Short-term surrogate biomarkers of chronic lesion expansion

Abstract

Objectives: Slow expansion of multiple sclerosis (MS) lesions has been shown to significantly contribute to disease progression. However, accurate assessment of this metric remains challenging. We investigated whether the long-term damage caused by slow-burning inflammation at the rim of chronic MS lesions can be predicted within timeframe of a typical clinical trial, using surrogate imaging markers. Methods: Pre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 42 patients with MS. Lesion expansion was analysed annually between baseline and 48 months. The volume of chronic lesion expansion was stratified by the degree of tissue damage within the expanding component of the lesion, measured by a progressive volume/severity index (PVSI). Central brain atrophy (CBA) and the degree of tissue loss inside chronic lesions (measured by the change of T1 intensity and MD) were used as surrogate markers. Results. CBA measured after 2 years of follow-up predicted PVSI at 4 years with a high degree of accuracy (r=0.90, p<0.001, ROC area under the curve 0.92, sensitivity of 94%, specificity of 85%). Increased MD within chronic lesions measured over 2 years was also strongly associated with future PVSI (r=0.80, p<0.001, ROC area under the curve 0.87, sensitivity of 81% and specificity of 81%). In contrast, change in lesion T1 hypointensity poorly predicted future PVSI (best sensitivity and specificity 60% and 59% respectively). Interpretation. CBA and, to a lesser degree, the change in MD within chronic MS lesions, measured over 2 years are reliable and sensitive predictors of the extent and severity of long-term lesion expansion.