Short-term surrogate biomarkers of chronic lesion expansion

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Supported by the National Multiple Sclerosis Society (NMSS), Multiple Sclerosis Research Australia (MSRA) and Sydney Medical School. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by University of Sydney and Macquarie University Human Research Ethics Committees and followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors