Detecting early brain susceptibility changes before demyelination in cuprizone mouse model using quantitative susceptibility mapping (QSM)

Multiple sclerosis (MS) is a neurological disease that affects the central nervous system through demyelination and inflammation. Animal model, including the cuprizone (CPZ) model, provides a robust platform for studying demyelination and remyelination in MS. While conventional MRI techniques are sensitive to myelin changes, quantitative susceptibility mapping (QSM) offers additional advantages by capturing both myelin- and iron-related pathology. In this study, we performed longitudinal whole-brain multimodal magnetic resonance imaging (MRI), including T2-weighted imaging, magnetization transfer imaging, and QSM, in CPZ-treated mice across multiple stages covering pre-demyelination, acute demyelination, chronic demyelination, and remyelination. Regional analyses focused on the corpus callosum (CC) and anterior commissure (AC), complemented by histological validation. All three MRI modalities detected demyelination, characterized by increased T2 signal, decreased magnetization transfer ratio (MTR), and increased susceptibility, with partial recovery during remyelination. QSM demonstrated unique sensitivity by identifying susceptibility decreases at week 2, before apparent demyelination, corresponding to early oligodendrocyte dysfunction. Regional heterogeneity was observed, with the CC showing rapid alterations during acute demyelination and the AC exhibiting steadier changes across acute and chronic phases. These results establish QSM as a sensitive imaging biomarker capable of detecting early MS pathology and tracking dynamic changes in oligodendrocytes. By complementing conventional MRI techniques, QSM enhances the characterization of white matter injury in the CPZ model and holds translational potential for monitoring disease progression and therapeutic response in MS.