MRI quantifies neuromuscular disease progression
Authors: Sean C Forbes, Rebecca J Willcocks, William D Rooney, Glenn A Walter, Krista Vandenborne
Journal: The Lancet Neurology (2015)

Several studies provide compelling support for the use of MRI as a sensitive non-invasive method to assess skeletal muscle disease progression in various neuromuscular diseases, including Duchenne muscular dystrophy1Willcocks RJ Arpan IA Forbes SC et al.Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: effects of age and disease progression.Neuromuscul Dis. 2014; 24: 393-401Summary Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 2Bonati U Hafner P Schädelin S et al.Quantitative muscle MRI: a powerful surrogate outcome measure in Duchenne muscular dystrophy.Neuromuscul Dis. 2015; 25: 679-685Summary Full Text Full Text PDF PubMed Scopus (78) Google Scholar and limb girdle muscular dystrophy type 2I.3Willis TA Hollingsworth KG Coombs A et al.Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I: a multicentre longitudinal study.PLoS One. 2013; 8: e70993Crossref PubMed Scopus (132) Google Scholar In The Lancet Neurology, Jasper Morrow and colleagues4Morrow JM Sinclair CDJ Fischmann A et al.MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study.Lancet Neurol. 2015; (published online Nov 5.)http://dx.doi.org/10.1016/S1474-4422(15)00242-2PubMed Google Scholar now report the sensitivity of MRI to track disease progression in 20 patients with Charcot-Marie-Tooth disease 1A and 20 patients with inclusion body myositis. The investigators used a comprehensive study design that included magnetic resonance measures of muscle fat fraction, transverse relaxation time constant (T2), and magnetisation transfer ratio (MTR), along with relevant clinical functional tests (lower limb myometry, Medical Research Council score, Short-Form 36 Quality of Life Score, and Charcot-Marie-Tooth examination score or inclusion body myositis functional rating scale). In this study, the validity of the magnetic resonance measures was supported by strong correlations with clinical functional measures and the responsiveness to disease progression over 1 year was shown to be better with MRI than with the clinical functional tests. Notably, standardised response mean values were greater than 1 in inclusion body myositis and greater than 0·8 in Charcot-Marie-Tooth disease 1A, indicating that magnetic resonance measures are highly sensitive to disease progression and more responsive than established clinical measures. Even though Charcot-Marie-Tooth disease 1A progresses slowly, magnetic resonance measures detected substantial increases in disease pathological changes in 1 year. Thus, the encouraging results of Morrow and colleagues' study might have a profound effect on clinical trials, potentially leading to a need for fewer participants to show efficacy or futility, shorter trials, and ultimately more rapid approval of treatments. An additional advantage of magnetic resonance measures compared with timed functional and strength measures, which are highly relevant to paediatric neuromuscular diseases, is that they are not dependent on participant motivation, an issue that has been of concern in Duchenne muscular dystrophy trials.5Hoffman EP Connor EM Orphan drug development in muscular dystrophy: update on two large clinical trials of dystrophin rescue therapies.Discov Med. 2013; 16: 233-239PubMed Google Scholar Along with showing that MRI is a sensitive measure of disease progression in Charcot-Marie-Tooth disease 1A and inclusion body myositis, Morrow and colleagues also report that MRI-measured T2 and MTR are abnormal in these diseases even when fat fraction values are within normal limits. The authors interpret this to suggest that tissue water distribution changes before fat infiltration. Because MRI-measured T2 and MTR are affected by both fat and water content, the interpretation of these measures can be difficult in the context of neuromuscular diseases, and several analysis approaches are being developed to address this concern.6Azzabou N Carlier P Fat quantification and T2 measurement.Pediatr Radiol. 2014; 44: 1620-1621Crossref PubMed Scopus (9) Google Scholar, 7Rooney WD Pollaro J Forbes SC Wang DJ Vandenborne K Walter GA Application of the extended phase graph technique to improve T2 quantitation across sites.Proc Intl Soc Mag Reson Med. 2011; 19: 138Google Scholar, 8Li K Dortch RD Welch EB et al.Multi-parametric MRI characterization of healthy human thigh muscles at 3.0 T—relaxation, magnetization transfer, fat/water, and diffusion tensor imaging.NMR Biomed. 2014; 27: 1070-1084Crossref PubMed Scopus (59) Google Scholar Alternatively, magnetic resonance spectroscopy (MRS) could be used to more directly measure 1H2O T2 (figure) and MTR, and this would avoid the influence of fat.9Machannab J Schick F Jacob S Lutz O Claussen CD An interleaved sampling strategy for MR spectroscopy in vivo: applications on human calf musculature.Magn Reson Imaging. 