According to our Special Topics analysis
on Multiple Sclerosis research over the past decade, the
scientist whose work ranks at #1 by total cites and by
number of papers is Dr. Massimo Filippi, with 253
qualifying papers cited a total of 6,334 times. InEssential
Science IndicatorsSM from
Thomson
Reuters, Dr. Filippi's record includes 455 papers
published between January 1, 1998 and June 30, 2008, cited
a total of 9,821 times.
Dr. Filippi is the Director of the Neuroimaging
Research Unit in the Department of Neurology at the
Scientific Institute and University Ospedale San Raffaele
in Milan, Italy. He also holds the positions of Adjunct
Professor in the Department of Neurosurgery at the Temple
University School of Medicine in Philadelphia,
Pennsylvania; the John Whitaker Professor of the American
Neurological Association; and Visiting Professor in the
School of Medicine at the University of Belgrade in
Serbia.
In
the interview below, he talks with ScienceWatch.com
about his highly cited work on multiple
sclerosis.
Please tell us a little about your
research and educational background.
I received my M.D. in 1986 and my Post- Graduate Degree in Neurology in
1990 from the University of Milan. I am a clinical neurologist and my
research field is in the application of magnetic resonance (MR)-based
techniques to the study of central nervous system diseases, particularly
multiple sclerosis (MS) and other white matter disorders. Currently, I am
the Director of the Neuroimaging Research Unit, Department of Neurology,
Scientific Institute and University Ospedale San Raffaele, Milan, Italy.
I am also member of various Scientific Societies and Academies (Executive
Committee of the European Neurological Society [ENS]; Director of the
Neuroimaging Study Groups of the ENS, the European Federation of
Neurological Societies [EFNS] and the Italian Neurological Society [SIN];
Steering Committee of the European MRI network MAGNIMS; MS Differential
Diagnosis Task Force of the US MS Society; ISMRM Workshop Committee) and
have relevant roles in the coordination of clinical trials of MS. I am
reviewer and member of the Editorial Boards of several international
scientific journals. I'm author or co-author of more than 530 peer-reviewed
papers; and a co-editor of books and journal supplements.
What first attracted you to multiple sclerosis
research?
"Recent years have witnessed
impressive advancements in the use of MRI for
the assessment of patients with
MS."
The possibility to improve our understanding of how neurological diseases
determine progressive accumulation of irreversible physical disability and
cognitive impairment.
Your most-cited paper in our analysis is the 2001
Lancet article, "Effect of early interferon treatment on
conversion to definite multiple sclerosis: A randomised study." Would
you sum up this paper—its aims and findings—for our
readers?
In this paper, we assessed the effect of interferon beta-1a on the
occurrence of relapses in patients after the first clinical episode of
central nervous system involvement and brain MRI lesions; these patients
are at high risk of conversion to clinically definite MS. Patients were
randomly assigned to interferon beta-1a 22 mcg or placebo subcutaneously
once weekly for two years.
We found that treatment with interferon beta-1a prevents the conversion to
clinically definite MS. The time at which 30% of patients had converted to
clinically definite MS was indeed longer in the interferon group than in
the placebo group, whereas the annual relapse rate was significantly lower.
Moreover, interferon beta-1a treatment showed a sustained
effectin preventing the accumulation of new T2-weighted MRI
lesions and the increase in lesion burden. This study suggested that
interferon beta-1a is effective in delaying evolution to clinically
definite disease and in reducing MRI-measured disease activity in patients
who present with clinically isolated syndromes suggestive of MS.
In a subsequent study (Filippi M, et al., "Interferon beta-1a for
brain tissue loss in patients at presentation with syndromes suggestive of
multiple sclerosis: a randomised, double-blind, placebo-controlled
trial," Lancet 2004),we aimed at assessing
whether this drug can also reduce the rate of brain-volume decrease (which
is usually considered as a marker of irreversible tissue loss) in these
patients. We found that the mean percentage brain volume change for
patients on placebo was -0.83% during the first year, -0.67% during the
second year, and -1.68% during the entire study period. Respective values
for treated patients were -0.62%, -0.61%, and -1.18%. The changes in brain
volume were significant in both groups at all time points, while a
significant treatment effect was detected for month 24 versus baseline
values.
