Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis

Filippi, Massimo; Horsfield, Mark A.; Adèr, H.J.; Barkhof, Frederik; Bruzzi, Paolo; Evans, Alan C.; Frank, Joseph A.; Grossman, Robert I.; McFarland, Henry F.; Molyneux, Pd; Paty, D. W.; Simon, Jack H.; Tofts, Paul S.; Wolinsky, Jerry S.; Miller, D. H.

doi:10.1002/ana.410430414

Cited by 152 publications

(106 citation statements)

References 55 publications

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“…24,25 Within this spectrum of measures, there are basically two avenues to obtain a measure of disease activity: 1) a marker directly linked (specific) to a particular physiological or pathological process, 2) a differential of disease severity measures, obtained at two or more different timepoints. An example of the first is the occurrence of gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) contrast enhancement, capturing active focal blood-brain barrier patency, and an example of the second is rates of change of brain parenchymal fraction.…”

Section: Mri Variablesmentioning

confidence: 99%

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

Meier

Weiner

2007

Neurotherapeutics

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Summary:This article discusses and reviews advanced forms of serial morphometry in the context of a disease progression model in multiple sclerosis (MS). This model of disease activity distinguishes between overall disease activity and the proportion thereof that becomes permanent damage. This translates into a progression model that features a repair potential, which, when exhausted, marks the conversion or progression from relapsing to progressive disease. The level of repair capacity at a given time determines the rate of progression. Both clinical and MRI variables appear to be in support of such a model. We examine possible MRI markers for this repair capacity, particularly the short-term behavior of new MRI lesions, quantified by methods of time-series analysis-that is, capturing lesion dynamics in the form of MRI intensity change directly, rather than shape or volume change. Lower rates of individual lesion recovery may represent lower repair and greater proximity to a progressive stage. Individuals with low transient lesion turnover appear to undergo more rapid progression and atrophy. Because disease-modifying therapies aim to alter the pathophysiological chain of inflammation, demyelination, and axonal loss, a therapeutic effect may therefore be more readily apparent as a change in lesion dynamics and recovery rate and level, rather than a change in total lesion burden or enhancing lesion number. Key Words: Multiple sclerosis, disease modeling, serial MRI, morphometry, lesion evolution, repair. THE REPAIR POTENTIAL HYPOTHESISMore than 80% of newly diagnosed cases of clinically definite multiple sclerosis (MS) fall into the relapsingremitting (RRMS) category. A large proportion of RRMS patients eventually convert to a secondary progressive stage (SPMS) within 6 -10 years. 1,2 The hallmark of this stage is a progressive worsening of disability in the absence of relapses, and a shift from inflammatory to degenerative activity, apparent on MRI as fewer contrast-enhancing lesions and accelerated brain parenchymal atrophy (FIG. 1). The etiology of this progression is not known, but a premise commonly offered is that of a threshold effect and the exhaustion of structural and functional redundancy, leading from inflammatory and relapsing to more diffuse and accelerated accrual of damage.Here we review and discuss this progression model, focusing on the concept of a hypothesized repair potential as a marker for progression. Of particular interest is the possibility of obtaining early MRI markers of this repair potential from advanced forms of serial quantitativ MRI. As new therapies with alternative mechanisms (other than broad or targeted immune suppression) become available to MS patients, specific markers that reliably predict long-term progression early in the disease are becoming increasingly critical.A growing body of evidence is congruent with a repair potential model: histopathological analyses have revealed a shift from focal inflammatory activity in RRMS to diffuse damage in SPMS 3 and overall reduced...

