Amyotrophic Lateral Sclerosis (ALS) is a fatal disease that primarily affects the human primary motor system. Selective neurodegeneration leads to systemic functional motor decay. We aimed to understand the relationship between cortical degeneration and the desintegration of the related motor corticospinal tract (CST) by applying both Diffusion Tensor Imaging (DTI) and the multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT). We found early changes in diffusion and relaxation measures indicating WM tract degeneration secondary to cortical neurodegeneration. Besides the loss of structural integrity early alterations of the myelin characteristics indicate toward changes of its compositional condition instead of early myelin loss.