MRI as a Potential Surrogate Marker MRI as a Potential Surrogate Marker in the ADCS MCI Trialin the ADCS MCI Trial
Michael Grundman, M.D., M.P.H.Michael Grundman, M.D., M.P.H.
FDA PCNS Advisory Committee Meeting on Brain Imaging as an Outcome Measure in Phase III Trials for AD
Gaithersberg, MDNovember 18, 2002
Decline in Mini-Mental State During Decline in Mini-Mental State During Progression to ADProgression to AD
20.00
21.00
22.00
23.00
24.00
25.00
26.00
27.00
28.00
29.00
30.00
Time
MM
SE
Sco
re
Normal
MCI
AD
Mild Cognitive Impairment: Key CriteriaMild Cognitive Impairment: Key Criteria
Memory Complaint Verified by Informant
Objective Memory Impairment
Generally Normal Cognition Other than Memory
Generally Normal Daily Function
Rate of Decline to AD among MCI Rate of Decline to AD among MCI Subjects and Normal ControlsSubjects and Normal Controls
YEARS OF FOLLOW UP
543210
PR
OP
OR
TIO
N D
EM
EN
TIA
FR
EE 1.00
.95
.90
.85
.80
.75
.70
.65
.60
.55
.50
.45
.40
.35
.30
.25
.20
.15
.10
.050.00
NORMAL CONTROLS
MCI SUBJECTS
MCI Trial with Vitamin E and DonepezilMCI Trial with Vitamin E and Donepezil
Vitamin E
Donepezil
Placebo
0 18126 3024 36MONTHS
Memory
Impairment
Alzheimer’s
Disease
Recruit people with MCI3 Treatments
Vitamin E – 2000 IU/dayDonepezil – 10mg/dayPlacebo
Study objectivesPrevent development of Alzheimer’s diseaseSlow decline on cognition and functionReduce rate of atrophy on MRI
3 Year duration769 Participants 69 Centers
MCI Trial with Vitamin E and DonepezilMCI Trial with Vitamin E and Donepezil
Baseline Score on ADAS Cog Total in Baseline Score on ADAS Cog Total in Normals, MCI and ADNormals, MCI and AD
Normals
MCI
AD
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
24.00
26.00
28.00
ADAS Cog Total
AD
AS
To
tal S
co
res
MRI as Potential Surrogate MarkerMRI as Potential Surrogate Marker
Hippocampal atrophy on MRI has high face validity because it occurs early and appears to be substantially affected by the AD pathology and contribute to the memory impairment observed in AD.
Percent Annual Change in Hippocampal Percent Annual Change in Hippocampal Volume by Clinical GroupVolume by Clinical Group
Clinical Group Percent Change
Control -stable -1.7 0.9 MCI-stable -2.5 1.5MCI-decliner -3.7 1.5AD -3.5 1.8
Jack Jr. C.R., et al, Neurology 2000, Vol 55 p.484-489
Possible Stages of Decline in Hippocampal Possible Stages of Decline in Hippocampal Volume Leading to ADVolume Leading to AD
Time
Hip
po
cam
pal
Vo
lum
e
Normal
MCI
AD
Mild Cognitive Impairment Trial: Mild Cognitive Impairment Trial: MRIs Performed to DateMRIs Performed to Date
Timing: MRIs Performed at Baseline, Time of
Conversion or Study Completion
193 Baseline Scans
57 Second Scans
Hippocampal volume at baseline will correlate with cognitive and functional performance
MRI hippocampal volume at baseline will predict crossover to AD
Rate of volume loss will be greater in subjects who decline clinically
MRI volumetric analysis will be a useful surrogate for measuring therapeutic response
Neuroimaging HypothesesNeuroimaging Hypotheses
Hippocampal Volume is Correlated Hippocampal Volume is Correlated with Baseline Memory Functionwith Baseline Memory Function
NYU Delayed Paragraph Recall Scores NYU Delayed Paragraph Recall Scores (# Correct) were lower in Subjects with (# Correct) were lower in Subjects with
Smaller Hippocampal VolumeSmaller Hippocampal Volume
3.1
3.7
4.7
2.0
2.5
3.0
3.5
4.0
4.5
5.0
NY
U D
elay
ed P
arag
rap
h R
ecal
l Sco
res
at
Bas
elin
e
Lowest Middle Highest
Normalized Hippocampal Tertiles
Baseline Hippocampal Volume Thus Far Baseline Hippocampal Volume Thus Far Appears to Predict Future Conversion Appears to Predict Future Conversion
to AD and Change on Clinical Measuresto AD and Change on Clinical Measures
10008006004002000
1.0
.9
.8
.7
.6
.5
Conversion to AD by Conversion to AD by Hippocampal Volume at BaselineHippocampal Volume at Baseline
Time on MCI Study (days)
Pro
bab
ility
of N
ot C
onve
rtin
g to
AD
0.5
0.8
0.7
0.6
0.9
1.0
4002000 800600
Top 50%
Bottom 50%
