Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging

Abstract

Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.

Keywords: demyelination; diffusion microstructural modelling; multiple sclerosis; myelin water imaging; neurodegeneration.

Figure 1

Axial images in one exemplary multiple sclerosis patient. (A) FLAIR, (B) MWF map, (C) NODDI-NDI map, (D) MP2RAGE, (E) 3D-EPI QSM and (F) 3D-EPI unwrapped phase. Red/Blue triangles show white matter lesions (A–C), cortical lesions (D) and lesions with paramagnetic rim (E and F).

Figure 2

MWF and NODDI-NDI in different types of multiple sclerosis lesions. (A and B) Box plots showing that MWF and NDI in white matter lesions (WMLs) is lower than MWF and NDI in NAWM and white matter in healthy controls (WM-HC). (C) NDI-MWF scatter plots in white matter lesions. (D and E) Box plots showing that MWF and NDI in cortical lesions (CL) is lower than in NAGM and grey matter in healthy controls (GM-HC). (F) NDI-MWF scatter plots in cortical lesions. (G and H) MWF and NDI are lower in periventricular (PV) lesions than in juxtacortical (JC) lesions. (I) NDI-MWF scatter plot in periventricular and juxtacortical lesions. (J and K) MWF and NDI are lower in Rim+ lesions than in Rim− lesions. (L) NDI-MWF scatter plot for white matter lesions with and without paramagnetic phase rim on both 3D EPI unwrapped phase and 3D EPI QSM images. (M and N) MWF and NDI were not different between RRMS and PMS. (O) NDI-MWF scatter plots for white matter lesions in RRMS versus PMS. NDI; NODDI-NDI. ***P < 0.0001; **P < 0.001; *P < 0.05. ns = not significant; WM = white matter.

Figure 3

Peri-plaque white matter around multiple sclerosis lesions. (A) Axial 3D FLAIR image [with segmentation of white matter lesions (WMLs; red), PP-1st (blue) and PP-2nd (green)]. (B and C) Box plots showing that MWF and NDI gradually increase from white matter lesions to PP-1st and PP-2nd. (D and E) Box plots showing that MWF and NDI in cortical lesions (CL) are less than in PP-1st and PP-2nd. ***P < 0.0001; **P < 0.001; *P < 0.05. ns = not significant.

Figure 4

Comparison of NDI and MWF in normal-appearing brain tissue between patients and controls. Top row: (A–D) Compared to healthy subjects (HC), multiple sclerosis (MS) patients show a widespread NODDI-NDI reduction in normal-appearing white matter and—to a smaller extent—a diffuse MWF reduction. Bottom row: There are patchy reductions in MWF and NODDI-NDI in the normal-appearing cortical surface of multiple sclerosis patients versus healthy controls and in PMS versus RRMS patients.

Figure 5

Alteration in MWF versus NDI in multiple sclerosis white matter lesions. (A) Percentage of MWF and NODDI-NDI decline for individual white matter (WM) lesions relative to mirror region of interest in contralateral hemisphere (individual multiple sclerosis white matter lesions are shown with numbers). (B) Bar graph shows that NODDI-NDI decreases more than MWF in multiple sclerosis lesions (***P < 0.0001).