Pathologic correlates of the magnetization transfer ratio in multiple sclerosis

Objective To identify pathologic correlates of magnetization transfer ratio (MTR) in multiple sclerosis (MS) in an MRI-pathology study. Methods We acquired MTR maps at 3T from 16 fixed MS brains and 4 controls, and immunostained 100 tissue blocks for neuronal neurofilaments, myelin (SMI94), tissue macrophages (CD68), microglia (IBA1), B-lymphocytes, T-lymphocytes, cytotoxic T-lymphocytes, astrocytes (glial fibrillary acidic protein), and mitochondrial damage (COX4, VDAC). We defined regions of interest in lesions, normal-appearing white matter (NAWM), and cortical normal-appearing gray 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 regions of interest and between cases and controls); a multivariate linear mixed-effects model identified the best pathologic correlates of MTR. Results MTR was the lowest in white matter (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 (coefficient 0.31; 95% confidence interval [CI] 0.07-0.55), macrophages (coefficient 0.03; 95% CI 0.01-0.07), and astrocytes (coefficient 0.51; 95% CI 0.02-1.00), and with greater mitochondrial damage (coefficient 0.31; 95% CI 0.07-0.55). Based on interaction terms, MTR was more strongly associated with myelin in WM (coefficient 1.58; 95% CI 1.09-2.08) and gray matter (GM) lesions (coefficient 0.66; 95% CI 0.13-1.20), and with macrophages (coefficient 1.40; 95% CI 0.56-2.25), astrocytes (coefficient 2.66; 95% CI 1.31-4.01), and mitochondrial damage (coefficient -12.59; 95% CI -23.16 to -2.02) in MS brains than controls. In the multivariate model, myelin immunostaining intensity was the best correlate of MTR (coefficient 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.