imaging disease progression in ms - c.ymcdn.comc.ymcdn.com/sites/ · imaging disease progression in...
TRANSCRIPT
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
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
2
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
10
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
11
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
12
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).
13
Magnetisation transfer ratio (MTR) image generation
14
Content courtesy of Prof. Doug Arnold (McGill University).
MTR: imaging remyelination with MS
15
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
17
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
20
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
21
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
23
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?
24
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
25
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