Use of Magnetic
Resonance Imaging In
Multiple Sclerosis Trials
Richard A. Rudick, M.D.
Mellen Center for Multiple Sclerosis, Neurological Institute,
Cleveland Clinic
March 7, 2009
Conflict of Interest Statement
Cleveland Clinic has accepted research
funding from NIH (NINDS, NCRR), NMSS,
Biogen Idec, and Nancy Davis Center
Without Walls for my research
 I have accepted honoraria or consulting
fees (< $10,000 per annum) from Biogen
Idec, Millenium, Genzyme, Teva, and
Novartis

Grant Support For Work Presented Today
NIH PO1 NS38667
Project 3 and MRI/Pathology Core
Pathogenesis of Multiple Sclerosis (Brain
atrophy in multiple sclerosis)
NIH RO1 NS38667; NMSS RG 3099
MSCRG Trial of IM IFN-1a for RR-MS
NMSS RG 3099
Brain atrophy in CIS
NMSS PP0540
MS image analysis methodology
Biogen Idec (BGEN 801)
F/U of IFN-1a study
Nancy Davis Center Without Walls
Clinical trial methodology
Outline of Talk
MRI / Clinical Correlations
Relapses / Disability
Use of MRI in MS Trials
Hot topics
MRI Defined Rx Response
Gray Matter Pathology
Multiple Sclerosis: Clinical Course
Preclinical
Relapsing-Remitting
Disability 
MS Relapses
Secondary Progressive
Progressive
Disability
SUBCLINICAL
(5-25 years)
Time 
MRI in Multiple Sclerosis
Useful in diagnosis, management
 Used to test new treatments
 Provides insight into pathogenesis

Evolution of MS MRI lesions
GAD
Richert N. unpublished (1998)
T2 lesion
Black Hole
MRI in MS
FLAIR/T2:
all “lesions” (edema, inflammation,
demyelination, gliosis, axonal loss)
Gad-enhancing:
breakdown of blood-brain barrier,
active inflammation
T1 hypointense:
axonal loss, severe tissue destruction
MTR hypointense:
demyelination, axonal loss
Low Correlation Between MRI
Lesions and Relapses (SLC data)



MRI lesions did not predict relapses in a multivariate
model (n = 306); Held et al, Neurology 2005:
The project to validate MRI lesions as a relapse
surrogate was stopped since the pre-requisite of
correlation between MRI lesions and relapses was not
met (n = 208); Petkau et al, Mult Scler 2008:
Retrospectice analysis of 31 placebo arms of RCT: no
correlation between Gad lesions and relapses (n = 409)
Daumer et al, Neurology 2009
Low Correlation Between MRI
Lesions and Relapses
Most lesions are clinically silent
 Kinetics (particularly as relates to disability)

Low Correlation Between MRI
Lesions and Relapses
Most lesions are clinically silent
 Kinetics (particularly as relates to disability)

Disease Activity Over 6.5 Years
If 90% Of New Lesions Are Subclinical, The Correlation
Between New Lesions And Relapses Would Be 0.34
Annals of Neurology, 2009, in press



23 RCTs with MRI and relapse data
Does the treatment effect on MRI lesions
correlate with the treatment effect on relapses?
A weighted linear regression was run
Number
of
patients
#
TRIAL
Follow
up
372
14
Filippi 2006
14
15
Kappos 2006
6
16
O'Connor
2006
9
17
Polman 2006
24
Natalizumab 300 mg
942
18
Hauser 2008
6
Rituximab 1000 mg
104
19
Garren 2008
12
20
Comi 2008
9
#
TRIAL
Follow
up
1
Paty 1993
24
2
Durelli 1994
6
IFNα-2a 9 MIU
20
3
Andersen 1996
6
Linomide 2.5 mg
31
4
Jacobs 1996
24
IFNb-1a 6 MIU
301
5
Millefiorini 1997
24
MTX 8 mg/m2
51
6
PRISMS 1998
24
7
OWIMS 1999
12
8
Lenercept MS
1999
Active arm
IFNb-1b 1.6 MIU
IFNb-1b 8 MIU
IFNb-1a 22 mg
IFNb-1a 44 mg
IFNb-1a 22 mg
IFNb-1a 44 mg
560
293
Lenercept 10 mg
6
Lenercept 50 mg
168
Lenercept 100 mg
IFN-α2a 4.5 MIU
21 Fazekas 2008
9
Myhr 1999
6
10
Brod 2001
9
11
Comi 2001
9
GA 20 mg
239
12
Bech 2002
6
Valacyclovir 1g
70
13
Miller 2003
6
IFN-α2a 9 MIU
IFN-α2a 10000 IU
IFN-α2a 30000 IU
Natalizumab 3 mg/Kg
Natalizumab 6 mg/Kg
12
97
30
213
Active arm
oral GA 5 mg
oral GA 50 mg
FTY720 1.25 mg
FTY720 5.0 mg
Teriflunomide 7 mg
Teriflunomide 14 mg
BHT-3009 0.5 mg
BHT-3009 1.5 mg
Laquinimod 0.3 mg
Laquinimod 0.6 mg
IVIG 0.2g
IVIG 0.4g
Number
of
patients
1651
281
179
267
306
127
Ustekinumab 27 mg
22
Segal 2008
6
Ustekinumab 90 mg q8w
Ustekinumab 90 mg
249
Ustekinumab 180 mg
23
Mostert 2008
TOT
6
Fluoxetine 20 mg
40
63 (40)
6591
log(REL effect) =
-0.01 + 0.57 log (MRI effect)
Validation with separate studies
In groups, the effect of a
treatment on new lesions
explains > 80% of the variance
of the relapse treatment effect
Low Correlation Between MRI
Lesions and Relapses
Most lesions are clinically silent
 Kinetics (particularly as relates to disability)

