Multi-omics validation of myelin water fraction as a myelin-specific MRI biomarker

• Multi-omics validation for Myelin Water Fraction as a specific myelin marker • Plasma proteins link MWF to oligodendrocyte function and myelination • Myelin Basic Protein gene expression strongly correlates with regional MWF The myelin sheath is critical for efficient neural signaling and central nervous system function, yet noninvasive methods to quantify myelin content in vivo remain limited and require robust biological validation. Myelin Water Fraction (MWF) derived from the Bayesian Monte Carlo analysis of multicomponent Driven Equilibrium Single Pulse Observation of T 1 and T 2 (BMC-mcDESPOT) imaging method offers a promising biomarker of myelin content, but its biological specificity requires further validation. To elucidate the molecular underpinnings of MWF derived using BMC-mcDESPOT, we integrated this advanced MRI method with high-throughput plasma proteomics and spatial transcriptomics across major white and deep gray matter regions in adults. Plasma protein analyses using the SomaScan 7k platform revealed nominal associations (p < 0.05, unadjusted) between MWF and several proteins highly expressed by oligodendrocytes, a key cell type for myelin synthesis and maintenance. Furthermore, spatial mapping of Myelin Basic Protein ( MBP ) gene expression obtained from the Allen Human Brain Atlas demonstrated a strong positive correlation with regional MWF values, consistent with known myelin distribution patterns. These convergent findings provide supportive evidence for the biological relevance of MWF as a myelin-sensitive imaging marker, and highlight the potential of integrating omics data to validate and enhance in vivo neuroimaging biomarkers. Our work evinces and advances the utility of MWF for studying white matter myelination and integrity in health and disease, offering new avenues for clinical and translational neuroscience.