Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, characterised by progressive degeneration of both the upper (UMN) and lower (LMN) motor neurones in the brain and spinal cord¹. Diffusion Tensor imaging (DTI) has been applied to the study of ALS, and has consistently demonstrated microstructural damage in the corticospinal tract (CST), corpus callosum, and primary motor cortices, in the absence of macroscopic alterations². This is primarily through the assessment of changes in fractional anisotropy (FA). FA, however, is sensitive to both orientation dispersion and fibre density, and is of little use in cortical grey matter. Neurite orientation dispersion and density imaging (NODDI³) is an alternative quantitative diffusion MRI technique that overcomes some of the limitations of DTI. NODDI has demonstrated specificity at localising abnormalities in various disease states⁴, as well as grey matter (GM) alterations associated with aging⁵. The aim of this work was to assess whether voxelwise analysis of NODDI parameters could provide a more comprehensive picture than DTI in assessing the microstructural changes associated with ALS.Data from 17 patients with ALS (mean age=65.41 years, range=46-73 years) and 19 healthy controls (mean age=60.74 years, range=43-76 years) were acquired on a 1.5T MRI scanner, including multi-shell diffusion-weighted data (10 b=0 volumes, 9 directions with b=300 smm^-2, 30 directions with b=800 smm^-2 and 60 diffusion directions with b=2400 smm^-2), optimised for NODDI. The diffusion data were analysed using the NODDI toolbox³, to yield maps of the orientation dispersion index (ODI), the neurite density index (NDI), and the volume of the isotropic component (F_ISO). The same data were also used to derive FA maps using single tensor fitting, performed using FSL 5.0.7⁶. All the parametric maps were non-linearly co-registered using the Advanced Normalization Tools (ANTs) 2.1.0⁷ to bring all maps into the same space. The resulting maps were then warped to MNI space. Smoothing at 6mm FWHM and VBA were performed using SPM12⁸. Participant age was included as a covariate. Results are accepted as significant for p<0.05 after FWE correction at cluster level, clusters formed with p<0.001.Consistent with previous studies, significantly reduced FA was found in patients compared to controls in portions of the CST, the genu of the corpus callosum and the thalamus. Mean diffusivity was increased near the ventricles and in the insular cortex (see Fig 1). When looking at the NODDI maps, significant reductions in neurite density (NDI) were found along the whole CST, bilaterally, and including the primary motor cortex (Fig 2). Both increased and decreased ODI were found in patients, respectively, in the thalamus and in the precentral gyrus (bilaterally), in the right CST, and in the frontal pole (Fig 2). No differences in the isotropic component were found between groups; however, F_ISO was significantly associated with increasing age, in all the areas known to shrink with aging (hippocampus/parahippocampus, precuneus, cingulate cortex, see Fig 3).This study confirms that DTI indices are sensitive to pathological changes in ALS. However, MD and FA changes appear to be located not only in areas where microstructural changes are likely to occur, but also where age-related atrophy typically develops. NODDI indices indicate loss of neurites within the origin and in the course of the CST, with less specific changes in other areas, summarised by ODI. The striking correlations we found between F_ISO and age confirm the accurate modelling of this component, thanks to which NODDI results were not affected by atrophy as much as DTI measures were. We conclude that NODDI adds to our understanding of the nature and distribution of neuronal damage in ALS.