Assessing the differential sensitivities of wave-CAIPI ViSTa myelin water fraction and magnetization transfer saturation for efficiently quantifying tissue damage in MS

https://doi.org/10.1016/j.msard.2021.103309Get rights and content

Highlights

  • ViSTa MWF and MTsat show differential sensitivities to brain tissue microstructure.

  • ViSTa MWF and MTsat can be jointly collected to quantify tissue damage in MS.

  • MWF exhibits higher sensitivity for detecting demyelination in MS white matter.

  • A tissue-specific linear relationship between vista MWF and MTsat was identified.

  • MWF in MS normal-appearing white matter correlated with MS disease duration.

Abstract

Background

Wave-CAIPI Visualization of Short Transverse relaxation time component (ViSTa) is a recently developed, short-T1-sensitized MRI method for fast quantification of myelin water fraction (MWF) in the human brain. It represents a promising technique for the evaluation of subtle, early signals of demyelination in the cerebral white matter of multiple sclerosis (MS) patients. Currently however, few studies exist that robustly assess the utility of ViSTa MWF measures of myelin compared to more conventional MRI measures of myelin in the brain of MS patients. Moreover, there are no previous studies evaluating the sensitivity of ViSTa MWF for the non-invasive detection of subtle tissue damage in both normal-appearing white matter (NAWM) and white matter lesions of MS patients. As a result, a central purpose of this study was to systematically evaluate the relationship between myelin sensitivity of T1-based ViSTa MWF mapping and a more generally recognized metric, Magnetization Transfer Saturation (MTsat), in healthy control and MS brain white matter.

Methods

ViSTa MWF and MTsat values were evaluated in automatically-classified normal appearing white matter (NAWM), white matter (WM) lesion tissue, cortical gray matter, and deep gray matter of 29 MS patients and 10 healthy controls using 3T MRI. MWF and MT sat were also assessed in a tract-specific manner using the Johns Hopkins University WM atlas. MRI-derived measures of cerebral myelin content were uniquely compared by employing non-normal distribution-specific measures of median, interquartile range and skewness. Separate analyses of variance were applied to test tissue-specific differences in MTsat and ViSTa MWF distribution metrics. Non-parametric tests were utilized when appropriate. All tests were corrected for multiple comparisons using the False Discovery Rate method at the level, α=0.05.

Results

Differences in whole NAWM MS tissue damage were detected with a higher effect size when using ViSTa MWF (q = 0.0008; ƞ2 = 0.34) compared to MTsat (q = 0.02; ƞ2= 0.24). We also observed that, as a possible measure of WM pathology, ViSTa-derived NAWM MWF voxel distributions of MS subjects were consistently skewed towards lower MWF values, while MTsat voxel distributions showed reduced skewness values. We further identified tract-specific reductions in mean ViSTa MWF of MS patients compared to controls that were not observed with MTsat. However, MTsat (q = 1.4 × 10−21; ƞ2 = 0.88) displayed higher effect sizes when differentiating NAWM and MS lesion tissue. Using regression analysis at the group level, we identified a linear relationship between MTsat and ViSTa MWF in NAWM (R2 = 0.46; p = 7.8 × 10−4) lesions (R2 = 0.30; p = 0.004), and with all tissue types combined (R2 = 0.71; p = 8.4 × 10−45). The linear relationship was also observed in most of the WM tracts we investigated. ViSTa MWF in NAWM of MS patients correlated with both disease duration (p = 0.02; R2 = 0.27) and WM lesion volume (p = 0.002; R2 = 0.34).

Conclusion

Because ViSTa MWF and MTsat metrics exhibit differential sensitivities to tissue damage in MS white matter, they can be collected in combination to provide an efficient, comprehensive measure of myelin water and macromolecular pool proton signals. These complementary measures may offer a more sensitive, non-invasive biopsy of early precursor signals in NAWM that occur prior to lesion formation. They may also aid in monitoring the efficacy of remyelination therapies.

Introduction

Reliable, in vivo quantification of myelin in human brain white matter (WM) is vital for the study of demyelinating diseases, human brain development, and healthy aging (Laule and Moore, 2018). In this context, Magnetization Transfer saturation (MTsat) (Mohammadi et al., 2015) is a recognized technique that employs the exchange of semi-solid, macromolecular protons with free water to sensitize the MRI signal to detect myelin. Myelin Water Fraction (MWF) imaging, by comparison, seeks to extract a relative measure of myelin based on the fraction of water molecules localized between the myelin bilayers. This is traditionally carried out using multi-component decay analysis of either the transverse relaxation time (T2) (MacKay et al., 1994) or apparent transverse relaxation time (T2*) spectrum (Hwang et al., 2010). When applied in concert, MTsat and MWF imaging offer important, complementary information about white matter damage due to neuroinflammation, axonal loss and demyelination in MS (Kolind et al., 2008, Laule et al., 2003).

