Pathological correlates of the magnetization transfer ratio in multiple sclerosis

Marcello Moccia, Steven van de Pavert, Arman Eshaghi, Lukas Haider, Jonas Pichat, Marios Yiannakas, Sebastien Ourselin, Yi Wang, Claudia Wheeler-Kingshott, Alan Thompson, Frederik Barkhof, Olga Ciccarelli
Neurology 2020 September 16

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 <u>(23.4±9.4%), and the highest in</u> NAWM <u>(38.1±8.7%)</u>. In MS brains, lower MTR was associated with lower immunostaining intensity for myelin <u>(Coeff=0.31; 95% confidence interval (CI)=0.07,0.55)</u>, macrophages <u>(Coeff=0.03; 95%CI=0.01,0.07)</u>, and astrocytes <u>(Coeff=0.51; 95%CI=0.02,1.00)</u>, and with greater mitochondrial damage <u>(Coeff=0.31; 95%CI=0.07,0.55)</u>. <u>Based on interaction terms,</u> MTR was more strongly associated with myelin in WM <u>(Coeff=1.58; 95%CI=1.09,2.08)</u> and GM lesions <u>(Coeff=0.66; 95%CI=0.13,1.20),</u> and with macrophages <u>(Coeff=1.40; 95%CI=0.56,2.25)</u>, astrocytes <u>(Coeff=2.66; 95%CI=1.31,4.01)</u>, and mitochondrial damage <u>(Coeff=-12.59; 95%CI=-23.16,-2.02)</u> in MS brains than controls. In the multivariate model, myelin immunostaining intensity was the best correlate of MTR <u>(Coeff=0.31; 95%CI=0.09,0.52; p=0.004)</u>.

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.

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