Table Of ContentTopics in Neuroscience
Managing Editor:
GIANCARLO COMI
Co-Editor:
JACOPO MELDOLESI
Associate Editors:
MASSIMO FILIPPI
LETIZIA LEOCANI
GIANVITO MARTINO
Early treatment in multiple sclerosis with intravenous immunoglobulin III
M. Filippi (cid:2) M. Rovaris (cid:2) G. Comi (Eds)
Neurodegeneration
in Multiple Sclerosis
IV A.Achiron et al.
MASSIMOFILIPPI GIANCARLOCOMI
Neuroimaging Research Unit Department of Neurology
Department of Neurology Scientific Institute and
Scientific Institute and University Ospedale San Raffaele
University Ospedale San Raffaele Milan,Italy
Milan,Italy
MARCOROVARIS
Neuroimaging Research Unit
Department of Neurology
Scientific Institute and
University Ospedale San Raffaele
Milan,Italy
The Editors and Authors wish to thank Bayer Healthcare–Bayer Schering Pharma
for the support and help in the realization and promotion ofthis volume
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Early treatment in multiple sclerosis with intravenous immunoglobulin V
Introduction
Multiple sclerosis (MS) leads to the formation ofmacroscopic,discrete foci oftis-
sue damage in the central nervous system (CNS).These lesions can be seen on con-
ventional magnetic resonance imaging (MRI) scans,making this technique a sen-
sitive tool for diagnosing MS and for monitoring its evolution,although it is inca-
pable of disentangling the heterogeneous features of MS lesion pathology,which
may range from edema to permanent loss ofmyelin and axons.Moreover,it is now
well known that MS does not spare the normal-appearing white (NAWM) and gray
(NAGM) matter,i.e.,those portions of the CNS which appear intact on conven-
tional MRI scans.Normal-appearing tissue changes seem to be either secondary to
intrinsic damage caused by T2-visible lesions (via Wallerian degeneration offibers
passing through macroscopic abnormalities) or the result of independent patho-
logical processes. In the NAWM, the main pathological findings are gliosis,
microglial activation,disturbances ofthe blood-brain barrier,and also demyelina-
tion and loss of axons. In the NAGM, less inflammatory changes are seen, but
numerous lesions can be identified ex vivo, which may be associated with irre-
versible axonal and neuronal loss.All these findings indicate that MS does not have
to be considered a purely inflammatory condition, but rather a disease where
inflammation and neurodegeneration play complementary pathogenetic roles.
The past 10years have seen continuous advances in MS treatment.Following
the approval of interferon (cid:2)-1b as a disease-modifying therapy for relapsing-
remitting MS, other immunomodulating and immunosuppressive treatments
have demonstrated significant success in reducing the activity of the disease,in
terms ofclinical relapses and MRI lesions.Nevertheless,this treatment efficacy is
not accompanied by an equal ability to prevent or slow down the progressive
clinical deterioration which occurs in MS,even independently of acute relapses.
It is conceivable that the accumulation of MS-related neurological disability is
secondary to the neurodegenerative components ofMS pathology and,as a con-
sequence,ad hoc therapeutic strategies are warranted.For this reason,future MS
trials will need reliable in vivo surrogates ofneurodegeneration in order to better
assess the efficacy oftreatments aimed at preventing its evolution.In this context,
several MR-based techniques have been investigated as tools capable ofproviding
reliable pieces ofinformation on neurodegeneration in MS.