Another of your highly cited papers is the 2001
Annals of Neurology article, "European/Canadian multicenter,
double-blind, randomized, placebo-controlled study of the effects of
glatiramer acetate on magnetic resonance imaging-measured disease
activity and burden in patients with relapsing multiple sclerosis."
Would you talk a little bit about this study and why it is so
important?
Glatiramer acetate (GA) reduces relapse rates in patients with relapsing
remitting MS (RRMS). This study was designed to determine the effect,
onset, and durability of any effect of GA on disease activity monitored
with MRI in patients with RRMS. Two hundred thirty-nine eligible patients
were randomized to receive either 20 mg GA or placebo by daily subcutaneous
injection. During the study, patients underwent monthly MRI scans and
clinical assessments over 9 months.
Treatment with GA showed a sustained effect in preventing the
accumulation of enhancing lesions and T2 disease burden in RRMS patients
compared with placebo. Moreover, the relapse rate was significantly
reducedby 33% for GA-treated patients. All effects increased
over time. This study showed, for the first time, that GA significantly
reduced MRI-measured disease activity and burden in RRMS patients.
One of your more recent papers is the Jan 2008
Neurology article, "The mirror-neuron system in MS: A 3 tesla
fMRI study." Would you walk us through this study and its
conclusions?
In MS patients, the strength of the correlation between clinical and MRI
findings is weak. One of the potential factors which might explain this
clinical/MRI discrepancy is the presence of functional cortical changes.
Such changes might contribute to the maintenance of a normal level of
function despite the presence of widespread tissue damage. Functional MRI
studies of the sensorimotor network in MS have shown an increased
recruitment of several brain regions. Many of these studies also showed a
strong correlation between the extent of functional cortical changes and
several MRI metrics of structural tissue damage, indicating that cortical
reorganization might yet be an additional factor with the potential to
limit the clinical impact of MS-related injury.
Some of the areas that have been described as having an increased
activation in MS patients are part of the "mirror-neuron system" (MNS), a
system that, in humans, is thought to be involved in action observation,
action imitation, and learning. To explain its increased activation in MS
patients, we suggested that MS patients, when performing a simple motor
task, might tend to activate regions that are activated in normal
individuals when performing complex tasks as a result of the presence of
structural disease-related damage.
In this study, we investigated the properties of the MNS in patients with
MS using functional MRI obtained with a high-field scanner. Patients and
controls were scanned during the performance of two motor tasks with
different levels of complexity, one of which was specifically designed to
activate the MNS. We found that in patients with MS, part of the regions of
the MNS were more active not only during the MNS task but also during the
simple task. In conclusion, this study suggests increased activation of the
MNS in patients with MS with a normal level of function and widespread
brain damage. The potentialities of this system in facilitating clinical
recovery in patients with MS and other neurologic conditions should now be
investigated.
Are there any other papers, regardless of
citations, that you feel are important to your field, and if so, what
are they and why are they important?
The spinal cord is a clinically eloquent region, whose damage has the
potential to dramatically affect the functional outcome of patients with
MS. The recent development of sophisticated MR coils and fast imaging
techniques has led to an improved capability for studying spinal cord
reliably. This includes the possibility to perform magnetization transfer
and diffusion tensor MRI of the cervical cord; these techniques hold
promise to obtain accurate estimates of the extent of tissue damage to this
critical structure of the central nervous system.
"In MS patients, the strength of the
correlation between clinical and MRI findings
is weak."
