Abstract
Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single-molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing–remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation and neurite orientation dispersion and density imaging diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 versus 0.57, difference 0.036, 95% CI: 0.029–0.043, P < 0.001). Lesion volume (Spearman’s rho rs= 0.38, P < 0.001) and g-ratio (rs= 0.24, P < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) [11/23 (48%) versus 2/15 (13%), P < 0.05]. These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity and help to identify individuals with a high degree of axonal damage at disease onset.
Highlights
Multiple sclerosis is an unpredictable neurological disease characterized by immune-mediated myelin loss and axonal degeneration.[1]
We first looked at the difference in g-ratio between normal-appearing white matter (NAWM) and white matter lesions (WML) in newly diagnosed relapsing–remitting multiple sclerosis (RRMS) patients
WML g-ratio varied widely, and identified individuals with both normal and elevated WML g-ratio at diagnosis (Fig. 2B and C), suggesting the potential for g-ratios to identify a subset of patients with severe myelin disruption at diagnosis
Summary
Multiple sclerosis is an unpredictable neurological disease characterized by immune-mediated myelin loss and axonal degeneration.[1]. Advances in MR imaging and ultrasensitive protein detection technologies offer new opportunities for quantified in vivo study of myelin integrity and axonal damage at critical timepoints in multiple sclerosis, such as the point of diagnosis. Quantitative magnetization transfer (MT) and water molecule diffusion-derived MRI methods allow non-invasive evaluation of microstructural integrity and myelin pathology,[4,5,6] and have the potential to provide insights into myelin loss in multiple sclerosis in vivo. The gratio is defined as the ratio of the inner to outer radius of the myelin sheath (Fig. 1A) and provides a specific measure of myelin integrity.[7] An MR-derived ‘aggregate gratio’ can be estimated in defined regions of the brain by combining MT and diffusion biomarker data.[8,9] The MR g-ratio has previously been validated against tissue measures in both healthy controls and people with multiple sclerosis. High g-ratios indicate disruption of myelin.[10,11]
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