Quantitative evaluation of brain myelination has drawn considerable attention. Conventional diffusion-based magnetic resonance imaging models, including diffusion tensor imaging and diffusion kurtosis imaging (DKI),1 have been used to infer the microstructure and its changes in neurological diseases. White matter tract integrity (WMTI) was proposed as a biophysical model to relate the DKI-derived metrics to the underlying microstructure. Although the model has been validated on ex vivo animal brains, it was not well evaluated with ex vivo human brains. In this study, histological samples (namely corpus callosum) from postmortem human brains have been investigated based on WMTI analyses on a clinical 3T scanner and comparisons with gold standard myelin staining in proteolipid protein and Luxol fast blue. In addition, Monte Carlo simulations were conducted to link changes from ex vivo to in vivo conditions based on the microscale parameters of water diffusivity and permeability. The results show that WMTI metrics, including axonal water fraction AWF, radial extra-axonal diffusivity De⊥, and intra-axonal diffusivity Da were needed to characterize myelin content alterations. Thus, WMTI model metrics are shown to be promising candidates as sensitive biomarkers of demyelination.