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      Regional Distribution and Evolution of Gray Matter Damage in Different Populations of Multiple Sclerosis Patients

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          Abstract

          Background

          Both gray-matter (GM) atrophy and lesions occur from the earliest stages of Multiple Sclerosis (MS) and are one of the major determinants of long-term clinical outcomes. Nevertheless, the relationship between focal and diffuse GM damage has not been clarified yet. Here we investigate the regional distribution and temporal evolution of cortical thinning and how it is influenced by the local appearance of new GM lesions at different stages of the disease in different populations of MS patients.

          Methods

          We studied twenty MS patients with clinically isolated syndrome (CIS), 27 with early relapsing-remitting MS (RRMS, disease duration <5 years), 29 with late RRMS (disease duration ≥ 5 years) and 20 with secondary-progressive MS (SPMS). The distribution and evolution of regional cortical thickness and GM lesions were assessed during 5-year follow-up.

          Results

          The results showed that new lesions appeared more frequently in hippocampus and parahippocampal gyri (9.1%), insula (8.9%), cingulate cortex (8.3%), superior frontal gyrus (8.1%), and cerebellum (6.5%). The aforementioned regions showed the greatest reduction in thickness/volume, although (several) differences were observed across subgroups. The correlation between the appearance of new cortical lesions and cortical thinning was stronger in CIS (r 2 = 50.0, p<0.001) and in early RRMS (r 2 = 52.3, p<0.001), compared to late RRMS (r 2 = 25.5, p<0.001) and SPMS (r 2 = 6.3, p = 0.133).

          Conclusions

          We conclude that GM atrophy and lesions appear to be different signatures of cortical disease in MS having in common overlapping spatio-temporal distribution patterns. However, the correlation between focal and diffuse damage is only moderate and more evident in the early phase of the disease.

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          Most cited references20

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          Multiple Sclerosis

          New England Journal of Medicine, 343(13), 938-952
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            Measurement and clinical effect of grey matter pathology in multiple sclerosis.

            During the past 10 years, the intense involvement of the grey matter of the CNS in the pathology of multiple sclerosis has become evident. On gross inspection, demyelination in the grey matter is rather inconspicuous, and lesions in the grey matter are mostly undetectable with traditional MRI sequences. However, the results of immunohistochemical studies have shown extensive involvement of grey matter, and researchers have developed and applied new MRI acquisition methods as a result. Imaging techniques specifically developed to visualise grey matter lesions indicate early involvement, and image analysis techniques designed to measure the volume of grey matter show progressive loss. Together, these techniques have shown that grey matter pathology is associated with neurological and neuropsychological disability, and the strength of this association exceeds that related to white matter lesions or whole brain atrophy. By focusing on the latest insights into the in-vivo measurement of grey matter lesions and atrophy, we can assess their clinical effects. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Neocortical neuronal, synaptic, and glial loss in multiple sclerosis.

              Recent pathologic investigations have shown that neocortical lesions are frequent in multiple sclerosis (MS). Structural MRI has shown that neocortical atrophy occurs early and can be substantial, but the specific substrate for this atrophy has not been defined quantitatively. To investigate cortical thickness as well as neuronal, glial, and synaptic densities in MS. We studied brain samples from 22 patients with MS and 17 control subjects. Neocortical lesions and cortical thickness were assessed on sections stained for myelin basic protein. Neuronal, glial, and synaptic densities were measured in type I leukocortical lesions, nonlesional neocortex, and non-MS control cortex. Immunoautoradiography was used to quantify synaptic densities. Neocortical lesions were common in patients with MS. Subpial type III (44%) and leukocortical type I (38%) lesions were more abundant than intracortical type II (18%) lesions. An overall relative neocortical thinning of 10% (p = 0.016) was estimated for the patients. Within the type I lesions, we found evidence for substantial cell (glial, 36%, p = 0.001; neuronal, 10%, p = 0.032) and synaptic (47% decrease in synaptophysin, p = 0.001) loss. Nonlesional neocortex did not show significant relative changes in neuronal, glial, or synaptic density. Neocortical neuronal and glial degeneration is significant in multiple sclerosis. Synaptic loss was particularly striking in the neocortical lesions, which should make a major independent contribution to the expression of pathology. New therapies should be directed toward limiting this damage.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 August 2015
                2015
                : 10
                : 8
                : e0135428
                Affiliations
                [1 ]Neurology Section, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy
                [2 ]Neuroimaging Unit, Euganea Medica, Padova, Italy
                [3 ]Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
                [4 ]Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy
                [5 ]Department of Information Engineering, University of Padova, Padova, Italy
                [6 ]Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories, Imperial College London, London, United Kingdom
                [7 ]Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
                [8 ]Department of Biology, University of Padova, Padova, Italy
                University of Jaén, SPAIN
                Author notes

                Competing Interests: M. Calabrese received consultancy fees from Biogen Idec, Genzyme, Novartis Pharma, and Teva Pharmaceutical Industries towards this study. R. Reynolds received consultancy fees from EMD Serono towards this study. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: M. Calabrese. Performed the experiments: M. Calabrese M. Castellaro AM. Analyzed the data: M. Calabrese RR RM M. Castellaro AM AS GF CR AG MP MDB SM. Contributed reagents/materials/analysis tools: M. Calabrese M. Castellaro. Wrote the paper: M. Calabrese RR RM M. Castellaro AM AS GF CR AG MP MDB SM.

                Article
                PONE-D-15-14599
                10.1371/journal.pone.0135428
                4534410
                26267665
                33ab8842-abb6-4196-a1c8-1044ce3e0923
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 3 April 2015
                : 21 July 2015
                Page count
                Figures: 3, Tables: 2, Pages: 12
                Funding
                M. Calabrese received consultancy fees from Biogen Idec, Genzyme, Novartis Pharma, and Teva Pharmaceutical Industries. R. Reynolds received consultancy fees from EMD Serono. R. Magliozzi, M. Castellaro, M. Morra, A. Scalfari, G. Farina, C. Romualdi, A. Gajofatto, M. Pitteri, M.D. Benedetti, and S. Monaco have nothing to disclose. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funding is not specifically related to this study.
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                Research Article
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                All relevant data are within the paper and its Supporting Information files.

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