Hippocampal Volume
1000
CDR Sum of Boxes Change ScoresCDR Sum of Boxes Change Scores by Hippocampal Volume at Baseline by Hippocampal Volume at Baseline
56 %
44 %
Hippocampal Volume
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
0 6 M onths 12 M onths 18 M onths 24 M onths
Ch
an
ge
Sc
ore
Bottom 50% Top 50%
Characteristics of an Optimal Characteristics of an Optimal Surrogate MarkerSurrogate Marker
Rapidly ascertainable
Correlated with the clinical outcome
Fully capture the treatment’s “net effect”
Able to be collected consistently
Precede clinical decline or failure
Observations that Would Support Observations that Would Support Brain Atrophy as a Surrogate Marker Brain Atrophy as a Surrogate Marker
for Disease Modificationfor Disease Modification
Reduced rate of brain atrophy
Slower rate of clinical declineTreatment
Determine Rate of Decline in Hippocampal Determine Rate of Decline in Hippocampal Volume in Individual SubjectsVolume in Individual Subjects
TIME
3.53.02.52.01.51.0.50.0-.5
RA
W7000
6000
5000
4000
3000
Time in Study (Years)
Hip
po
cam
pal
Vo
lum
e
SCAN_2TM
3.53.02.52.01.51.0.50.0
NO
RM
_CP
.05
0.00
-.05
-.10
-.15
-.20
-.25
Determine if the Mean Rate of Hippocampal Atrophy Determine if the Mean Rate of Hippocampal Atrophy Accurately Predicts Clinical Outcome (AD)Accurately Predicts Clinical Outcome (AD)
Time in Study (Years)
Per
cen
t C
han
ge
in N
orm
aliz
ed H
ipp
oca
mp
al V
olu
me
Non-Converters
Converters
SCAN_2TM
3.53.02.52.01.51.0.50.0
NO
RM
_CP
.05
0.00
-.05
-.10
-.15
-.20
-.25
Determine if the Mean Rate of Hippocampal Determine if the Mean Rate of Hippocampal Atrophy is Slowed by TreatmentAtrophy is Slowed by Treatment
Time in Study (Years)
Per
cen
t C
han
ge
in N
orm
aliz
ed H
ipp
oca
mp
al V
olu
me
Treatment
Placebo
Possible Reasons Why Brain Atrophy May Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate MarkerNot Always Be a Reliable Surrogate Marker
Brain atrophy may not always be in the direct causal pathway of the disease. Weight loss, diuretics or dehydration may also contribute to brain atrophy.
The intervention may reduce the rate of brain atrophy and not improve the clinical outcome. Agents that disrupt the BBB or induce an inflammatory response could lead to brain swelling but not improve clinical symptoms.
The intervention could interfere with causal pathways without slowing brain atrophy. Amyloid-lowering agents that are disease modifying might increase brain atrophy in the short run by ridding the brain of space occupying amyloid.
0
20
40
60
80
100
1st
Qtr
2nd
Qtr
3rd
Qtr
4th
Qtr
East
West
North
MEN
WOMEN
MESIAL TEMPORAL VOLUME/CRANIAL VOLUME X 100
3.53.02.52.01.51.0
BO
DY
MA
SS
IN
DE
X
32
30
28
26
24
22
20
18
16
Body Mass Index and Mesial Temporal Cortex Body Mass Index and Mesial Temporal Cortex Volume in Alzheimer’s Disease PatientsVolume in Alzheimer’s Disease Patients
Possible Reasons Why Brain Atrophy May Possible Reasons Why Brain Atrophy May Not Always Be a Reliable Surrogate MarkerNot Always Be a Reliable Surrogate Marker
The intervention could improve the clinical outcome without reducing the rate of brain atrophy. A clinical benefit might occur with agents that enhance synaptic transmission without altering the neurodegenerative process or resulting brain atrophy.
Unexpected adverse events could occur despite a beneficial effect on the surrogate. Clinical benefit and reduction in brain atrophy could occur with unacceptable side effects.
Erroneous decisions could be made based on rates of brain
atrophy alone. It seems premature to accept differences in
brain atrophy as a primary outcome measure in the absence
of supportive clinical data.
In conjunction with slowing of decline on clinical measures
and a good safety profile, slowing of brain atrophy could
support a disease modification claim.
If brain imaging could be validated in AD or MCI trials for a
particular agent it might be used to support an efficacy claim
in subsequent trials while more clinical data was collected.
ConclusionsConclusions