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Updated: May 8, 2026
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
Quantitative MRI and ultrastructural examination of the cuprizone mouse model of demyelination
Jonathan D Thiessen1, Yanbo Zhang, Handi Zhang
1Department of Physics and Astronomy, University of Manitoba, Winnipeg, MB, Canada; Department of Radiology, University of Manitoba, Winnipeg, MB, Canada.
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.
Insights
This study used the cuprizone mouse model to link white matter changes to MRI results. Quantitative MTI metrics, particularly the bound pool fraction (ƒ), strongly indicated myelin content and tissue structure changes in demyelination.
Area of Science:
- Neuroimaging
- Demyelination Research
- White Matter Integrity
Background:
- The cuprizone mouse model is widely used to study demyelination and its effects on brain tissue.
- Magnetic Resonance Imaging (MRI) techniques are crucial for non-invasively assessing white matter integrity.
- Understanding the relationship between MRI metrics and underlying cellular changes is vital for diagnosing and monitoring demyelinating diseases like multiple sclerosis.
Purpose of the Study:
- To investigate the influence of white matter changes on various MRI results using the cuprizone mouse model.
- To correlate quantitative MRI metrics with cellular changes in demyelinated white matter.
- To identify the most sensitive MRI indicators of myelin content and structural alterations.
Main Methods:
- In vivo T2-weighted and magnetization transfer imaging (MTI) were performed weekly in control and cuprizone-fed mice.
- Ex vivo analysis included diffusion tensor imaging (DTI), quantitative MTI (qMTI), and T1/T2 relaxation measurements.
- Electron microscopy was used to quantify cellular distributions in the corpus callosum.
Main Results:
- Cuprizone-fed mice showed increased T2 signal intensity and decreased magnetization transfer ratio in the corpus callosum.
- Significant differences in qMTI metrics, fractional anisotropy (lower), and diffusivity (higher) were observed in cuprizone-fed mice.
- The bound pool fraction (ƒ) strongly correlated with myelin sheath fraction (r = 0.98), predicting myelin content.
Conclusions:
- Quantitative MTI metrics, especially the bound pool fraction (ƒ), are highly sensitive to myelin content changes.
- MRI-derived diffusivity measurements reflect alterations in white matter tissue structure during demyelination.
- This study highlights the utility of advanced MRI techniques in characterizing demyelination and its cellular correlates.
