Quantitative Muscle MRI as an Assessment Tool for Monitoring Disease Progression in LGMD2I: A Multicentre Longitudinal Study

<div><p>Background</p><p>Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups.</p><p>Objective</p><p>To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period.</p><p>Methods</p><p>32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (<i>FKRP</i>) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale.</p><p>Results</p><p>There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T₁w images.</p><p>Conclusions</p><p>Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.</p></div

Quantitative Magnetic Resonance Imaging in Limb-Girdle Muscular Dystrophy 2I: A Multinational Cross-Sectional Study

<div><p>We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (<i>FKRP</i>) gene were recruited. In each patient, T1-weighted (T₁w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I.</p></div

Percentage of LGMD2I patients in each category of each semi-quantitative grade for individual muscle groups using the Mercuri et al. scale, with the median grade for each muscle.

<p>Percentage of LGMD2I patients in each category of each semi-quantitative grade for individual muscle groups using the Mercuri et al. scale, with the median grade for each muscle.</p

Median qualitative grades for selected muscles at baseline and at 12 months.

<p>Number of patients with the same, an increased or decreased qualitative grade at the 12 months follow up compared to the baseline grade is given. Non-parametric paired Wilcoxon signed rank test was used to assess change.</p>*<p>BFSH was graded in 29 participants. BFSH in 3 subjects could not be graded due to poor visualisation. GM = Gluteus Maximus, BFLH = Biceps Femoris long head, ST = Semitendinosus, SM = Semimembranosus, BFSH = Biceps Femoris short head, SAR = Sartorius, VM = Vastus Medialis, GRAC = Gracilis, VL = Vastus Lateralis, RF = Rectus Femoris, MG = Medial Gastrocnemius, LG = Lateral Gastrocnemius, PL = Peroneus Longus, SOL = Soleus, TA = Tibialis Anterior.</p

Median values of the fat fractions at baseline and follow up.

<p>The non-parametric paired Wilcoxon signed rank test was used to test significance.</p>§<p>significant differences between baseline and 12 month follow-up.</p>*<p>possible muscles for future longitudinal analysis; In lower leg; MG, In thigh; SAR, GRAC, VL and RF.</p><p>BFLH = Biceps Femoris long head, ST = Semitendinosus, SM = Semimembranosus, BFSH = Biceps Femoris short head, SAR = Sartorius, VM = Vastus Medialis, GRAC = Gracilis, VL = Vastus Lateralis, RF = Rectus Femoris, MG = Medial Gastrocnemius, LG = Lateral Gastrocnemius, PL = Peroneus Longus, SOL = Soleus, TA = Tibialis Anterior.</p

Summary table of the clinical characteristics of the LGMD2I cohort (n = 38).

<p>Summary table of the clinical characteristics of the LGMD2I cohort (n = 38).</p

Quantitative fat fraction images at baseline in an individual patient (a – mid lower leg level, c – mid thigh level) and at 12 months follow-up (b – mid lower leg level, d – mid thigh level).

<p>Analysis reveals an increase in fat fraction of the medial and lateral gastrocnemius, peroneus longus, vastus lateralis and medialis, semimembranosus, semitendinosus, sartorius and gracilis.</p

The median values of fat fraction (%) in the patient group and the control group.

<p>The p values represent Mann-Whitney U test between patients and controls.</p

Median values of fat fraction for the study cohort stratified by gender (19 males and 19 females).

<p>It illustrates significant differences between the anterior thigh muscles in the male group and preferential sparing of the gracilis compared to sartorius. These features are not found in the female group.</p><p>^* p = 0.05 compared to male ST.</p><p>^** p = 0.01 compared to male SAR.</p>§<p>p<0.005 compared to male VL.</p>†<p>p = 0.05 compared to male MG.</p

Quantitative fat images of the thigh in LGMD2I patients with increasing stages of severity and increasing fat fraction (a–e), and in a control subject (f).

<p>In (a) this is almost normal, however in (e) only sparing of gracilis (fat fraction 13.7%) and sartorius (24.0%) is seen. (SM =  semimembranosus, ST =  semitendinosus, GRAC =  gracilis, SAR =  sartorius).</p