Investigating Microstructural Changes in White Matter in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging

Abstract

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 microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and 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, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. 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. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger's tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each 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 the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.

Keywords: MS; NODDI; multi-compartment diffusion; multi-shell diffusion; multiple sclerosis; neurite orientation dispersion and density imaging.

Figure 1

Prisma flow diagram showing the systematic search strategy, study identification, screening, and eligibility and inclusion criteria.

Figure 2

Forest plot for the standardised mean difference of the NDI in MS WM lesions (MS vs. control) [20,23,24,25,26,29]. Abbreviations: SD = standard deviation; CI = confidence interval; NDI = Neurite Density Index; MS = multiple sclerosis; WM = white mater; vs. = versus; and I2 = Heterogeneity Index.

Figure 3

Funnel plot for the NDI in MS WM lesions (MS vs. control).

Figure 4

Forest plot for the standardized mean difference of the NDI in NAWM (MS vs. control) [20,23,24,25,26,27,29]. Abbreviations: SD = standard deviation; CI = confidence interval; NDI = Neurite Density Index; MS = multiple sclerosis; NAWM = normal-appearing white matter; vs. = versus; and I2 = Heterogeneity Index.

Figure 5

Funnel plot for the NDI in NAWM (MS vs. control).

Figure 6

Forest plot for the standardised mean difference of the ODI in MS WM lesions (MS vs. control) [20,23,24,25,26]. Abbreviations: SD = standard deviation; CI = confidence interval; ODI = Orientation Dispersion Index; MS = multiple sclerosis; WM = white mater; vs. = versus; and I2 = Heterogeneity Index.

Figure 7

Forest plot for the standard mean difference of the ODI in NAWM (MS vs. control) [20,23,24,25,26,27]. Abbreviations: SD = standard deviation; CI = confidence interval; ODI = Orientation Dispersion Index; MS = multiple sclerosis; NAWM = normal-appearing white matter; vs. = versus; and I2 = Heterogeneity Index.

Figure 8

Illustrates NODDI metrics in a single slice of one MS subject. The MS lesion in the major white matter tracts (blue arrow) and periventricular lesion (green arrow) are marked in a structural MRI image (A), NDI map (B), and ODI map (C). Both the NDI and ODI are decreased in the MS lesion [20].