Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases

Abstract

Objective: The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases.

Methods: MTR was measured in the SN of patients with CMT type 1A (CMT1A, n = 10), CMT type 2A (CMT2A, n = 3), hereditary neuropathy with liability to pressure palsies (n = 3), and healthy controls (n = 21). Additional patients without a genetically confirmed subtype (n = 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated.

Results: Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 ± 3.3 percent units) and CMT2A (31.5 ± 1.9 percent units) relative to controls (37.2 ± 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p = 0.01 for genetically confirmed patients only, p = 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels.

Conclusions: MTR measurements may be a viable biomarker of proximal nerve pathology in patients with CMT.

Figure 1. Representative anatomical images from each cohort

Representative coronal T₁-weighted scout image (A) and axial magnetization transfer (MT) images for each cohort (B). The length (L) of the femur was measured from the coronal scout image, and the axial MT volumes were centered 1/3 this length (L/3), as measured from the lower extremity. The most proximal (blue line, B.a) and distal slices (green line, B.b) are shown along with the region of interest (red overlay) for the sciatic nerve (SN). The tibial and common peroneal branches of the SN were resolvable in the more distal slices. Note the hypertrophy of the SN in the patient with Charcot-Marie-Tooth type 1A (CMT1A) and the muscle atrophy and fat replacement in the patient with Charcot-Marie-Tooth type 2A (CMT2A) (white arrow). HNPP = hereditary neuropathy with liability to pressure palsies.

Figure 2. Representative magnetization transfer ratio maps before and after B₁ correction

Representative uncorrected magnetization transfer ratio (MTR) maps (A), relative B₁ maps (B, B₁ given as a percentage of the desired value), and B₁-corrected MTR maps (C) from a control subject (top row) and patient with Charcot-Marie-Tooth type 1A (CMT1A) (bottom row). Slices were taken from center of the volume (at L/3 from the lower extremity as indicated in figure 1), and all images were masked to eliminate background voxels as well as voxels that had been partially volume averaged with fat. Note that most of the shading in the uncorrected MTR maps was removed by the B₁ correction process (the regions labeled 1, 2, and 3 in the uncorrected CMT1A map contain hues ranging from green to red, while the same regions in the corrected map contain more homogenous yellow hues). Consistent with the general trend (table), lower MTR values were observed in the sciatic nerve (zoomed inset) of the patient with CMT1A (blue hues) than the control subject (yellow hues).

Figure 3. Mean volumetric magnetization transfer ratio data for control subjects and patients with neuropathy

Scatterplots of magnetization transfer ratio values calculated across the entire volume (MTR_v) vs age (A) and body mass index (BMI) (B) are given for male (gray dots) and female (black dots) participants. Age, BMI, and sex did not have a significant effect on MTR_v in the control cohort. The boxplot of cohort MTR_v values (C) demonstrates the significant intercohort variation in MTR_v. Post hoc analysis identified significance between the following cohort pairs: control/Charcot-Marie-Tooth type 1A (CMT1A) and control/Charcot-Marie-Tooth type 2A (CMT2A). The scatterplot of MTR_v vs clinical Charcot-Marie-Tooth neuropathy score (CMTNS_C) (D) demonstrates the significant relationship between MTR_v and clinical disability. This regression was performed across control (red dots), CMT1A (dark blue), CMT2A (light blue), and hereditary neuropathy with liability to pressure palsies (HNPP) (orange) cohorts. In A, B, and D, the black lines are the result of a simple linear regression across all data in each scatterplot, and the shaded areas are the corresponding 95% confidence intervals.

Figure 4. Representative interscan and inter-rater data

Representative interscan and inter-rater magnetization transfer ratio values calculated for each slice (MTR_s). For the interscan data, the control subjects with the smallest (A) and largest (C) root mean squared (RMS) difference across scans are given. The mean values across scans (red and dark blue lines) were repeatable at the slicewise (MTR_s) and volumetric levels (magnetization transfer ratio values calculated across the entire volume [MTR_v]); however, differences were observed in distal slices in a few subjects (see the MTR overcorrection in C, which is most likely due to artifacts in this subject's B₁ map). For the inter-rater data, the control (B) and patient (D) with the median RMS difference are given. In all cases, the mean values across raters (black and light blue lines) were highly repeatable.