INTRODUCTION

Facioscapulohumeral muscular dystrophy (FSHD) is a severe neuromuscular disorder characterized by structural changes affecting skeletal muscle tissues (inflammation, necrosis and fat infiltrations), resulting in progressive muscle wasting and dysfunction. Qualitative T1-weighted imaging is often used in this condition to evaluate the pattern of muscles affected by fatty infiltrations. Fat suppressed T2-weighted imaging has also been suggested to detect edema, as an early indicator of disease progression¹. Because innovative therapeutic approaches are about to be evaluated in clinical trials², quantitative imaging biomarkers reflecting the different pathological processes are needed to objectively assess treatment efficacy. It is well accepted that intramuscular fat fraction (FF), measured by Dixon sequences, represents a robust biomarker of disease severity in neuromuscular diseases (NMDs). Water T2 has been considered for decades as an efficient biomarker of disease activity³. Tissue sodium concentration (TSC), as measured by ²³Na MRI, has also been shown to be a sensitive marker of cell integrity and energy metabolism, for example in DMD⁴ and in myotonic dystrophy patients⁵. Very recently, water T1, as measured by MR fingerprinting with water and fat separation (MRF T1-FF)⁶, has also been proposed for monitoring disease activity in NMDs. The aim of our study was to determine the value of these quantitative state of the art ¹H and ²³Na MRI to provide imaging biomarkers of disease activity and disease severity in patients with FSHD.

METHODS

Sixteen patients (33 - 67 years, 13 men) with genetically confirmed FSHD, and 9 age-matched volunteers (30 - 70 years, 8 men) were recruited for this prospective study. Images were acquired in the dominant leg with a 3T scanner (Magnetom Skyra, Siemens Healthcare).
A 15-channel quadrature knee coil (Siemens Healthcare) was used for 1H imaging. FF was measured using a 3D 3-point Dixon method (3 TEs = 2.75/ 3.95/ 5.15 ms, TR = 10 ms, FA = 3°, 64 slices, 5 mm, T_acq = 3 min 12 s). Fat-suppressed T2 weighted (STIR T2w) images were acquired to qualitatively detect muscle edema (TI = 220 ms, TE = 69 ms, TR = 6.9s, FA = 145°, 23 slices, 5 mm, T_acq = 3 min 29 s). A multi- spin-echo (MSE) sequence was acquired (32 echoes: TEs ranging from 9.5 ms to 304 ms, TR = 3 s, 5 slices, 10 mm, T_acq = 3 min 41 s) from which T2_H2O values were calculated based on a tri-exponential fitting procedure⁷. A MRF T1-FF sequence was acquired (train of 1400 spokes, varying TE, TR and FA, 3 slices, 10mm, T_acq = 30s) to generate T1_H2O maps using a bi-component model⁵.
Sodium imaging was performed using a ²³Na birdcage knee coil (Stark Contrast). All ²³Na images were acquired using a density-adapted 3D-radial readout scheme⁸. For TSC, the following parameters were used: TE = 0.3 ms, TR = 120 ms, 5384 projections, T_acq = 10 min 46 s. Inversion recovery (IR-²³Na) images were acquired with a TI of 34 ms to reduce the signal originating from free ²³Na⁹ (TE = 0.3 ms, TR = 124 ms, 4760 projections, T_acq = 9 min 50 s). TSC and IR-²³Na signals were calibrated using reference phantoms and corrected for the non-negligible sodium signal of fat⁴.
The different ¹H and ²³Na indices were estimated in the following muscles of the leg: gastrocnemius medialis, soleus, tibialis anterior, and tibialis posterior.

RESULTS

Figure 1 represents examples of FF maps, STIR T2w images, and corresponding T2_H2O, T1_H2O, TSC and IR-²³Na maps in a 30-year old healthy volunteer and a 47-year old FSHD patients. Fatty infiltrations as well as edema-like changes, increased T2_H2O, T1_H2O, TSC and IR-²³Na signals were present in the FSHD patient compared to the control. Muscles of FSHD patients were gathered in 3 groups according to their intramuscular fat fraction (FF < 0.1, 0.1<FF<0.5 and FF>0.5). Muscles with FF < 0.1 were not different than healthy muscles for all disease activity indices. Both groups with FF > 0.1 had higher T1_H2O and TSC values than muscles with FF < 0.1. IR-²³Na values were statistically increased in the group with FF > 0.5 compared to other groups. Interestingly, even if increased T2_H2O values were observed in some muscles of FSHD patients, T2_H2O was not significantly different between the different FF groups. The most important changes of the different variables were observed for a subgroup of muscles with intermediate FF (Figure 2). Significant correlations were measured between the different indices (Figure 3): the tightest being observed between the two ²³Na variables (R = 0.73) and between T1_H2O and TSC (R = 0.87).

DISCUSSION AND CONCLUSION

Here, we evaluated different state of the art ¹H and ²³Na MRI approaches for providing quantitative indices related to disease severity (FF) and disease activity (T2_H2O, T1_H2O, TSC and IR-²³Na) in patients with FSHD. We determined that most of these variables can differentiate patients from healthy controls. From these data, it seems that T2_H2O values were more influenced than the others by fatty infiltrations. Imaging variables related to water mobility (T1_H2O) and ion homeostasis (TSC) were increased at an early stage of the tissue degeneration process in several muscles and represent potential candidates for assessing early treatment response in clinical trials related to FSHD.

Acknowledgements

No acknowledgement found.