Lesional magnetization transfer ratio: a feasible outcome for remyelinating treatment trials in multiple sclerosis

2010 ◽  
Vol 16 (6) ◽  
pp. 660-669 ◽  
Author(s):  
IJ van den Elskamp ◽  
DL Knol ◽  
H. Vrenken ◽  
G. Karas ◽  
A. Meijerman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Magnetization Transfer ◽  
Primary Outcome Measure ◽  
Magnetization Transfer Ratio ◽  
Power Calculations ◽  
Transfer Ratio ◽  
Feasible Outcome

Magnetization transfer ratio (MTR) is a sensitive parameter to quantify the integrity of myelinated white matter in patients with multiple sclerosis. Lesional MTR decreases in the acute phase due to demyelination, and subsequently shows recovery depending on the degree of remyelination in the absence of axonal loss. Recovery of average lesion MTR therefore might prove a viable outcome measure to assess the effect of remyelinating agents. Our objective was to determine the required sample size for phase II multicentre clinical trials using the recovery of average lesion MTR as primary outcome measure. With 7-monthly MRI scans, the MTR evolution of 349 new enhancing lesions before and after enhancement was assessed in 32 MS patients from 5 centres. Multilevel models were fitted to the data yielding estimates for the variance components, which were applied in power calculations. Sample sizes were determined for placebo-controlled, multicentre trials using lesional MTR recovery post-enhancement as primary outcome measure. Average lesion MTR decreased slightly in the build-up to enhancement, decreased dramatically during enhancement and showed recovery in the period after cessation. The power calculations showed that for a power of 80%, approximately 136 patients per trial (mean number of 6 lesions per patient) are required to detect a 30% increase in lesional MTR post-enhancement compared with placebo, whereas 48 subjects are required to detect a 50% increase in lesional MTR compared with placebo. Recovery of lesion MTR is a feasible outcome measure for future multicentre clinical trials measuring the effect of remyelinating agents.

The role of MRI as a surrogate outcome measure in multiple sclerosis

2002 ◽  
Vol 8 (1_suppl) ◽  
pp. 40-51 ◽  
Author(s):  
HF McFarland ◽  
F. Barkhof ◽  
J. Antel ◽  
DH Miller
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Imaging Techniques ◽  
Primary Outcome Measure ◽  
New Therapies ◽  
Surrogate Outcome ◽  
Underlying Pathology ◽  
Surrogate Outcome Measure

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sclerosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on clinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration. Multiple Sclerosis (2002)8, 40-51

The role of MRI as a surrogate outcome measure in multiple sclerosis

2002 ◽  
Vol 8 (1) ◽  
pp. 40-51 ◽  
Author(s):  
H F McFarland ◽  
F Barkhof ◽  
J Antel ◽  
D H Miller
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Imaging Techniques ◽  
Primary Outcome Measure ◽  
New Therapies ◽  
Surrogate Outcome ◽  
Underlying Pathology ◽  
Surrogate Outcome Measure

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sclerosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on clinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.

Cervical cord magnetization transfer ratio and clinical changes over 18 months in patients with relapsing-remitting multiple sclerosis: a preliminary study

2006 ◽  
Vol 12 (5) ◽  
pp. 662-665 ◽  
Author(s):  
A Charil ◽  
D Caputo ◽  
R Cavarretta ◽  
M P Sormani ◽  
P Ferrante ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Relapse Rate ◽  
Magnetization Transfer ◽  
Small Sample ◽  
Cervical Cord ◽  
Magnetization Transfer Ratio ◽  
Short Term ◽  
Disease Evolution ◽  
Transfer Ratio ◽  
Relapsing Remitting

Background Magnetization transfer ratio (MTR) permits the quantitative estimation of cervical cord tissue damage in patients with multiple sclerosis (MS). Objective To determine whether a single time-point MTR scan of the cervical cord is associated with short-term disease evolution in patients with relapsing-remitting (RR) MS. Methods Using a 1.5-T magnetic resonance imaging (MRI) system with a tailored cervical cord phased array coil, fast short-tau inversion recovery (fast-STIR) and MTR scans were obtained from 14 untreated patients with RRMS at baseline. Cervical cord MTR histograms were derived. Over the 18- month follow-up period, relapse rate was measured and disability assessed by the Expanded Disability Status Scale (EDSS) score. Results Average cervical cord MTR was correlated with relapse rate ( r= -0.56, P = 0.037). A moderate correlation ( r values ranging from -0.33 to -0.36) between baseline cervical cord MTR metrics and EDSS changes over 18 months was also noted, albeit statistical significance was not reached ( P = 0.26 and 0.21, respectively) perhaps because of the relatively small sample size. Conclusions This study suggests that a ‘snapshot’ MT MRI assessment of the cervical cord may detect cervical cord tissue changes associated with short-term disease evolution in RRMS.

