Preceptorship on Advances in Multiple Sclerosis (MS) and ... · 7/5/2015  · 27 Motor Neuron...

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IMPROVING THE PATIENT’S LIFE THROUGH

MEDICAL EDUCATION

Preceptorship on Advances in Multiple Sclerosis (MS) and Neuro-Myelitis Optica (NMO)

6-8 July 2015 - Vancouver, Canada

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Advanced MRI

Shannon Kolind, PhD

Department of Medicine, Division of Neurology

University of British Columbia, Vancouver, BC, Canada

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Learning Objectives

1. Gain an overview of novel and advanced MRI techniques.

2. Understand the relative sensitivity and specificity of these MRI

techniques to various biological and pathological features.

3. Consider the use of MRI beyond anatomical assessment in

clinical trials for neurological disease therapies.

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Overview

Goal: To move beyond “conventional” MRI in clinical trials and even clinical

practice

• Example application: multiple sclerosis (MS)

• Example advanced MRI technique: myelin water

imaging

• Example clinical trial: Orchestra

• Introduction to other advanced MRI techniques in

Orchestra

• Summary of the sensitivity, specificity and

practicality of these advanced MRI techniques

d’Entremont and UBC team, ISMRM 2014

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Why move beyond conventional MRI in MS?

• Multiple Sclerosis involves

- Chronic inflammation

- Edema

- Gliosis

- Oligodendrocyte loss

- Axonal loss

- Demyelination

• Conventional images

- Lack specificity

- Lack sensitivity for non-lesional disease

- Are qualitative

• Clinical relevance

- Weak link between traditional imaging metrics & disability/progression

Same disability score

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Candidates for non-conventional MRI in neurological disease

• Myelin Water Imaging

• Magnetization transfer imaging

• Frequency shift imaging

(Susceptibility weighted imaging)

• Magnetic resonance spectroscopy

• Resting state functional MRI

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Myelin Water Imaging

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Myelin Water Imaging

Myelin water

Intra/Extra-cellular

(free) water

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Myelin Water Imaging

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Observed Spin Echo Signal

Intra / Extra Cellular

Water Signal

Myelin Water

Signal

Myelin water

Intra/ Extra-cellular (free)

water

Echo Time (ms)

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Myelin Water Imaging

Intra/extracellular (free) water

40-200ms

Myelin water

0-40ms Myelin Water

Fraction

=

+

Myelin Water

Fraction Map

MacKay, MRM 1994;31:673.

T2 (ms)

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Myelin Water Imaging

Laule, Neuroimage 2008;40:1575.

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Myelin Water Imaging

Meyers, MRI 2009;27:1096. Prasloski, Neuroimage 2012;63:533. Zhang, ISMRM 2015.

3D multi-echo T2

relaxation: 7 slices in

20 minutes

3D GRASE (combined

gradient and spin echo)

acquisition: 20 slices in

15 minutes

3D GRASE (optimized) acquisition: 20 slices

in under 8 minutes

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Myelin Water Imaging Applications

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Myelin Water Imaging in Primary Progressive MS

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Primary Progressive MS

• Primary Progressive MS (PPMS)

- More diffuse myelin and axonal damage

• Challenge:

- No approved therapies

- Current diagnostic markers based ineffective for clinical trials

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PPMS Myelin Reductions (Group Level)

Kolind, Neuroimage

2012;60:263.

R"R"

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Individual Patient Variations

Myelin Water Fraction

Control Average

Myelin Water Fraction

Control Standard Deviation

Kolind, Neuroimage

2012;60:263.

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Individual Patient Variations

4 02 -2 -4<-5.4(significant)

Kolind, Neuroimage

2012;60:263.

EDSS 1.5

4 2 0 -2 -4 Myelin Water Fraction

Z-score

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Individual Patient Variations

EDSS 1.5

EDSS 6.5

Kolind, Neuroimage

2012;60:263.

4 02 -2 -4<-5.4(significant)

Myelin Water Fraction

Z-score 4 2 0 -2 -4

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Localized Clinical Correlations with MWF in MS

Mental Functional System Score

Sensory Functional System Score

Kolind, Neuroimage 2012;60:263.

