47%
14%
36%
44%
AV45-  AV45+
N= 8 (4% of all florbetapir- subjects)
Florbetapir Increasing
N=68
2/31 (6%) converters
27%
17%
10%
3%
Florbetapir +
not increasing
N=73
12%
29%
14%(23%) converters
9/40
49%
Florbetapir +
Increasing
N=87
15%
Visit 1
26%
26% (24%) converters
13/55
Visit 2
Visit 1
Visit 2
Visit 1
Visit 2
34%
Visit 1
Vis it 2
Total N=384
Florbetapir change
Annual
florbetapir
change
Normal
N=135
EMCI
N=144
LMCI
N=70
AD
N=35
Florbetapir cortical SUVR
Florbetapir not increasing
N=156
Florbetapir Increasing
N=68
2.1%
2.2%
2.1%
Florbetapir +
not increasing
N=73
Florbetapir +
Increasing
N=87
2.6%
Visit 1
Visit 2
2.1%
Visit 1
2.4%
Visit 2
Visit 1
Visit 2
2.5%
Visit 1
Vis it 2
Total N=384
Florbetapir cortical annual SUVR change
Florbetapir change
y = -0.2x2 + 0.35x - 0.14
Cutoff = 0.79
Whole cereb ref units
.8
1.1
1.4
Baseline florbetapir cortical SUVR
1.8
Florbetapir cortical SUVR
Florbetapir cortical annual SUVR change
Florbetapir change
Cutoff = 0.79
Baseline florbetapir cortical SUVR
Cutoff = 0.79
Normal
mean = 0.70
1 SD = 0.03
Time (yrs)
Florbetapir cortical annual SUVR change
Florbetapir change
N
mean
cutoff peak Aβ
10y
.8
13y
7y
0.97
Whole cereb ref units
1.1
AD
mean
1.25
Approx 30 yrs
from N to AD
1.4
Baseline florbetapir cortical SUVR
1.8
Florbetapir cortical annual SUVR change
Florbetapir change
1 SD = 0.03
2 SDs  9
yrs
SD of N
mean
peak Aβ
cutoff
9y
10y
7y
13y
AD
mean
Approx 30 yrs
from N to AD
Baseline florbetapir cortical SUVR
Conversion Rates By Scan Abnormality
287 ADNI2/GO EMCIs/LCMIs with >1 yrs post-florbetapir followup
36 converters (13%)
50
50
40
40
37
%
30
44%
30
24%
20
20
10
10
5%
2%
10%
9%
1%
0
0
FDG-
10/213
FDG+
AV45-
AV45+
26/73
3/149
33/138
FDG-/AV45- FDG+/AV45- FDG-/AV45+ FDG+/AV45+
1/121
9/89
2/23
24/54
Conversion Rates By Scan Abnormality
116 ADNI2/GO EMCIs/LCMIs with >2 yrs post-florbetapir followup,
12 converters (10%)
50
50
40
47%
40
36
%
30
30
21%
20
20
10
10
3%
9%
0%
2%
0
6%
0
FDG-
2/87
FDG+
AV45-
AV45+
10/28
1/64
11/52
FDG-/AV45- FDG+/AV45- FDG-/AV45+ FDG+/AV45+
0/50
2/36
1/11
9/19
Potential PET Aims for ADNI3
1. Tau imaging
2. Continue longitudinal amyloid imaging
3. Early stage – pre amyloid positive
Issues
1. Continue FDG?
2. Which – or multiple – tau tracers?
Other possible goals
1. Open ADNI to other amyloid tracers?
2. Inflammation tracers?
3. Dopamine tracers?
Initial Experience with Tau PET
MGH and the Harvard Aging Brain Study
Keith A Johnson, M.D.
Massachusetts General Hospital
[18F] T807
Chien et al., JAD 2013; Xia et al., Alz and Dem 2013
• Rapid uptake and washout of tracer from brain
• Low white matter binding
• immunochemistry of tau aggregates in autopsy specimens
PHF tau IHC (AT8)
[18F] T807 autoradiography
Amyloid b IHC
T807 Tau PiB Amyloid-β
A
75 year-old
Normal
Amyloid MMSE 30
B
79 year-old
Normal
Amyloid +
MMSE 29
C
70 year-old
MCI
Amyloid +
MMSE 28
D
68 year-old
AD Dementia
Amyloid +
MMSE 23
Can we stage AD using Tau PET ?
Consistent with Braak Staging? Indicate incident impairment due to AD?
T807
SUVR
74 y/o Normal; MMSE=30
AT8 Histochemistry
2.0
PiB (mcDVR = 1.23)
1.0
Braak 2012
2.0
1.4
SUVR
Braak 2006
Aim 1
T807 Binding, Correspondence to Higher Braak Stages
2.0
1.0
SUVR
2.0
1.4
Age
70
59
70
71
52
MMSE
27
26
23
23
24
PiB (DVR) Pos (1.5)
Pos (1.7)
Pos (1.7)
Pos (1.5)
Pos (1.5)
Dx
MCI
MCI
MCI
AD
AD
Braak?
