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MRI markers to understand progression mechanisms by Maria A. Rocca Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
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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
• 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
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
Tu
bri
dy e
t al
., N
euro
log
y 1
99
8
Kh
alee
li e
t al
., M
ult
Scl
er 2
01
0
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
MRI & Progressive MS
Brain WM lesions / Enhancement
Khaleeli et al., Ann Neurol 2008
101 PPMS followed up for 10 yrs
MRI & Progressive MS
Brain WM lesions / Prognosis
Mes
aro
s et
al.
, J
Neu
rol
20
08
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
MRI & Progressive MS
Brain WM lesions / Distribution
Cec
care
lli
et a
l., N
euro
Imag
e 2
00
8
CIS RR SP PP
T2 lesion maps
Bodin
i et
al.
, JN
NP
2011
T2 lesion location vs disability worsening
T1 lesion maps PPMS
PP vs RR: 29 vs 19% peak probability
Di
Per
ri e
t al
., A
rch N
euro
l 2008
• 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 MRI & Progressive MS
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] Ro
var
is e
t al
., B
rain
20
01
PPMS SPMS Controls
• 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
MRI & Progressive MS
Outline of presentation
Atrophy
MRI & Progressive MS
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
Ven
tric
ula
r v
olu
me
chan
ge
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
MRI & Progressive MS
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
MRI & Progressive MS
Outline of presentation
• 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
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
MD
F
A
RRMS vs BMS
t value
t value
SPMS vs RRMS SPMS vs PPMS
Preziosa et al., Radiology 2011
MRI & Progressive MS NAWM damage
p=0.003
p=0.01
-
p=0.004
RRMS BMS
SPMS PPMS
Tortorella et al., Neurology 2000
MRI & Progressive MS
Outline of presentation
• 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
Kutzelnigg et al., Brain 2005
Focal demyelinated plaques in WM Cortical demyelination Demyelinated plaques in deep GM
MRI & Progressive MS 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 lesions Multi-slab 3D DIR
Geu
rts
et a
l.,
Rad
iolo
gy 2
00
5
vs. SE = +538%; vs. FLAIR = +152%
RRMS PPMS
Cal
abre
se e
t al
., N
euro
log
y 2
01
0
Cohen-Adad et al.,
NeuroImage 2011
T2*-w / 7 T
Power to discriminate SPMS from BMS
Fil
ipp
i et
al.
, M
SJ
20
12
MD FA
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
MRI & Progressive MS 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
MRI & Progressive MS
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
MRI & Progressive MS
“Regional” GM damage
SPMS vs RRMS
SPMS vs PPMS
Ceccarelli et al., NeuroImage 2008
Selective GM loss
MRI & Progressive MS
Outline of presentation
• 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
C
MRI & Progressive MS Spinal cord / Atrophy
CSAn vs EDSS: r=-0.49, p<0.0001 EDSS C
SA
n
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)
Ro
cca
et a
l.,
Neu
rolo
gy 2
011
Ro
cca
et a
l.,
JNN
P 2
01
3
BMS vs RRMS SPMS vs RRMS SPMS vs BMS SPMS vs PPMS PPMS 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 SPMS CIS
MRI & Progressive MS 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
MRI & Progressive MS 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 [%]
No
rmali
zed
pix
el c
ou
nt
SPMS
PPMS
MRI & Progressive MS 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
MRI & Progressive MS
Outline of presentation
• 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
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
MRI & Progressive MS
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
MRI & Progressive MS
CNS reorganization / Brain
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)
Ro
cca
et a
l.,
Neu
rolo
gy 2
01
0
DMN fluctuations in progressive MS patients
HC PPMS SPMS
MRI & Progressive MS
CNS reorganization / Brain
HC R
ACC
MCC
OFC
MTG
ITG Cereb
(cr I)
Cereb (cr II)
L
ACC
SFG Precun MCC
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
ITG Sup TP Cereb
(cr I)
Cereb (cr II)
Thal Caud
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
Precun MCC
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
ITG SupTP 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 Ling SupTP
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
Ling MTG OFC
Cer-
lobule-VI
Cer-
crus-I
MCC
ACC
OFC ITG
MTG Ling
Pall
Thal
Cer-crus-I
Cer-crus-II
Cer-lobule-VIII
R L MRI & Progressive MS
CNS reorganization / Brain
Tactile stimulation of the palm of the R hand
Progressive MS vs controls: p=0.003
SPMS vs PPMS: p=0.05
Co
rd a
ver
ag
e si
gn
al
cha
ng
e (%
) Controls
SPMS
PPMS
Valsasina et al., Hum Brain Mapp 2011
MRI & Progressive MS
CNS reorganization / Spinal cord
Valsasina et al., JNNP 2010
Controls RRMS SPMS
3.9 %
1.3 % 3. 3 % 1.1 %
2.7 %
0.7 %
Tas
k-r
elat
ed a
ver
age
sig
nal
ch
ang
e [%
]
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
MRI & Progressive MS
Outline of presentation
• T2 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
MRI & Progressive MS
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/PPMS CIS Time
Sev
erit
y
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