Quantification of normal-appearing white matter damage in early relapse-onset multiple sclerosis through neurite orientation dispersion and density imaging

Background Neurodegeneration is a major contributor of neurological disability in multiple sclerosis (MS). The possibility to fully characterize normal appearing white matter (NAWM) damage could provide the missing information needed to clarify the mechanisms beyond disability accumulation. Objective In the present study we aimed to characterize the presence and extent of NAWM damage and its correlation with clinical disability. Methods We applied Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) in a cohort of 27 early relapse-onset MS patients (disease duration < 5 years) compared to a population of 26 age- and sex-matched healthy controls (HCs). All patients underwent a neurological examination, including the Expanded Disability Status Scale (EDSS). Results MS patients showed lower fractional anisotropy (FA) and higher mean diffusivity (MD) values in the main WM bundles, such as the corticospinal tract, corpus callosum, superior and middle cerebellar peduncles, posterior thalamic radiation (which includes optic radiation), cingulum and external capsule. All brain areas with reduced FA/increased MD also displayed a reduction in neurite density index (NDI). However, comparing individual voxels of the WM skeleton between MS and HCs, a higher number of NDI significant voxels was disclosed compared to FA/MD (56.4% vs 11.2%/41.2%). No significant correlations were observed between DTI/NODDI metrics and EDSS. Conclusions Our findings suggest that NDI may allow for a better characterization and understanding of the microstructural changes in the NAWM since the early relapsing-remitting MS phases. Future longitudinal studies including a larger cohort of patients with different clinical phenotypes may clarify the association between NODDI metrics and disability progression