Correlation just below threshold (p < 0.07) Significant correlation (p < 0.05)

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Myelin Water Imaging in NMO and RRMS

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Neuromyelitis Optica

• Neuromyelitis optica (NMO)

- Was thought to be a subtype of MS

- Clinical similarities to relapsing remitting MS (RRMS)

- Focused on optic nerve and spinal cord

• Recent evidence revealed

- Antibody against a specific water channel

- Different mechanism of demyelination

• Challenges:

- Prognosis and treatment differ!

- Still controversial whether normal appearing tissue is affected in NMO

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Differentiating Between MS and NMO

Cervical Spinal Cord

Matthews, Kolind, in press.

Mye

lin W

ater

Fra

ctio

n

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Differentiating Between MS and NMO

Lesion mask Significantly reduced myelin water fraction (Z<-4)

Lesion mask Significantly reduced myelin water fraction (Z<-4)

M S patient: Age 33, EDSS 5, disease duration 50 months

NM O patient: Age 33, EDSS 4, disease duration 48 months

FLAIR

FLAIR

Matthews, Kolind, in press.

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Differentiating Between MS and NMO

Lesion mask Significantly reduced myelin water fraction (Z<-4)

Lesion mask Significantly reduced myelin water fraction (Z<-4)

M S patient: Age 33, EDSS 5, disease duration 50 months

NM O patient: Age 33, EDSS 4, disease duration 48 months

FLAIR

FLAIR

Matthews, Kolind, in press.

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Myelin Water Imaging in Motor Neuron Disease

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Motor Neuron Disease

• Characterised by progressive weakness with variable muscle wasting.

• Amyotrophic Lateral Sclerosis (ALS)

- Involves upper & lower motor neurons of brainstem and spinal anterior horns

- Median survival 2-3 years from symptom onset, but heterogeneous

• Primary Lateral Sclerosis (PLS)

- Involves only upper motor neurons

- Prolonged disease course (10-20 years)

- Takes 4 years for confident diagnosis

• Demyelination

- Is present

- Presumed secondary to axonal damage

- Not well studied

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Comparing Types of Motor Neuron Disease

0.05<p<0.10

Myelin water fraction reductions: PLS < Controls

p<0.05

Kolind, ALS & FTD 2013; 14:562.

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What’s Next?

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So far…

• We’ve shown that Myelin Water Imaging

- Detects differences in people with neurological disease

- Detects differences between neurological diseases

- Is sensitive to clinical measures

• What about…

- Changes over time?

- Effects of treatment?

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UBC Orchestra Advanced MRI Substudy

• “Advanced MRI measures of repair in Ocrelizumab treated patients”

• AIM

- To demonstrate…

- Repair (remyelination)

- Neuroprotection (normal appearing brain tissue myelin and axon stability)

• HYPOTHESES

- Ocrelizumab is superior to interferon (RRMS) and placebo (PPMS) on all

advanced MRI outcomes

• ADDITIONAL AIMS

- Assess relationship between advanced MRI outcomes and clinical scores

- Understand interplay between various advanced MRI techniques

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Advanced MRI in Orchestra Substudy

• Myelin Water Imaging

• Magnetization transfer imaging

• Frequency shift imaging

(Susceptibility weighted imaging)

• Magnetic resonance spectroscopy

• Resting state functional MRI

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Magnetization Transfer Imaging

=

-

• Based on magnetization

interaction between:

- Bulk water protons

- Macromolecular protons

• Magnetization transfer ratio

(MTR) affected by…

- Demyelination

- Remyelination

- Axonal damage

- Macrophage infiltration

- Activated microglia

- Inflammation / Edema

• Measure of “badness”

MTR

M0 Msat

M0

%

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Magnetic Resonance Spectroscopy

• Measures the concentrations

of brain metabolites

• N-acetylaspartate (NAA)

- Neurons and

oligodendrocytes

• Choline (Cho)

