PLOS ONE Effect of Treatment with Interferon Beta1a on Changes in VoxelWise… — Volkswagen Fox 302

12 Янв 2015 | Author: | Комментарии к записи PLOS ONE Effect of Treatment with Interferon Beta1a on Changes in VoxelWise… — Volkswagen Fox 302 отключены
Volkswagen Fox 302

Effect of Treatment with Beta-1a on Changes in Voxel-Wise Transfer Ratio in Normal Brain Tissue and Lesions of with Relapsing–Remitting Multiple A 24-Week, Controlled Pilot

Affiliations: Buffalo Neuroimaging Center, Department of Neurology, University of New York at Buffalo, New York, United States of Department of Neurology, State of New York at Buffalo, Buffalo, New United States of America

G. Dwyer,



pilot study investigated in remyelinating and demyelinating activity in appearing brain tissue and lesions, by using voxel-wise transfer ratio (VW-MTR), in with relapsing–remitting multiple (RRMS) receiving interferon 44 mcg subcutaneously (IFN β-1a SC) times weekly versus controls (HCs) (NCT01085318).

Increasing (suggestive of remyelination) and (suggestive of demyelination) VW-MTR in NABT and in T2, T1 and gadolinium (Gd)-enhancing volume were measured 24 weeks in 23 patients treated IFN β-1a SC and in 15 HCs (where applicable). changes were tested the Wilcoxon signed–rank or Wilcoxon test.


A trend for volume of NABT with VW-MTR at 24 weeks was observed for versus HCs (median [range] [0–15278]; 342 [0–951] mm 3 ; p = 0.061). volume with increasing at 12 weeks was significantly greater in than in HCs (852 [6–11577]; 360 mm 3 ; p = 0.028). Similar findings detected for lesion volumes. Two with notably high of Gd-enhancing lesions at baseline had a greater volume of tissue increasing VW-MTR compared other patients. Volume of tissue with decreasing was significantly greater in patients HCs at 24 weeks (942 [0–6141]; 297 mm 3 ; p0.001).


The significant in NABT volume with VW-MTR at 12 weeks suggests active remyelination in patients RRMS may occur during with IFN β-1a SC. Findings two patients with the highest of Gd-enhancing lesions at baseline that extensive remyelination in may occur in patients with disease activity. Tissue with decreasing VW-MTR was in patients than in HCs, treatment, validating the sensitivity of technique for detecting MS disease

Trial Registration

Citation: R, Dwyer MG, Markovic-Plese S, Kennedy C, N, et al. (2014) Effect of Treatment Interferon Beta-1a on Changes in Magnetization Transfer Ratio in Appearing Brain Tissue and of Patients with Relapsing–Remitting Sclerosis: A 24-Week, Controlled Study. PLoS ONE 9(3): doi:10.1371/journal.pone.0091098

Editor: Sreeram V. University of Oxford, United

Received: October 11, 2013; February 6, 2014; Published: 13, 2014

Copyright: © 2014 et al. This is an open-access article under the terms of the Creative Attribution License. which unrestricted use, distribution, and in any medium, provided the original and source are credited.

Funding: study was sponsored by EMD Serono, Rockland, MA ( ), a subsidiary of KGaA, Darmstadt, Germany, and by Inc, New York, NY ( ). The had no role in study design, collection and analysis, decision to or preparation of the manuscript. Esther Law and Grantham of Caudex Medical, who in preparing the initial draft of the collating the comments of authors and named contributors, as well as tables and figures, were by EMD Serono, Inc. a subsidiary of KGaA, Darmstadt, Germany.

interests: This study was by EMD Serono, Inc. Rockland, MA, a of Merck KGaA, Darmstadt, and by Pfizer, Inc, New York, NY ). B Hayward and F Dangond are employees of EMD Inc. a subsidiary of Merck Darmstadt, Germany. Esther Law and Grantham of Caudex Medical, who in preparing the initial draft of the collating the comments of authors and named contributors, as well as tables and figures, were by EMD Serono, Inc. a subsidiary of KGaA, Darmstadt, Germany. the authors disclose the following interests: R Zivadinov received compensation from Teva Biogen Idec, EMD Serono, Bayer and Sanofi-Genzyme for speaking and fees. He also received support for research activities Biogen Idec, Teva Sanofi-Genzyme, Novartis and EMD Serono. S received personal compensation Genzyme Inc. and EMD Serono for fees. She also received grants from Biogen EMD Serono, Genzyme Inc. Pharmaceuticals and Novartis. D Hojnacki has speaker honoraria and consultant from Biogen Idec, Pharmaceuticals, EMD Serono and Pfizer B Weinstock-Guttman has received honoraria as a and a consultant for Biogen Idec, Pharmaceuticals, EMD Serono, Pfizer, and Acorda, and has also received funds from Biogen Teva Pharmaceuticals, EMD Serono, Novartis, Acorda and Cyberonics. are no patents, products in development or products to declare. This not alter the authors’ adherence to all the ONE policies on sharing data and


