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      • Record: found
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      Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective:

          We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS.

          Methods:

          Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years.

          Results:

          Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume ( p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume ( p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count ( p < 0.001, both), and number of confirmed on-study relapses ( p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL.

          Conclusions:

          Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.

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          Most cited references20

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

          Robert A Bermel, Rohit Bakshi (2006)
          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.
          Article 0 comments Cited 134 times – based on 0 reviews     Review now
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            Clinical relevance of brain volume measures in multiple sclerosis.

            Nicola De Stefano, Laura Airas, Nikolaos Grigoriadis … (2014)
            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.

              X Montalban, M. Battaglini, Aron Fazekas … (2010)
              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.
              Article 0 comments Cited 111 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Ernst-Wilhelm Radue:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. Dr. Radue received speaker honoraria and and travel compensation from Bayer Schering, Biogen Idec, Genzyme, Novartis, Merck-Serono, MorphoSys, Synthon.

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. Dr. Radue received consultancy fees from Bayer-Schering, Biogen Idec, Genzyme, Novartis, Merck-Serono, Synthon, MorphoSys.

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. Dr. Radue received institutional research support from Novartis, Biogen Idec, Merck-Serono, Actelion, Basilea, SAKK, Synarc.

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Frederik Barkhof:
                Comment :

                Scientific Advisory Boards:

                1. Scientific consultant to Bayer-Schering, Sanofi- Aventis, Synthon, Novartis, Biogen-IDEC, Merck-Serono, Toshiba Medical systems, Roche, Janssen, TEVA, Genzyme

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. Editorial board member for Brain, Eur Radiol, Multiple Sclerosis Journal, Neuroradiology, Radiology, Neurology

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. Consultant for Sanofi-Aventis, Synthon, Janssen, Novartis, Biogen-Idec, Roche, TEVA

                Speakers' Bureaus:

                1. Novartis symposium speaker 2014 Biogen-sponsored symposium speaker 2014 Medscape CME speaker 2011 and 2012

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. Neugrid4you (FP7 european committee)

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. Dutch foundation for MS Research - centre grant 2010-2014

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Ludwig Kappos:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. (1)Multiple Sclerosis Journal, (2)Multiple Sclerosis and Related Disorders (3)Journal of Neurology

                Patents:

                1. NONE

                Publishing Royalties:

                1. all less than 500 USD

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. (1)Actelion, (2)Addex,(3)Bayer Health Care,(4)Biogen Idec, (5)Biotica, (6)CSL Behring, (7)Genzyme,(8)Lilly,(9) Merck Serono, (10)Mitsubishi, (11)Novartis,(12)Ono Pharma, (13)Pfizer, (14) Receptos, (15) Roche, (16)Sanofi- aventis, (17)Santhera, (18)Siemens, (19)Teva, (20)UCB, (21)Xenoport I have also lectured at medical conferences or in public on various aspects of the diagnosis and management of multiple sclerosis. In many cases these talks have been sponsored by non-restricted educational grants from one or another of the above listed companies. Honoraria and other payments for all these activities have been exclusively used for funding of research of my department. Research and the clinical operations (nursing and patient care services) of the MS Center in Basel have been supported by non-restricted grants from one or more of these companies.

                Research Support, Government Entities:

                1. Research support by the Swiss National Research Foundation and the European Union

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. The Swiss MS Society and Novartis and Roche Research Foundations.

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Till Sprenger:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for travel or speaker honoraria:

                1. (1) Pfizer, travel support (2) Bayer Schering, travel support (3) Eli Lilly, travel support (4) Biogen (5) Genzyme, travel support

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. (1) Swiss MS Society (2) Swiss National Science Foundation

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Dieter A. Häring:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Novartis Pharma AG, Biostatistician, 6 years

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Ana de Vera:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. A.de Vera is Global Program Medical Director at Novartis AG

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Philipp von Rosenstiel:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Novartis Pharam AG, Global Program Medical Director, 5 years

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. Salary from Novartis Pharma AG

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Jeremy R. Bright:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Oxford PharmaGenesis Ltd, Medical Writer, 4 years

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Gordon Francis:
                Comment :

                Scientific Advisory Boards:

                1. NONE

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. NONE

                Employment, Commercial Entity:

                1. Novartis, Clinical Development, 5 years ended in September 2014. Now retired.

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. NONE

                Research Support, Government Entities:

                1. NONE

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. NONE

                Stock/Stock Options/Board of Directors Compensation:

                1. Novartis

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. Novartis stock related to employment status with Novartis

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Jeffrey A. Cohen:
                Comment :

                Scientific Advisory Boards:

                1. EMD Serono 1/23/2014, Consulting meeting, $4620 Genentech 4/5/2014, Consulting meeting, $3000 Genzyme/Sanofi 10/24/2013, Consulting meeting, $4985 Innate Immunotherapeutics 1/16/14, Consulting meeting, $2800 Novartis 5/6/13, Steering Committee teleconference, $410 5/22/13, Steering Committee teleconference, $410 6/5/13, Steering Committee teleconference, $410 7/17/13, Steering Committee teleconference, $410 10/3/13, Steering Committee teleconference, $410 Vaccinex 11/3/2013, Consulting meeting, $4000

                Gifts:

                1. NONE

                Funding for Travel or Speaker Honoraria:

                1. NONE

                Editorial Boards:

                1. NONE

                Patents:

                1. NONE

                Publishing Royalties:

                1. Cambridge University Press, JA Cohen and RA Rudick, eds, Multiple Sclerosis Therapeutics, 4th edition, 2011

                Employment, Commercial Entity:

                1. NONE

                Consultancies:

                1. NONE

                Speakers' Bureaus:

                1. NONE

                Other Activities:

                1. NONE

                Clinical Procedures or Imaging Studies:

                1. NONE

                Research Support, Commercial Entities:

                1. Research support paid to my institution from Biogen Idec, Genzyme, Novartis, Receptos, Synthon, Teva, and Vaccinex

                Research Support, Government Entities:

                1. Department of Defense, PR093324, PI, 2010-14 NIH, 1 RO1 NS074787, 2011-4

                Research Support, Academic Entities:

                1. NONE

                Research Support, Foundations and Societies:

                1. National MS Society, PP1752, PI, 06/2012-11/2013 Consortium of MS Centers, FWA00005367, PI, 12/2012-11/2013

                Stock/Stock Options/Board of Directors Compensation:

                1. NONE

                License Fee Payments, Technology or Inventions:

                1. NONE

                Royalty Payments, Technology or Inventions:

                1. NONE

                Stock/Stock Options, Research Sponsor:

                1. NONE

                Stock/Stock Options, Medical Equipment & Materials:

                1. NONE

                Legal Proceedings:

                1. NONE

                Journal
                Journal ID (nlm-ta): Neurology
                Journal ID (iso-abbrev): Neurology
                Journal ID (hwp): neurology
                Journal ID (publisher-id): neur
                Journal ID (pmc): neurology
                Journal ID (publisher-id): NEUROLOGY
                Title: Neurology
                Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )
                ISSN (Print): 0028-3878
                ISSN (Electronic): 1526-632X
                Publication date (Print): 24 February 2015
                Publication date PMC-release: 24 February 2015
                Volume: 84
                Issue: 8
                Pages: 784-793
                Affiliations
                From the Medical Image Analysis Centre (E.-W.R.), University Hospital, University of Basel, Switzerland; Image Analysis Center (F.B.), VU Medical Centre, Amsterdam, the Netherlands; Departments of Medicine and Clinical Research, Neurology (L.K., T.S.) and Radiology (T.S.), Division of Neuroradiology, University Hospital, Basel, Switzerland; Novartis Pharma AG (D.A.H., A.d.V., P.v.R.), Basel, Switzerland; Oxford PharmaGenesis Ltd. (J.R.B.), Tubney, Oxford, UK; Novartis Pharmaceuticals Corporation (G.F.), East Hanover, NJ; and Neurological Institute (J.A.C.), Cleveland Clinic, OH.
                Author notes
                Correspondence to Prof. Kappos: ludwig.kappos@ 123456usb.ch

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by the sponsor of the analysis, Novartis Pharma AG, Basel, Switzerland.

                Article
                Publisher ID: NEUROLOGY2014590216
                DOI: 10.1212/WNL.0000000000001281
                PMC ID: 4339126
                PubMed ID: 25632085
                SO-VID: 7e00cfa1-ef97-4e62-91c9-6e063466d1f1
                Copyright © © 2015 American Academy of Neurology
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                Date received : 16 April 2014
                Date accepted : 07 November 2014
                Categories
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                Subject: Article
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