MRI markers to understand progression

Neuroimaging Research Unit, Institute of Experimental
Neurology, Division of Neuroscience, San Raffaele Scientific
Institute, Vita-Salute San Raffaele University, Milan, Italy.
MRI MARKERS
TO UNDERSTAND PROGRESSION
MECHANISMS
Maria A. Rocca

• WM lesions: brain, spinal cord
• Atrophy
• WM damage: extent, topography
• GM damage: cortical lesions, diffuse
and regional damage
• Spinal cord damage
• CNS reorganization (brain, spinal cord)
• Conclusions
• Atrophy
and regional damage
• Conclusions
MRI & Progressive MS
Outline of presentation

SPMS
60 SPMS with monthly brain MRI for 4 months
32 (53%) had enhancing lesions at baseline
42 (70%) displayed one or more new enhancing lesions
at follow-up
14 (23%) showed no enhancing lesions either at baseline
or follow-up
Tubridyetal.,Neurology1998
Khaleelietal.,MultScler2010
PPMS
45 PPMS with brain and spinal cord MRI for 5
years
15 (33%) had enhancing lesion at baseline
12 (26%) had enhancing lesion at 5 year
26 (58%) had ≥1 enhancing lesion during the study
19 (42%) had no enhancing lesion during the study
Brain WM lesions / Enhancement

Khaleeli et al., Ann Neurol 2008
101 PPMS followed up for 10 yrs
Brain WM lesions / Prognosis
Mesarosetal.,JNeurol2008
RRMS
Sormani et al., Neurology 2009
• Similar slope of the relationship
between baseline T2LV and
EDSS in RRMS and SPMS
• Median yearly T2LV change:
0.27 mL in RRMS, and 0.30 mL
in SPMS (p=0.59)
T2 lesions

Brain WM lesions / Distribution
Ceccarellietal.,NeuroImage2008
CIS RR SP PP
T2 lesion maps
Bodinietal.,JNNP2011
T2 lesion location vs disability worsening
T1 lesion maps
PPMS
PP vs RR: 29 vs 19% peak probability
DiPerrietal.,ArchNeurol2008
• Higher T1 lesion occurrence in the CC,
CST and other tracts adjacent to the lateral
ventricles in SPMS vs RRMS
Filli et al., MSJ 2012

Multiple hyperintense
lesions in the spinal cord
Rovaris et al., Brain 2001
Spinal cord / T2 lesions
Number of cord lesions Number of damaged
cord segments
0.0
1.0
2.0
3.0
4.0
5.0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
p = 0.03
0.0
30.0
60.0
90.0
Cord area [mm2]
Rovarisetal.,Brain2001
PPMSSPMSControls

• Atrophy
and regional damage
• Conclusions

Atrophy
1 y FU: 963 untreated MS patients
De Stefano et al., Neurology 2010
p = 0.003


Dalton et al., Neurology 2006
CIS MS
(<1 year)
RRMS SPMS
n.s.
p=0.003
p=0.001
p=0.001
Ventricularvolumechange
21 CIS, 30 early relapse-onset,
41 RRMS, 23 SPMS

Atrophy
Fisher et al., Ann Neurol 2008
GM atrophy rates:
CIS→RRMS and RRMS stable > HC (p=0.05)
RRMS→SPMS and SPMS > HC (p= 0.005)
WM atrophy rates similar in all disease groups
NGMV
NWMV
** p<0.001
* p<0.01
GM atrophy explains physical disability and
cognitive impairment better than WM volume
Roosendaal et al., MSJ 2011
** p<0.001
* p<0.01

• Atrophy
and regional damage
• Conclusions

Pulizzi et al., Arch Neurol 2007
CIS vs HC PPMS vs HC
1
2
3
4
5
t value
2
4
6
8
t value
MDFA
RRMS vs BMS
t value
t value
SPMS vs RRMS SPMS vs PPMS
Preziosa et al., Radiology 2011
NAWM damage
p=0.003
p=0.01
-
p=0.004
RRMS BMS
SPMS PPMS
Tortorella et al., Neurology 2000

Kutzelnigg et al., Brain 2005
Focal demyelinated plaques in WM
Cortical demyelination
Demyelinated plaques in deep GM
GM damage / Cortical lesions
Extensive subpial
demyelination of the
cerebellum in a
PPMS case

