Objective:To identify the best quantitative fat-water MRI biomarker for disease progression of leg muscles in Becker muscular dystrophy (BMD) by applying a stepwise approach based on standardized response mean (SRM) over 24 months, correlations with baseline ambulatory tests and reproducibility.Methods:Dixon fat-water imaging was performed at baseline (n=24) and 24 months (n=20). Fat fractions (FF) were calculated for three center slices and the whole muscles for 19 muscles and six muscle groups. Contractile cross sectional area (cCSA) was obtained from the center slice. Functional assessments included knee extension and flexion force, and three ambulatory tests (North Star Ambulatory Assessment (NSAA), 10-meter run, six-minute walking test). MR parameters were selected using SRM (≥0.8) and correlation with all ambulatory tests (rho≤-0.8). Parameters were evaluated based on intraclass correlation coefficient (ICC) and standard deviation (SD) of the difference. Sample sizes (SS) were calculated assuming 50% reduction in disease progression over 24 months in a clinical trial with 1:1 randomization.Results:Median whole muscle FF increased between 0.2-2.6% without consistent cCSA changes. High SRMs and strong functional correlations were found for eight FF but no cCSA parameters. All parameters showed excellent ICC (≥0.999) and similar SD of the inter-rater difference. Whole thigh three center slices FF was the best biomarker (SRM=1.04, correlations rho≤-0.81, ICC=1.00, SD=0.23%, SS=59) based on low SD and acquisition and analysis time.Conclusion:In BMD, median FF of all muscles increased over 24 months. Whole thigh three center slices FF reduced the SS by approximately 40% compared to NSAA.
Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra‐ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye‐motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2 water ) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2 water values were determined in 12 HC (aged 22‐65 years), 11 MG (aged 28‐71 years) and six GO (aged 28‐64 years) patients at 7 T using Dixon and multi‐echo spin‐echo sequences. The EOM were semi‐automatically 3D‐segmented by two independent observers. MANOVA and t‐tests were used to assess differences in FF, T2 water and volume of EOM between groups ( P < .05). Bland–Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was −0.7% (LoA: ±2.1%) for the different observers; the bias in FF was −0.3% (LoA: ±2.8%) and 0.03 cm 3 (LoA: ± 0.36 cm 3 ) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm 3 ) and MG (0.8 ± 0.2 cm 3 ) compared with HC (0.6 ± 0.2 cm 3 ). The average T2 water for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2 water was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.
Glucocorticoids influence a wide range of metabolic processes in the human body, and excessive glucocorticoid exposure is known to contribute to the development of metabolic disease. We evaluated the utility of the novel glucocorticoid receptor (GR) antagonist CORT125281 for its potential to overcome adiposity, glucose intolerance, and dyslipidemia and compared this head-to-head with the classic GR antagonist RU486 (mifepristone). We show that, although RU486 displays cross-reactivity to the progesterone and androgen receptor, CORT125281 selectively inhibits GR transcriptional activity. In a mouse model for diet-induced obesity, rhythmicity of circulating corticosterone levels was disturbed. CORT125281 restored this disturbed rhythmicity, in contrast to RU486, which further inhibited endogenous corticosterone levels and suppressed adrenal weight. Both CORT125281 and RU486 reduced body weight gain and fat mass. In addition, CORT125281, but not RU486, lowered plasma levels of triglycerides, cholesterol, and free fatty acids and strongly stimulated triglyceride-derived fatty acid uptake by brown adipose tissue depots. In combination with reduced lipid content in brown adipocytes, this indicates that CORT125281 enhances metabolic activity of brown adipose tissue depots. CORT125281 was also found to increase liver lipid accumulation. Taken together, CORT125281 displayed a wide range of beneficial metabolic activities that are in part distinct from RU486, but clinical utility may be limited due to liver lipid accumulation. This warrants further evaluation of GR antagonists or selective modulators that are not accompanied by liver lipid accumulation while preserving their beneficial metabolic activities.
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Objective:To study the potential of quantitative MRI (qMRI) fat fraction (FF) as biomarker in non-ambulant Duchenne muscular dystrophy (DMD) patients, we assessed the additive predictive value of elbow flexor FF to age on loss of hand-to-mouth movement.Methods:Non-ambulant DMD patients (≥8 years) were included. 4-point Dixon MRI scans of the right upper arm were performed at baseline and at 12, 18 or 24 months follow-up. Elbow flexor FFs were determined from five central slices. Loss of hand-to-mouth movement was determined at study visits and by phone-calls every four months. FFs were fitted to a sigmoidal curve using a mixed model with random slope to predict individual trajectories. The added predictive value of elbow flexor FF to age on loss of hand-to-mouth movement was calculated from a Cox model with the predicted FF as a time varying covariate, yielding a hazard ratio.Results:Forty-eight MRIs of 20 DMD patients were included. The hazard ratio of a percent-point increase in elbow flexor FF for the time to loss of hand-to-mouth movement was 1.12 (95%-confidence interval 1.04-1.21; p=0.002). This corresponded to a 3.13-fold increase of the instantaneous risk of loss of hand-to-mouth movement in patients with a 10 percent-points higher elbow flexor FF at any age.Conclusion:In this prospective study, elbow flexor FF predicted loss of hand-to-mouth movement independent of age. qMRI measured elbow flexor FF can be used as surrogate endpoint or stratification tool for clinical trials in non-ambulant DMD patients.Classification of Evidence:This study provides Class II evidence that qMRI FF of elbow flexor muscles in patients with DMD predicts loss of hand-to-mouth movement independent of age.
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