Investigating microstructural changes in white matter in multiple sclerosis: A systematic review and individual participant data meta-analysis of neurite orientation dispersion and density imaging

Abstract

Background: Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite Orientation Dispersion and Density Imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructure. NODDI maps can be calculated for neurite density index (NDI), orientation dispersion index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, being more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations.Aims: We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS.Methods: Three reviewers conducted the literature search of four electronic databases (Medline, Embase, Scopus, and PubMed). We performed a random-effect meta-analysis. The extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger's tests were used to assess publication bias.Result: We identified 7 studies analysing 374 participants (202 MS, 172 controls). NDI in WM lesions and NAWM were significantly reduced compared to healthy WM. The standardised mean difference was -3.08 (95%CI -4.22 to (-1.95), p=<0.00001, I2=88%) and -0.70 (95%CI -0.99 to (-0.40), p=<0.00001, I2=35%) respectively. There was no statistically significant difference of ODI in MS WM lesions and NAWM compared to healthy controls. The standardised mean difference was -0.44 (95%CI -1.60 to (-0.71), p=0.45, I2=95%) for WM lesions and -0.46 (95%CI -2.07 to (-1.15), p=0.58,