NODDI, diffusion tensor microstructural abnormalities and atrophy of brain white matter and gray matter contribute to cognitive impairment in multiple sclerosis

Pathologically specific MRI measures may elucidate in-vivo the heterogeneous processes contributing to cognitive impairment in multiple sclerosis (MS).Using diffusion tensor and neurite orientation dispersion and density imaging (NODDI), we explored the contribution of focal lesions and normal-appearing (NA) tissue microstructural abnormalities to cognitive impairment in MS.One hundred and fifty-two MS patients underwent 3 T brain MRI and a neuropsychological evaluation. Forty-eight healthy controls (HC) were also scanned. Fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICV_f) and orientation dispersion index (ODI) were assessed in cortical and white matter (WM) lesions, thalamus, NA cortex and NAWM. Predictors of cognitive impairment were identified using random forest.Fifty-two MS patients were cognitively impaired. Compared to cognitively preserved, impaired MS patients had higher WM lesion volume (LV), lower normalized brain volume (NBV), cortical volume (NCV), thalamic volume (NTV), and WM volume (p ≤ 0.021). They also showed lower NAWM FA, higher NAWM, NA cortex and thalamic MD, lower NAWM ICV_f, lower WM lesion ODI, and higher NAWM ODI (false discovery rate-p ≤ 0.026). Cortical lesion number and microstructural abnormalities were not significantly different. The best MRI predictors of cognitive impairment (relative importance) (out-of-bag area under the curve = 0.727) were NAWM FA (100%), NTV (96.0%), NBV (84.7%), thalamic MD (43.4%), NCV (40.6%), NA cortex MD (26.0%), WM LV (23.2%) and WM lesion ODI (17.9%).Our multiparametric MRI study including NODDI measures suggested that neuro-axonal damage and loss of microarchitecture integrity in focal WM lesions, NAWM, and GM contribute to cognitive impairment in MS.