Baseline CL volume: B: -0.525, p <0.001
Baseline T2-WM-LV: B: -0.448, p <0.001
48 PPMS patients followed up
for 2 years
Calabrese et al., Neurology 2009
DIR and disease evolution
MRI & PROGRESSIVE MS
GM damage / Cortical lesionsMulti-slab 3D DIR
Geurtsetal.,
Radiology2005
vs. SE = +538%; vs. FLAIR = +152%
RRMS PPMS
Calabreseetal.,Neurology2010
Cohen-Adad et al.,
NeuroImage 2011
T2*-w / 7 T

Power to discriminate SPMS from BMS
Filippietal.,MSJ2012
MDFA
Age: OR 1.2, p =0.001
Baseline CL volume: OR 1.7, p <0.001
Baseline cerebellar cortical volume:
OR 0.2, p <0.001
334 relapse-onset MS patients, 5 years FU
Calabrese et al., Ann Neurol 2013
GM damage / Cortical lesions
Baseline CL volume:
entire group: B=0.511; p<0.001
RRMS: B=0.512; p<0.001
SPMS: B=0.495; p<0.001
107 relapse-onset MS patients, 3-year FU
Calabrese et al., Ann Neurol 2010

Baseline GMF: OR 0.79, p=0.01
C index: 69%
73 relapse-onset MS patients followed up for 13 years
Evolution to SPMS at 13 year FU:
Baseline T2 LV (OR=1.13, p=0.005)
Baseline GMF (OR=0.71, p=0.04)
C-index: 84%
Cognitive deterioration at 13 year FU:
Baseline average GM MTR (OR=0.87, p=0.03)
Baseline disease duration (OR=1.50, p=0.08)
C-index: 97%
Baseline GMF: OR 0.79 (CI 0.7–0.9)
Baseline EDSS: OR 2.88 (CI 1.9–4.36)
241 relapse-onset
MS patients followed up for 9 years
Lavorgna et al., MSJ 2013
“Diffuse” GM damage
Filippi et al., Neurology 2013

“Regional” GM damage
SPMS vs RRMS
SPMS vs PPMS
Ceccarelli et al., NeuroImage 2008
Selective GM loss

C
Spinal cord / Atrophy
CSAn vs EDSS: r=-0.49, p<0.0001 EDSS
CSAn
Differential effect among disease clinical phenotypes (p<0.001):
no association in CIS and BMS patients
association in RRMS (r=-0.30), SPMS (r=-0.34) and PPMS patients (r=-0.27)
Roccaetal.,Neurology2011

Roccaetal.,JNNP2013
BMS vs RRMS SPMS vs RRMS SPMS vs BMS SPMS vs PPMSPPMS vs HC
P A L R P A L R P A L R P A L R P A L R
T2 lesion
probability
RRMS BMS PPMS SPMSCIS
Spinal cord damage

Average MD
[x10-3mm2s-1] (SD)
Mean FA
(SD)
Controls
1.203
(0.09)
0.42
(0.04)
PPMS
1.280
(0.10)
0.38
(0.05)
p
0.024
0.007
Agosta et al., Neurology 2005
Spinal cord / Diffuse damage
Composite MR model vs EDSS:
Cord area + cord MTR peak height
(r=0.21, p=0.04)
Rovaris et al., Brain 2001
0
10
20
30
40
50
60
70
0 10 20 30 40 50 60 70 80
Controls
MTR [%]
Normalizedpixelcount
SPMS
PPMS

Spinal cord damage
Baseline cross-sectional area and FA
vs EDSS at follow-up:
r = -0.40; p = 0.01
Agosta et al., Brain 2007
-10% -5% 0 +5% +10% +15% +20%
FA
MD
Cross-
sectional
area
RRMS
SPMS
PPMS
Overall
UCCA, T1LV, diffuse abnormalities and number of
involved segments were significant explanatory factors for
clinical disability (R2 = 0.564)
Lukas et al., Radiology 2013

CIS vs
non-disabled RRMS
SMC
Non-disabled vs mildly
disabled RRMS
SMC, SMA
Mildly disabled RRMS
vs SPMS
Thalamus
SII
SPMS vs
mildly disabled RRMS
Precuneus,
IPL, MFG
MFG, IPL
Precuneus,
CMA, MFG
Rocca et al., Lancet Neurol 2005
CNS reorganization / Brain

SPMS (reduced activations)
L SMA
L putamen
R cerebellum
Rocca et al., Neurology 2010
BMS
L SMC vs T2 lesion volume:
r = 0.63, p < 0.001
Rocca et al., Neurology 2010
STG
MFG
Insula
PPMS
Filippi et al., NeuroImage 2002

