Normal-appearing White and Grey Matter Damage in Multiple Sclerosis

158 Pages·2004·4.48 MB·English

by  W. Brück

Topics in Neuroscience
Managing Editor:
GIANCARLO COMI
Co-Editor:
JACOPO MELDOLESI
Associate Editors:
MASSIMO FILIPPI
LETIZIA LEOCANI
GIANVITO MARTINO
M. Filippi. G. Comi • M. Rovaris (Eds)
Normal-appearing White and
Grey Matter Damage in
Multiple Sclerosis
~ Springer
MASSIMO FILIPPI GIANCARLO COMI
Neuroimaging Research Unit Department of Neurology
Department of Neuroscience Scientific Institute and University
Scientific Institute and University Ospedale San Raffaele, Milan, Italy
Ospedale San Raffaele, Milan, Italy
MARCO ROVARIS
Neuroimaging Research Unit
Department of Neuroscience
Scientific Institute and University
Ospedale San Raffaele, Milan, Italy
The Editors and Authors wish to thank SCHERING S.p.A. for the support and
help in the realization and promotion of this volume
Library of Congress Cataloging-in-Publication Data: Applied for
ISBN 978-88-470-2175-4 ISBN 978-88-470-2127-3 (eBook)
DOI 10.1007/978-88-470-2127-3
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Introduction
M. FILIPPI, M. ROVARIS, G. COMI
The pathological process of multiple sclerosis (MS) leads to the formation of
macroscopic discrete foci of tissue damage in the central nervous system (eNS).
These lesions can be seen on conventional magnetic resonance imaging (MRI)
scans, making conventional MRI an extremely sensitive tool with which to diag
nose MS and monitor its evolution. Nevertheless, there are discrepancies between
the clinical and the neuroradiological aspects of MS: MRI-visible damage is not
sufficient to explain the entire spectrum of manifestation of the disease.
There is a growing body of evidence that MS pathology does not spare the
normal-appearing white (NAWM) and grey (NAGM) matter, since a wide range
of abnormalities are detectable outside MS lesions using either histopathological
or MRI techniques. Such changes may be either secondary to intrinsic damage of
lesions visible on T z-weighted MRI, via wallerian degeneration of fibres passing
through macroscopic abnormalities, or they may be the result of an independent
pathological process affecting the normal-appearing tissues. In the NAWM, the
main pathological findings are gliosis, microglial activation, disturbances of the
blood-brain barrier and loss ofaxons. In the NAGM, less inflammatory changes
are seen, but numerous lesions can be identified ex vivo which are not detectable
on T 2-weighted MRI. In the last few years, the hypothesis that the accumulation
ofNAWM and NAGM damage may contribute to the progression of MS-related
neurological disability has led to the challenge of quantifying in vivo the extent of
such damage and to define the patterns of its changes over time. In this context,
several MR-based techniques have been interrogated as tools able to provide reli
able information about the heterogeneous aspects ofNAWM and NAGM pathol
ogyofMS.
MR-based measurements of white and grey matter volumes represent a pre
liminary but useful tool to assess the final outcome of NAWM and NAGM dam
age, i.e. the occurrence and progression of tissue atrophy. The poor correlation
between atrophy and T z-visible lesion load, consistently reported by several stud
ies of MS, supports the notion that white and grey matter volume reductions
may primarily reflect MRI -occult pathology.
Among the more sophisticated and modern MR-based methodologies, mag
netization transfer (MT) MRI is now widely applied in the study of MS, and the
results of preliminary studies with this technique have provided the earliest in
vivo evidence of NAWM and NAGM damage in MS. All these studies analysed
VI M. Filippi, M. Rovaris, G. Comi
the MT ratio (MTR) as a measure of the magnetization exchange between free
and bound protons, whose decrease reflects a loss of the latter compartment.
Correlative studies have confirmed that a significant relationship exists between
decreased MTR and increased loss of myelin and axons, both within MS lesions
and in the NAWM, and that NAWM MTR changes may precede the formation of
new, MRI-visible lesions. Moreover, reduced NAWM MTR has been found to
increase with increasing disease duration and disability. More recent data indi
cate that a similar MTR decrease can also be found in the NAGM from the earli
est and non-disabling phases of MS.
The measurement of T 1 and T 2 relaxation characteristics may also enable us to
detect subtle changes of tissue microstructure. The recent availability of 3-T
magnets has made it possible to obtain whole-brain quantitative Tl maps in a
few minutes, whereas it remains challenging to obtain T 2 decay curves from large
portions of the brain. Both histogram analysis of T c relaxation times and evalu
ation of T 2 decay curves in the NAWM of MS patients indicate that myelin loss is
the dominant pathological process in this tissue compartment. Preliminary stud
ies have also interrogated T1-relaxation time changes following gadolinium injec
tion as a measure of subtle blood-brain barrier permeability breakdown in the
NAWM, with the aim of achieving a more complete assessment of the MS-relat
ed inflammatory processes. Interestingly, other preliminary data seem to indicate
a decrease of Tcrelaxation times in the NAGM, which may reflect pathological
processes other than loss of myelin and axons, such as the deposition of iron
accompanying neurodegeneration.
