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WEST PALM BEACH, Fla. — Paramagnetic rim lesions (PRLs) in the central nervous system (CNS) provide a specific diagnosis of multiple sclerosis (MS), but emerging evidence suggests PRLs are associated with a distinct immune cell profile, offering new insights into the biological significance of these lesions and potential therapeutic targets.

As a type of compartmentalized inflammation in the CNS, the specific immune cell profile of PRLs might not just be a path for understanding the biology of these lesions but also allow clinical studies to be enriched for a subset of patients who are candidates for targeted therapies, said Simon Thebault, MD, an assistant professor at the Montreal Neurological Institute-Hospital.

Amid a growing and intensifying focus on PRLs, Thebault wanted to link PRL burden to a specific immune cell profile by analyzing both blood and cerebrospinal fluid (CSF). The hypothesis was that distinct biomarkers, including immune cells and proteins, could be identified to characterize the compartmentalized inflammation that PRL burden appears to represent.

The hypothesis was supported when PRL volume was positively correlated with specific immune cell subsets on the basis of flow cytometry, said Thebault.

The findings were presented on February 27 at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2025.

Prognostically Important

The investigators found that PRL burden was positively correlated with more measures in the CSF than in blood, a signal that supports the concept of CNS compartmentalized inflammation, Thebault said.

Although these findings are exploratory — drawn from just 21 patients with recently diagnosed, untreated MS — they gain significance in the context of growing interest in PRLs. Multiple studies suggest that the presence and burden of PRLs identify a subset of patients with accelerated disease progression and poorer prognosis, Thebault noted.

“It is widely speculated that PRLs may be one of several substrates for progression in MS,” he explained. However, the biology of PRLs, a potential therapeutic target, has not been well described previously.

Present in a subset of patients with MS, the body of evidence supporting PRLs as prognostically important has grown steadily in the relatively short time that PRLs have been recognized. 

In a recently published review examining the prognostic importance of PRLs, the presence of PRLs was associated with higher Expanded Disability Status Scale (EDSS) scores at baseline in all seven included studies.

In addition, most of the studies linked PRLs to greater EDSS progression over time. In the only study among the seven that looked at the issue, PRLs were associated with greater progression independent of relapse activity.

Thebault and colleagues found that 19 of the 21 patients with newly diagnosed and untreated MS had PRLs. The number of PRLs varied but ranged up to 21. There was also substantial variation in the volume of PRLs. The mean age of the study population was 38 years. PRL volume was inversely associated (P =.0082) with younger age. 

PRLs have been previously associated with increased markers of neuroinflammation and CNS damage, including increased IgG Index, serum glial fibrillary acidic protein, and soluble CD163, said Thebault, who conducted this research during his fellowship training with Amit Bar-Or, MD, at the University of Pennsylvania, Philadelphia.

Of the 450 T-cell, B-cell, natural killer (NK)–cell, and monocyte parameters evaluated in this study, the most frequent positive correlates were with antibody-secreting B cells and NK cells in the CSF. The top negative correlates included CSF-to-blood monocyte ratio and blood CD4 regulatory T-cell frequency.

“The identification of biomarkers for this specific target will be important if we want to enrich clinical trials with patients who have the profile most likely to benefit from therapy,” Thebault said.

Currently, the clinical value of PRLs is limited to confirming a diagnosis of MS, which is most useful in those with ambiguous findings by other methods. 

If the prognostic importance of PRLs is confirmed and is meaningful to therapeutic choices for MS, it is likely to become a standard step in the workup, said Thebault, who noted that only limited additional steps and time are needed when performing an MRI to look for PRLs.

The work in PRLs appears to be relevant only to patients with MS who have these lesions, but it is consistent with the concepts that the inflammation that drives MS is heterogeneous and that therapies will be increasingly individualized to address specific patterns of neuroinflammation, said Thebault.

Timely Research

Commenting on the research, Veronique Miron, PhD, professor of neurology at the University of Toronto, who chaired the ACTRIMS Forum Scientific Program Committee this year, described it as “timely.”

The importance of this work is that PRLs are increasingly “considered important drivers of disease and progression, yet the underlying biology is unclear,” she said. 

“Results of this study highlight the complex nature of the immune response associated with PRLs, involving multiple cell types that change sometimes in surprising directions,” Miron added, noting that this study is one of many presented at the ACTRIMS Forum 2025 exploring PRLs as an important marker of MS pathology.

Thebault and Miron reported no financial relationships relevant to this topic.