Demyelination, axonal damage and inflammation are critical indicators of the onset and progress of neurodegenerative diseases such as multiple sclerosis (MS) in patients. Due to physical limitations of imaging such as acquisition time and imaging resolution, a voxel in a MR image is heterogeneous in terms of tissue microstructure such as myelin, axons, intra and extra cellular fluids and free water. We present a multi-compartment tissue model which estimates the water fraction (WF) of tissues with short, medium and high T 2 relaxation times in a T 2 relaxometry MRI voxel. The proposed method is validated on test-retest data of healthy controls. This model was then used to study longitudinal trends of the tissue microstructures for two sub-regions of the lesions: gadolinium enhanced (E+) and non-enhanced (L−) regions of MS lesions in 10 MS patients over a period of three years. The water fraction values in E+ and L− regions were found to be significantly different (p < 0.05) over the period of first three months. The results of this study also showed that the estimates of the proposed T 2 relaxometry model on brain tissue microstructures have potential to distinguish between regions undergoing active blood brain barrier breakdown from the other regions of the lesion.