Unidad de Resonancia MagnéticaServicio de RadiologíaHospital Vall d’Hebron.

Barcelona. Spainalex.rovira@idi-cat.org

Àlex Rovira

“MRI in MS: the radiologist perspective”

MS Preceptorship - Updating Knowledge in Multiple Sclerosis -June, 1-3 2010

Barcelona

Increased water content (edema, acute demyelination, tissue disruption)Increased BBB permeability (acute inflammation)

T2-weighted Post-contrastT1-weighted

Conventional MRI measuresT2 and CE T1-WI

• Highly sensitive for detecting MS plaques• Provide quantitative assessment of inflammatory activity and lesion load• Most important paraclinical tool for diagnosing and monitoring MS

Preclinical Relapsing-Remitting MS Secondary Progressive MS

Lesion LoadT2

Brain Volumeatrophymeasures

EDSS (clinical deficit)

Time

Inflammation Degeneration/ nervoussystem damage

Two Overlapping Pathogenetic Components of MS

Antiinflammatory/immunomodulatory

therapiesMyelin/neural repair/

neuroprotection

Modified from Roland Martin

Clinico-radiological paradoxDiscrepancy between cMRI and clinical measures

Non specificity of the underlying lesion substrate

Insensitivity to quantify extent of damage in NAWM and spinal cord, which

substantially contribute to disability

Insensitivity to reveal cortical lesions

Inability to assess cortical adaptive reorganization

How can we overcome limits of conventionalbrain MRI in MS ?

Application of MR techniques that selectively detect specificpathological substrates (lesions and NABT)

Putative markers of matrix destruction: axonal density,myelination

•T1 Black holes•MTR•Atrophy•MRS

Outcome measures in clinical trials (neuroprotective agents for myelin repair)

1997 2002 20031995 2005

IMAGING IRREVERSIBLE TISSUE DAMAGET1 Black holes

Van Waesberghe et al. Ann Neurol. 1999

2

50%

2

2: mildly hypointense

1

Axonal density40%

1

1: strongly hypointense

3

90%

3

3: slightly hypointense

IMAGING IRREVERSIBLE TISSUE DAMAGET1 Black holes

• Chronic black hole lesions: T1 hypointense lesions (SE sequences)persisting 6 months or longer indicate

– Significant demyelination– Axonal loss

• This tissue damage is irreversible• Correlation with disability is strong

IMAGING IRREVERSIBLE TISSUE DAMAGET1 Black holes

Gd + (90%)New T2 lesion

T2 +

T1 + (80%)

Evolution of lesion appearance over time

Modified from R. Zivadinov Neurology 2007

Timet10

t26 -12 months

Gd + (90%)New T2 lesion

T2 +

T1 + (80%)

T2 + / T1 +(20-40%)

T2 + / T1 -(60-80%)

T2 - / T1 -(3-5%)

Evolution of lesion appearance over time

remyelination

Modified from R. Zivadinov Neurology 2007

demyelinationremyelination

severe tissuedestruction

Timet10

t26 -12 months

Ring-enhancing lesionsLarge lesionsPV lesions

baseline 12 months

Tracking individual lesion evolution

80% of gad-enhancing lesions are hypointense on T1Most became isointense

Interferon beta reduces the frequency of new BH formationRR MS patients

Bagnato et al. Arch Neurol. 2005

Natural history

Therapy phase

ProsT1 Black holes

Specific marker of severe tissue destruction

T1W sequences easy to obtain, not time-consuming

Improve correlations with disability

Sensitive to changes over time (disease progression

under treatment)

Biomarker of neuroprotective effect

ConsT1 Black holes

Definition is arbitrary and highly operatordependent

Do not provide quantitative assessment

No graded information about intrinsic pathology (invivo MRS extremely variable)

Difficult to detect in the brainstem, spinal cord andoptic nerve

MTRT1PD

•Quantitative measure•Marker of demyelination (significant correlation between myelin content and MTR)•Focal and global tissue assessment

Magnetization Transfer Ratio (MTR)MTR = 40-50%

MTR = 37%

MTR = 21%

MTR = 0%

•Decreases with demyelination (reduced proton exchange)•Increases with remyelination

