Imaging Disease Progression in MS Paul M. Matthews, MD, D Phil, FRCP, FMedSci

Edmond and Lily Safra Chair, Division of Brain Sciences, Imperial College London

p.matthews@imperial.ac.uk

Disclosures

Consultancies with IXICO, GlaxoSmithKline, Biogen

Speakers fees from Adelphi Communications, Novartis, Biogen

Support for CPD meetings from Novartis, Biogen

Research support from GlaxoSmithKline, Biogen

Stock in GlaxoSmithKline

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Inflammatory cells (blue) Myelin (green) Axons (in red)

Courtesy of Dr. D. Arnold, McGill Univ, adapted from animation courtesy of Bruce D. Trapp, 2002, © Cleveland Clinic Foundation

Gd-enhanced, T1 weighted MRI

Disease progression in MS: the acute plaque

Acute demyelination initiates local remyelination

4

RJ Franklin, C ffrench-Constant Nature Rev Neurosci 9 (2008)

839

Myelin structure is distinct in healthy myelinatedand demyelinated segments

Acute demyelination initiates local remyelination

5

RJ Franklin, C ffrench-Constant Nature Rev Neurosci 9 (2008)

839

Brains from 3 patients with demyelination (red) and remyelination (blue)

Myelin structure is distinct in healthy myelinatedand demyelinated segments

Astrocytic “scar””(orange)

lesions on T1-weighted images

Disease progression in MS: the chronic plaque

Courtesy of Dr. D. Arnold, McGill Univ, adapted from animation courtesy of Bruce D. Trapp, 2002, © Cleveland Clinic Foundation

T1-weighted MRI

Neuronal and axonal loss is the major pathological mechanism for disability

From Trapp et al. N Engl J Med 338 (1998) 278

BD Trapp et al. N Engl J Med 338 (1998) 278-85

Evangelou N, et al. Ann Neurol 2000;47:391–395

Control post-mortem corpus

callosum section (silver stain)

MS post-mortem corpus

callosum section (silver

stain)

Pathological sodium channel expression along demyelinated axons

8 M. Craner et al. Proc Natl Acad Sci 101 (2004) 8168-73

Sections of post-mortem spinal cord of white matter from healthy subjects (A,B)

and patients with MS (C-L) immunostainedto show:

• Nav1.6 (red)• Nav 1.2 (red)• Caspr (paranodal junctions) (green)• Neurofilaments (blue)

Chronic macrophage or microglia mediated damage

Axonal injury correlates with active demyelination and inflammation

Antibody destruction via Fc / complement receptors

Release of inflammatory mediators cytokines

- TNF-a

- Nitric Oxide

- Proteases

Kuhlmann T et al. Brain 2002;125:2202-2212

Technique Marker Influenced byUsability(Practicality for Clinical Trials)

Myelin Water Imaging

Myelin Water Fraction (MWF)

Myelin (intact, debris) Not yet available as product sequence

Magnetisation Transfer Imaging

Magnetisation Transfer Ratio (MTR)

Changes in myelin protein associated water

Axons Myelin Other macromolecules

Commonly available but not standardized

Varies between vendors

Imaging Markers for Myelin

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Content courtesy of S Kolind, C Laule, A MacKay, A Traboulsee, I Vavasour (University of British Columbia).

Myelin Water Imaging

Magnetisation Transfer Imaging

Myelin Water has a shorter T2 “relaxation time” than free water

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Intra/extracellular water

40–200 ms

Myelin water15–40 ms

Myelin water images of thewhole cerebrum, derived from

T2 relaxation, can be acquired in less than 15 minutes

A(T

2)

MWF+

=

Whittall KP et al. Magn Reson Med. 1997;37:34-43;Adapted from Prasloski T et al. Neuroimage. 2012;63:533-539;Content courtesy of S Kolind, C Laule, A MacKay, A Traboulsee, I Vavasour (University of British Columbia).

Myelin Water

Patient 2

Patient 1

Conventional MRI

Demyelination-remyelination

Myelin water: imaging of MS lesions andremyelination

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Little/No Myelin

Reduced Myelin

Content courtesy of S Kolind, C Laule, A MacKay, A Traboulsee, I Vavasour (University of British Columbia).