Correlations between  DMN fluctuations and:
PASAT (r=0.42, p<0.001)
CC FA and JD (r ranging from 0.54 to 0.87, p<0.001)
Cingulum FA (r=0.83, p<0.001)
Roccaetal.,Neurology2010
 DMN fluctuations in progressive MS patients
HC
PPMS
SPMS

HC
R
ACC
MCC
OFC
MTG
ITG
Cereb
(cr I)
Cereb (cr II)
L
ACC
SFG
PrecunMCC
ITG
MTG
Cereb
(cr I)
Cereb (cr II)
Thal
Put
CP
ACC
MCC
OFC ITG
MTG
Cereb
(cr I)
Cereb (VIII)
Thal
Pall
ACC
MCC
OFC
MTG
ITGSup TP
Cereb
(cr I)
Cereb (cr II)
ThalCaud
CI
ACC
MCC
OFC
ITG
MTG
Cereb (cr I)
Put
MCC
ITG
MTG
Ling
Cereb (cr II)
Cereb (cr I)
Cereb
(IV-V)
Sup
TP
ACC
PrecunMCC
MTG
SFG
Put
ITG
Thal
Cer-crus-II
Cer-crus-I
MTG
MCC
ITG
ACC
OFC
Cer-crus-II
Cer-crus-I
MTG
MCC
ACC
ITGSupTP
Cer-crus-I
Cer-crus-II
BMS
ITG
MTG
MCC
SupTP
Thal
Cer-
crus-II
Cer-crus-I
Cer-lobule-VIII
Cer-lobule-IV-V
ITG
MTG
LingSupTP
PHG
Thal
Cer-crus-II
Cer-crus-I
Cer-lobule-IV-V
HCs
SPMS
RRMS
BMS
ACC
MCC
MTG
ITG
Pall
OFC
Put
Cer-crus-I
ACC
Pall
Put
Thal
ITG
PHG
LingMTG
OFC
Cer-
lobule-VI
Cer-
crus-I
MCC
ACC
OFC
ITG
MTG
Ling
Pall
Thal
Cer-crus-I
Cer-crus-II
Cer-lobule-VIII
RLMRI & Progressive MS

Tactile stimulation of the palm of the R hand
Progressive MS vs controls: p=0.003
SPMS vs PPMS: p=0.05
Cordaveragesignalchange(%)
Controls
SPMS
PPMS
Valsasina et al., Hum Brain Mapp 2011
CNS reorganization / Spinal cord
Valsasina et al., JNNP 2010
Controls RRMS SPMS
3.9 %
 1.3 %3. 3 %
 1.1 %
2.7 %
 0.7 %
Task-relatedaveragesignalchange[%]
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
p=0.05
vs controls
p=0.02
vs controls
Cord fMRI vs fatigue
Rocca et al., Mult Scler 2012

• T2 lesions: brain, spinal cord
• Atrophy
and regional damage
• Conclusions

Conclusions
Modality
Gd+ lesions
Focal lesions
Whole-brain atrophy
NAWM damage
GM damage
Spinal cord damage
Functional changes
Potential clinical
value
-
+
++
++
+++
+++
++
Feasibility
+++
+++
+++
++
++
++
+

RIS RRMS SPMS/PPMSCIS Time
Severity
T2 lesions
Atrophy
Functional
changes
NAWM
damage
Cord
damage
GM
damage
Gd+ lesions
MRI in SPMS
Theoretical background

Neuroimaging Research Unit & WM
diseases group
Director: M. Filippi
DIVISION OF NEUROSCIENCE INSTITUTE OF EXPERIMENTAL NEUROLOGY
Scientific coordinator: M.A. Rocca
Department of Neurology
G. Comi, B. Colombo,
M. Comola, F. Esposito, V. Martinelli, F.
Martinelli Boneschi,
L. Moiola, G. Pavan, M. Rodegher
Department of Neuroradiology
A. Falini
MAGNIMS
Physicians: M. Absinta
A. Bisecco
G. Boffa
S. Cirillo
E. De Meo
G. Longoni
F. Mele
R. Messina
M.E. Morelli
L. Parisi
P. Preziosa
G. Riccitelli
Physicists:
M. Copetti
E. Pagani
P. Valsasina
Technicians:
L. Dall’Occhio
A. Meani
P. Misci
M. Petrolini
S. Sala
M. Sibilia
R. Vuotto
University of Belgrade
V.S. Kostic,
J. Drulovic, S. Mesaros
Gallarate Hospital, MS Centre
A. Ghezzi

MRI markers to understand progression

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