Schmierer et al. Arch Neurol 2004

Demyelination / RemyelinationPostmortem MTR

remyelinated

demyelinated

T2 MTR

LFB

LFB

MTR / Myelin contentr = -0.84 p <0.001

Magnetization Transfer RatioSequential analysis in acute/chronic MS plaques

van Waesberghe et al. Am J Neuroradiol 1998

.48

.46

.44

.42

.40

.38

.36

.34

.32–1 0 1 3 5 7

Months of Follow-Up

NAWMNAWMPattern A

Pattern DPattern B

Isointense

36%5%

15%

Chronicblack holespermanent

Initiallyisointense

20%

Hypointense80%

Acute blackholes

Pattern C 44%

Mean MTR

remyelination

demyelination

Chen et al. Ann Neurol 2008

Quantitave and continuous measure

Related to axonal loss and degree of demyelination

Proposed as a surrogate marker of remyelination

Information of the entire brain

Correlated with the degree of disability and cognitive

impairment

Sensitive to changes over time

ProsMTR in MS

ConsMTR in MS

Time consuming

Variability

Optimization and standarization across multiplesites and over time is challenging

Technical demands have limited its use intherapeutic trials to single centers

Edema (dilution effect) and T1 relaxation influenceMT effect

IMAGING IRREVERSIBLETISSUE DAMAGE

Brain atrophy

1997 2002 20031995 2005

Loseff et al. Brain 1996

No definite change in EDSSp <0.05 by 18 months

-1.8mL/year

Definite change in EDSSp <0.05 by 6 months

-6.4mL/year

Months

basal 1 y 2 y 3 y 4 y

Effect of DMT on brain atrophy prevention in MS

Zivadinov et al. J Neurol 2008

Untreated

Low dose INF

Natalizumab

GA

High dose INF / Chemotherapeuthics

Year 0 – Year 5 Year 0 – Year 1(Pseudoatrophy)

Year 1 – Year 5

Khan O. et al., AAN 2008.

-3,8

-2,2-1,83

-1,48

-4

-3

-2

-1

0

Control IFNß-SC IFN ß-IM GAn = 34 91 47 102

-0,95 -1,01

-0,79 -0,79

-1,5

-1

-0,5

0

-4,75

-3,21-2,62

-2,27

-5

-4

-3

-2

-1

0

Control IFNß-SC IFN ß-IM GAn = 34 91 47 102

Control IFNß-SC IFN ß-IM GAn = 34 101 53 121

•• All therapies areAll therapies aresignificantly better thansignificantly better thancontrols (p < 0.001)controls (p < 0.001)

•• All therapies areAll therapies aresignificantly better thansignificantly better thancontrols (p < 0.001)controls (p < 0.001)

p<

0.00

01

p=

0.00

36

p < 0.0001

p=

0.02

01

p=

0.00

56

p < 0.0001

p<

0.00

01

Brain Atrophy in MSEffect of Therapies on Brain Volume Change (%)

1 monthbaseline 3 months 1 year6 months

Brain volume changes in ADEMEffect of steroids

Hoogervorst et al. Mult Scler 2002

• Pseudoatrophy– Resolving inflammation– Loss of inter/intracellular water– Changes in electrolyte balance

• Atrophy– Natural history

• Demyelination– Partially reversible (remyelination)

• Loss of glial cells– Partially reversible (recruitment,

differentiation)• Axonal loss

– Irreversible– DMA related

• Protein catabolism• Chemotoxicity• Inhibition of good inflammation

– DMA induced• Resolving inflammation• Loss of inter/intracellular water• Changes in electrolyte balance

Mechanisms that may decrease brain volume in multiple sclerosis

Reversible Irreversible

Modified from Zivadinov et al. Neurology 2008

• MS results in tissue loss of Regional brain atrophy, both GM and WM, but at differentrates

(Chard 2002; Dalton 2004; Valsasina 2005)

• GM and WM atrophy relate differently to disability / cognitive impairment(Sanfilipo 2005;Tedeschi 2005; Amato 2007; Fisniku 2008)

Rudick RA, et al. J Neurol Sciences 2009

(n=29) (n=34)

Fisher, et al, Ann Neurol 2008

Regional brain atrophy- Rationale

2.23.1 3.43.5 3.2

8.1

5.24.4

12.4

5.8

3.3

14.0

-2

0

2

4

6

8

10

12

14

16

?BPF ?WMF ?GMF

HC (n=17)

CIS (n=7)

CIS->RRMS(n=8)

RRMS (n=28)

RRMS->SPMS(n=7)

SPMS (n=19)

Fold

Incr

ease

(rel

ativ

eto

cont

rols

)

6.3

14.2

3.82.8

MS Prog MS Stable

Fol

dIn

crea

seO

verH

Cs

+S

EGM Atrophy WM Atrophy

-0.46% (Dalton, 2004)

-0.58% (Paolillo, 2004)

-1.06% (Hardmeier, 2003)-1.84% (Saindane, 2000)

