T1w/FLAIR ratio standardization as a myelin marker in MS patients

Abstract

Introduction: Calculation of a T1w/T2w ratio was introduced as a proxy for myelin integrity in the brain of multiple sclerosis (MS) patients. Since nowadays 3D FLAIR is commonly used for lesion detection instead of T2w images, we introduce a T1w/FLAIR ratio as an alternative for the T1w/T2w ratio.

Objectives: Bias and intensity variation are widely present between different scanners, between subjects and within subjects over time in T1w, T2w and FLAIR images. We present a standardized method for calculating a histogram calibrated T1w/FLAIR ratio to reduce bias and intensity variation in MR sequences from different scanners and at different time-points.

Material and methods: 207 Relapsing Remitting MS patients were scanned on 4 different 3 T scanners with a protocol including 3D T1w, 2D T2w and 3D FLAIR images. After bias correction, T1w/FLAIR ratio maps and T1w/T2w ratio maps were calculated in 4 different ways: without calibration, with linear histogram calibration as described by Ganzetti et al. (2014), and by using 2 methods of non-linear histogram calibration. The first nonlinear calibration uses a template of extra-cerebral tissue and cerebrospinal fluid (CSF) brought from Montreal Neurological Institute (MNI) space to subject space; for the second nonlinear method we used an extra-cerebral tissue and CSF template of our own subjects. Additionally, we segmented several brain structures such as Normal Appearing White Matter (NAWM), Normal Appearing Grey Matter (NAGM), corpus callosum, thalami and MS lesions using Freesurfer and Samseg.

Results: The coefficient of variation of T1w/FLAIR ratio in NAWM for the no calibrated, linear, and 2 nonlinear calibration methods were respectively 24, 19.1, 9.5, 13.8. The nonlinear methods of calibration showed the best results for calculating the T1w/FLAIR ratio with a smaller dispersion of the data and a smaller overlap of T1w/FLAIR ratio in the different segmented brain structures. T1w/T2w and T1w/FLAIR ratios showed a wider range of values compared to MTR values.

Conclusions: Calibration of T1w/T2w and T1w/FLAIR ratio maps is imperative to account for the sources of variation described above. The nonlinear calibration methods showed the best reduction of between-subject and within-subject variability. The T1w/T2w and T1w/FLAIR ratio seem to be more sensitive to smaller changes in tissue integrity than MTR. Future work is needed to determine the exact substrate of T1w/FLAIR ratio and to obtain correlations with clinical outcome.

Keywords: Image calibration; Integrity; Multiple sclerosis; T1w/FLAIR ratio; T1w/T2w ratio.

Fig. 1

Image processing pipeline for the different calibration methods. Raw T1w, T2w and FLAIR images undergo a bias correction and rigid registration process. The unbiased and registered T1w and FLAIR images are used for structure segmentation and lesion segmentation. The pipeline describes the warping of the eye/muscle and extra-cerebral masks from MNI space to subject space and the creation of an own population extra-cerebral mask. Finally, T1w/T2w ratio and T1w/FLAIR ratio maps are calculated after each calibration method. The script can be downloaded from GitHub website: https://github.com/treanus/KUL_NIS. Abbreviations: BIDS, brain imaging data structure; GM, grey matter; WM, white matter; CSF, cerebrospinal fluid; LC, linear calibration; NLG, nonlinear Ganzetti calibration; NLS, nonlinear subject template calibration; MTI: magnetization transfer imaging; MNI, Montreal Neurological Institute; MTR, magnetization transfer ratio.

Fig. 2

Intensity histograms, input images and computed T1w/T2w ratio and T1w/FLAIR ratio maps. T1w, T2w and FLAIR intensity histograms and input images in [A], [B] and [C], respectively, from 2 different patients scanned (subject 001 and subject 229) on a different MR device on different dates. Top raw without calibration, 2nd raw with linear calibration, 3rd raw with NLG calibration and bottom raw with NLS calibration. T1w/T2w ratio and T1w/FLAIR ratio maps for the 2 patients [D] and [E]. Top raw without calibration, 2nd raw with linear calibration, 3rd raw with NLG calibration and bottom raw with NLS calibration. Abbreviations: L calibration, linear calibration; NLG, nonlinear Ganzetti calibration; NLS, nonlinear subject template calibration;

Fig 3

Dispersion in the data due to intensity scale variation. T1w/T2w ratio [A] and T1w/FLAIR ratio [B] in NAWM with 4 different calibration methods: NC, LC, NLS and NLG calibration. In [A], T1w/T2w, LC and T1w/T2w, NLG are located on the primary axis; T1w/T2w, NC and T1w/T2w, NLS are located on the secondary axis. Abbreviations: NAWM, normal appearing white matter; NC, no calibration; LC, linear calibration; NLG, nonlinear Ganzetti calibration; NLS, nonlinear subject template calibration; CV, coefficient of variation.

Fig 4

Correlation of T1w/T2w ratio and T1w/FLAIR ratio in NAWM, NAGM and MS lesions to MTR. [A, B] T1w/T2w ratio and T1w/FLAIR ratio without calibration. [C,D] T1w/T2w ratio and T1w/FLAIR ratio with linear calibration by Ganzetti et al (Beer et al., 2016). [E,F] T1w/T2w ratio and T1w/FLAIR ratio with nonlinear calibration conform to the method of Ganzetti et al (NLG). [G,H] T1w/T2w ratio and T1w/FLAIR ratio with nonlinear calibration with own subject template (NLS). Abbreviations: NAWM, normal appearing white matter; NAGM, normal appearing grey matter; MTR, magnetization transfer ratio.