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Neurite orientation dispersion and density imaging (NODDI), a MRI multi-shell diffusion technique, has offered new insights for the study of microstructural changes in neurodegenerative diseases. Mainly, the present study aimed to determine the connection between NODDI-derived parameters and changes in white matter (WM) abnormalities at early stages of amyotrophic lateral sclerosis (ALS). Spinal cords from ALS mice (G93A-SOD1 mice) were scanned in a Bruker Avance III HD 17.6 T magnet. Fluorescent axonal-tagged mice (YFP, G93A-SOD1 mice) were used for quantitative histological analysis. NODDI showed a decrease in intra-cellular volume fraction (− 24%) and increases in orientation dispersion index (+ 35%) and isotropic volume fraction (+ 33%). In addition, histoathological results demonstrated a reductions in axonal area (− 11%) and myelin content (− 29%). A histological decrease in WM intra …