MT Image

MT Pulse

MT

Principles of magnetisation transfer ratio (MTR) imaging

Magnetisation Transfer (MT) Image

Selectively excite bound water

Magnetisation is transferred to free water

Pre-excited molecules provide less signal on T1W images

O

OH

OH

NH

OO

HH

H

H

HOH

OH

CH2OH

Signal

RF Pulse

T1W=T1 weighted; RF=radio frequency.Content courtesy of Prof. Doug Arnold (McGill University).

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Magnetisation transfer ratio (MTR) image generation

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Content courtesy of Prof. Doug Arnold (McGill University).

MTR: imaging remyelination with MS

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MTR=magnetisation transfer ratio. Content courtesy of Prof. Doug Arnold (McGill University).

Microstructure of the grey and white matter

• GM components:1,2

– Neuronal cell bodies– Dendritic arborisation– Some myelin fibres

• WM components:3-5

– Axons (~45%)– Myelin (~25%)– Glial cells (~17%)– Blood vessels and tissue fluids

(~13%)

GM, grey matter; WM, white matter1. Glees P. The Human Brain. Cambridge University Press; 1998; 2. Available from: http://what-when-how.com/child-development/brain-and-behavioral-development-ii-cortical-child-development/ (accessed 24 September 2014); 3. Allen NJ, Barres BA. Nature 2009;457:675–677; 4. Javier Urriola Y, Wenger C. Revista Chilena de Radiología. 2013;19(4): 166–173; 5. Miller DH et al. Brain 2002;123:1676–1695.

Whole brain atrophy in MS

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SPMSEDSS: 6.5

MS Duration: 18 years

BPF 0.70

RRMSEDSS: 1.5

MS Duration: 5 years

BPF 0.84

RRMSEDSS: 4.0

MS Duration: 10 years

BPF 0.80

Healthy Control

BPF 0.89

MS=multiple sclerosis; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS; BPF=brain parenchymal fraction.Bermel RA, Bakshi R. Lancet Neurol. 2006; 5: 158–70.

The absolute rate of brain atrophy is similar through the disease course

De Stefano et al. Neurology 2010;74:1868-1876

Atrophy arises from multiple pathophysiological mechanisms

1. Simon JH. Mult Scler 2006;12:679–687; 2. Draganski B. Curr Opin Neurol 2013;26:640–645; 3. Schroth G. Neuroradiol 1988;30:385–389; 4. Akiyama H. J Neurol Sci 1997;152:39–49; 5. Chetelet G. Rev Neurol 2013;169:729–736; 6. Schaechter JD. et al Brain 2006;129:1272–2733

Factors causing brain-volume reduction:• Tissue loss (such as myelin,

axons and possibly also astrocytes)1

• Fluid shift1

• Ageing2

• Alcohol3

• Smoking4

• ApoE?5

Factors causing brain-volume increase:• Neuronal repair6

• Remyelination1

• Astrogliosis1

• Fluid shift1

Optical coherence tomography (OCT): retinal structure reflects axonal injury in MS

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1. Frohmann E et al. Nat Clin Pract Neurol. 2008;4:664-675; 2. Frohmann E et al. Lancet Neurol. 2006;5:853-863; 3. Fisher JB et al. Ophthalmology. 2006;113:324-332.

Reflected Light

Transmitted Light

OCT allows rapid, noninvasive quantification of retinal layers by low-coherencenear-infrared light1–3

Characterizes neuronal injury in the retina1–3

OCT: Retinal Nerve Fiber Layer (RNFL) Thinning with Progressive MS

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RNFL Comparisons Between Controls and MS Subgroups by History of Optic Neuritis (ON)

0

20

40

60

80

100

120

Mic

ron

s

* †§

Controls MS Eyes NotAffected by ON

Unaffected Eyesof MS ON Patients

MS Eyes Affected by ON

RNFL Comparisons in MS Subtypes

0

20

40

60

80

100

120

Mic

ron

s

‡†

§

Controls RRMS PPMS SPMS

*P<0.05; †P<0.01; ‡P<0.001; §P<0.0001.OCT=optical coherence tomography.Pulicken M et al. Neurology. 2007;69:2085-2092.

