Clinically feasible MTR is sensitive to cortical demyelination in MS
ABSTRACT OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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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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 · 2.84 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.01/2013; 3(2). DOI:10.1016/j.msard.2013.09.007
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ABSTRACT: Cortical lesions account for a larger proportion of brain demyelination than white matter (WM) lesions. They are often missed on conventional MRI. Recently studies improved the detection of cortical lesions using 7T T2(⁎), 7T MPRAGE and 3T DIR but it seems that we are still able to detect only "the tip of the iceberg". In this study we report for the first time the systematic use of high resolution MTR in MS and compare MTR lesion detection with 7T MPRAGE, 7T T2(⁎) and 3T 3D DIR. We report the use of high resolution, fast, magnetisation transfer imaging (MTI) at 7T in MS focusing on the detection of cortical lesions. Eighteen patients with MS were scanned (Expanded Disability Status Scale score: 3.0, mean age: 48 years, mean disease duration: 7.25 years). The scans were compared to nine healthy control subjects (mean age 36.5 years). We acquired 7T MPRAGE images, 7T MTR maps, 7T T2(⁎)and 3T 3D DIR. The WM was segmented from the MPRAGE and removed to obtain only the cortical grey matter ribbon (cGMR) mask. The mask was then applied to the different modalities (MPRAGE, MTR, DIR, T2(⁎)w) previously registered onto the MPRAGE volume. The analysis of the cGMR was performed by two observers blinded to the disease state. In patients with MS 365 lesions in total were detected with 7T MTR (mean 20.28 lesions per patient), 289 lesions were detected with 7T MPRAGE (mean 16.06 lesions) and 231 lesions were detected with 7T T2(⁎) (mean 12.83 lesions). In the 8 MS subjects who had 3T 3D DIR acquired on the same day, a total of 136 lesions (mean 17 lesions per patient) were detected as opposed to 171 lesions with 7T MTR, 147 lesions were detected with 7T MPRAGE and 126 lesions with 7T T2(⁎) in the same patients. We found that 7T MTR, in less than 10min scanning time, was able to detect cortical lesions. In this study we found that 7T MTR was better in detecting intracortical lesions in comparison with 7T T2(⁎), 7T MPRAGE, and 3T 3D DIR. since only a very few intracortical lesions were detected in healthy controls in our blind assessment, it is likely that the lesions detected represent focal grey matter demyelination. High resolution MT imaging has especially revealed cortical changes that have not been recognised by other MR sequences. MTR maps were noisier than MPRAGE, T2(⁎) and DIR, but also better in localising cortical lesions. As MTR is more pathologically specific than other sequences in detecting tissue myelination, it raises the possibility that high resolution MTR will be able to demonstrate cortical remyelination in vivo. © 2013 Published by Elsevier B.V.01/2013; 3(2). DOI:10.1016/j.msard.2013.10.004