Does MRI Predict Future
Clinical Status?
Disability 
Preclinical
Relapsing-Remitting
MRI
Secondary Progressive
Disability
Or Atrophy
SUBCLINICAL
Variable
(5-25 years)
Time 
Do MRI Lesions Predict Future
Status?
MS patients F/U (yrs)
Reference
CIS
5, 10,14
Miller, Fillipi
CIS
14
Chard
RRMS
8, 13
Rudick
% EDSS > 3.0
Baseline T2 Lesion Load Predicts
Disability at 5 Years
Filippi et al. Neurology 1994; 44:635-641
T2 Lesion Growth In 5 Years Predicts
Disability at 14 Years
T2 Lesion Volume
30
SPMS
25
EDSS > 3
20
15
10
EDSS < 3
5
0
0
BL
5
5 years
1010
years
1414
years
Years from presentation
Brex et al. NEJM 2002:346;158-164:
T2 Lesion Growth In 5 Years Predicts
Brain Atrophy at 14 Years
T2 Lesion Load
SRCC
p Value
Baseline
-0.262
0.178
 BL to 5 Years
-0.528
0.004
 5 Years to 10 Years
-0.326
0.090
 10 Years to 14 Years
-0.016
0.936
Chard et al. JNNP 2003; 74:1551-1554
T2 Lesions In RRMS Predict Atrophy
and Clinical Disability after 13 Years
RRMS from Phase III trial (IFNB-1a)
MRI
Brain Atrophy
T2 LL Baseline
-0.66 (<0.0001)
∆ T2LL over 2 yr -0.40 (0.031)
MSFC
PASAT
-0.44 (0.02)
-0.50 (0.005) -0.54 (0.003)
No correlation between T2 LL and future EDSS
Rudick et al. Ann. Neurol.2006;60:236-242
Brain Atrophy in the IM IFNβ-1a
Clinical Trial (RRMS)
Healthy Controls
(n=16)
Mean +/- 2 SD
0.89
0.87
0.85
p < 0.0001
p = 0.0001
p = 0.0001
0.83
0.81
BPF = 0.830
z = - 5.2
BPF = 0.824
z = - 6.0
BPF = 0.820
z = - 6.5
0.79
Baseline
Year 1
Placebo Patients
(n=72)
Mean +/-SEM
Year 2
Rudick, et al. Neurology 1999; 53:1698-1704
Brain Atrophy During The Trial Correlates
With Disability At 8 Year F/U
55.9
% > EDSS 6.0 At F/U
60
50
40
30
20
29.4
28.6
-0.27 to -0.89
-0.90 to -1.7
14.3
10
0
1.3 to -0.26
-1.7 to -6.5
Quartiles of BPF  During 2 Year Clinical Trial
Fisher, et al. Neurology 2002
MRI Predicts EDSS > 6
Small
Medium
Large
T2 CHANGE
T1 HOLE
# GAD (BL,Y1,Y2)
BPF CHANGE
0
0.2
0.4
0.6
Estimated Effect Size
0.8
1
MRI / Clinical Correlations (in RRMS)
Lesions correlate with relapses in early
MS
 Effect of intervention on lesions correlates
strongly with relapse effect
 Lesions correlate with future disability and
brain atrophy
 Brain atrophy during RR-MS correlates
with future neurological disability

