The radial diffusivity and magnetization transfer pool size ratio are sensitive markers for demyelination in a rat model of type III multiple sclerosis (MS) lesions

Abstract

Determining biophysical sensitivity and specificity of quantitative magnetic resonance imaging is essential to develop effective imaging metrics of neurodegeneration. Among these metrics apparent pool size ratio (PSR) from quantitative magnetization transfer (qMT) imaging and radial diffusivity (RD) from diffusion tensor imaging (DTI) are both known to relate to histological measure of myelin density and integrity. However their relative sensitivities towards quantitative myelin detection are unknown. In this study, we correlated high-resolution quantitative magnetic resonance imaging measures of subvoxel tissue structures with corresponding quantitative myelin histology in a lipopolysacharide (LPS) mediated animal model of MS. Specifically, we acquired quantitative magnetization transfer (qMT) and diffusion tensor imaging (DTI) metrics (on the same tissue sample) in an animal model system of type III oligodendrogliopathy which lacked prominent lymphocytic infiltration, a system that had not been previously examined with quantitative MRI. We find that the qMT measured apparent pool size ratio (PSR) showed the strongest correlation with a histological measure of myelin content. DTI measured RD showed the next strongest correlation, and other DTI and relaxation parameters (such as the longitudinal relaxation rate (R1f) or fractional anisotropy (FA)) showed considerably weaker correlations with myelin content.

Age-Related Changes in Diffusion Tensor Imaging Metrics of Fornix Subregions in Healthy Humans

“…Our results are consistent with other literature which reports decreased FA values in the fornix with age [37,38]. While studies have shown that age-independent demyelination or axonal injury strongly correlates with specific DTI metrics such as RD or AD, respectively [39,40,41], it is unsurprising to see changes in FA, AD and RD in our current study sample given that multiple events involving different aspects of white matter integrity are involved in aging.…”

Quantitative Assessment of Normal Fetal Brain Myelination Using Fast Macromolecular Proton Fraction Mapping

“…1,23,24 A relatively high MPF and its correlation with GA in the thalamus are also in concordance with early myelination of this structure commencing at the 25th week. 25 While the myelin content provides the main determinant of the MPF in WM according to our results and other studies, [6][7][8][9][10] subtle effects of other tissue properties on this parameter are also discernible. An increased MPF in the germinal matrix observed in young fetuses suggests that unmyelinated brain tissue creates a low-signal background highlighting fine distinctions in the macromolecular content not related to myelin and probably associated with cellularity.…”

Fast Whole-Brain Three-dimensional Macromolecular Proton Fraction Mapping in Multiple Sclerosis

“…A limited capability of both lesion volume and MPF in lesions to explain clinical status supports the current understanding of MS as a whole-brain disease in which widespread microscopic demyelination in normal-appearing tissues mainly determines progression of disability (17,28). A decrease of MPF in all brain tissues is generally consistent with progressive demyelination as the primary pathologic substrate of neural tissue damage in MS (17) and strong associations between MPF and myelin content established in animal models (4,5,(12)(13)(14)(15)(16). While microscopic myelin damage is probably the dominant cause of MPF reduction in normal-appearing WM, pathologic changes of MPF in MS lesions may also be driven by edema associated with inflammation because an increase in water content causes dilution of the total macromolecular concentration.…”

“…Practical interest in MPF as a prospective biomarker in MS is driven by a number of recent animal studies (4,5,(12)(13)(14)(15)(16) that demonstrated strong relationships between MPF and myelin. MPF has been highly positively correlated with histologic measurements of myelin density in animal models, including both normal brain tissues and demyelination (4,12,15,16).…”

“…MPF has been highly positively correlated with histologic measurements of myelin density in animal models, including both normal brain tissues and demyelination (4,12,15,16). Based on quantitative estimates from the literature (5), myelin provides an at least 75% contribution into the MPF measured in white matter (WM).…”