Brain atrophy and magnetization transfer ratio following methylprednisolone in multiple sclerosis: short-term changes and long-term implications

2005 ◽  
Vol 11 (2) ◽  
pp. 140-145 ◽  
Author(s):  
Robert J Fox ◽  
Elizabeth Fisher ◽  
Jean Tkach ◽  
Jar-Chi Lee ◽  
Jeffrey A Cohen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Magnetization Transfer ◽  
Magnetization Transfer Ratio ◽  
Short Term ◽  
Whole Brain ◽  
Transfer Ratio ◽  
Short Term Change ◽  
Term Change ◽  
The Impact

Background: The short-term effect of corticosteroids on MRI measures of multiple sclerosis (MS) is not well understood and may have a significant impact when using these quantitative measures to evaluate disease activity and changes following other therapeutic interventions. Objective: To determine the impact of a course of intravenous methylprednisolone (IVMP) on quantitative measures of disease activity and tissue injury in MS patients. Methods: We prospectively measured brain parenchymal fraction (BPF), magnetization transfer ratio (MTR, lesional and whole brain), and lesion volumes on nine weekly brain MRI studies in ten MS patients receiving a course of IVMP. A group of nine MS patients not receiving IVMP served as controls. Results: In comparison to untreated controls, BPF declined over the eight weeks following IVMP treatment (P<0.02). BPF decline was most prominent in patients with secondary progressive MS (SPMS, P<0.03), and was not seen in relapsing-remitting (RR) MS patients. Short-term change in BPF correlated with baseline BPF (r=0.62, P=0.05) and short-term change in lesional MTR (r=-0.55, P=0.03), but not with change in enhancing lesion volume. Short-term change in lesional MTR inversely correlated with baseline lesional and whole brain MTR (r=-0.79, P=0.04 for both). There was no significant difference between treated and control patients in measures of MTR or T2, T1 or enhancing lesion volumes. Conclusions: Patients with SPMS showed a greater decline in BPF following IVMP than RRMS patients. A correlation between changes in BPF and MTR suggest that these changes are secondary to altered water content within MS lesions. Differential response to a standardized therapeutic intervention in RRMS and SPMS suggests that responses to therapy may differ due to a fundamental pathologic difference between early and late stage MS.

Characterization of white matter damage in animal models of multiple sclerosis by magnetization transfer ratio and quantitative mapping of the apparent bound proton fraction f*

2009 ◽  
Vol 15 (1) ◽  
pp. 16-27 ◽  
Author(s):  
M Rausch ◽  
PS Tofts ◽  
P Lervik ◽  
AR Walmsley ◽  
A Mir ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Animal Models ◽  
Tissue Damage ◽  
Magnetization Transfer ◽  
Transverse Relaxation Time ◽  
Magnetization Transfer Ratio ◽  
White Matter Damage ◽  
Transfer Ratio ◽  
Quantitative Mapping

Quantitative magnetization transfer magnetic resonance imaging (qMT-MRI) can be used to improve detection of white matter tissue damage in multiple sclerosis (MS) and animal models thereof. To study the correlation between MT parameters and tissue damage, the magnetization transfer ratio (MTR), the parameter f* (closely related to the bound proton fraction) and the bound proton transverse relaxation time T2B of lesions in a model of focal experimental autoimmune encephalomyelitis (EAE) were measured on a 7T animal scanner and data were compared with histological markers indicative for demyelination, axonal density, and tissue damage. A clear spatial correspondence was observed between reduced values of MTR and demyelination in this animal model. We observed two different levels of MTR and f* reduction for these lesions. One was characterized by a pronounced demyelination and the other corresponded to a more severe loss of the cellular matrix. Changes in f* were generally more pronounced than those of MTR in areas of demyelination. Moreover, a reduction of f* was already observed for tissue where MTR was virtually normal. No changes in T2B were observed for the lesions. We conclude that MTR and qMT mapping are efficient and reliable readouts for studying demyelination in animal models of MS, and that the analysis of regional f* might be even superior to the analysis of MTR values. Therefore, quantitative mapping of f* from human brains might also improve the detection of white matter damage in MS.