2000; 18: 189-197Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar This method has already been applied to neuromuscular diseases10Forbes S Willcocks R Triplett W et al.Magnetic resonance imaging and spectroscopy assessment of lower extremity skeletal muscles in boys with duchenne muscular dystrophy: a multicenter cross sectional study.PLoS One. 2014; 9: e106435Crossref PubMed Scopus (91) Google Scholar, 11Arpan I Willcocks RJ Forbes SC et al.Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS.Neurology. 2014; 83: 974-980Crossref PubMed Scopus (110) Google Scholar 1H2O T2 has been shown to differentiate boys with Duchenne muscular dystrophy and healthy individuals, even at a young age, when muscle fat fraction levels are normal.10Forbes S Willcocks R Triplett W et al.Magnetic resonance imaging and spectroscopy assessment of lower extremity skeletal muscles in boys with duchenne muscular dystrophy: a multicenter cross sectional study.PLoS One. 2014; 9: e106435Crossref PubMed Scopus (91) Google Scholar Furthermore, 1H2O T2 measured with MRS decreases with corticosteroid treatment in Duchenne muscular dystrophy, presumably because of reduced inflammation.11Arpan I Willcocks RJ Forbes SC et al.Examination of effects of corticosteroids on skeletal muscles of boys with DMD using MRI and MRS.Neurology. 2014; 83: 974-980Crossref PubMed Scopus (110) Google Scholar Therefore, although lacking in spatial resolution, MRS is a high-fidelity approach to calculate 1H2O T2 and MTR measurements in neuromuscular diseases. In view of the low prevalence of neuromuscular diseases, standardisation of methods over several sites will be crucial to the successful implementation of magnetic resonance biomarkers in clinical trials. Although challenging, when standardised protocols are carefully implemented across sites, several important magnetic resonance measures can be reproducibly obtained, including MRI-measured T2 and MRS measures of fat fraction and 1H2O T2.12Forbes SC Walter GA Rooney WD et al.Skeletal muscles of ambulant children with duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy.Radiology. 2013; 269: 199-207Crossref Scopus (70) Google Scholar Similar to neuroimaging and musculoskeletal studies, for larger trials, incorporation of an infrastructure that enables automated or semi-automated processing, analysis, and quality control procedures that can detect and correct for system deviations, including instrument modifications and upgrades, will be particularly important. Importantly, Morrow and colleagues showed the effectiveness of monitoring disease progression using magnetic resonance sequences commonly available on clinical scanners. Although the measures used were highly effective in tracking progression, future studies might include some developments. For example, the accuracy of fat fraction from the Dixon fat-water imaging sequence might be further improved by correcting for T2*, accounting for noise bias, and using a multipeak Dixon model specific to skeletal muscle.13Triplett WT Baligand C Forbes SC et al.Chemical shift-based MRI to measure fat fractions in dystrophic skeletal muscle.Magn Reson Med. 2014; 72: 8-19Crossref PubMed Scopus (73) Google Scholar, 14Loughran T Higgins DM McCallum M Coombs A Straub V Hollingsworth KG Improving highly accelerated fat fraction measurements for clinical trials in muscular dystrophy: origin and quantitative effect of R2* Changes.Radiology. 2015; 275: 570-578Crossref PubMed Scopus (36) Google Scholar As suggested by Morrow and colleagues, the optimum outcome measures will depend on the pathophysiology, stage of disease, muscles affected, and intervention to be tested. This could include different types of magnetic resonance measures and analysis procedures. For example, targeting of specific muscles might be optimum for certain stages of a particular disease. Also, use of large regions of interest that encompass the entire muscle might be needed to detect pathological changes and improve responsiveness in some diseases, by contrast with small portions of the muscle, as used by Morrow and colleagues to measure T2 and MTR. Overall, this study by Morrow and colleagues clearly shows the value of MRI to monitor disease progression and sets the stage for its potential use in clinical trials for Charcot-Marie-Tooth disease 1A and inclusion body myositis. With increased evidence of the validity and sensitivity of magnetic resonance biomarkers in neuromuscular diseases, the path for biomarker qualification (eg, their approval by the Food and Drug Administration) should be carefully explored, with the ultimate goal of using magnetic resonance measures as surrogate endpoints in clinical trials. The ImagingDMD study is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Neurological Disorders and Stroke (RO1AR056973/R01AR065943). We declare no competing interests. MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort studyMRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. Full-Text PDF Open Access