Amount Of CNS Injury
Natural History Of Multiple Sclerosis
“Typical MS”
SP-MS 10-20
Years After Onset
“Severe MS”
SP-MS After 5 Years
Progressive Disability Threshold
“BenignMS”
Never Progresses
0
5
10
15
20
Years After MS Onset
25
30
Outline of Talk
UseMRI / Clinical Correlations
Relapses / Disability
MRI in MS Trials
Hot topics
MRI Defined Rx Response
Gray Matter Pathology
MRI Parameters in MS Trials
Gadolinium lesions are the primary
outcome measure used to screen
treatments
 Secondary outcome measures for
registration trials

 Gad
lesions / T2 lesions
 T1 holes / brain atrophy
Disease Modifying Drugs: Clinical and MRI Outcomes
IM IFNb-1a
SC IFNb-1a
(44-µg)
IFNb-1b
(8-MIU)
Glatiramer
Acetate
Relapse rate
% reduction
32
p=0.002
32
p<0.005
34
p=0.0001
29
p=0.007
Disability progression
% reduction
37
p=0.02
31
p<0.05
29
p=NS
12
p=NS
Number of Gd+ lesions
% reduction
52
p=0.05
84*
p<0.001
NR
29*
p=0.00331
N/E T2 lesion number
% reduction
33
p=0.002
78
p<0.0001
83
p=0.009
31*
p<0.003
* = at 9 months
Disease Modifying Drugs: Clinical and MRI Outcomes
IM IFNb-1a
SC IFNb-1a
(44-µg)
IFNb-1b
(8-MIU)
Glatiramer
Acetate
Relapse rate
% reduction
32
p=0.002
32
p<0.005
34
p=0.0001
29
p=0.007
Disability progression
% reduction
37
p=0.02
31
p<0.05
29
p=NS
12
p=NS
Number of Gd+ lesions
% reduction
52
p=0.05
84*
p<0.001
NR
29*
p=0.00331
N/E T2 lesion number
% reduction
33
p=0.002
78
p<0.0001
83
p=0.009
31*
p<0.003
* = at 9 months
Brain Atrophy in MS Trials
Measured in nearly all trials (usually brain
volume normalized to brain size)
 Issues

 Slow
rate of atrophy, short trial durations
 Kinetic issues - fluid shifts and time course of
neurodegeneration
Multiple studies show reduced atrophy
with anti-inflammatory therapies in RRMS
 No study has shown an atrophy effect in
SPMS or PPMS

MRI Parameters in MS Trials

Newer measures
 Diffusion
Tensor Imaging
 Magnetic Resonance Spectroscopy
 Magnetization Transfer Imaging
 T1, T2 Relaxation Times
 Functional MRI

NYRFPT
Outline of Talk
Use of MRI in MS Trials
MRI / Clinical Correlations
Relapses / Disability
Hot Topics
MRI Defined Rx Response
GM Pathology
Original Avonex Study
The 2-year cohort
167 patients
Classification of responders
Relapses in 2yr – cutoff 2 or more
Gd+ lesions (yr 1 + yr2) – cutoff 2 or more
New T2 at yr 2 (versus baseline)- cutoff 3 or more
Outcome: EDSS, MSFC, BPF
EDSS Change In Responder Groups
Based on T2 Lesions
Mean Change in EDSS
4
3.5
3
2.5
2
1.5
n=62
n=20
P=0.05
0.78
1
0.5
n=46
n=39
P=0.48
0.6
0.82
0.03
0
IFN
Placebo
Responders
Rudick et al, Annals of Neurology 2004
Non Responders
Mean Change in BPF
P<0.01
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
-4
-4.5
-5
p=0.45
-0.67
-1.11
-1.35
-1.88
n=47
n=18
IFN
n=36
n=33
Placebo
Responders
Rudick et al, Annals of Neurology 2004
Non Responders
Do Lesions During Initial
2 Years Predict Outcome
(EDSS 6) At 15 Years?
p = 0.03
n=36
n=30
p = 0.59
n=36
n=30
p = 0.04
n=35
n=32
p = 1.0
n=35
n=32
Author
Responder Classification
Results
Rudick
Number of N/E T2 lesions at 2 yrs in 172 pts studied for 2 years. > 3 new lesions
PLC-controlled trial of IM IFNβ- predicted worse disease progression over 2
1a; Gad lesions at Yr 1 and 2
years; f/u at 15 years confirmed findings
Pozzilli
Gad lesions or new T2 lesions 1
year after beginning IFNβ
101 of 242 pts had MRI activity as defined.
Higher likelihood of relapses in the 4-year
observation (OR 3.6)
Tomassini
Gad lesions 1 year after beginning
IFNβ; NAb while on IFN
68 patients followed for 6 years. Gad lesions
predicted relapse or disability (OR 7.9); NAb
associated with poor outcome (OR 7.3)
Rio
N/E T2 lesions or Gad lesions 1 year 152 pts studied for 2 years. >2 active lesions at
after starting IFNβ
1 year was the primary factor predicting
sustained EDSS progression (OR 8.3)
Durelli
Gad or T2 lesions 6 months after
starging IFNβ; and IFNβ NAb
during study
147 pts studied for 2 years. MRI lesions and/or
NAb predicted relapse or sustained EDSS
increase in the next 18 months
Kinkel
Gad or new T2 lesions 6 months
after starting IFNβ in CIS
383 pts with CIS studied up to 2 years. Active
MRI lesions predicted CDMS in IFNβ-1a but not
placebo patients
Longitudinal studies consistently
indicate that MRI activity while
using IFNβ indicates patients with a
relatively poor response to therapy
and poor prognosis
Outline of Talk
Use of MRI in MS Trials
MRI / Clinical Correlations
Relapses / Disability
Hot Topics
MRI Defined Rx Response
GM Pathology
Cortical Pathology in MS
Post-Mortem Studies