Sodium MRIA measure of both intracellular sodium accumulation and cell loss

22 D. Paling et al. Brain 136 (2013) 2305-17

Imaging of activated microglia with PET using 18 kDmitochondrial translocator protein (TSPO) radioligands

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T2 FLAIR [18F]PBR111 TSPO SignalOverlaid on FLAIR Image

RRMS

Modified from Fig. 5 in Colasanti A et al. J Nucl Med. 2014;55:1112-1118.

[18F]PBR111 microglial imaging for treatment monitoring?

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Visit 1Before natalizumab (failing IFNβ)

Visit 2After 6 months of natalizumab treatment

Age=39 years; disease duration=20 years; EDSS=4.0

IFNβ=interferon beta. Content courtesy of Prof. Paul Matthews (Imperial College London).

Summary: advanced imaging measures in MS provide new tools for assessing disease and treatment response

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Positron Emission Tomography (PET) Imaging

Microglial activation

GM Atrophy

Cortical mapping

Spinal Cord Atrophy

Correlation with disability

Retinal Optical Coherence Tomography (OCT)

Rapid, direct measure of retinal pathology

Myelin Water Imaging

Pathological myelinmicrostructure

Magnetisation Transfer Ratio (MTR)

Completeness of recovery

Sodium imaging

Pathological sodium accumulation and cell loss

Why do we care about imaging measures of disease progression?

26 PM Matthews et al. Nature Rev Neurol 10(2014)15

Greater increase of lesion volume in SPMSover the first 5 years

CIS, clinically isolated syndrome; RRMS, relapse-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosisFisniku LK, et al. Brain 2008;131;808–817

Med

ian

T2

lesi

on v

olum

e

CIS

RRMS

SPMS

Brain atrophy in MS: correlation with disability

R=−0.23p=0.030

Annu

alis

ed c

hang

e in

ED

SS

1

−1

PBVC / year

0

2

−3 −2 −1 0 1

1

0

−1

−3

PB

VC

/ ye

ar

−2

No progression

Progression

Rate of atrophy and annualised change in EDSS vs. PBVC/year1

Rig

ht s

uper

ior

fron

tal G

MF

0.55

0.25

SDMT raw scores

0.45

0.65

20 30 40 50 70

0.35

60

7.5

0.0

SDMT raw scores

5.0

10.0

20 30 40 50 70

2.5

60

Thi

rd v

entr

cle

wid

th

SDMT performance in superior right frontal GM fraction

and third ventricle width2

EDSS, Expanded Disability Status Scale; GMF, grey-matter fraction; PBVC, percentage brain volume change; MS, multiple sclerosis; SDMT, Symbol DigitModalities Test; WMF, white-matter fraction1. Minneboo A, et al. J Neurol Neurosurg Psychiatry 2008;79:917–923; 2. Tekok-Kilic A, et al. Neuroimage 2007;36:1294–1300.

Meta-analysis of randomised clinical trials in RRMSLesions, brain atrophy and clinical disability as predictors of subsequent disability progression over 2 years

Sormani MP, et al. Ann Neurol 2014;75:43–49.

R2 = 0.61, p<0.001

R2 = 0.48, p<0.001

R2 = 0.75, p<0.001

T2 lesions aloneBrain atrophy alone Combined lesions

and atrophy

Includes data from >13,500 patients

Defining brain volume cut-offs to predict disability progression in MS: analysis of a large cohort of RRMS patients

Baseline NBV (assessed by SIENAX) was comparable across different trials

Patients with a small NBV (adjusted for age and MS disease characteristics) were at higher risk of subsequent disability progression over 2 or 4 years

Sormani MP, et al. Presented at ECTRIMS-ACTRIMS 2014 (Abstract PS12.3)MS, multiple sclerosis; NBV, normalised brain volume; RRMS, relapsing remitting multiple sclerosis

32 M. Battaglini et al. J Magn Reson 39 (2014) 1543

Standardising automated T2 lesion change measures

PD MRI at baseline

PD MRI at 6 mos

Automated extraction of

new PD lesions

High correlation (r=0.77, p<0.001) between automated PD difference imaging over 76 weeks and cumulative Gd-

enhancing lesion count with serial MRI

http://applications.eu-decide.eu/gridmriseg

Standardising automated brain volume measures

http://applications.eu-decide.eu/gridmriseg