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Assessment of white matter damages in Multiple Sclerosis using normative templates of conventional and inhomogeneous Magnetization Transfer
Lucas Soustelle1,2, Andreea Hertanu1,2, Arnaud Le Troter1,2, Soraya Gherib1,2, Samira Mchinda1,2, Patrick Viout1,2, Lauriane Pini1,2, Claire Costes1,2, Sylviane Confort-Gouny1,2, Adil Maarouf1,2,3, Bertrand Audoin1,2,3, Audrey Rico1,2,3, Clémence Boutière1,2,3, Maxime Guye1,2, Jean-Philippe Ranjeva1,2, Gopal Varma4, David C. Alsop4, Jean Pelletier1,2,3, Guillaume Duhamel1,2, and Olivier M. Girard1,2
1Aix Marseille Univ, CNRS, CRMBM, Marseille, France, 2APHM, Hôpital Universitaire Timone, CEMEREM, Marseille, France, 3APHM, Hôpital Universitaire Timone, Service de neurologie, Marseille, France, 4Division of MR Research, Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Synopsis

Characterization of Multiple Sclerosis (MS) is of paramount importance for patient care. In this work, we compare inhomogeneous (ihMT) and conventional magnetization transfer (MT) MRI techniques for white matter (WM) evaluation in a group comparison analysis after normalization in a standard space (templates of MS patients and healthy controls). Regions of interest, voxel-based morphometry and histogram analyses revealed that signal changes in pathological WM are not equivalent for ihMT and MT, highlighting that both metrics provide complementary information.

Introduction

The evaluation of myelinated tissues is crucial for the characterization of myelin disorders like Multiple Sclerosis (MS). Advanced imaging methods such as inhomogeneous Magnetization Transfer (ihMT) has shown a great specificity to myelination in mice brains1, and a sensitivity to the MS pathology in the adult brain2. The conventional MT sequence is often employed in MS studies3, and the method is known to be sensitive to demyelination as well as inflammation and edema4-6.

White matter (WM) damages in MS patients are focal (lesions characterized by abnormal T2-weighed (T2w) and T1-weighted (T1w) signal3), but also diffuse (lowered conventional MT signal and mild T2-hyperintense regions7-9 in normal-appearing WM; NAWM). In this work, we aim to compare the ihMT ratio (ihMTR) and conventional MT ratio (MTR) for the characterization of the WM in MS patients using normative templates of age-matched healthy controls (HC) population in a standard space.

Methods

Population and MR protocol: Eleven relapsing-remitting MS patients (age=31.0±10.4 years; 2:9 men:women; EDSS score of 1.07±1.27) and sixteen healthy controls (age=29.4±7.8 years; 10:6 men:women) underwent a 3D MRI protocol on a 1.5T MRI system (Avanto, Siemens Healthineers, Erlangen, Germany) with body coil transmission and a 32-channel receive-only head coil. The protocol included 1-mm isotropic T1w-MPRAGE and T2w-FLAIR, as well as ihMT (sensitivity-enhanced gradient echo sequence10) and MT protocols as described in Table 1.

Post-processing and template creation: IhMTR was motion-corrected11 and computed using available pipelines (https://github.com/lsoustelle/ihmt_proc). For each subject, FLAIR, ihMTR and MTR images were rigidly co-registered onto their respective anatomic T1w-MPRAGE volume using the Advanced Normalization Tools (ANTs; v2.3.3)12. Lesions masks were manually segmented by an expert on the re-aligned T2w-FLAIR volumes. A three-stages rigid, affine and non-linear (SyN13) registration was then performed on the MPRAGE from the subject space to the MNI152 template (symmetric, 1-mm isotropic), and transformations were applied to the respective MTR, ihMTR and lesions mask images. MTR and ihMTR volumes were then averaged across all subjects in each group, while discarding the lesions’ contribution (voxelwise) in MS patients.

