Clinically feasible MTR is sensitive to cortical demyelination in MS

and McConnell Brain Imaging Centre (J.T.-H.C., D.L.A.), Montreal Neurological Institute, McGill University, Montreal, Canada.
Neurology (Impact Factor: 8.29). 12/2012; 80(3). DOI: 10.1212/WNL.0b013e31827deb99
Source: PubMed


Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.

MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density-weighted images with/without a magnetization transfer pulse for calculation of MTR. The brains were rapidly removed and placed in fixative. Multiple cortical regions from each brain were immunostained for myelin proteolipid protein and classified as mostly myelinated (MM(ctx)), mostly demyelinated (MD(ctx)), or intermediately demyelinated (ID(ctx)). MRIs were registered with the cortical sections so that the cortex corresponding to each cortical section could be identified, along with adjacent subcortical white matter (WM). Mean cortical MTR normalized to mean WM MTR was calculated for each cortical region. Linear mixed-effects models were used to test if mean normalized cortical MTR was significantly lower in demyelinated cortex.

We found that mean normalized cortical MTR was significantly lower in cortical tissue with any demyelination (ID(ctx) or MD(ctx)) compared to MM(ctx) (demyelinated cortex: least-squares mean [LSM] = 0.797, SE = 0.007; MM(ctx): LSM = 0.837, SE = 0.006; p = 0.01, n = 89).

This result demonstrates that clinically feasible MTR imaging is sensitive to cortical demyelination and suggests that MTR will be a useful tool to help detect MS cortical lesions in living patients with MS.

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    • "Recently, MTR was mapped in the cortex of MS patients (Chen et al., 2013; Derakhshan et al., 2014) and showed similarities between myelinated regions and high MTR values. However, MTR is only a semi-quantitative metric as it depends on sequence parameters, B1 profile and T 1 relaxation (Berry et al., 1999; Pike Bruce, 1996). "
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    ABSTRACT: Recently, T2* imaging at 7 tesla (T) MRI was shown to reveal microstructural features of the cortical myeloarchitecture thanks to an increase in contrast-to-noise ratio. However, several confounds hamper the specificity of T2* measures (iron content, blood vessels, tissues orientation). Another metric, magnetization transfer ratio (MTR), is known to also be sensitive to myelin content and thus would be an excellent complementary measure because its underlying contrast mechanisms are different than that from T2*. The goal of this study was thus to combine MTR and T2* using multivariate statistics in order to gain insights into cortical myelin content. Seven healthy subjects were scanned at 7T and 3T to obtain T2* and MTR data, respectively. A multivariate myelin estimation model (MMEM) was developed, and consists in (i) normalizing T2* and MTR values and (ii) extracting their shared information using independent component analysis (ICA). B0 orientation dependence and cortical thickness were also computed and included in the model. Results showed high correlation between MTR and T2* in the whole cortex (r=0.76, p<10(-16)), suggesting that both metrics are partly driven by a common source of contrast, here assumed to be the myelin. Average MTR and T2* were respectively 31.0 +/- 0.3% and 32.1 +/- 1.4ms. Results of the MMEM spatial distribution showed similar trends to that from histological work stained for myelin (r=0.77, p<0.01). Significant right-left differences were detected in the primary motor cortex (p<0.05), the posterior cingulate cortex (p<0.05) and the visual cortex (p<0.05). This study demonstrates that MTR and T2* are highly correlated in the cortex. The combination of MTR, T2*, CT and B0 orientation may be a useful means to study cortical myeloarchitecture with more specificity than using any of the individual methods. The MMEM framework is extendable to other contrasts such as T1 and diffusion MRI. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 06/2015; 119. DOI:10.1016/j.neuroimage.2015.06.033 · 6.36 Impact Factor
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    • "MTI is based on the exchange of magnetization between tissue water and protons bound to macromolecules (Graham and Henkelman, 1997). Histopathological correlations demonstrated the association of lower magnetization transfer ratios (MTR) with decreasing myelin content and axonal count in both the white matter (WM) and cortex (Schmierer et al., 2007; Chen et al., 2013). In a previous study of our own group, we found a significant MTR decrease in normal appearing white matter (NAWM) and cortex with advancing age (Fazekas et al., 2005). "
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    ABSTRACT: Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38-86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia.
    Frontiers in Aging Neuroscience 09/2014; 6:263. DOI:10.3389/fnagi.2014.00263 · 4.00 Impact Factor
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    ABSTRACT: Enhancing remyelination in MS might improve function and protect axons from future damage. Lesion magnetisation transfer ratio (MTR) is sensitive to myelin content, and may be a useful measure for trials evaluating potential remyelinating agents. Estimating sample sizes required for a parallel group, placebo-controlled trial in MS using change in mean MTR of all T2lesions as a primary outcome measure. The primary sample size calculation was derived from data from a natural history study of relapsing remitting MS (n=18). The MTR values observed in demyelinated and remyelinated lesions in an ex vivo study were used to estimate the effect of remyelination on lesion MTR. The ex vivo data were also used to independently calculate sample sizes in order to inform the robustness of the in vivo estimates. Calculations suggest that 30% remyelination of T2 lesions could be detected with 80% power in 38 (95% confidence interval 12-96) patients per arm based on the in vivo data, and in 66 per arm based on the ex vivo data. The sample sizes derived are in a range that makes MTR a feasible outcome measure for proof-of-concept trials of putative therapies achieving remyelination in MS lesions. © 2013 The Authors. Published by Elsevier B.V. All rights reserved.
    Multiple Sclerosis and Related Disorders 01/2013; 3(2). DOI:10.1016/j.msard.2013.09.007 · 0.88 Impact Factor
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