We developed a novel diffusion tensor MRI sequence which has made it
possible to achieve an accurate estimate of the extent of the overall
cervical cord damage in patients with different MS phenotypes and in
patients with neuromyelitis optica. More recently, we also demonstrated
that cervical cord grey matter is not spared by MS pathology and such
damage is an additional factor contributing to the disability of these
patients. Finally, since it is conceivable that functional MRI might be
able to detect neuronal activity in the human spinal cord, we obtained a
functional mapping of this clinically eloquent structure in patients with
RRMS. Compared to controls, MS patients showed, on average, a 20% higher
cord functional MRI signal change during proprioceptive and tactile
stimuli, suggesting an abnormal recruitment of spinal cord interneurons.
MRI of the spinal cord is indeed providing useful pieces of information
both for the diagnostic work-up of patients suspected of having MS and to
grade the severity of the pathological damage.
How would you define the progress that has been
made in MS research over the past decade: more or less than
expected?
Recent years have witnessed impressive advancements in the use of MRI for
the assessment of patients with MS. Complementary to the clinical
evaluation, conventional MRI provided crucial pieces of information for the
diagnosis of MS, for the understanding of its natural history, and for
monitoring the efficacy of experimental treatments. However, it only
provided limited information about MS pathology in terms of both accuracy
and specificity. This is where new quantitative MRI markers of MS evolution
come into play. By providing information about the most destructive aspects
of MS pathology, techniques such as magnetization transfer MRI, diffusion
tensor MRI with fiber tractography, and proton magnetic resonance
spectroscopy are contributing to providing a more complete picture of the
complex pathological mechanisms of MS.
In addition, in recent years, the use of functional MRI to study the
mechanisms of brain adaptation in response to MS-related damage has further
extended our ability to understand the functional significance of
pathological changes in MS. Finally, the development of high-field MR
systems offered a full range of advantages and exciting possibilities, and
has strengthened the role of MRI as the most sensitive paraclinical tool
available for early diagnosis of MS. So the final answer to your question
is: "more," but there is still a long way ahead of us!
Where do you see your research going in the next
decade?
MS is such a complex disease that future multi-parametric MR approaches
should be developed and validated. Considering that none of the available
MRI techniques taken in isolation is able to provide a complete picture of
the complexity of the MS process, the definition of aggregates of MRI
quantities, thought to reflect different aspects of MS pathology, is a
promising way to increase further our understanding of the mechanisms
underlying the accumulation of irreversible disability in MS. As a
consequence, one of the most important tasks for the future is to establish
how these advances in MRI technology might contribute to a better
correlation between clinical and MRI findings, thus providing relevant
information to improve prognosis and predict therapeutic response.
Future MRI work should also focus on refinements in spinal-cord imaging,
optic-nerve imaging, perfusion MRI, and functional MRI. Finally, both
conventional and non-conventional MR techniques will take advantage of the
use of ultra-high-field MR scanners to study MS. Advances in MRI may
certainly improve our ability to diagnose, monitor, and understand the
pathophysiology of the disease.
What should the "take-away lesson" about your work
be for the general public?
The extensive application of conventional and modern MR-based techniques to
the study of MS has undoubtedly improved our ability to diagnose and
monitor the disease, as well as our understanding of disease
pathophysiology. Nevertheless, many challenges remain. New techniques need
to be refined and validated before they can be properly integrated into
clinical research and practice.
Massimo Filippi, M.D.
Director, Neuroimaging Research Unit
Scientific Institute and University
San Raffaele, Milan, Italy
and
John Whitaker Professor of the American Neurological Association
and
Adjunct Professor, Department of Neurosurgery
School of Medicine
Temple University
Philadelphia, PA, USA
and
Visiting Professor
School of Medicine
University of Belgrade
Belgrade, Serbia
Comi G, et al., "Effect of early interferon
treatment on conversion to definite multiple sclerosis: A
randomised study," Lancet 357(9268): 1576-82, 19
May 2001. Source:
Essential Science Indicators from
Thomson
Reuters.