Quantitative MRI Biomarkers of Myelin: Cross-Validation and Diagnostic Performance in Multiple Sclerosis

Quantitative magnetic resonance imaging (MRI) of myelin is essential for understanding demyelination and remyelination in neurological diseases such as multiple sclerosis (MS). Several imaging biomarkers have been proposed, including myelin proton fraction (MPF), myelin water fraction (MWF), macromolecular proton fraction (MMF), and magnetization transfer ratio (MTR), but their concordance remains uncertain. We evaluated the relationships between these biomarkers using recently developed MRI techniques: short-TR adiabatic recovery ultrashort echo time (STAIR-UTE) for MPF, STAIR short echo time (STAIR-STE) for MWF, and magnetization transfer imaging for MMF and MTR. Ten healthy volunteers and five MS patients were scanned on a 3 T clinical system using sequences with a 3D cone trajectory. Biomarkers were quantified in white matter (WM), gray matter (GM), and lesions, and analyzed with correlation testing, group comparisons, and receiver operating characteristic (ROC) analysis. All four biomarkers demonstrated strong positive correlations (R = 0.74-0.94) across tissue types. WM values were significantly higher than GM values, and MS lesions showed marked reductions in the four biomarkers relative to normal-appearing WM (p < 0.05). ROC analyses indicated good-to-excellent performance in distinguishing healthy controls and patients, with MPF, MMF, and B₁-corrected MTR (i.e., MTR_c) achieving the highest accuracy (area under the curve ≥ 0.9). These findings show that MPF, MWF, MMF, and MTR provide convergent but distinct information about myelin content. While MPF, MMF, and MTR_c demonstrated potential diagnostic utility, further histological validation is required to establish biological specificity and facilitate clinical translation.