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      Gray matter–related proteins are associated with childhood-onset multiple sclerosis

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          Abstract

          Objective:

          To identify CSF biomarkers for multiple sclerosis (MS) in children with an initial acquired CNS demyelinating syndrome (ADS).

          Methods:

          CSF was collected from a cohort of 39 children with initial ADS, 18 of whom were diagnosed with MS and 21 of whom had a monophasic disease course. Proteomic analysis of trypsinized CSF (20 μL) was performed by nano-liquid chromatography Orbitrap mass spectrometry. Univariate statistical analysis was used to identify differentially abundant proteins between childhood-onset MS and monophasic ADS.

          Results:

          A total of 2,260 peptides corresponding to 318 proteins were identified in the total set of samples. Of these 2,260 peptides, 88 were identified as being most distinctive between MS and ADS. Fifty-three peptides, corresponding to 14 proteins, had higher abundance in children with MS compared to children with monophasic ADS. Twelve of these 14 proteins were linked to neuronal functions and structures, such as synapses, axons, and CNS proteases (e.g., neurofascin, carboxypeptidase E, brevican core protein, and contactin-2). The other 2 were functionally related to immune function. The 35 peptides identified with decreased abundance in children with MS corresponded to 7 proteins. Six of them were linked to innate immune function (e.g., haptoglobin, haptoglobin-related protein, C4b-binding protein alpha chain, and monocyte differentiation antigen CD14) and 1 was linked to cellular adhesion (protein diaphanous homolog 1).

          Conclusion:

          At first onset of ADS, CSF of children diagnosed with MS showed increased abundance of CNS gray matter–related proteins, whereas CSF of children with a monophasic disease course showed increased abundance of innate immunity–related proteins.

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          Most cited references 39

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          A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking.

          There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in CSF are being used in clinical practice. One of the most critical factors in CSF biomarker research is the inadequate powering of studies because of the lack of sufficient samples that can be obtained in single-center studies. Therefore, collaboration between investigators is needed to establish large biobanks of well-defined samples. Standardized protocols for biobanking are a prerequisite to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by preanalytical factors. Here, a consensus report on recommendations for CSF collection and biobanking is presented, formed by the BioMS-eu network for CSF biomarker research in multiple sclerosis. We focus on CSF collection procedures, preanalytical factors, and high-quality clinical and paraclinical information. The biobanking protocols are applicable for CSF biobanks for research targeting any neurologic disease.
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            International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.

            There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.
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              Consensus definitions proposed for pediatric multiple sclerosis and related disorders.

              The CNS inflammatory demyelinating disorders of childhood include both self-limited and lifelong conditions, which can be indistinguishable at the time of initial presentation. Clinical, biologic, and radiographic delineation of the various monophasic and chronic childhood demyelinating disorders requires an operational classification system to facilitate prospective research studies. The National Multiple Sclerosis Society (NMSS) organized an International Pediatric MS Study Group (Study Group) composed of adult and pediatric neurologists and experts in genetics, epidemiology, neuropsychology, nursing, and immunology. The group met several times to develop consensus definitions regarding the major CNS inflammatory demyelinating disorders of children and adolescents. Clinical definitions are proposed for pediatric multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), recurrent ADEM, multiphasic ADEM, neuromyelitis optica, and clinically isolated syndrome. These definitions are considered operational and need to be tested in future research and modified accordingly. CNS inflammatory demyelinating disorders presenting in children and adolescents can be defined and distinguished. However, prospective research is necessary to determine the validity and utility of the proposed diagnostic categories.
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                Author and article information

                Contributors
                Journal
                Neurol Neuroimmunol Neuroinflamm
                Neurol Neuroimmunol Neuroinflamm
                nnn
                NEURIMMINFL
                Neurology® Neuroimmunology & Neuroinflammation
                Lippincott Williams & Wilkins (Hagerstown, MD )
                2332-7812
                24 September 2015
                October 2015
                24 September 2015
                : 2
                : 5
                Affiliations
                From the MS Centre ErasMS, Department of Neurology, Erasmus MC, Rotterdam, the Netherlands.
                Author notes
                Correspondence to Dr. Hintzen: r.hintzen@ 123456erasmusmc.nl

                Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the authors.

                Article
                NEURIMMINFL2015005363
                10.1212/NXI.0000000000000155
                4582906
                © 2015 American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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