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

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


Brain WM lesions / Enhancement

Khaleeli et al., Ann Neurol 2008

101 PPMS followed up for 10 yrs


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


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


• 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

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


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

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




• Atrophy



and regional damage



• 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


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




• Atrophy



and regional damage



• 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




• Atrophy



and regional damage



• 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


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)

Ro

cca

et a

l.,

Neu

rolo

gy 2

01

0

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 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


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


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



• 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/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

mri markers to understand progression

Health & Medicine