This study uses NODDI, a novel tool, to quantify changes of white matter (WM) skeleton in patients with ALS. By TBSS analysis, significant FA reductions were demonstrated within the (pre)frontal WM, partial parietal WM, corpus callosum and partial corticospinal tract. Similarly, significant Ficvf reductions were found within almost all the WM skeleton, which was more extensive than that of FA. In contrast, ODI showed no significant changes in all the WM skeleton. Therefore, NODDI is a more potential tool to demonstrating the neurite density reductions for ALS patients, which will help lead to earlier diagnosis and treatment for ALS.