Analysis: Regions of interest were selected from the JHU tractography atlas14 for evaluation of both ihMTR and MTR in each group in the subject space (discarding lesions). A Voxel-Based Morphometry (VBM) analysis was performed for MTR and ihMTR between control and patients groups using the FMRIB Software Library (FSL v6.0.3, randomise routine) with the threshold-free cluster enhancement (TFCE) option15 and family-wise error (FWE) p-value correction (10000 permutations). Voxels were considered to be significantly different between groups when their value on the p-value maps was below 0.0516. The overlapping factor of thresholded p-value maps (p<0.05) between MTR and ihMTR were quantified with the Dice similarity coefficient (DSC)17. Finally, k-density smoothed bivariate histograms of WM, NAWM and lesions contributions were generated from images in the MNI space.

Results

Representative axial views of ihMTR and MTR templates of the control group are provided in Figure 1.

Barplots of ihMTR and MTR evaluated in the selected JHU regions in NAWM are shown in Figure 2. The higher contrast of ihMTR compared to that of MTR resulted in a higher variance (F-test, p<0.001) for healthy controls. Mean ihMTR and MTR values of MS patients deviated from the healthy controls (significant unpaired t-test in posterior corona radiata and splenium of the corpus callosum; p<0.01), indicating actual NAWM changes.

Figure 3 shows the MNI template overlaid with (1-p)-value maps of ihMTR and MTR from the VBM analysis. The modest overlapping of MTR and ihMTR clusters (DSC=0.67) indicates spatial WM changes from different nature.

Figure 4a presents a 2D histogram of ihMTR and MTR with distinct clusters of normal WM (healthy controls) and intensity-lowered NAWM (MS patients) with a median difference of 0.8% for ihMTR and 1.2% for MTR, respectively. Histograms of MS lesions present wide ihMTR values with interquartile range of 3.5% (median=10.9%), whereas MTR presents an interquartile range of 6.4% (median=42.9%). Figure 4b and 4c show 2D histograms combining normal WM (healthy controls) and NAWM (MS patients) data, for both ihMTR and MTR, respectively. A rather global offset of pathological WM compared to the control group (parallel deviation from the line of unity) is observed for ihMTR, while MTR deviates in a more dispersed fashion.

Discussion and conclusion

We compared ihMTR and MTR on a group of MS patients using a normative healthy control group. It was shown that ihMTR and MTR differ in terms of detection (VBM) and quantification of WM damages, which can be explained by the different sensitivity and specificity of both metrics to the underlying physiology. Characterization of the MS pathology is crucial for patients’ care, and ihMTR proves to provide additional and useful information in this scope.

Acknowledgements

This work was supported by the SATT Sud-Est (France), the French Association pour la Recherche sur la Sclérose En Plaques (ARSEP), Roche Research Foundation (Switzerland) and French National Research Agency, ANR [ANR‐17‐CE18‐0030].

References

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Figures

Table 1: Detailed parameters of ihMT and MT protocols (GRE: gradient echo; TRO: inter-readout pulse delay; Δt: inter-off-resonance pulse delay).

Figure 1: Representative views of MTR and ihMTR template maps from the healthy control population.

Figure 2: Barplots of ihMTR (top) and MTR (bottom) in selected JHU structures for healthy controls (grey) and MS patients (red) groups. Mean and standard deviations are computed in each group in the subject space. Significant mean differences (unpaired t-test) between groups are indicated with an asterisk (p<0.01).

Figure 3: FWE-corrected (1-p)-value maps of the voxel-based analysis in the MNI space between MS and HC subjects for ihMTR (yellow) and MTR (blue). (1-p)-value maps are shown in a range spanning from 0.95 to 1.00.

Figure 4: Bivariate histogram plot with k-density smoothing of ihMTR vs. MTR in normal WM (blue) of the HC group, and NAWM (red) and lesions (green) of the MS group (a), and of ihMTR (b) and MTR (c) in NWM (HC group) and NAWM (MS group). The solid black line corresponds to the line of unity.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)
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