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Multiple Sclerosis - September 2008
Interview Date: October 2008
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Filippi Dr. Massimo Filippi
From the Special Topic of Multiple Sclerosis

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. In Essential 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 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 effect in 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 reduced by 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
John Whitaker Professor of the American Neurological Association
Adjunct Professor, Department of Neurosurgery
School of Medicine
Temple University
Philadelphia, PA, USA
Visiting Professor
School of Medicine
University of Belgrade
Belgrade, Serbia

Dr. Massimo Filippi's current most-cited paper in Essential Science Indicators, with 288 cites:
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.

Keywords: multiple sclerosis, MRI, cognitive impairment, physical disability, interferon, early treatment, clinically definite MS, conversion, relapse rate, glatiramer acetate, mirror-neuron system, spinal cord, diffusion tensor imaging.

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Special Topics : Multiple Sclerosis : Massimo Filippi