The direct Visualization of Short Transverse relaxation time component (ViSTa) method was recently introduced to selectively image the short T1, myelin water signal component in human brain white matter (Choi et al., 2019; Oh et al., 2013). Compared to other MWF mapping techniques, ViSTa has the advantage of not requiring the fitting of an ill-posed signal model and additionally providing high quality images (Jung et al., 2018; Oh et al., 2013). However, a challenge related to its application is the longer overall MRI acquisition time associated with ViSTa scans, relative to more standard the T2 relaxation based approaches (Labadie et al., 2014; MacKay et al., 1994). In this study, we addressed this challenge using an accelerated wave encoding scheme for human brain myelin water imaging at 3 T. Wave encoding is a recently introduced, data sampling technique that enables imaging at high acceleration factors, while significantly mitigating signal-to-noise ratio penalty (Bilgic et al., 2015; Gagoski et al., 2015; Wu et al., 2018).

Herein, we systematically evaluated the relationship between MWF, quantified using T1-based Wave-CAIPI ViSTa (Wu et al., 2018) and MTsat (Helms et al., 2008) in MS and healthy brain tissue. No previous comparative evaluation exists of the relationship between MTsat and quantitative T1-based myelin water fraction methods. Further, there is very limited precision analysis in the literature regarding the application of ViSTa MWF for monitoring NAWM changes in MS. As an additional feature, we evaluated the relationship between the myelin sensitive MRI parameters and MS clinical measures to probe their potential clinical utility.

Section snippets

Study design

Our MRI study was approved by the local institutional review board of the McGill University Health centre. Thirty-nine participants were recruited for our study. Twenty-nine clinically confirmed MS patients were recruited from the Multiple Sclerosis Clinic of the Montreal Neurological Institute (MNI) and Hospital and underwent MRI scanning. Patients were enrolled in our study if they were greater than 18 years of age and had been diagnosed with MS by a neurologist at the MNI. All subjects in

Results

Fig. 3 presents an example of co-registered ViSTa MWF and MTsat images in the 1 mm3 isotropic MNI space. Automatic tissue classifications of NAWM, high confidence CGM, DGM and MS white matter lesions are overlaid in red for the images in the bottom row. Fig. 4 demonstrates examples of automatically segmented lesions overlaid on ViSTa MWF, MTsat and FLAIR images. Representative, magnified views of white matter lesions, along with the corresponding lesion segmentations derived from the Bayesian

Discussion

Our study documents the combined application of Wave-CAIPI ViSTa MWF and MTsat for robust, efficient quantitative imaging of tissue damage in NAWM, white matter lesions, CGM, and DGM tissue of MS patients. MWF derived from the ViSTa sequence demonstrated higher sensitivity compared to MTsat, for quantifying signals of demyelination in MS normal-appearing white matter. This was true for all the statistical measures we tested, including median, IQR and skewness. Notably however, MTsat proved more

Conclusions

We implemented a fast, practical method to measure MWF in healthy control and MS patient brain by sensitizing the MRI signal to the short T1 relaxation, myelin water component. We also characterized, for the first time, group-level distributions of ViSTa MWF and MTsat in NAWM, CGM, DGM and WM lesions. The distributions were rigorously compared using generalized statistical measures. ViSTa MWF demonstrated higher sensitivity to signals related to demyelination in MS normal-appearing white

CRediT authorship contribution statement

Ahmed M. Elkady: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. Zhe Wu: Conceptualization, Methodology, Software, Validation, Investigation, Data curation, Writing – review & editing. Ilana R. Leppert: Methodology, Software, Validation, Investigation, Data curation. Douglas L. Arnold: Investigation, Resources, Writing – review & editing, Funding acquisition. Sridar Narayanan: Conceptualization,

Declarations of Competing Interest

None.

Acknowledgments

We are especially grateful to all the participants in our study. The authors also wish to thank Ms. Rozie Arnaoutelis for her invaluable assistance obtaining ethics approvals and consents, as well as scheduling examinations for both patients and controls.

Funding

The authors gratefully acknowledge funding support for this study from the Canadian Institutes of Health Research (grant No. 201610PJT-377721). Ahmed Elkady gratefully acknowledges scholarship support from MITACS Accelerate (award number FR33832).

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