- Cell membranes

• Creatine (Cr)

- Energy storage

• Glutamate (Glu)

- Neurotransmitter

• Myo-Inositol (mI)

- Glial cells

NAA

Lactate

Glu Gln NAA

Cr

Cho

mI

Cr

mI

Glu

Gln

Dr Erin MacMillan

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Frequency Shift Imaging

• MRI data has magnitude and

phase

• Frequency shift calculated

from phase data

• Frequency shifts influenced by

- Iron

- Tissue microstructure

- Myelin

• Acquisition:

- Fast, high resolution

gradient echo scan

FLAIR

T1W Post-gad

Frequency Shift

Vanessa Wiggermann, Dr Alex Rauscher

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Resting State Functional MRI

• rs-fMRI

- Sensitive to plastic and degenerative changes in functional architecture

- Measures the pathological effects of MS beyond focal damage.

Suejin Lin, Dr Martin McKeown

MS Group Control Group

Connectivity

Map

Lin, ECTRIMS 2014:P538. Lin, AAN 2015.

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Advanced MRI in Substudy – Take Home

• Myelin Water Imaging

- Very specific

• Magnetization transfer imaging

- Sensitive but less specific

• Frequency shift imaging

- Sensitive but less specific, very

high resolution, practical

• Magnetic resonance

spectroscopy

- Metabolite specific, but limited

resolution/coverage

• Resting state functional MRI

- May provide complementary

functional information

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Concluding Remarks

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Working Toward Unconventional MRI in Clinical Trials and Clinical Practice

• Current projects include:

- Clinical trials in MS and NMO

- Applications to stroke, PD, and brain and spinal cord injury

- Combining structural imaging with functional imaging and cognition

- Developing more new sensitive and specific biomarkers with MRI

• Still be done:

- Understand all imaging parameters and their use in research & practice

- Show the predictive power of these techniques for disease progression

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Acknowledgments

University of British Columbia

Tony Traboulsee

Alex MacKay

David Li

Irene Vavasour

Erin MacMillan

Roger Tam

Yinshan Zhao

Alex Rauscher

Linda Chandler

Aaron Khung

Laura Harvey

Andrew Riddehough

Trudy Harris

Laura Barlow

Corree Laule

Martin McKeown

Rob Carruthers

Wayne Moore

Katrina McMullen

Emil Ljungberg

Anna Combes

Praveena Manogaran

Youngjin Yoo

Saurabh Garg

Alice Lee

Julia Schubert

Suejin Lin

Sandra Meyers

Emma Eberts

Lisa Tang

Vanessa Wiggermann

Jing Zhang

Rita Gorodezky

Anna Bley

Elisabeth Baumann

Clara Tabea Strunk

Shuhan Xiao

Anika Wurl

Funding

Milan &

Maureen Ilich

Foundation,

Roche,

Genzyme,

Chugai,

iCord,

Michael Smith

Foundation for

Health

Research,

MS Society of

Canada

Volunteers and their families

Our MR technologists

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Summary of Candidates for Non-Conventional MRI in Neurological Disease

TECHNIQUE SENSITIVE TO PRACTICALITY FOR CLINICAL

TRIALS Multi-Spin Echo Myelin Water

Imaging (MWF) myelin (intact and debris)

not yet available as product sequence

mcDESPOT (fM) myelin, water content acquisition more commonly

available but complicated analysis

Magnetization Transfer Imaging (MTR)

water content, axons, myelin, other macromolecules

commonly available but not standardized, varies between

vendors

Frequency Shift Imaging (fs) iron, tissue microstructure,

myelin, water content commonly available

Magnetic Resonance Spectroscopy (Cho, free lipids)

metabolites commonly available but limited resolution/volumetric coverage

Resting State Functional MRI (connectivity)

connectivity, motion commonly available acquisition but not standardized, analysis

highly variable

Dr Corree Laule, Dr David Li, Dr Alex MacKay, Dr Irene Vavasour, Dr Tony Traboulsee, Dr Alex Rauscher, Dr Shannon Kolind.