In the current work two novel parameters, fiber density (FD) and mean diffusion signal (MDS) are investigated for evaluating neurodegenerative processes in amyotrophic lateral sclerosis (ALS). The MDS provides a measure of the FD but is derived directly from the diffusion signal. Using tract-based spatial statistics (TBSS), pathological changes across the entire white matter and changes in the parameters over time were evaluated. The results were related to those obtained using the fractional anisotropy (FA) value. A widespread pattern of significantly decreased FD and MDS values was observed. A strong trend towards statistical significance was seen in similar white matter structures using TBSS analysis based on the FA value. Longitudinal analysis of the FD values demonstrated continuing deterioration of the same fiber tracts that were shown to be impaired in the group analysis. The findings suggest that MDS and in particular FD show great promise for evaluating microstructural white matter changes in ALS and may be more sensitive than the more commonly used FA value.