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Section: Mri Variablesmentioning

confidence: 99%

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

Meier

Weiner

2007

Neurotherapeutics

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“…and the analysis procedure (by defining rules) [6][7][8][9]. The MAGNIMS (magnetic resonance in multiple sclerosis) study group defined many guidelines for multicentre MR studies in MS [10,11]. At times this involved MR physicists travelling to different sites within Europe, sometimes with phantoms, to improve the protocol matching [8].…”

Section: Concepts In Multicentre Studiesmentioning

confidence: 99%

Multicentre imaging measurements for oncology and in the brain

Tofts

Collins²

2011

BJR

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ABSTRACT. Multicentre imaging studies of brain tumours (and other tumour and brain studies) can enable a large group of patients to be studied, yet they present challenging technical problems. Differences between centres can be characterised, understood and minimised by use of phantoms (test objects) and normal control subjects. Normal white matter forms an excellent standard for some MRI parameters (e.g. diffusion or magnetisation transfer) because the normal biological range is low (,2-3%) and the measurements will reflect this, provided the acquisition sequence is controlled. MR phantoms have benefits and they are necessary for some parameters (e.g. tumour volume). Techniques for temperature monitoring and control are given. In a multicentre study or treatment trial, between-centre variation should be minimised. In a cross-sectional study, all groups should be represented at each centre and the effect of centre added as a covariate in the statistical analysis. In a serial study of disease progression or treatment effect, individual patients should receive all of their scans at the same centre; the power is then limited by the within-subject reproducibility. Sources of variation that are generic to any imaging method and analysis parameters include MR sequence mismatch, B 1 errors, CT effective tube potential, region of interest generation and segmentation procedure. Specific tissue parameters are analysed in detail to identify the major sources of variation and the most appropriate phantoms or normal studies. These include dynamic contrast-enhanced and dynamic susceptibility contrast gadolinium imaging, T 1 , diffusion, magnetisation transfer, spectroscopy, tumour volume, arterial spin labelling and CT perfusion. There have been many approaches to carrying out multicentre imaging studies. A common difficulty is a measurement made at one centre is often not reproducible at another centre and to pool measurements from several centres into a large trial reduces its statistical power. Yet there is a strong imperative to be able to carry out meaningful multicentre studies so clinical drug trials with a large number of subjects can take place in a reasonable time. Analysing the sources of intercentre variation, with insight into the MR physics aspects of the imaging process, and then reducing them where possible has allowed progress to be made. Measuring actual quantities, such as volume, relaxation time or transfer constant, has meant in principle we are able to obtain values independent of the scanner used and the particular way the measurement was carried out.Multicentre imaging studies are desirable for several reasons. 1. In clinical treatment trials, they are usually the only way of achieving the large number of patients needed to statistically power the study. 2. Measurement of good intercentre agreement demonstrates the imaging technique is good and the results of clinical or scientific research can be applied to other centres. 3. Good intercentre agreement also demonstrates that the physical factors involv...

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“…Nonetheless, these estimates show sensitivity to change over time and for detecting treatment effects. [47][48][49][50][51] As seen in Table 1, the longitudinal changes on various measures of T2-hyperintense lesions in placebo-assigned subjects have varied among studies. Some of these differences can be attributed to patient characteristics with activity levels over a given time interval seemingly higher in the earlier stages of the disease than in cohorts selected for secondary progressive (SP) disease at entry, by enrichment for subjects with active MRI scans at entry into short-term trials, and by improvements in imaging protocols over time.…”

Section: Figmentioning

confidence: 99%

Imaging of multiple sclerosis: Role in neurotherapeutics

Bakshi¹,

Minagar²,

Jaisani³

et al. 2005

Neurotherapeutics

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Summary:Magnetic resonance imaging (MRI) plays an everexpanding role in the evaluation of multiple sclerosis (MS). This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected clinically isolated syndromes. In addition, MRI is a key tool in providing primary therapeutic outcome measures for phase I/II trials and secondary outcome measures in phase III trials. The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called normalappearing brain tissue). However, all current MRI methodology suffers from limited specificity for the underlying histopathology. Conventional MRI techniques, including lesion detection and measurement of atrophy from T1-or T2-weighted images, have been the mainstay for monitoring disease activity in clinical trials, in which the use of gadolinium with T1-weighted images adds additional sensitivity and specificity for areas of acute inflammation. Advanced imaging methods including magnetization transfer, fluid attenuated inversion recovery, diffusion, magnetic resonance spectroscopy, functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS and may provide methods to monitor therapies more sensitively in the future. However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on neurotherapeutics.

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Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis

Cited by 152 publications

References 55 publications

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

Multicentre imaging measurements for oncology and in the brain

Imaging of multiple sclerosis: Role in neurotherapeutics

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