Skeletal Muscle Magnetic Resonance Biomarkers in GNE Myopathy

Abstract

Objective: To characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS).

Methods: Skeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes.

Results: The cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages.

Conclusion: MRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy.

Clinicaltrialsgov identifier: NCT01417533.

© 2020 American Academy of Neurology.

Figures

Figure 1. MRI Findings in GNE Myopathy

Representative T1-weighted (T1W) coronal and axial MRI of lower legs and thighs and corresponding axial short tau inversion recovery (STIR) images in patients with GNE myopathy. (A–D) MRI of a patient early in the disease progression (lower extremity [LE] strength: 94%) shows (A) minimal changes on T1W images and (B) STIR hyperintensity of the anterior tibialis, extensor digitorum longus (EDL), extensor hallucis longus (EHL), and gastrocnemius medialis muscles, and minimal changes in the thigh muscles (C and D). (E–H) A patient with intermediate disease progression (LE strength: 73%) showing 4 stages of muscle involvement identified by MRI: stage I: muscles with no visible abnormalities on T1W or STIR soleus (F) and quadriceps (G) muscles; stage II: STIR hyperintense muscle with minimal or no fat infiltration: gastrocnemius medialis (F) and muscles of the medial and posterior compartments of the thigh (G and H); stage III: muscles with fat infiltration and STIR hyperintensity: tibialis posterior and peroneus brevis (F); stage IV: complete fat replacement: anterior tibialis, EHL, and EDL muscles (F). (I–L) Patient with more advanced disease progression (LE strength: 39%); MRI shows the majority of lower leg muscles at stage IV (J), and involvement of the medial and posterior thigh muscles (K, L). In the anterior thigh compartment, there is STIR hyperintensity of the rectus femoris and vastus intermedius (stage II), with no visible abnormalities of the vastus lateralis (L). (M–P) Patient with advanced disease progression (LE strength: 16%); most of the lower extremity muscles were at stage IV (M, N, O), except for portions of the vastus lateralis and medialis, which show STIR hyperintensity (O, P).

Figure 2. Thigh Muscle Volume

(A) Sample axial slice of the thigh including T1-weighted (top), short tau inversion recovery (STIR) (center), and volumetric thigh tissue composition (bottom) showing regions of unaffected muscle (red), STIR hyperintense muscle (yellow), and intramuscular fat (IMF) (purple). (B) Correlations between the volume of unaffected muscle (blue) and the combined volume of unaffected and STIR hyperintense muscle (red) in the thigh are shown. The correlation coefficients decrease when IMF volume is included (not shown): thigh strength (r = 0.38), lower extremity (LE) strength (r = 0.37), Inclusion Body Myositis Functional Rating Scale (IBMFRS) (r = 0.14), 6-minute walk test (6MWT) (r = 0.32), Adult Myopathy Assessment Tool (AMAT) total score (r = 0.28), and Activities-Specific Balance Confidence Scale (ABC) score (r = 0.30).

Figure 3. MRI Stages of Muscle Involvement

(A) Muscle regions representative of stages of muscle involvement as seen on T1-weighted (T1W) and short tau inversion recovery (STIR) images of the lower leg: stage I: soleus muscle with no visible abnormalities on T1W or STIR images (blue voxel); stage II: gastrocnemius muscle showing STIR hyperintensity muscle and no fat infiltration (purple voxel); stage III: posterior tibialis muscle with fat infiltration and STIR hyperintensity (green voxel); stage IV: complete fat replacement of the anterior tibialis (red voxel). (B) Comparison of different MRI and proton magnetic resonance spectroscopy measures by stage. Boxes represent mean, whiskers show SD. p Values of the difference between contiguous stages are shown. (C) T1 and T2 plotted as a function of fat fraction and T1 plotted as a function of T2 are shown for each stage of muscle involvement. Cr = total creatine; EMCL = extramyocellular lipid; IMCL = intramyocellular lipid; TMA = trimethylamines.