> 90% of MS patients have
cortical lesions (Lumsden 1970)
Percentage of demyelinated
area significantly higher in cortex
than WM - 26.5% vs. 6.5%
(Bo, et al. 2003)
Most cortical lesions are not
detectable on conventional MRI
(Geurts, et al. 2005)
SPMS
Focal demyelinated
WM plaque
Cortical
demyelination
Kutzelnigg et al Brain 2005
Gray Matter Atrophy



Segmentation of gray
matter based on
intensity and anatomic
probability
Gray matter fraction:
GMF = GM volume /
brain volume
Provides estimate of
overall amount of GM
tissue damage
T2w
Anatomical
GM
Final GM
Nakamura and Fisher. NeuroImage 2009
Gray Matter Atrophy in Multiple
Sclerosis: NIH Longitudinal Study

87 subjects followed over 4 years
 17
controls
 7 CIS
 37 RRMS
 26 SPMS

Measured EDSS, MSFC, change in fractional
brain volumes, lesion volumes, MTR
Fisher, et al. Ann Neurol 2008
Atrophy Rates Relative to
Healthy Controls
16
14.0
Fold Increase (relative to controls)
14
12.4
12
10
8.1
8
6
5.2
5.8
4.4
3.5
4
3.1 3.2
3.3
3.4
2.2
CIS
(n=7)
CIS->RRMS
(n=8)
RRMS
(n=28)
RRMS->SPMS
(n=7)
2
0
-2
ΔBPF
HC
(n=17)
ΔWMF
ΔGMF
SPMS
(n=19)
Fisher, et al. Ann Neurol 2008
Gray Matter Atrophy Correlates with
MS Disability Progression

87 subjects followed over 6.5 years
 17
healthy controls
 7 CIS
 36 RRMS
 27 SPMS


Measured EDSS, MSFC, changes in fractional
brain volumes
Categorized patients as “progressed” or “stable”
based on MSFC change over 6.5 years
Rudick, et al. (JNNP 2009)
Gray Matter Atrophy Correlates with
MS Disability Progression
Rudick, et al. (JNNP 2008)
Gray Matter Pathology in MS
Gray matter pathology increasingly
dominates the pathology
 Gray matter atrophy correlates with
disability progression
 Is MS a gray matter disease?

Outline of Talk
MRI / Clinical Correlations
Relapses / Disability
Use of MRI in MS Trials
Hot topics
MRI Defined Rx Response
Gray Matter Pathology
Future MRI Directions
More specific MRI measures of MS
pathology
Imaging markers for GM pathology
Use of MRI in neuroprotection trials
Use of MRI to monitor / manage Rx
Collaborators
Acknowledgements
Biomedical Engineering:
Elizabeth Fisher, Ph.D.
Raghavan Gopalakrishnan, M.S.
Patricia Jagodnik, B.S.
Kunio Nakamura, B.S.
Smitha Thomas, M.D.
Bhaskar Thoomukuntla, M.S.
Neurosciences:
Angela Chang, M.D.
Richard Ransohoff, M.D.
Susan Staugaitis, M.D., Ph.D.
Bruce Trapp, Ph.D.
Radiology:
John Cowan, R.T.
Mark Lowe, Ph.D.
Mike Phillips, M.D.
Derek Tew, R.T.
Mellen Center:
Jeff Cohen, M.D.
Bob Fox, M.D.
Claire Hara-Cleaver, RN, NNP
Dee Ivancic
Lael Stone, M.D.
Biostatistics:
Jar-Chi Lee, M.S.
Thank You For Your Attention