Automated Separation of Diffusely Abnormal White Matter from Focal White Matter Lesions on MRI in Multiple Sclerosis

ABSTRACT Background Previous histopathology and MRI studies have addressed the differences between focal white matter lesions (FWML) and diffusely abnormal white matter (DAWM) in multiple sclerosis (MS). These two categories of white matter T2-weighted (T2w) hyperintensity show different degrees of demyelination, axonal loss and immune cell density on histopathology, potentially offering distinct correlations with symptoms. Objectives 1) To automate the separation of FWML and DAWM using T2w MRI intensity thresholds and to investigate their differences in magnetization transfer ratios (MTR), which are sensitive to myelin content; 2) to correlate MTR values in FWML and DAWM with normalized signal intensity values on fluid attenuated inversion recovery (FLAIR), T2w, and T1-weighted (T1w) contrasts, as well as with the ratio of T2w/T1w normalized values, in order to determine whether these normalized intensities can be used as myelin-sensitive markers when MTR is not available. Methods Using similar 3T MRI protocols, 2 MS cohorts of 20 participants each were scanned in 2 centers, including: 3D T1w (MP2RAGE), 3D FLAIR, 2D T2w, and 3D magnetization-transfer (MT) contrasts. We used the first dataset to develop an automated technique to separate FWML from DAWM and the second one to validate the automation of the technique. We applied the automatic thresholds to both datasets and assessed the overlap of the manual and the automated masks using Dice kappa. We also assessed differences in mean MTR values between NAWM, DAWM and FWML, using manually and automatically derived masks in both datasets. Finally, we used the mean intensity of manually-traced areas of NAWM on T2w images as the normalization factor for each MRI contrast, and compared these with the normalized-intensity values obtained using automated NAWM (A-NAWM) masks as the normalization factor. Paired t-tests assessed the MTR differences across tissue types. Wilcoxon Signed Rank test and paired t-tests assessed FWML and DAWM differences in manual and automated derived volumes. Pearson correlations assessed the relationship between MTR and normalized intensity values in the manual and automated derived masks. Results The mean Dice-kappa values for dataset 1 were: 0.8 for DAWM masks and 0.7 for FWML masks. In dataset 2, mean dice-kappa values were: 0.8 for DAWM and 0.8 for FWML. Also, manual and automated DAWM and FWML volumes were not significantly different in both datasets. MTR values (expressed as mean and standard deviation, arbitrary units) were significantly lower in manually derived FWML compared with DAWM in both datasets: 1) FWML: 37.1 ± 3.2 vs DAWM: 43.3 ± 2.1; t=13.2; p<0.0001, and 2) FWML: 32.5 ± 3.9 vs DAWM: 38.8 ± 1.7; t=9.8; p<0.0001. Similar results were obtained using the automatic derived masks in both datasets: 1) FWML: 35.8 ± 2.8 vs DAWM: 43.1 ± 1.6; t=15.3; p<0.0001, and 2) FWML: 31.3 ± 3.1 vs DAWM: 38.1 ± 1.5; t=12.8; p<0.0001. MTR was also significantly lower in manually derived DAWM masks compared with normal appearing white matter (NAWM) in both datasets: 1) NAWM: 46.7 ± 1.3; t=10.1; p<0.0001, and 2) NAWM: 39.3 ± 0.8; t=3.1; p=0.003. Similar results were obtained using the automatic derived masks in both datasets: 1) NAWM: 46.3 ± 1.1; t=13.7; p<0.0001, and 2) NAWM: 39.9 ± 1.1; t=9.6; p<0.0001. In both datasets, manually derived FWML and DAWM MTR values showed significant correlations with normalized FLAIR (r=−0.35 to −0.67; p=0.06 to <0.0001), T2w (r=−0.60 to −0.72; p=0.003 to <0.0001), T1w/T2w (r=0.63 to 0.77; p=0.002 to <0.0001), and T1w (r=0.77 to 0.92; p<0.0001) intensities. Finally, normalized intensity values obtained using automatic derived masks were significantly correlated with the manually derived values in both datasets. Conclusions The separation of FWML and DAWM on MRI scans of MS patients using automated intensity thresholds on T2w images is feasible. MTR values are significantly lower in FWML than DAWM, and DAWM values are significantly lower than NAWM, reflecting potentially greater demyelination within focal lesions. Normalized intensity values of different MRI contrasts exhibit a significant correlation with MTR values in both tissues of interest and could be used as a proxy to assess demyelination when MTR images are not available.

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