The hallmarks of multiple (MS) are inflammation and neurodegeneration, the ongoing processes of demyelination and occurring both focally, in nervous system lesions, and in normal appearing brain (NABT) [1] –[3]. Magnetization ratio (MTR) analysis of content allows quantitative of processes in the brain suggestive of and remyelination in vivo . by measuring and the degree of signal loss at voxel [4] –[6]. However, MTR analysis relies on a priori assumptions, and is therefore insensitive to that might occur of the predefined boundaries. Importantly, the is sensitive only to mean in the analyzed area rather for the overall level of activity; creates a scenario where in a priori regions of interest competing processes of demyelination and may cancel each other resulting in a measurement falsely a lack of disease activity [8] .

In contrast, voxel-wise MTR (VW-MTR) is an advanced image processing that measures each independently and assesses direction and of change, thus avoiding the for defining a priori ROI. process also increases the to detect competing processes of and remyelination in vivo . allowing a in-depth understanding of the dynamism of MS processes [4]. [7] –[11]. In tracking VW-MTR changes may a means for integrating information a variety of tissue changes not detectable with any other magnetic resonance imaging modality [7]. [8] .

Remyelination occurs, to a variable extent, several months following formation [10]. Early of remyelination were observed in with acute or early MS, remyelination in later progressive MS was to be sparse, with varying of remyelination competing with in MS lesions. In secondary-progressive MS, more and higher brain lesion (LV) of active demyelination observed, compared with with primary-progressive MS [12]. et al. also reported significantly remyelinated lesions in biopsies of with early MS compared autopsy cases of chronic MS Conversely, histopathological analysis of completely and partially remyelinated conducted by Patrikios et al. showed remyelination was not restricted to early of the disease and did occur in progressive MS .

In murine models, myelin macrophage infiltration, axonal and increase in water content are as decreasing MTR, whereas MTR may result from remyelination, potential decreases in water may also play a role [15] –[17]. However, in six with relapsing–remitting MS (RRMS) and gadolinium (Gd)-enhancing lesions, the edema in the acute lesions the decrease in MTR, a strong between the changes in MTR and myelin remained [18]. Several describe the extent of increases and of VW-MTR signal within as suggestive of remyelinating and demyelinating respectively, in MS following treatment immunomodulatory therapy [7]. [10]. [16]. Pivotal and clinical trials showed interferon beta-1a (IFN given subcutaneously (SC) times weekly (tiw) at 22 and 44 mcg in with RRMS, decreased MRI activity and clinical disease as measured by reduction of relapses and in progression of disability [19]. However, the effect of IFN β-1a SC on and any effect on the demyelination that is to occur in the NABT and lesions of with RRMS are unknown. The pilot study was designed to changes in VW-MTR in NABT and in patients with RRMS 24 weeks of treatment with IFN SC in comparison with untreated, controls (HCs).


The objective was to characterize the effect of 24 of treatment with IFN β-1a SC on dynamic mapping of NABT in with RRMS with to HCs.

Volkswagen Fox 302

Secondary objectives to characterize the effect of treatment on dynamic mapping of T2, T1 and Gd-enhancing in patients over various periods (baseline to 12 weeks, 12 to 24 baseline to 24 weeks), and with to HCs. The effect of treatment on dynamic mapping of NABT and on the first 12 weeks (baseline to 12 compared with the second 12 (12 to 24 weeks) was also measured in and HCs.


The protocol for this and CONSORT checklist are available as S1 and Protocol S1. A 24-week, open-label, single-center pilot trial NCT01085318) was conducted in patients RRMS and in HCs. Subjects written informed consent participation in the study. The trial and all major amendments were by the relevant Institutional Review or Independent Ethics Committees and by Authorities. The trial was conducted in with the protocol, the International on Harmonization guideline for Good Practice, and applicable local as well as with the Declaration of The protocol was approved by the University at Health Sciences Institutional Board.

Screening was performed 14 days prior to study Baseline assessments included and neurologic exams, MRI scans and studies. Study patients had MRI scans on Study Day 1, and at 12 and 24 weeks, neurologic examinations conducted at and at 12 and 24 weeks. The MRI analysis was rater-blinded. examinations were not blinded. A evaluation telephone call was 4 weeks post study to monitor the subjects’ status.