MR-based measurements of CNS “atrophy”represent a useful tool to assess the
final outcome of neurodegeneration.The poor short- to medium-term correlation
between atrophy and T2-visible lesion load,which has been consistently reported by
several studies, supports the notion that tissue volume reductions may primarily
VI Introduction
reflect “occult”neurodegeneration and give complementary information to that pro-
vided by conventional MRI. The assessment of the burden of T1 “black holes”is
another,easily implementable,technique to quantify the extent ofMRI-visible tissue
disruption,which is related to a decrease in axonal loss.Measuring the deposition of
iron,as reflected by T2 relaxation time abnormalities,can also provide estimates of
the extent of MS neurodegeneration in clinically eloquent brain areas,such as the
basal ganglia and the cortical GM.Among more sophisticated MR-based method-
ologies,both magnetization transfer (MT) and diffusion tensor (DT) MRI are now
widely applied in the study ofMS.Correlative studies have confirmed that a signifi-
cant relationship exists between decreased MT ratio or increased diffusivity and
increased loss ofmyelin and axons,both within and outside focal MS lesions;there-
bymaking these techniques potential candidates for monitoring trials of neurode-
generation in MS. Proton magnetic resonance spectroscopy (1H-MRS) has the
unique advantage that it can provide information with a high biochemical specifici-
ty for ongoing tissue changes.Among 1H-MRS-derived metabolic measures,the lev-
els ofN-acetylaspartate (NAA) represent a highly specific correlate ofneuronal and
axonal viability.The information provided by structural MR-based techniques on
the neurodegenerative components of MS pathology can be integrated with those
coming from functional MRI (fMRI) studies.With the latter technique,the ability of
the MS brain to limit the consequences ofirreversible tissue damage can be explored.
fMRI data indicate that cortical reorganization in MS patients begins soon after the
clinical onset ofthe disease and continues through the entire course ofthe disease.
Although new MRI modalities are likely to provide us with more specific in
vivo measures reflecting the neurodegenerative features of MS pathology, their
application to clinical trial monitoring requires a careful preliminary considera-
tion ofseveral methodological issues,including the need to achieve a satisfactory
trade-off between pathological specificity, sensitivity to longitudinal changes,
and the feasibility oftheir use in the setting oflarge-scale,multicenter studies.In
other words, MR-derived measures of neurodegeneration, although promising,
need to be properly validated as surrogates of MS.In this context,useful lessons
can be learned by studies ofother neurodegenerative conditions,as well as by the
application ofother paraclinical biomarkers.
With this book,we aim to provide a complete and up-to-date overview oftech-
nical,methodological,and clinical issues related to the application ofMRI in MS
trials ofneurodegeneration.This review is the result ofan international workshop
held in Milan on 10 June 2005,during the Ninth Annual Advanced Course on the
Use ofMagnetic Resonance Techniques in Multiple Sclerosis,and subsequent dis-
cussions among the authors. We hope that, for clinicians and researchers, this
book will be ofhelp for setting up the scenario they will have to face when assess-
ing the efficacy offuture therapeutic strategies in the treatment ofMS.
Milan,March 2007 M.Filippi
M.Rovaris
G.Comi
Early treatment in multiple sclerosis with intravenous immunoglobulin VII
Table of Contents
Background
Chapter 1 – Neuropathological Advances in Multiple Sclerosis
E.CAPELLO,A.UCCELLI,M.PIZZORNO,G.L.MANCARDI . . . . . . . . . . . . . . . . . . 3
Chapter 2 – Neurophysiology
L.LEOCANI,G.COMI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
MRI Techniques to Assess Neurodegeneration
Chapter 3 – Atrophy
W.RASHID,D.T.CHARD,D.H.MILLER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Chapter 4 – T1 Black Holes and Gray Matter Damage
M.NEEMA,V.S.R.DANDAMUDI,A.ARORA,J.STANKIEWICZ,R.BAKSHI . . . . . . . 37
Chapter 5 – Magnetization Transfer Imaging
M.INGLESE,Y.GE,R.I.GROSSMAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Chapter 6 – Perfusion MRI
Y.GE,M.LAW,M.INGLESE,R.I.GROSSMAN . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Chapter 7 – Diffusion-Weighted Imaging
M.ROVARIS,E.PEREGO,M.FILIPPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Chapter 8 – Proton MR Spectroscopy
