Quantitative MRI and histopathology detect remyelination in inactive multiple sclerosis lesions

Magnetic resonance imaging (MRI) of focal or diffuse myelin damage or remyelination may provide important insights into disease progression and potential treatment efficacy in multiple sclerosis (MS). We performed post-mortem MRI and histopathological myelin measurements in seven progressive MS cases to evaluate the ability of three myelin-sensitive MRI scans to distinguish different stages of MS pathology, particularly chronic demyelinated and remyelinated lesions. At 3 Tesla, we acquired two different myelin water imaging (MWI) scans and magnetization transfer ratio (MTR) data. Histopathology included histochemical stainings for myelin phospholipids (LFB) and iron as well as immunohistochemistry for myelin proteolipid protein (PLP), CD68 (phagocytosing microglia/macrophages) and BCAS1 (remyelinating oligodendrocytes). Mixed-effects modelling determined which histopathological metric best predicted MWF and MTR in normal appearing and diffusely abnormal white matter, slowly expanding, inactive, remyelinated and ischemic lesions. Both MWI measures correlated well with each other and histology across regions, reflecting the different stages of MS pathology. MTR data showed a considerable influence of components other than myelin and a strong dependency on tissue storage duration. Both MRI and histology revealed increased myelin densities in inactive compared with slowly expanding lesions. Chronic inactive lesions harboured single scattered myelin fibres indicative of low-level remyelination. Mixed-effects modelling showed that smaller differences between white matter areas were linked to PLP densities and only to a smaller extent confounded by iron. MWI reflects differences in myelin lipids and proteins across all levels of myelin densities encountered in MS, including low-level remyelination in chronic inactive lesions. ### Competing Interest Statement All authors have completed the ICMJE uniform disclosure form at [www.icmje.org/coi_disclosure.pdf][1] and declare: no support from any organisation for the submitted work; RH has received speaker honoraria from Euroimmun, Novartis and Biogen; VW is board member of NeuroImage:Clinical; no other relationships or activities that could appear to have influenced the submitted work. ### Funding Statement This study was supported by the Research Methodology Grant from the BC Childrens Hospital Research Institute (former CFRI) and funding from the National Multiple Sclerosis Society (RG-1507-05301). VW was supported by a graduate student award from the Multiple Sclerosis Society of Canada (EGID 2002). VE was supported by funding from the National Multiple Sclerosis Society (RG-1507-05301). EHT was supported by Consejo Nacional de Ciencia y Tecnologia (237961). We are grateful for additional support from NSERC (402039-2011, 2016-05371), CIHR (RN382474-418628) and the Milan and Maureen Ilich Foundation. AR is supported by Canada Research Chairs (950-230363). ### 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 IRB of the University of British Columbia gave ethical approval for this work. The IRB of the Medical University of Vienna gave ethical approval for this work. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data are available from the corresponding author upon reasonable request. [1]: http://www.icmje.org/coi_disclosure.pdf