Quantitative MRI and ultrastructural examination of the cuprizone mouse model of demyelination

Abstract

The cuprizone mouse model of demyelination was used to investigate the influence that white matter changes have on different magnetic resonance imaging results. In vivo T2 -weighted and magnetization transfer images (MTIs) were acquired weekly in control (n = 5) and cuprizone-fed (n = 5) mice, with significant increases in signal intensity in T2 -weighted images (p < 0.001) and lower magnetization transfer ratio (p < 0.001) in the corpus callosum of the cuprizone-fed mice starting at 3 weeks and peaking at 4 and 5 weeks, respectively. Diffusion tensor imaging (DTI), quantitative MTI (qMTI), and T1/T2 measurements were used to analyze freshly excised tissue after 6 weeks of cuprizone administration. In multicomponent T2 analysis with 10 ms echo spacing, there was no visible myelin water component associated with the short T2 value. Quantitative MTI metrics showed significant differences in the corpus callosum and external capsule of the cuprizone-fed mice, similar to previous studies of multiple sclerosis in humans and animal models of demyelination. Fractional anisotropy was significantly lower and mean, axial, and radial diffusivity were significantly higher in the cuprizone-fed mice. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: T1 versus the myelinated axon fraction (ρ = -0.90), the bound pool fraction (ƒ) versus the myelin sheath fraction (ρ = 0.93), and axial diffusivity versus the non-myelinated cell fraction (ρ = 0.92). Using Pearson's correlation coefficient, ƒ was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37ƒ - 0.25). Of the calculated MRI metrics, ƒ was the strongest indicator of myelin content, while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure.

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…We opted to investigate the well-established CPZ mouse model for MS, whose strengths lie in the localization of the lesions, their well-known pathogenesis, and their reproducibility in time and space, allowing for longitudinal validation of imaging methods (37,47,48). In this model, the vast majority of activated MPs are endogenous microglia, not peripheral macrophages (49)(50)(51)(52).…”

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

“…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).…”

Comparison of Tractography in Mouse Models of Multiple Sclerosis and Alzheimer’s Disease

“…On the other hand, some believe myelin does not play a large role in restricting diffusion and thus demyelination will not affect DTI (5)(6)(7)(8).…”