Diffusion-weighted imaging (DWI) is sensitive to the microscopic random
motion of water molecules, which is the result of the interactions with structur
al barriers that can restrict it. Using DWI, the brain tissue microstructure can be
interrogated, by means of quantitative indices such as the mean diffusivity (MD),
which is a measure of the average molecular motion and is affected by cellular
size and integrity, and fractional anisotropy (FA), which reflects the degree of
alignment of cellular structures within fibre tracts, as well as their structural
integrity. In MS patients, several studies have found significantly increased MD
values and reduced FA values in the NAWM and NAGM. Since "inflammatory"
changes and gliosis can potentially restrict water molecular motion, myelin and
axonal damage appear to be the most likely contributors to the loss of barriers
limiting water motion (increased MD) and to tissue structural organization
(decreased FA). The recent development of DWI tractography offers a promising
tool for exploring the involvement of clinically eloquent pathways in the NAWM
of MS patients, as well as its relationship with concomitant grey matter damage
and cortical functional changes.
Magnetic resonance spectroscopy (MRS) has the unique advantage of provid
ing information with a high biochemical specificity for ongoing tissue changes.
Single-voxel MRS and spectroscopic imaging data suggest that both inflamma
tion and loss ofaxons contribute to NAWM pathology in MS, whereas the latter
is largely predominant in the pathogenesis of NAGM damage. Longitudinal MRS
Introduction VII
studies have also provided evidence that NAWM pathology can be at least par
tially reversible when related to sub-lethal axonal damage of fibres crossing new
ly formed MS lesions.
The information provided by structural MR-based techniques about NAWM
and NAGM damage in MS can be integrated with the data coming from func
tional MRI (fMRI) studies. This technique allows the ability of the MS brain to
limit the consequences of irreversible tissue damage to be explored. fMRI data
indicate that cortical reorganization in MS patients begins soon after the clinical
onset of the disease and continues through the entire course of the disease. The
extent of cortical reorganization has been found to correlate with the severity of
NAWM and NAGM damage, as quantified by MTI, DWI, and MRS. All of this
suggests that the rate of disability progression in MS might not only be a func
tion of irreversible tissue damage, but also of the failure of cortical adaptive
capacities.
Although new imaging modalities are needed that provide more specific in
vivo measures of the various components of NAWM and NAGM pathology in
MS, the contributions given by currently available structural and functional MR
based techniques are likely to be already valuable for monitoring the natural his
tory of MS and its modification by treatment. In this book, we aim to provide an
extensive summary of the state of the art and set the scenario for future research
in the field of NAWM and NAGM damage in MS. We hope that the book will be
of help to clinical neurologists and researchers, not\ only by allowing them to go
deeper into this complex issue, but also by stimul~ting new ideas and further
investigations.
Table of Contents
Normal-Appearing White Matter
Chapter 1 - Pathology of the Normal-Appearing White Matter
in Multiple Sclerosis
W. BROCK, C. STADELMANN ...........•••..•.••••••••••••••••••••.. 3
Chapter 2 - Measurement of Blood-Brain Barrier Permeability
in Multiple Sclerosis
D. SOON, D. MILLER. . • • • • • • • • • . • . . • . • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 9
Chapter 3 - Measuring and Interpreting White Matter Volume Changes
in Multiple Sclerosis
C. WEGNER, S. SMITH, P.M. MATTHEWS •••••••••••••••..••••••••.••••• 23
Chapter 4 - Normal-Appearing White Matter Changes in Multiple Sclerosis:
Magnetization Transfer
F. FAZEKAS, C. ENZINGER, S. ROPELE • • • • • • • • • • • • • . . • . . . . . . . . . . . . . . . . . . 37
Chapter 5 - The Short T2 Component in Normal-Appearing White Matter
in Multiple Sclerosis
A. MACKAY, C. LAULE, I. VAVASOUR, B. MADLER,A. TRABOULSEE, D. PATY,
W. MOORE, D. LI ••••••.••••••••••.••••••.•••.•••••••..•••••••... 47
Chapter 6 - Rapid, Whole-Brain T1 Relaxation Time Measurements for the
Quantitative Definition of Pathological Changes in Multiple Sclerosis
A.M. PARRY, S. CLARE, P.M. MATTHEWS. • • • • • . . . . . . . . . . . . . . . • . . • . • . . • • 63
Chapter 7 - Diffusion-Weighted Imaging of the Normal-Appearing
White Matter in Multiple Sclerosis
M. ROVARIS, M. FILIPPI .....•..................................... 79
Chapter 8 - The Relevance of Normal-Appearing White Matter Pathology
in Multiple Sclerosis
M. MAcINNES, D. ARNOLD • • • • • • • • • • • • • • • • • • • • • . . . . . . . . . . . . . . . . . . . . 91
Norma/-Appearing Grey Matter
Chapter 9 - Grey Matter Pathology in Multiple Sclerosis
B.P. BRINK, S.J. MORK, P. VAN DER VALK, 1. BO . . . . . . . . . . . . . . . . . . . • • . . . .. 101
Chapter 10-Imaging Cerebral Grey Matter Volume in Multiple Sclerosis
N.DESTEFANO .••...•••••••••.•••.•.•..•••••...............••.• III
Chapter 11 - The Grey Matter Component of MS Pathology: Magnetization
Transfer and Diffusion-Weighted Imaging
M.A. ROCCA, M. FILIPPI •••••••••••••••.•••••••••••••••••.•••••••• 121
Chapter 12 - MR Spectroscopy of the Normal-Appearing Grey Matter
C. GONEN, M. INGLESE, R.I. GROSSMAN ..............................• 129
Chapter 13 - Functional MRI in Multiple Sclerosis
M. FILIPPI, M.A. ROCCA. . . . . . . . . . . . . . . • . • • . . . • • • • . • • • . . • • . . • • • • • •• 145
Subject Index .................................................. 157
List of Contributors
Arnold D.L. Enzinger C.
