Pathologic correlates of the magnetization transfer ratio in multiple sclerosis

Abstract

Objective.To identify pathological correlate(s) of magnetization transfer ratio (MTR) in multiple sclerosis (MS) in a MRI-pathology study.Methods.We acquired MTR maps at 3T from 16 fixed MS brains and four controls, and immunostained 100 tissue blocks for neuronal neurofilaments, myelin (SMI94), tissue macrophages (CD68), microglia (IBA1), B-lymphocytes, T-lymphocytes, cytotoxic T-lymphocytes, astrocytes (GFAP), and mitochondrial damage (COX4, VDAC). We defined regions-of-interest in lesions, normal-appearing white matter (NAWM) and cortical normal-appearing grey matter (NAGM). Associations between MTR and immunostaining intensities were explored using linear mixed-effects models (with cassettes nested within patients), and interaction terms (for differences between ROIs and between cases and controls); a multivariate linear mixed-effects model identified the best pathological correlate(s) of MTR.Results.MTR was the lowest in WM lesions (23.4±9.4%), and the highest in NAWM (38.1±8.7%). In MS brains, lower MTR was associated with lower immunostaining intensity for myelin (Coeff=0.31; 95% confidence interval (CI)=0.07,0.55), macrophages (Coeff=0.03; 95%CI=0.01,0.07), and astrocytes (Coeff=0.51; 95%CI=0.02,1.00), and with greater mitochondrial damage (Coeff=0.31; 95%CI=0.07,0.55). Based on interaction terms, MTR was more strongly associated with myelin in WM (Coeff=1.58; 95%CI=1.09,2.08) and GM lesions (Coeff=0.66; 95%CI=0.13,1.20), and with macrophages (Coeff=1.40; 95%CI=0.56,2.25), astrocytes (Coeff=2.66; 95%CI=1.31,4.01), and mitochondrial damage (Coeff=-12.59; 95%CI=-23.16,-2.02) in MS brains than controls. In the multivariate model, myelin immunostaining intensity was the best correlate of MTR (Coeff=0.31; 95%CI=0.09,0.52; p=0.004).Conclusions.Myelin was the strongest correlate of MTR, especially in WM and cortical GM lesions, but additional correlates should be kept in mind when designing and interpreting MTR observational and experimental studies in MS.

B Cells in the CNS at Postmortem Are Associated With Worse Outcome and Cell Types in Multiple Sclerosis

“…This is an original analysis on an already existing data set (16 MS brains and 4 controls). 18 Tissue for this study was provided by the UK MS Tissue Bank at the Imperial College London, under ethical approval from the National Research Ethics Committee. The study followed Human Tissue Act guidelines.…”

Reliability and reproducibility of sciatic nerve magnetization transfer imaging and T2 relaxometry

“…MTI works by a pair of MR sequences, one with and one without a preceding off-resonance saturation pulse. By calculating the relative difference between signals, the MTR can be determined, which reflects the concentration of bound protons and their interaction with protons in free water and is considered a biomarker of demyelination [22,23].…”

Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis

“…In addition, very recent MRI-pathology studies demonstrate that MTR sampled in lesion and non-lesion tissue in multiple sclerosis brains is weakly associated not only with myelin density [coefficient (95% confidence interval, CI): 0.31 (0.07 to 0.55), P = 0.01], but also with greater numbers of astrocytes [coefficient (95% CI): 0.51 (0.02 to 1), P = 0.04] and damaged mitochondria [coefficient (95% CI): 0.53 (−0.95 to −0.12), P = 0.01]. 55 …”