Statistical analysis, trial design and duration in Alzheimer's disease clinical trials: a review

2011 ◽  
Vol 24 (5) ◽  
pp. 689-697 ◽  
Author(s):  
P. A. Thompson ◽  
D. E. Wright ◽  
C. E. Counsell ◽  
J. Zajicek
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Statistical Analysis ◽  
Statistical Methods ◽  
Outcome Measures ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Primary Outcome Measure ◽  
Primary Analysis

ABSTRACTBackground: The social and economic burden of Alzheimer's disease (AD) and its increasing prevalence has led to much work on new treatment strategies and clinical trials. The search for surrogate markers of disease progression continues but traditional parallel group trial designs that use well-established, but often insensitive, clinical outcome measures predominate.Methods: We performed a systematic search across the Cochrane Library and PubMed abstracts published between January 2004 and August 2009. Information regarding the clinical trial methodology, outcome measures, intervention type and primary statistical analysis techniques was extracted and categorized, according to a standard protocol.Results: We identified 149 papers describing results from clinical trials in AD containing sufficient detail for our purposes. The largest proportion (38%) presented results of trials based on tests of cognition as the primary outcome measure. The primary analysis in most papers (85%) was a univariate significance test of a single primary outcome measure.Conclusions: The majority of trials reported a comparison of baseline and end-point assessment over relatively short patient follow-up periods, using univariate statistical methods to compare differences between intervention and control groups in the primary analysis. There is considerable scope to introduce newer statistical methods and trial designs in treatment evaluations in AD.

Voxel-based analysis of grey matter magnetization transfer ratio maps in early relapsing remitting multiple sclerosis

2007 ◽  
Vol 13 (4) ◽  
pp. 483-489 ◽  
Author(s):  
B. Audoin ◽  
G. Davies ◽  
W. Rashid ◽  
L. Fisniku ◽  
A.J. Thompson ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Grey Matter ◽  
Morphological Changes ◽  
Magnetization Transfer ◽  
Histogram Analysis ◽  
Magnetization Transfer Ratio ◽  
Transfer Ratio ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

Previous studies using magnetization transfer ratio (MTR) histogram analysis have demonstrated the existence of global grey matter (GM) abnormalities in patients with early relapsing-remitting multiple sclerosis (RRMS). However, MTR histogram analysis does not provide any information on the localization of the morphological changes within the GM. The aim of this study was to investigate the localization of GM injury in early RRMS, performing voxel-based analysis of GM MTR maps. Statistical mapping analysis of GM MTR maps was performed in a group of 38 patients with early RRMS and 45 healthy controls. Between-group comparisons (P<0.05, corrected for multiple comparisons) demonstrated significant GM MTR decrease in patients located in the bilateral lenticular nuclei, the bilateral insula, the left posterior cingulate cortex, and the right orbitofrontal cortex. To limit the potential confounding effect of regional GM atrophy, the percentages of GM were assessed in the regions showing significant MTR decrease, and no GM atrophy was evidenced in these regions. This study demonstrates that several GM regions are commonly affected in patients with early RRMS. Predominant involvement of these structures may be partly related to their vulnerability to anterograde or retrograde degeneration from transected axons in the white matter and/or to the predominant localization of GM demyelinating lesions in such regions. Multiple Sclerosis 2007; 13: 483-489. http://msj.sagepub.com

Surface-in pathology in multiple sclerosis: a new view on pathogenesis?

Brain ◽  
2021 ◽  
Author(s):  
Matteo Pardini ◽  
J William L Brown ◽  
Roberta Magliozzi ◽  
Richard Reynolds ◽  
Declan T Chard
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Grey Matter ◽  
Magnetization Transfer ◽  
Neuronal Loss ◽  
Magnetization Transfer Ratio ◽  
Supporting Evidence ◽  
Transfer Ratio ◽  
Meningeal Inflammation

Abstract While multiple sclerosis can affect any part of the CNS, it does not do so evenly. In white matter it has long been recognized that lesions tend to occur around the ventricles, and grey matter lesions mainly accrue in the outermost (subpial) cortex. In cortical grey matter, neuronal loss is greater in the outermost layers. This cortical gradient has been replicated in vivo with magnetization transfer ratio and similar gradients in grey and white matter magnetization transfer ratio are seen around the ventricles, with the most severe abnormalities abutting the ventricular surface. The cause of these gradients remains uncertain, though soluble factors released from meningeal inflammation into the CSF has the most supporting evidence. In this Update, we review this ‘surface-in’ spatial distribution of multiple sclerosis abnormalities and consider the implications for understanding pathogenic mechanisms and treatments designed to slow or stop them.

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