MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

Abstract

Background: A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range.

Methods: We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11.2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes-fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)-were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group.

Findings: Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1.2%, 95% CI 0.5-1.9, p=0.002) but not thigh level (0.2%, -0.2 to 0.6, p=0.38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2.6%, 1.3-4.0, p=0.002) and thigh level (3.3%, 1.8-4.9, p=0.0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=-0.64, p=0.002) and the Charcot-Marie-Tooth examination score (ρ=0.63, p=0.003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4.0 ms [SE 0.5], calf 3.5 ms [0.6]; Charcot-Marie-Tooth 1A thigh 1.0 ms [0.3], calf 2.0 ms [0.3]) and MTR reduced compared with controls (inclusion body myositis thigh -1.5 percentage units [pu; 0.2], calf -1.1 pu [0.2]; Charcot-Marie-Tooth 1A thigh -0.3 pu [0.1], calf -0.7 pu [0.1]).

Interpretation: MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials.

Funding: Medical Research Council UK.

Figure 1

Flow chart of patient assessments and dropout CMT1A=Charcot-Marie-Tooth 1A. IBM=inclusion body myositis. *11 controls were common to both disease control groups. †Three controls dropped out because they had undertaken baseline assessments accompanying patients who dropped out before repeat assessments.

Figure 2

Regions of interest and sample axial images of left lower limb In each panel the upper row shows the mid-thigh level and the lower row shows the mid-calf level. (A) Unprocessed Dixon sequence (echo time=3·45 ms) in a healthy control (left), with overlaid whole muscle regions of interest (centre) and small regions of interest (right) for the same participant. (B) Fat-fraction map of a participant from each group. (C) Transverse relaxation time (T2) map of a participant from each group. (D) Magnetisation transfer ratio map of a participant from each group. RF=rectus femoris. VL=vastus lateralis. VM=vastus medialis. VI=vastus intermedius. Sa=sartorius. G=gracilis. AM=adductor magnus. SM=semimembranosus. ST=semitendinosus. BF=biceps femoris. TA=tibialis anterior group. MG=medial head of gastrocnemius. So=soleus. TP=tibialis posterior. PL=peroneus longus. LG=lateral head of gastrocnemius. pu=percentage units.

Figure 3

Cross-sectional data (A) Overall fat fraction is significantly increased at both thigh and calf level in patients with inclusion body myositis and at calf level in patients with CMT1A compared with matched controls. Boxes represent median and IQR, whiskers show range, and filled circles are outliers. (B) Combination of all muscles without substantial intramuscular fat accumulation shows that muscle T2 is increased and MTR is reduced in muscles from patients with IBM, showing early pathological changes. Similar significant differences of lower magnitude were also identified in CMT1A. (C) Fat-fraction maps of the right thigh in a healthy control and a patient with IBM. In the patient, fatty infiltration of muscles is greatest in the quadriceps (red region of interest), which also has a reduced CSA. The mean fat fraction and CSA can be combined to calculate the composite MRI metric, RMA. (D) RMA of quadriceps muscle showed significant correlation with knee extension strength in patients with IBM, CMT1A, and controls. Equivalent graphs of other movements are shown in the appendix. (E) Strong correlations were observed between mean thigh fat fraction and IBMFRS-LL (r=–0·64) for patients with IBM. FF=fat fraction. IBM=inclusion body myositis. CMT1A=Charcot-Marie-Tooth 1A. T2=transverse relaxation time. MTR=magnetisation transfer ratio. CSA=cross-sectional area. RMA=remaining muscle area. IBMFRS-LL=inclusion body myositis functional rating score lower limb.

Figure 4

Longitudinal data Boxes represent median and IQR, whiskers show range and filled circles are outliers. (A) Fat-fraction maps of the right calf at baseline and after 1 year are shown for control participants and patients with CMT1A and IBM. Minimal change is seen in the mean overall fat fraction in the control, but an increase of 2·0% is shown in the patient with CMT1A and of 7·9% in the patient with IBM. (B) Group comparison against matched controls shows significant increases in overall mean fat fraction in patients with IBM at thigh and calf level and in patients with CMT1A at calf level. (C) Change in quadriceps RMA correlated with change in quadriceps strength over 12 months in patients with IBM for both left and right legs. No significant correlations were seen between 1-year changes in myometric and MRI measures in the CMT1A group. CMT1A=Charcot-Marie-Tooth 1A. IBM=inclusion body myositis. FF=fat fraction. RMA=remaining muscle area.