III/IV
III/IV
III/IV
V/VI
V/VI
3
Aim 1
T807 Binding, Correspondence to Lower Braak Stages
2.0
1.0
SUVR
2.0
1.4
Age
33
71
74
84
70
MMSE
30
30
30
30
27
PiB (DVR) Neg (1.0)
Neg (1.0)
Pos (1.2)
Pos (1.2)
Pos (1.5)
Dx
Normal
Normal
Normal
Normal
MCI
Braak?
0
I/II
III/IV
III/IV
III/IV
4
Ab 
Age 
F18 T807
SUVR=1
2
Ab 
68y Ab=1.46
68y Ab=1.84
74y Ab=1.20
75y Ab=1.55
84y Ab=1.63
68y Ab=1.25
67y Ab=1.52
73y Ab=1.18
79y Ab=1.26
86y Ab=1.52
68y Ab=1.15
68y Ab=1.19
71y Ab=1.15
75y Ab=1.17
85y Ab=1.17
68y Ab=1.14
69y Ab=1.18
69y Ab=1.13
75y Ab=1.15
88y Ab= 1.10
65y Ab=1.07
68y Ab=1.11
71y Ab=1.11
81y Ab=1.10
83y Ab=1.09
52y Ab=1.06
68y Ab=1.07
70y Ab=1.06
80y Ab=1.05
82y Ab=1.09
Age 
F18 T807
SUVR=1
2
Cortical Anatomy of Elevated 18F-T807 Binding
MCI/AD (N=11) v.
Cognitively Normal (N=75)
t=
6
5
4
3
2
1
0
Regional T807 Binding
Harvard Aging Brain Study subjects (N= 56) vs. MCI/AD (N=10)
**
*
*
* p<0.003
** p<0.0001
2=0.24, p<10-4
R
SUVRPV
= Standardized Uptake Value Ratio
(Cerebellar Grey), Partial Volume Corrected
Amyloid Status:
Negative ≤1.15<
Positive
5
Relationship of T807 tau and PiB Aβ PET
Entorhinal Tau Related to Global Amyloid-β
HAB subjects: N= 56, R2=0.24, p<10-4
79 y/o Normal
70 y/o MCI
68 y/o AD
Normal, N = 23
T807
(Fischl et al., 2009)
PiB
2=0.24, p<10-4
R
SUVRPV
= Standardized Uptake Value Ratio
(Cerebellar Grey), Partial Volume Corrected
Amyloid Status:
Negative ≤1.15<
7
Positive
Perirhinal T807 vs. MMSE
(Augustinack et al., 2013)
R2=0.
24,
SUVRPV = Standardized Uptake Value Ratio
(Cerebellar Grey), Partial Volume Corrected
Amyloid Status:
Negative ≤1.15<
Positive
LMDR Slope (change/year)
LMDR Slope (change/year)
LMDR Slopes versus T807
6
4
2
0
-2
0.9
1.0
1.1
1.2
1.3
EC T807
1.4
1.5
1.6
6
4
p < 0.005
2
0
-2
0.9
1.0
1.1
1.2
1.3
1.4
1.5
1.6
Inf Temp T807
Age-adjusted
Motivation:
Correlation with severity – outcome biomarker
Subject selection – “AD pathway”
Tau-targeted therapy
Currently 3 potential compounds
PBB3 with [11C] label
[18F]T807 and [18F]THK5117
2 ADNI Pilot Grants proposing T807 are pending – 1
DOD, 1 ADNI Supplement
Tau Imaging – Key Questions
Which Ligand?
How many will be ready for distribution?
Advantages of more diverse data (multiple
tracers) vs less comparability across
participants
Retain FDG?
FDG vs Tau will be interesting
But this will require 3 imaging visits
Use early frames data? (# of sites?)
Use MR perfusion? (# of sites?)
Pre-Amyloid Positive
How many normals can be retained?
What is the conversion rate for our normals
with florbetapir?
Should we enrich sample?
Which is more important: Conversion (crossing
a threshold) or simply increasing SUVrs?
Other Possible Aims
Additional Amyloid imaging agents
Is it too late?
How to prioritize between 3 other tracers?
Inflammation
An area of considerable interest
Is there a good ligand?
Dopamine
Diagnostically useful
Do clinical trial participants have DLB?
Sub study?
Is this “mission critical”?
Acknowledgements
Susan Landau, Allie Fero, Suzanne Baker, Bob Koeppe,
Eric Reiman, Kewei Chen, Norman Foster, Chet Mathis
Core Leaders
Site PIs
Participants