We studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchenne muscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction (FF) to age on loss of ambulation (LoA).VL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies in Leiden University Medical Center (LUMC) and Cincinnati Children's Hospital Medical Center (CCHMC). CCHMC included ambulant patients, while LUMC included a mixed ambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The additive value of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.Eighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age, 6-minute walking test distances were smaller and VL FFs were correspondingly higher in LUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF for the time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05-1.26; p = 0.003) and 0.96 for CCHMC (95% CI 0.84-1.10; p = 0.569).The hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA in patients with a 10% higher VL FF at any age. Although results should be confirmed in a larger cohort with prospective determination of the clinical endpoint, this added predictive value of VL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool in clinical trials.
Background The monoexponential water T 2 (T 2‐mono ) is a proven biomarker of disease activity in neuromuscular disorders (NMDs). However, it lacks specificity, being elevated in the presence of several pathological processes and pathomorphological alterations in the muscle tissue. Purpose To investigate the multiexponential behavior of the water T 2 ‐relaxation in the skeletal muscle of NMD patients, aiming to identify more sensitive and specific biomarkers of disease activity. Study Type Retrospective case–control. Population Thirty Duchenne muscular dystrophy and 114 inclusion body myositis patients and 55 control subjects. Field Strength/Sequence 3T/Single‐voxel proton spectroscopy ( 1 H‐MRS) and multispin‐echo (MSE) imaging. Assessment Water T 2 ‐decay curves generated from 1 H‐MRS data acquired at 14 echo‐times were fitted to mono‐ and biexponential models and the adjusted R 2 of each fit was computed. Additionally, T 2 spectra were generated from a regularized inverse Laplace transform. For comparison, water T 2 maps were generated from the MSE data. The performances of the different variables at identifying patients were assessed via receiver operating characteristic (ROC)‐curve analysis. Statistical Tests Chi‐square, Kruskal–Wallis, and Mann–Whitney with Bonferroni correction for multiple comparisons. Results T 2‐mono was elevated in patients ( P <0.05), but could not distinguish inclusion body myositis (IBM) from Duchenne muscular dystrophy (DMD). While 79% of IBM data presented a biexponential behavior, this was only 16% and 10% for DMD and control data, respectively ( P <0.05). All T 2 spectra presented an intermediate‐T 2 peak characterized by an elevated T 2 in patients ( P <0.05) and by a relative fraction that was abnormally smaller in IBM patients ( P <0.05). Also, a long‐T 2 peak was exclusively observed in IBM patients. A combination of T 2 ‐spectrum variables performed best at identifying patients. Data Conclusion T 2 spectra not only provided more sensitive and specific markers of disease presence than the T 2‐mono , but also allowed distinguishing IBM from DMD patients. This must reflect distinct predominant pathological alterations between these diseases, suggesting that these markers provide additional pathophysiological/histopathological information that are missing from T 2‐mono . Level of Evidence 3 Technical Efficacy Stage 3
Skeletal muscle phosphorus‐31 31 P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31 P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31 P MRS methods can probe it. Here we consider basic signal‐acquisition parameters related to radio frequency excitation, TR, TE , spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31 P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near‐infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1 H MRS measurements) can help in the physiological/metabolic interpretation of 31 P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.
Aging is a multi-factorial process and studies in the lower leg are scarce. We performed a multi-contrast protocol in 51 volunteers from 20 to 81 y.o. We found an age-related increase of muscle water T1(water-fat separation,MR fingerprinting), fat fraction, water T2 and T2 heterogeneity in the anterior and posterior compartments. Phosphodiesters and mitochondrial stress biomarkers also increased with age. Through bi-compartment water T2 CPMG measures, age-related increases of the long water T2 relative fraction were observed relative to the short water T2 (T2-H2O-CPMG-short) fraction, but T2-H2O-CPMG-short values were unaltered with age, suggesting inflammation with preservation of the intracellular water compartment.
In recent years, quantitative nuclear magnetic resonance imaging and spectroscopy (NMRI and NMRS) have been used more systematically as outcome measures in natural history and clinical trial studies for Duchenne muscular dystrophy (DMD). Whereas most of these studies have emphasized the evaluation of the fat fraction as an assessment for disease severity, less focus has been placed on metabolic indices measured by NMRS. 31 P NMRS in DMD reveals an alkaline inorganic phosphate (P i ) pool, originating from either leaky dystrophic myocytes or an increased interstitial space. 1 H NMRS, exploiting the pH‐sensitive proton resonances of carnosine, an intracellular dipeptide, was used to distinguish between these two hypotheses. NMR data were obtained in 23 patients with DMD and 14 healthy subjects on a 3‐T clinical NMR system. Both 31 P and 1 H NMRS data were acquired at the level of the gastrocnemius medialis muscle. A multi‐slice multi‐echo imaging acquisition was performed for the determination of water T 2 and fat fraction in the same region of interest. Whereas nearly all patients with DMD showed an elevated pH compared with healthy controls when using 31 P NMRS, 1 H NMRS‐determined pH was not systematically increased. As expected, the carnosine‐based intracellular pH was never found to be alkaline in the absence of a concurrent P i ‐based pH elevation. In addition, abnormal intracellular pH, based on carnosine, was never associated with normal water T 2 values. We conclude that, in one group of patients, both 1 H and 31 P NMRS showed an alkaline pH, originating from the intracellular compartment and reflecting ionic dysregulation in dystrophic myocytes. In the other patients with DMD, intracellular pH was normal, but an alkaline P i pool was still present, suggesting an extracellular origin, probably revealing an expanded interstitial volume fraction, often associated with fibrotic changes. The data demonstrate that 1 H NMRS could serve as a biomarker to assess the normalization of intramyocytic pH and sarcolemmal permeability following therapy inducing dystrophin expression in patients with DMD.
The 255th ENMC workshop on Muscle Imaging in Idiopathic Inflammatory myopathies (IIM) aimed at defining recommendations concerning the applicability of muscle imaging in IIM. The workshop comprised of clinicians, researchers and people living with myositis. We aimed to achieve consensus on the following topics: a standardized protocol for the evaluation of muscle images in various types of IIMs; the exact parameters, anatomical localizations and magnetic resonance imaging (MRI) techniques; ultrasound as assessment tool in IIM; assessment methods; the pattern of muscle involvement in IIM subtypes; the application of MRI as biomarker in follow-up studies and clinical trials, and the place of MRI in the evaluation of swallowing difficulty and cardiac manifestations. The following recommendations were formulated: In patients with suspected IIM, muscle imaging is highly recommended to be part of the initial diagnostic workup and baseline assessment. MRI is the preferred imaging modality due to its sensitivity to both oedema and fat accumulation. Ultrasound may be used for suspected IBM. Repeat imaging should be considered if patients do not respond to treatment, if there is ongoing diagnostic uncertainty or there is clinical or laboratory evidence of disease relapse. Quantitative MRI is established as a sensitive biomarker in IBM and could be included as a primary or secondary outcome measure in early phase clinical trials, or as a secondary outcome measure in late phase clinical trials. Finally, a research agenda was drawn up.
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