Quantitative Imaging of White and Gray Matter Remyelination in the Cuprizone Demyelination Model Using the Macromolecular Proton Fraction

Abstract

Macromolecular proton fraction (MPF) has been established as a quantitative clinically-targeted MRI myelin biomarker based on recent demyelination studies. This study aimed to assess the capability of MPF to quantify remyelination using the murine cuprizone-induced reversible demyelination model. MPF was measured in vivo using the fast single-point method in three animal groups (control, cuprizone-induced demyelination, and remyelination after cuprizone withdrawal) and compared to quantitative immunohistochemistry for myelin basic protein (MBP), myelinating oligodendrocytes (CNP-positive cells), and oligodendrocyte precursor cells (OPC, NG2-positive cells) in the corpus callosum, caudate putamen, hippocampus, and cortex. In the demyelination group, MPF, MBP-stained area, and oligodendrocyte count were significantly reduced, while OPC count was significantly increased as compared to both control and remyelination groups in all anatomic structures (p < 0.05). All variables were similar in the control and remyelination groups. MPF and MBP-stained area strongly correlated in each anatomic structure (Pearson’s correlation coefficients, r = 0.80–0.90, p < 0.001). MPF and MBP correlated positively with oligodendrocyte count (r = 0.70–0.84, p < 0.01 for MPF; r = 0.81–0.92, p < 0.001 for MBP) and negatively with OPC count (r = −0.69–−0.77, p < 0.01 for MPF; r = −0.72–−0.89, p < 0.01 for MBP). This study provides immunohistological validation of fast MPF mapping as a non-invasive tool for quantitative assessment of de- and remyelination in white and gray matter and indicates the feasibility of using MPF as a surrogate marker of reparative processes in demyelinating diseases.

An interactive meta-analysis of MRI biomarkers of myelin

“…The drawback of qMT is the requirement for a longer and more complex acquisition. Recently, there have been alternative techniques to estimate only MPF, resulting in faster acquisitions with similar results ( Khodanovich et al, 2019 ; Khodanovich et al, 2017 ; Yarnykh, 2012 ). Despite being focused on macromolecular contributions, these approaches are not strictly specific to myelin ( Sled, 2018 ): in this sense, an important limitation is that MT effects are sensitive to the pH of the targeted tissue and therefore changes in the pH (caused for example by inflammation processes) will affect MT-based measures of myelin ( Stanisz et al, 2004 ).…”

“…Even in this case, the acquisition time still reaches 15 min for acquiring roughly the whole brain with an isotropic resolution of 2 mm. Complex MT acquisitions such as qMT suffer from the same problem, although it is possible to use optimized and faster protocols to focus specifically on MPF ( Khodanovich et al, 2019 ; Khodanovich et al, 2017 ; Yarnykh, 2012 ).…”

An interactive meta-analysis of MRI biomarkers of myelin

“…The drawback of qMT is the requirement for a longer and more complex acquisition. Recently there have been alternative techniques to estimate only MPF, resulting in faster acquisitions with similar results (M. Khodanovich et al, 2019; M. Y. Khodanovich et al, 2017; Yarnykh, 2012).…”

“…Even in this case, the acquisition time still reaches 15 minutes for acquiring roughly the whole brain with an isotropic resolution of 2mm. Complex MT acquisitions such as qMT suffer from the same problem, although it is possible to use optimized and faster protocols to focus specifically on MPF (M. Khodanovich et al, 2019; M. Y. Khodanovich et al, 2017; Yarnykh, 2012).…”

Revealing architectural order with quantitative label-free imaging and deep learning

“…The human brain undergoes rapid myelination during late development as measured with magnetic resonance imaging (MRI) ( Heath et al, 2018 ). Interpretation of the myelination from MRI contrast requires establishing its correlation with histological measurements of myelin levels ( Khodanovich et al, 2019 ). Robust measurements of myelination in postmortem human brains can provide new insights in myelination of human brain during development and during degeneration.…”