Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging
Authors: Rahmanzadeh Reza , Lu Po-Jui , Barakovic Muhamed , Weigel Matthias , Maggi Pietro , Nguyen Thanh D , Schiavi Simona , Daducci Alessandro , La Rosa Francesco , Schaedelin Sabine , Absinta Martina , Reich Daniel S , Sati Pascal , Wang Yi , Bach Cuadra Meritxell , Radue Ernst-Wilhelm , Kuhle Jens , Kappos Ludwig , Granziera Cristina 
Published: March 2021

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 &lt; 0.0001) and peri-plaque white matter (P &lt; 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P &lt; 0.0001 and P &lt; 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P &lt; 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 &lt; 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 &lt; 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 &lt; 0.01, beta = −3.60 and P &lt; 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.