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Multi-parametric MR shows increased T2 heterogeneity in fat infiltrated muscles in Becker Muscular Dystrophy

M.T. Hooijmans¹, C. Baligand², M. Froeling³, J.J.G.M Verschuuren⁴, A.G. Webb², E.H. Niks⁴, and H.E. Kan²

¹Radiology, Amsterdam Medical Center, Amsterdam, Netherlands, ²Radiology; C.J. Gorter Center for High Field MRI, Leiden University Medical Center, Leiden, Netherlands, ³Radiology, University Medical Center Utrecht, Utrecht, Netherlands, ⁴Neurology, Leiden University Medical Center, Leiden, Netherlands

Synopsis

Quantitative MR is increasingly used to assess muscle damage in muscular dystrophies, including BMD. Early markers that reflect changes in muscle tissue are becoming increasingly important with therapies aimed at preserving muscle tissue. This study used a multi-modal MR approach to examine diffusion properties, the average water T2 and SD of the water T2 in non-fat-infiltrated and fat-infiltrated muscles in BMD. Our results indicate that none of the proposed measures are sensitive to muscle tissue changes prior to the replacement of muscle tissue by fat and that only T2 heterogeneity is sensitive to muscle tissue changes in the presence of fat in patients with BMD.

Introduction:

In Becker muscular dystrophy (BMD), muscles are progressively infiltrated with fat and fibrosis resulting in muscle weakness¹. Quantitative MR is increasingly used to assess muscle damage in muscular dystrophies (MD)^2-3, including BMD^4-5. Therapy development in MD is aimed at preserving muscle tissue and the replacement of muscle tissue by fat is considered an irreversible process. Therefore, non-invasive outcome measures that reflect changes in muscle tissue itself and/or that are sensitive to changes occurring prior to fat infiltration are critically needed. Good candidate MR techniques could be Diffusion Tensor Imaging (DTI), as it is sensitive to micro-structural changes in muscle injury⁶ and both the average water T2 and water T2 heterogeneity as they have shown to be sensitive to inflammation and fibrosis in MD^7-8.The aim of this study was to examine diffusion properties and water T2 relaxation times in fat infiltrated and non-fat infiltrated lower leg muscles of BMD patients.

Methods:

MR datasets were acquired in the lower leg of 22 BMD patients (age: 41.4±13.6 yrs) and 13 controls (age: 43±13.7 yrs) on a Philips Ingenia 3T system using a 16-channel receive coil. The protocol consisted of DTI (SE; TR/TE 2990/49ms; NSA 6; b-values 0/450 s/mm2; voxel size 2x2x6mm; no gap; 12 slices; SSGR, SPAIR and selective suppression of the olefinic fat⁹), 3-point DIXON images to determine muscle fat fraction (TR/TE/∆TE 210/4.41/0.76ms; FA 8°; voxel size 1x1x10mm; gap 5mm;) and multi-echo SE images to assess the mean and SD of water T2 relaxation times (17echoes;TR/TE/∆TE 3000/7.6/7.6ms; voxel size 1.4x1.8x10mm; gap 20mm; 5 slices).

Data-analysis:

Diffusion data were de-noised, registered and corrected for eddy currents. Eigenvalues were estimated according to a WLLS fit and FA and MD were obtained. Fat fraction maps were reconstructed using a 6 peak fat model. Water T2 maps were reconstructed using an EPG algorithm¹⁰. DTI-datasets with SNR levels >20 and %fat >50 were excluded from the analysis¹¹. All outcome parameters were determined in ROIs drawn for the gastrocnemius medialis (GCM) and lateralis (GCL), soleus (SOL) peroneus (PER), tibialis anterior (TA) and posterior (TP) muscle and reported as their mean value over multiple slices. All muscles of the BMD patients were classified into two groups according to their fat fraction: Non Fat Infiltrated muscles BMD (NFI BMD) and Fat Infiltrated muscles BMD (FI BMD). Cut-off values were based on the mean fat fraction +2*SD of that specific muscle in controls¹². Differences between the groups were assessed on a muscle by muscle basis using a Kruskal-Wallis test corrected for multiple comparisons, the p-value was set to <0.001.