-0.61% (Rudick, 1999)

-1.88% (Inglese, 2004)

-0.88% (Kalkers, 2002)

-0.7% (Kalkers, 2002)

-1% 0%-2%

-0.5% (Kalkers, 2002)

-0.9% (Fox, 2000)

-0.8% (Fox, 2000)

-0.6% (Fox, 2000)

-1.33% (Sormani, 2004)

-1.23% (Tiberio, 2004)

CIS

RR MS

PP MS

SP MS

Whole brain(yearly atrophy estimates)

-0.4% (Filippi, 2000)

-0.28% (Stevenson, 2002)

-2.0% (Ge, 2000)

-1.5% (Ge, 2000)

-1.17% (Zivadinov, 2001)

Healthypopulation

Jaume Sastre-Garriga. Institute of Neurology, University College London, Queen Square

Variaciones anuales

Courtesy of Jaume Sastre-Garriga.

Brain volume loss in multiple sclerosis

Brain atrophyPros

Quantitative and continuous measure

Marker of irreversible tissue damage

Information of the entire brain

Regional measure (gray / white matter)

Correlated with the degree of disability and cognitive impairment

Sensitive to changes over time (disease progression under treatment)

Brain atrophyCons

Pathologic basis still unclearNon-specific brain response: drug use, aging, and different neurodegenerativediseasesSmall changes over timeConfounding effect:

Gliosis/ inflammation prevents atrophyFluctuations of tissue water (paradoxal therapeutic effect)

PrednisoloneImmunomodulatory drugs

NAA immunohistochemicalstaining

Sim

mon

set

al.,

1991

NAA

IMAGING IRREVERSIBLE TISSUE DAMAGE1H-MRS and MS

•Decrease in brain NAA/Cr ratio hasbeen shown to be indicative ofirreversible axonal dysfunction andreduced cerebral volume

•Reports have shown an annualdecline of 4% to 6% in NAA/Cr ratioin MS patients

De Stefano et al., Brain 1998

Grade III astro

Acute MS

T2 T1 gad Cholin map

Role of advanced MR techniques: controversialProton MR spectroscopy

Majós et al. Am J Neuroradiol 2009

Glioma

Pseudotumor

NAA/Cr ratio progressively increased, and relapse rate, disability,and T2W and T1W lesion load progressively decreased in treated

patients over 4 yrs

1,9

2

2,1

2,2

2,3

2,4

BL Y1 Y2 Y3 Y4

Mea

nN

AA

/Cr

VOINAWMHC

+9.6%P = .04

+12.7%P = .03

(n = 18) (n = 15)

VOI = Volume of InterestNAWM = Normal-Appearing White MatterHC = Healthy Control

Khan O et al. J Neuroimaging 2008

ProsMRS in MS

Quantitative and continuous measure related to neuroaxonal loss

/dysfunction

Assessment of normal appearing brain tissue

Information about tissue injury in a large segment of brain tissue

Sensitive to disease changes over time

Correlated with disability

ConsMRS in MS

Time consuming

Quantification relies on ratios (NAA/creatine)

Optimization and standarization across multiple sites andover time is challenging

Technical demands have limited its use in therapeutic trialsto single centers with conflicting results generally reportedfrom small patient cohorts

Guidelines for using proton MR spectroscopy in multicenter clinical MS studiesDe Stefano et al. Neurology 2007

Conclusions

MRI provides information of the inflammatory andneurodegenerative components of MS

MRI should be considered as a marker of neurodegenerationin clinical trials

Not enough evidence to support the use of MRI formonitoring the neurodegenerative component of the diseasein individual patients

Neuroimmunology Unit (Dr. Montalban) MRI Neuro Unit

T1 gad

Flair

MTR

baseline 2 w 2 mo 1 year

% MTR

15

17

19

21

23

25

27

29

31

15

17

19

21

23

25

27

29

31

33

baseline 2 w 2 mo 1 year

Magnetization Transfer RatioSequential analysis in acute MS plaque

Voxel-wise changes in magnetization transfer ratioA sensitive method for identifying focal demyelination and

remyelination in patients with multiple sclerosis

Dwyer et al. J Neurol Sci 2009

Misclassification of MS Lesions as GM

Effect:

Lesion volume GM volume

Trials:

Could under-estimate a treatment effecton GM atrophy

Research:

Could obscure correlations

SPM52% of lesion voxels misclassified as

GM(Chard, et al. Brain 2002)

GM / WM volume in RR MS

GM volume in RR MSMask

No mask

WM volume in RR MSMask

No mask

T2 lesion volume