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      Reliable measurements of brain atrophy in individual patients with multiple sclerosis

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          Abstract

          Introduction

          As neurodegeneration is recognized as a major contributor to disability in multiple sclerosis ( MS), brain atrophy quantification could have a high added value in clinical practice to assess treatment efficacy and disease progression, provided that it has a sufficiently low measurement error to draw meaningful conclusions for an individual patient.

          Method

          In this paper, we present an automated longitudinal method based on Jacobian integration for measuring whole‐brain and gray matter atrophy based on anatomical magnetic resonance images ( MRI), named MS metrix. MS metrix is specifically designed to measure atrophy in patients with MS, by including iterative lesion segmentation and lesion filling based on FLAIR and T1‐weighted MRI scans.

          Results

          MS metrix is compared with SIENA with respect to test–retest error and consistency, resulting in an average test–retest error on an MS data set of 0.13% ( MS metrix) and 0.17% ( SIENA) and a consistency error of 0.07% ( MS metrix) and 0.05% ( SIENA). On a healthy subject data set including physiological variability the test–retest is 0.19% ( MS metrix) and 0.31% ( SIENA).

          Conclusion

          Therefore, we can conclude that MS metrix could be of added value in clinical practice for the follow‐up of treatment and disease progression in MS patients.

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          Most cited references30

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          The measurement and clinical relevance of brain atrophy in multiple sclerosis.

          Brain atrophy has emerged as a clinically relevant component of disease progression in multiple sclerosis. Progressive loss of brain tissue bulk can be detected in vivo in a sensitive and reproducible manner by MRI. Clinical studies have shown that brain atrophy begins early in the disease course. The increasing amount of data linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is an important determinant of disease progression to a greater extent than can be explained by conventional lesion assessments. In this review, we will summarise the proposed mechanisms contributing to brain atrophy in patients with multiple sclerosis. We will critically discuss the wide range of MRI-based methods used to quantify regional and whole-brain-volume loss. Based on a review of current information, we will summarise the rate of atrophy among phenotypes for multiple sclerosis, the clinical relevance of brain atrophy, and the effect of disease-modifying treatments on its progression.
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            Clinical relevance of brain volume measures in multiple sclerosis.

            Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.
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              Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.

              To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS). The percent brain volume change (PBVC) was computed on existing longitudinal (2 time points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12-68). There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease. This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.
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                Author and article information

                Contributors
                dirk.smeets@icometrix.com
                Journal
                Brain Behav
                Brain Behav
                10.1002/(ISSN)2157-9032
                BRB3
                Brain and Behavior
                John Wiley and Sons Inc. (Hoboken )
                2162-3279
                19 July 2016
                September 2016
                : 6
                : 9 ( doiID: 10.1002/brb3.2016.6.issue-9 )
                : e00518
                Affiliations
                [ 1 ] R&Dicometrix LeuvenBelgium
                [ 2 ] BioImaging LabUniversiteit Antwerpen AntwerpBelgium
                [ 3 ] Department of Neurology Center for NeurosciencesUniversitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB) BrusselBelgium
                [ 4 ] Department of Neurology and Center of Clinical Neuroscience Charles University in PragueFirst Faculty of Medicine and General University Hospital PragueCzech Republic
                [ 5 ] Department of Radiology 1st Faculty of Medicine and General University HospitalCharles University PragueCzech Republic
                [ 6 ]National Multiple Sclerosis Centrum MelsbroekBelgium
                Author notes
                [*] [* ] Correspondence

                Dirk Smeets, icometrix, Leuven, Belgium. Email: dirk.smeets@ 123456icometrix.com

                Article
                BRB3518
                10.1002/brb3.518
                5036437
                27688944
                543241d9-db68-4fe5-acec-d3a46092b4a3
                © 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 July 2015
                : 09 May 2016
                : 11 May 2016
                Page count
                Figures: 6, Tables: 0, Pages: 12, Words: 8437
                Funding
                Funded by: TRANSACT
                Award ID: FP7‐PEOPLE‐2012‐ITN‐316679
                Funded by: CENTER‐TBI
                Award ID: FP7‐COOPERATION‐2013‐602150
                Funded by: BRAINPATH
                Award ID: FP7‐PEOPLE‐2013‐IAPP‐612360
                Funded by: Czech Ministries of Education and Health
                Award ID: NT13237‐ 4/2012
                Award ID: PRVOUK‐P26/LF1/4
                Award ID: RVO‐VFN64165/2012
                Funded by: Seventh Framework Programme
                Award ID: FP7‐COOPERATION‐2013‐602150
                Award ID: FP7‐PEOPLE‐2013‐IAPP‐612360
                Award ID: FP7‐PEOPLE‐2012‐ITN‐316679
                Categories
                Methods
                Methods
                Custom metadata
                2.0
                brb3518
                September 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:22.09.2016

                Neurosciences
                brain atrophy,magnetic resonance images,msmetrix,multiple sclerosis
                Neurosciences
                brain atrophy, magnetic resonance images, msmetrix, multiple sclerosis

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