Results:

Multi-parametric axial images of a representative BMD patient are shown in figure 1. The NFI/FI BMD subgroups were divided as follows; GCM/TA/SOL n=4/18, GCL n= 5/17 PER n= 6/16, TP n=9/13. The distribution in %fat in the FI BMD group is shown in figure 1e. Error maps of the residual of the EPG fit were homogeneous and consistent in all datasets (Fig.2). Between group-analysis showed similar DTI and average water T2 values for all groups, except for a significantly elevated water T2 in the GCM and GCL muscle in FI BMD group compared to controls (p-value <0.0003)(Fig.3-4). The SD T2 was significantly elevated for all analysed muscles in the FI BMD group(p-value <0.0001), except for the TP muscle (p-value= 0.21)(Fig.5).

Discussion:

Only muscles that are far in the disease process in BMD, as defined by elevated fat fractions, showed changes in our multi-modal MR protocol. The similar diffusion properties between the groups indicate that the possible changes in muscle microstructure cannot be detected by SE-DTI in BMD. This could be related to the partially functioning dystrophin protein, or to the limited sensitivity of the SE-DTI technique due to the short diffusion times. The minor increase in average T2 in two FI muscles suggests that there is no clear inflammatory component in BMD, which is in agreement with previous work^13-14. Although an increase in T2 heterogeneity could be detected, it was only observed in highly infiltrated muscles. The consistency in error maps across FI and NFI datasets indicates that this increase is not likely to be confounded by fat but rather reflects an actual increase in heterogeneity. This could potentially be caused by the competing effects of fibrosis and inflammation on the water T2¹⁵.

Conclusion

Our results indicate that none of the proposed measures are sensitive to muscle tissue changes prior to the replacement of muscle tissue by fat and that only T2 heterogeneity is sensitive to muscle tissue changes in the presence of fat in patients with BMD.

Acknowledgements

No acknowledgement found.

References

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11] Hooijmans MT, Damon, BM, Froeling M, Versluis MJ, Burakiewicz J, Vershuuren JJGM, et al. Evaluation of skeletal muscle DTI in patients with duchenne muscular Dystrophy NMR in Biomed. 2015 Nov; 28(11):1589:97

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Figures

Figure 1: Multi-parametric axial images of the lower leg of a BMD patient; (a) 1th echo of a multi-spin-echo image with ROIs for the six lower leg muscles - medial and lateral head of gastrocnemius (GM, GL), soleus (SOL), anterior tibialis (TA) peroneus (PER) and the posterior tibialis (TP) muscles; (b) reconstructed T2 map using EPG algorithm; (c) SE-EPI images with diffusion weighting (b = 450 s/mm2); (d) reconstructed water map; (e)Scatter dot plots of the mean fat fraction (%fat) with the 95% confidence interval in FI BMD muscles for the GCM, GCL, PER, SOL, TA and TP muscle.

Figure 2: Multi-spin echo images, reconstructed T2 maps using EPG fit and error maps of the residual of the EPG fit are shown for the middle slice in a control, mildly affected BMD patient and severely affected BMD patient. Fat fraction for the individual leg muscles in the mildly/severely affected BMD patient were as follows; GCL 6.4/ 51.7%; GCM 7.7/46.9%; Sol 5.3/51.2%; PER 10.2/66.9%; TA 4.8/42.2%; TP 4.5/6.9%. Note the increase in error of the residuals near the arteries.

Figure 3: Scatter dot plots of the MD, FA and the three eigenvalues with the 95% confidence interval in healthy controls (black), NFI BMD group (grey) and FI BMD group (red) for the SOL muscle. Significant differences between groups are indicated with *.

Figure 4: Scatter dot plots of the mean water T2 relaxation times (water T2(ms)) with the 95% confidence interval in healthy controls (black), NFI BMD group (grey) and FI BMD group (red) for the GCM, GCL, PER, SOL, TA and TP muscle. Significant differences between groups are indicated with *.

Figure 5: Scatter dot plots of the SD of the water T2 relaxation times (SD T2) with the 95% confidence interval in healthy controls (black), NFI BMD group (grey) and FI BMD group (red) for the GCM, GCL, PER, SOL, TA and TP muscle. Significant differences between groups are indicated with *. Note the lack of change in the TP muscle which is also the muscle with the lowest increase in %fat (see figure 1e).

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)

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