Quantification of the Innate Immune Activity within Chronic Lesions as a Novel Treatment Biomarker in Multiple Sclerosis

Project Summary/Abstract The objective of this proposal is to utilize quantitative susceptibility mapping (QSM) to establish a clinically feasible, accurate, and robust treatment biomarker for chronic inflammation in multiple sclerosis (MS). Chronic active lesions (CALs) characterized by persistent smoldering inflammation significantly contribute to progressive cognitive and ambulatory decline in MS. Within a subset of CALs, a distinct subgroup has been identified as paramagnetic rim lesions (PRLs), where iron-laden pro-inflammatory immune cells are localized at the edge of the lesion. Leveraging the quantitative capabilities of QSM, we have made a significant observation regarding the inflammatory trajectory of PRLs. These lesions exhibit an initial increase in susceptibility, followed by a subsequent decrease, signifying the transition from a chronic active to a chronic inactive MS lesion. Notably, our findings have also indicated that QSM can detect the longitudinal susceptibility changes in PRLs resulting from the administration of current disease modifying therapies. Building on our promising preliminary data, our primary objectives are as follows: 1) develop a high-resolution, clinically feasible approach to accurately detect PRLs and identify their iron source; 2) provide in vivo validation for precise detection and quantification of inflammatory changes within individual PRLs; 3) identify existing disease- modifying therapies that target innate immune burden within lesions and 4) establish the positive impact of reducing inflammation in PRLs on clinical disability. To achieve these objectives, we have developed the Learned Acquisition and Reconstruction Optimization (LARO) approach, enabling rapid high-resolution QSM for PRL detection. We have also implemented a QSM post-processing method to eliminate the confounding effect of myelin, thereby enhancing rim iron detection sensitivity and quantification accuracy. In Aim 1, we hypothesize that these advancements in QSM technology will enhance PRL detection. Similarly, in Aim 2, we anticipate that our new approach will enable accurate quantification of the longitudinal inflammatory trajectory in PRLs, which we will validate through longitudinal in vivo monitoring of inflammation using TSPO PET. By building upon our preliminary work, in Aim 3, we will identify and evaluate current therapies that can effectively benefit patients with PRLs lesions, thereby advancing QSM as a treatment biomarker to target innate immune activity within chronic lesions. The overall impact of this proposal is to provide an innovative treatment target for chronic innate immune activity in MS, resulting in a paradigm shift in the care of patients with MS.