Paramagnetic rim lesions with lower rim susceptibility (Probable PRLs) represent older lesions with greater tissue damage, meaning rim disappearance at MRI cannot be interpreted unequivocally as resolving inflammation and may reflect natural lesion evolution.
Key Findings
Results
Probable PRLs demonstrated significantly greater tissue disruption than Definite PRLs on quantitative MRI metrics.
Probable PRLs showed higher mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and FISO compared to Definite PRLs (all p < 0.001)
Probable PRLs showed lower neurite density index (NDI) than Definite PRLs (p < 0.001)
Probable PRLs were also larger in lesion size than Definite PRLs (p < 0.001)
Definite PRLs showed higher rim susceptibility than Probable PRLs (22 vs 8 ppb, p < 0.001)
Results
Probable PRLs were significantly older than Definite PRLs, suggesting rim fading reflects natural lesion aging.
Lesion age was estimated using prior clinical MRI scans with an accelerated failure time model accounting for censoring
Participants with only Definite PRLs had shorter disease duration than those with ≥1 Probable PRL or no PRLs
Probable PRLs were 'significantly older' per the accelerated failure time model analysis
Higher PRL counts were associated with younger age (p < 0.001), and PRLs were more often Definite in younger participants (p < 0.0004)
Results
PRL prevalence and classification differed substantially across the progressive MS cohort, with only a minority having Definite PRLs.
The cohort included 106 people with progressive MS (34 primary progressive, 72 secondary progressive; age 56 ± 10 years; median EDSS 5.5; 44% on disease-modifying therapy)
52% of participants had ≥1 PRL; however, only 33% had Definite PRLs
A total of 155 PRLs were identified: 114 classified as Definite and 41 as Probable
Probable PRLs were more frequent in secondary progressive vs primary progressive MS (24% vs 9%, p = 0.05)
Discussion
Rim disappearance or attenuation cannot be unequivocally interpreted as resolution of chronic inflammation because chronic active lesions do not require iron pathologically and rims can fade over time.
Reduced susceptibility signal likely reflects decreased iron within the rim compartment
It remains uncertain whether reduced susceptibility signal represents true resolution of chronic inflammation, natural lesion aging, and/or advanced tissue degeneration
Probable PRLs with lower rim susceptibility appear to represent older lesions with greater tissue damage rather than resolved inflammation
The authors state: 'rim disappearance at MRI cannot be interpreted unequivocally as resolving inflammation and may reflect natural lesion evolution'
Conclusions
Rim persistence is proposed as a more informative marker of ongoing compartmentalized inflammation than rim disappearance is of its resolution, with implications for clinical trial design.
The findings raise concerns about using rim disappearance as a treatment response biomarker in clinical trials
The authors conclude: 'Rim persistence may be a more informative marker of ongoing compartmentalized inflammation than rim disappearance is of its resolution'
Cross-sectional classification of PRLs as Definite or Probable was enabled by variable rim conspicuity observed in the cohort
The study highlights impact on clinical trials in its title, suggesting that misinterpretation of rim fading as treatment response could confound trial outcomes
Methods
Whole-lesion, rim, and core regions were separately segmented using 3D-EPI and multishell diffusion MRI for quantitative analysis.
Imaging modalities included 3D-EPI, multishell diffusion MRI providing DTI and NODDI metrics, quantitative susceptibility mapping (QSM), and T1 signal intensity
Metrics analyzed included mean diffusivity, axial diffusivity, radial diffusivity, FISO (isotropic water fraction), and neurite density index (NDI)
All comparisons were performed after multiple comparison correction
Lesion age estimation used an accelerated failure time model that accounted for censoring from prior clinical MRI scans
What This Means
This research suggests that in multiple sclerosis (MS), a type of brain lesion called a paramagnetic rim lesion (PRL) — which is visible on specialized MRI scans because of iron deposits at its edge — can lose its bright iron 'rim' signal over time, not necessarily because the inflammation inside is resolving, but because the lesion is aging and the surrounding tissue is becoming more severely damaged. The study examined 106 people with progressive MS and found that lesions with a faint or reduced rim signal (called 'Probable' PRLs) were older, larger, and showed more signs of tissue destruction on advanced quantitative MRI compared to lesions with a strong rim signal ('Definite' PRLs). Only one-third of participants had the clearly visible 'Definite' type of PRL.
This matters because researchers and clinicians have been using the disappearance of the iron rim on MRI as a potential sign that a treatment is working to reduce inflammation in the brain. This study challenges that interpretation: the iron rim can fade naturally as the lesion ages, even without any treatment, while the underlying tissue damage may actually be getting worse. The authors suggest that seeing the rim persist over time may actually be a better indicator of ongoing chronic inflammation than seeing it disappear.
For clinical trials testing new MS therapies, this finding is significant because it raises the possibility that rim fading — if used as an outcome measure — could be misleading. A treatment might appear to be working simply because lesions are naturally aging and losing their iron signal, when in reality the disease process continues. This research suggests that future studies should focus on rim persistence rather than disappearance, and should combine MRI measures with quantitative tissue damage metrics to more accurately assess whether treatments are truly reducing chronic brain inflammation in progressive MS.
Sacco S, Zhao H, Cheng S, Akula A, Luskin E, Zhang J, et al.. (2026). Reduced Paramagnetic Rim Visibility Signals Lesion Aging and Tissue Degeneration in Progressive Multiple Sclerosis: Impact on Clinical Trials.. Neurology(R) neuroimmunology & neuroinflammation. https://doi.org/10.1212/NXI.0000000000200655