Modelling axonal loss caused by chronic demyelination and slow-burning inflammation at the rim of chronic lesions in MS patients

Objectives. Slow-burning inflammation at the edge of chronic multiple sclerosis lesions and loss of myelin in the depths of the lesions have emerged as a key components of disease progression. However, their relative contribution to progressive axonal damage has not been investigated. Therefore, the aim of the study was to examine relative weight of those factors in axonal attrition inside the chronic MS lesions by measuring tissue rarefication of the lesion core. Methods. Pre- and post-gadolinium 3D-T1, 3D FLAIR, diffusion tensor images, Optical Coherence tomography and multifocal visual evoked potentials were acquired from 52 patients. Analysis was performed between baseline and 48 months. Lesion expansion was measured using in-house software. The degree of lesional tissue damage was determined by measuring increase of Mean Diffusivity (MD) in lesion core normalised over MD dynamic range. Results. There were 104 expanding and 257 stable lesions. Rate of normalised MD (nMD) increase was several folds higher in expanding vs stable lesions (0.21% vs 1.12% per year, p=0.01). The magnitude of nMD change was significantly associated with the rate of lesion expansion (r=0.4, p<0.001). Analysis of visual system revealed the rate of axonal loss similar to the degree of tissue rarefication in stable lesions. Interpretation. The current study demonstrated a significant increase in water content in chronic MS lesions, which was, however, markedly higher in slowly expanding compared to stable lesions. This suggests that slow-burning inflammation at the lesion rim, when present, is likely to play a more significant role in axonal attrition than chronic demyelination ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### 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