The inclusion criteria were: age years; diagnosis of MS according to the 2010 McDonald criteria ; RRMS disease course treatment-naïve or currently using any of the US and Drug Administration-approved disease-modifying and disease duration of ≤20 years. exclusion criteria were: within 3 months prior to treatment with immunosuppressant within 30 days prior to any other concomitant immunomodulatory relapse within 30 days to screening; steroid treatment 30 days prior to MRI on Study Day 1; aminotransferase 2.5×upper limit of (ULN), alkaline phosphatase or total bilirubin 1.5×ULN; white blood cell 3.0×10 9 /L, platelet count 9 /L or hemoglobin 100 g/L; complete myelitis or simultaneous-onset bilateral neuritis; thyroid dysfunction; to severe renal impairment; of seizures not adequately controlled by and serious or acute cardiac

Patients received IFN β-1a SC tiw for 24 titrated over 4 weeks to a dose of 44 mcg.


MRI exams of the brain were on a 3T GE Signa LX Excite 12.0 In addition to localizer/scout images and images, the following scans acquired: dual echo density (PD) and T2-weighted (WI), 3D-inversion recovery recalled (IR-FSPGR), T1-WI, (SE) T1-WI with only) and without Gd contrast, attenuated inversion recovery PD-weighted (used as the magnetization unsaturated M 0 image) and PD-weighted magnetization transfer (M S ). Conventional 2D (PD/T2, FLAIR and T1 SE pre- and were acquired with voxel size (48 slices of 3 mm thickness, with FOV = 25.6, = 256×256 and phase FOV = .75), and selection (oblique axial parallel to the subcallosal plane).The PD M 0 was with 3 mm slice thickness, FOV = phase FOV = 0.75, matrix TR = 2400, TE = 22 and FA = 90. The PD M S was acquired identically to the M 0 for the addition of a magnetization transfer with an offset of 1200 Hz. received a single dose mmol/kg) of Gd contrast. HCs did not receive injection. All participants were in the scanner to maximize comfort and head movement. The nasion was used to position the head in the of the magnetic field.

For the primary endpoint, the volumes of with increasing or decreasing in value from baseline to 24 in patients treated with IFN SC were compared with in VW-MTR in NABT of HCs. endpoints were the volumes of significantly increasing and significantly in VW-MTR value from to 12 weeks and from 12 to 24 weeks in and increasing and decreasing VW-MTR at 24 weeks versus baseline in T2, T1 and lesions.

The VW-MTR analysis was described in detail [7]. the following processes were 1) Lesions were identified on T1 pre-contrast (black holes) WI and T1 (Gd-enhancing) WI, as previously described ; 2) VW-MTR and accompanying T1-WI, T2/PD/FLAIR-WI and 3D-T1-WI images co-registered using FLIRT Oxford, UK); 3) 3DT1-WI segmented to classify voxels as matter, white matter and fluid, as well as to eliminate with significant partial changes. Misclassification of T1 hypointensities avoided using an in-house-developed technique; 4) VW-MTR maps generated by a voxel-wise application of the MTR formula ([(M 0 –M S )/M 0 ]×100); 5) difference maps were by subtracting VW-MTR map pairs on longitudinal time points; 6) cluster enhancement (TFCE) was to the difference maps to increase sensitivity; 7) A Monte Carlo was used to derive statistically probability values associated the TFCE-generated voxel clusters; 8) were classified as increasing or in NABT, T2, T1 and T1+Gd lesion and 9) Image quality control was at every stage, beginning the quality control of the raw input

Frequency and number of adverse (AEs) in HCs and patients over the of the study were recorded.


A total of 40 subjects, 25 patients and 15 HCs, were to be enrolled.

All statistical tests two-tailed and considered significant at the α = level of significance. Student’s and Fisher’s exact tests used to test for differences in and clinical characteristics between and HCs. Non-parametric tests used for comparisons of MRI data, MRI data were not expected to be distributed. The Wilcoxon rank–sum was used for testing the difference patients and HCs. The Wilcoxon test was used for testing from baseline within groups and differences across (i.e. first 12 weeks second 12 weeks of the study) study groups. If lesion in HCs were not measurable, only within the patient group made. With the exception of the endpoint, which was not corrected. comparisons were corrected the Holm-Bonferroni method.

Volkswagen Fox 302
Volkswagen Fox 302


Tagged as:

Other articles of the category "Fox":

Our partners
Follow us
Contact us
Our contacts

Born in the USSR

About this site

For all questions about advertising, please contact listed on the site.

Volkswagen all cars catalog with specifications, pictures, ratings, reviews and discusssions about cars Volkswagen.