N.DESTEFANO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Chapter 9 – Functional MRI
M.A.ROCCA,M.FILIPPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
VIII Table of Contents
Evaluation of MRI Outcomes
Chapter 10 – Validation of MRI Surrogates
M.P.SORMANI,M.FILIPPI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Chapter 11 – Defining Responders and Non-responders
I.ABAN,G.CUTTER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Chapter 12 – Predictive Models in Multimodal Imaging
K.MOURIDSEN,L.ØSTERGAARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Lessons from Other Neurodegenerative Diseases
Chapter 13 – Alzheimer’s Disease
G.B.FRISONI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Chapter 14 – Other Neurodegenerative Conditions
M.MASCALCHI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Chapter 15 – Incorporation of Other Biomarkers
S.GNANAPAVAN,G.GIOVANNONI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Designing MS Trials for Neurodegeneration
Chapter 16 – Critical Review of Existing Trials
G.COMI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Chapter 17 – Design for the Next Trials of Neurodegeneration
P.SOELBERGSØRENSEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
List of Contributors IX
List of Contributors
Inmaculada Aban Venkata S.R.Dandamudi
Department ofBiostatistics Brigham & Women’s Hospital
University ofAlabama at Birmingham Harvard Medical School
Birmingham,AL,USA Boston,MA,USA
Ashish Arora Nicola De Stefano
Brigham & Women’s Hospital Department ofNeurological
Harvard Medical School and Behavioral Sciences
Boston,MA,USA University ofSiena
Siena,Italy
Rohit Bakshi
Brigham & Women’s Hospital Massimo Filippi
Harvard Medical School Neuroimaging Research Unit
Boston,MA,USA Department ofNeurology
Scientific Istitute and
Elisabetta Capello University Ospedale San Raffaele
Department ofNeuroscience Milan,Italy
Ophtalmology and Genetics
University ofGenoa Giovanni B.Frisoni
Genoa,Italy LENITEM - Laboratory ofEpidemiology
Neuroimaging & Telemedicine
Declan T.Chard IRCCS San Giovanni di Dio
NMR Research Unit The National Center forResearch
Department ofNeuroinflammation and Care ofAlzheimer’s Disease
Institute ofNeurology Brescia,Italy
University College London
London,UK Yulin Ge
Department ofRadiology
Giancarlo Comi Center for Biomedical Imaging
Department ofNeurology New York University School ofMedicine
Scientific Institute and New York,NY,USA
University Ospedale San Raffaele
Milan,Italy Gavin Giovannoni
Department ofNeuroscience
Gary Cutter Institute ofCell and Molecular Science
Department ofBiostatistics Queen Mary University ofLondon
University ofAlabama at Birmingham London,UK
Birmingham,AL,USA
X List of Contributors
Sharmilee Gnanapavan Kim Mouridsen
Department ofNeuroimmunology Centre for Functionally Integrative
Institute ofNeurology Neuroscience (CFIN)
London,UK Department ofNeuroradiology
Århus University Hospital
Robert I.Grossman Århus C,Denmark
Department ofRadiology
Center for Biomedical Imaging Mohit Neema
New York University School ofMedicine Brigham & Women’s Hospital
New York,NY,USA Harvard Medical School
Boston,MA,USA
Matilde Inglese
Department ofRadiology LeifØstergaard
Center for Biomedical Imaging Centre for Functionally Integrative
New York University School ofMedicine Neuroscience (CFIN)
New York,NY,USA Department ofNeuroradiology
Århus University Hospital
Meng Law Århus C,Denmark
Department ofRadiology
Center for Biomedical Imaging Elisabetta Perego
New York University School ofMedicine Neuroimaging Research Unit
New York,NY,USA Scientific Institute and
University Ospedale San Raffaele
Letizia Leocani Milan,Italy
Department ofNeurology
Scientific Institute and Matteo Pizzorno
University Ospedale San Raffaele Department ofNeuroscience
Milan,Italy Ophtalmology and Genetics
University ofGenoa
Giovanni Luigi Mancardi Genoa,Italy
Department ofNeuroscience
Ophtalmology and Genetics
Waq-ar Rashid
University ofGenoa
NMR Research Unit
Genoa,Italy
Department ofNeuroinflammation
Institute ofNeurology
Mario Mascalchi
University College London
Radiodiagnostic Section
London,UK
Department ofClinical Physiopathology
and Department ofNeurological Sciences
Maria A.Rocca
University ofFlorence
Neuroimaging Research Unit
Florence,Italy
Department ofNeurology
Scientific Istitute and
David H.Miller
University Ospedale San Raffaele
NMR Research Unit
Milan,Italy
Department ofNeuroinflammation
Institute ofNeurology
University College London
London,UK
