Background and Objectives: In relapsing-remitting multiple sclerosis (RRMS), smouldering inflammation at the rims of chronic active lesions has emerged as a crucial contributor to disease progression. Paramagnetic rim lesions (PRLs), has been proposed as the most pathologically validated marker for chronic active lesions. However, the strength of the association between PRLs and clinical or radiological measures of disease progression remains unclear, and the relationship between PRL presence and lesion-specific characteristics, such as lesion size and age, is not well understood. The objective of this study is to investigate the effect of PRL presence on clinical and radiological markers of disease progression, and its association with lesion characteristics such as size and age. Methods. 60 RRMS patients, each with at least five years of previous structural MRI data were investigated using SWAN protocols. Lesions exceeding a volume of 100 mm3 were included in analysis. Results. PRLs were present in 48% of patients, comprising 13% (80 out of 607) of the total lesion count. Patients with PRLs were significantly younger than those without (p<0.001). Furthermore, PRLs were significantly larger (p<0.0001) and exhibited more severe structural damage compared to non-PRLs (p<0.0001). These characteristics were consistent both within and between patients. PRL count and volume were significantly correlated with radiological measures of disease progression, including central and total brain atrophy (p<0.001 and <0.05 for PRL count and volume, respectively). Crucially, our results showed that all 32 lesions appearing within five years preceding SWAN imaging displayed a paramagnetic rim. This finding was validated in two independent international cohorts, reinforcing the link between PRLs and lesion age. Moreover, the proportion of rim-positive lesions decreased as lesion age increased. In a sub-set of patients with longitudinal susceptibility data the paramagnetic rim tended to diminish or disappear over time. Conclusion. Our findings indicate that the presence of a paramagnetic rim in MS lesions is a characteristic feature of all newly formed lesions that exceed a specific size threshold, and that this rim gradually diminishes as lesions age. As such, this study enhances the understanding of lesion formation and may also have significant implications for using PRLs as a biomarker of lesion activity.

SK has no competing interests. MAC has no competing interests. AR serves/ed on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, Roche, and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical. DP has no competing interests. TU has no competing interests. AK has no competing interests.

SK is the recipient of PhD scholarship from MS Research Australia. MAC is a 2023 ECTRIMS Postdoctoral Research Fellow and a recipient of the Skills Development Award from the UK MS Society. AR receives research support from Fondo de Investigacion en Salud (PI19/00950 and PI22/01589) from Instituto de Salud Carlos III, Spain. DP receives research support from Instituto Carlos III, Spain (PI18/00823, PI22/01709) cofunded by the European Union. AK receives research support from MS Research Australia

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The study was approved by the University of Sydney Human Research Ethics Committees and followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.

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All data produced in the present study are available upon reasonable request to the authors