Magnetic Resonance Spectroscopy Unit, Department of Neurology, Medical
Montreal Neurological Institute, McGill University Graz, Austria
University, Montreal, Quebec, Canada
Fazekas F.
Bo L.
Departments of Neurology and
Department of Pathology, MS Center, VU
Neuroradiology, Medical University Graz,
University Medical Center, Amsterdam,
Austria
The Netherlands. National Competence
Center for MS, Department of Neurology,
Filippi M.
Haukeland University Hospital,
Neuroimaging Research Unit,
Bergen, Norway
Department of Neurology, Scientific
Brink B.P. Institute and University
Department of Pathology, MS Center, VU Ospedale San Raffaele, Milan, Italy
University Medical Center, Amsterdam,
The Netherlands Gonen O.
Department of Radiology, New York
Bruck W University School of Medicine,
Department of Neuropathology, New York, USA
Georg-August University,
Gottingen, Germany Grossman R.I.
Department of Radiology, New York
Clare S.
University School of Medicine,
Centre for Functional Magnetic
New York, USA
Resonance Imaging of the Brain,
Department of Clinical Neurology,
Inglese M.
University of Oxford, UK
Department of Radiology, New York
University School of Medicine,
Comi G.
New York, USA
Multiple Sclerosis Centre, Department of
Neurology, Scientific Institute and University,
Laule C.
Ospedale San Raffaele, Milan, Italy
Department of Physics and Astronomy,
De Stefano N. University of British Columbia, Vancouver,
Department of Neurological British Columbia, Canada
and Behavioral Sciences
Siena, Italy
XII List of Contributors
LiD. Paty D.
Department of Radiology, University of Department of Neurology, University of
British Columbia, Vancouver, British Columbia, Vancouver,
British Columbia, Canada British Columbia, Canada
MacInnesM. RoccaM.A
Magnetic Resonance Spectroscopy Unit, Neuroimaging Research Unit,
Montreal Neurological Institute, Department of Neurology, Scientific
McGill University, Montreal, Institute and University
Quebec, Canada Ospedale San Raffaele, Milan, Italy
Madler B. Ropele S.
Philips Medical Systems, Vancouver, Departments of Neurology and
British Columbia, Canada Neuroradiology, Medical University Graz,
Austria
MacKay A
Departments of Physics and Astronomy RovarisM.
and Radiology, Neuroimaging Research Unit,
University of British Columbia, Vancouver, Department of Neurology, Scientific
British Columbia, Canada Institute and University
Ospedale San Raffaele, Milan, Italy
Matthews P.M.
Centre for Functional Magnetic Smith S.
Resonance Imaging of the Brain, Centre for Functional Magnetic
Department of Clinical Neurology, Resonance Imaging of the Brain,
University of Oxford, UK Department of Clinical Neurology,
University of Oxford, UK
Miller D.H.
NMR Unit, Institute of Neurology, Soon D.
Queen Square, London, UK NMR Unit, Institute of Neurology,
Queen Square, London, UK
Moore W.
Department of Pathology, University of Stadelmann C.
British Columbia, Vancouver, Department of Neuropathology,
British Columbia, Canada Georg-August University,
G6ttingen, Germany
Mark S,f.
Department of Pathology, Haukeland Traboulsee A
University Hospital, Bergen, Norway Department of Neurology, University of
British Columbia, Vancouver,
Parry AM. British Columbia, Canada
Centre for Functional Magnetic
Resonance Imaging of the Brain, van der Valk P.
Department of Clinical Neurology, Department of Pathology, MS Center, VU
University of Oxford, UK University Medical Center,
Amsterdam, The Netherlands