Contributions
Abstract: P727
Type: Poster
Abstract Category: Therapy - disease modifying - Tools for detecting therapeutic response
Background: Fingolimod is an oral drug approved for the treatment of multiple sclerosis. This drug has been shown to positively affect myelination, and compounding evidence suggests that treatment efficacy depends on dosage. Researchers have used diffusion-weighted imaging (DWI) in magnetic resonance imaging (MRI) to investigate dosage effects on diffusion metrics. Limitations of these findings involved the use of supra-clinical doses and a relapsing remitting animal model. Since DWI does not directly target myelination, MRI based measures of tissue magnetic susceptibility may provide additional sensitivity to dosage effects on myelination.
Objective: Assess impact of dosage on myelination via MRI contrasts sensitive to changes in magnetic susceptibility in acute and chronic cuprizone mice treated with fingolimod.
Methods: Eighty 6-week old C57BL/6 mice were separated into acute and chronic cohorts, each comprising of four groups. In each cohort, the four groups were normal diet, untreated cuprizone diet and cuprizone diet treated with either 0.1mg/kg fingolimod or the maximum equivalent clinical dose of 0.3mg/kg fingolimod. In vivo and ex vivo multiple echo time T2*-weighted gradient recalled echo data were obtained using a 9.4T Bruker animal scanner. The average voxel intensities of the white (corpus callosum) and grey (cortex) matter regions in each brain image were determined for T2*, frequency shift and susceptibility measures. Staining for myelin, oligodendrocytes, interneurons and microglia was performed.
Results: Both fingolimod dosages displayed an increase in grey-white matter contrast (p < 0.001) compared to the cuprizone diet for acute and chronic in vivo MRI measures. For in vivo T2*, frequency shift and susceptibility respectively, the 0.3mg/kg dosage showed an increase in grey-white matter contrast that was 68%, 81% or 207% greater than the increase observed for 0.1mg/kg in the acute stage, and 11%, 63% or 78% greater in the chronic stage. Ex vivo MRI and myelin-basic protein antibody results also exhibited an increase in grey-white matter contrast with fingolimod treatment.
Conclusions: Fingolimod treatment has a positive effect on myelination relative to the untreated cuprizone diet in both the acute and chronic demyelination stages, with a larger dosage amount showing a greater increase in grey-white matter contrast. Magnetic susceptibility was found to be the most sensitive to cuprizone and fingolimod induced changes.
Disclosure: The project was funded by Novartis Pharmaceuticals Pty. Ltd., Australia, as an investigator initiated trial.
Laura Ziser: nothing to disclose
Naja Meyer-Schell: nothing to disclose
Robert Sullivan: nothing to disclose
David Reutens: nothing to disclose
Nyoman Kurniawan: nothing to disclose
Min Chen: nothing to disclose
Viktor Vegh: nothing to disclose
Abstract: P727
Type: Poster
Abstract Category: Therapy - disease modifying - Tools for detecting therapeutic response
Background: Fingolimod is an oral drug approved for the treatment of multiple sclerosis. This drug has been shown to positively affect myelination, and compounding evidence suggests that treatment efficacy depends on dosage. Researchers have used diffusion-weighted imaging (DWI) in magnetic resonance imaging (MRI) to investigate dosage effects on diffusion metrics. Limitations of these findings involved the use of supra-clinical doses and a relapsing remitting animal model. Since DWI does not directly target myelination, MRI based measures of tissue magnetic susceptibility may provide additional sensitivity to dosage effects on myelination.
Objective: Assess impact of dosage on myelination via MRI contrasts sensitive to changes in magnetic susceptibility in acute and chronic cuprizone mice treated with fingolimod.
Methods: Eighty 6-week old C57BL/6 mice were separated into acute and chronic cohorts, each comprising of four groups. In each cohort, the four groups were normal diet, untreated cuprizone diet and cuprizone diet treated with either 0.1mg/kg fingolimod or the maximum equivalent clinical dose of 0.3mg/kg fingolimod. In vivo and ex vivo multiple echo time T2*-weighted gradient recalled echo data were obtained using a 9.4T Bruker animal scanner. The average voxel intensities of the white (corpus callosum) and grey (cortex) matter regions in each brain image were determined for T2*, frequency shift and susceptibility measures. Staining for myelin, oligodendrocytes, interneurons and microglia was performed.
Results: Both fingolimod dosages displayed an increase in grey-white matter contrast (p < 0.001) compared to the cuprizone diet for acute and chronic in vivo MRI measures. For in vivo T2*, frequency shift and susceptibility respectively, the 0.3mg/kg dosage showed an increase in grey-white matter contrast that was 68%, 81% or 207% greater than the increase observed for 0.1mg/kg in the acute stage, and 11%, 63% or 78% greater in the chronic stage. Ex vivo MRI and myelin-basic protein antibody results also exhibited an increase in grey-white matter contrast with fingolimod treatment.
Conclusions: Fingolimod treatment has a positive effect on myelination relative to the untreated cuprizone diet in both the acute and chronic demyelination stages, with a larger dosage amount showing a greater increase in grey-white matter contrast. Magnetic susceptibility was found to be the most sensitive to cuprizone and fingolimod induced changes.
Disclosure: The project was funded by Novartis Pharmaceuticals Pty. Ltd., Australia, as an investigator initiated trial.
Laura Ziser: nothing to disclose
Naja Meyer-Schell: nothing to disclose
Robert Sullivan: nothing to disclose
David Reutens: nothing to disclose
Nyoman Kurniawan: nothing to disclose
Min Chen: nothing to disclose
Viktor Vegh: nothing to disclose