Understanding the biology of paramagnetic rims in Multiple Sclerosis

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Some of you may have not yet heard about paramagnetic rims in MS lesions.

Their presence on MRI scans is felt to represent iron rich microglial inflammation in the brain occurring in a subset of individuals. Pathologically iron rims reflect slowly expanding chronically active MS lesions (see below).

Figure: Paramagnetic lesion arrowed in (a) in a 34 y with RRMS. [Source-this article]

The presence of these lesions have been linked to a greater disability and disease severity, as well as brain volume loss. By all means this is unlikely to be the only process that leads to this, but it is something of interest as there are currently drugs in clinical trial partially targeting microglial activity – the BTK inhibitors. BTKi also target B cells.

In this new study, the investigators again studied the clinical outcomes of having iron rims on scans, as well as some biological parameters, such as oligoclonal bands and blood brain barrier dysfunction. Other biomarkers, such as GFAP (a microglial marker) and neurofilament levels have not been assessed, which is a shame as the findings would have been more informative. Also, not certain what the relevance of OCBs in this context is as antibody production is a hallmark of B-cell and plasma cell activation and therefore highly sensitive and specific for MS, but what they’re not are markers of microglial activation.

Nonetheless, the authors demonstrate that those with iron rims tended to have more CSF-specific Oligoclonal bands (93.5% in those with iron rimmed lesions vs 72.7% without) and less significantly also had evidence of blood brain dysfunction as depicted by the albumin quotient (see Figure below).

Figure: Violin plot depicting the difference in albumin quotient between PRL+ (iron rim) and PRL− patients, with the unadjusted significance value displayed. This difference remained significant after adjustment for age and T2-hyperintense lesion volume (p = 0.003)

Personally, I don’t think that the Oligoclonal band status of the participants really links it to the iron rims, since the prevalence of oligoclonal bands is almost certainly a diagnostic entity within MS (i.e. you’re more likely to be diagnosed with MS if you have positive bands) and therefore a proportion of these individuals are going to have iron rims.

Clinically they also noted that those with iron rims tended to have larger lesions (as depicted by T2 Lesion Volumes), decreased brain volume and were more likely to have underlying tissue damage (as depicted by black holes, see [c] on the first figure).

Abstract

Mult Scler. 2022 Jun 24;13524585221102921.

Paramagnetic rim lesions are associated with pathogenic CSF profiles and worse clinical status in multiple sclerosis: A retrospective cross-sectional study

Christopher C Hemond Jonggyu Baek Carolina Ionete Daniel S Reich 

Background: Paramagnetic rims have been observed as a feature of some multiple sclerosis (MS) lesions on susceptibility-sensitive magnetic resonance imaging (MRI) and indicate compartmentalized inflammation.

Objective: To investigate clinical, MRI, and intrathecal (cerebrospinal fluid, CSF) associations of paramagnetic rim lesions (PRLs) using 3T MRI in MS.

Methods: This is a retrospective, cross-sectional analysis. All patients underwent 3T MRI using a T2*-weighted sequence with susceptibility postprocessing (susceptibility-weighted angiography (SWAN) protocol, GE). SWAN-derived filtered-phase maps and corresponding T2-FLAIR images were manually reviewed to determine PRL. Descriptive statistics, t-tests, and regression determined demographic, clinical, MRI, and CSF associations with PRL.

Results: A total of 147 MS patients were included; 79 of whom had available CSF. Forty-three percent had at least one PRL. PRL status (presence/absence) did not vary by sex or Expanded Disability Status Scale (EDSS) but was associated with younger age, shorter disease duration, worse disease severity, high-efficacy therapy use, and poorer dexterity, as well as lower age-adjusted brain volumes and cognitive processing speeds. PRL status was moreover associated with blood-brain barrier disruption as determined by pathologically elevated albumin quotient. Sensitivity analyses remained supportive of these findings.

Conclusion: PRLs, an emerging noninvasive biomarker of chronic neuroinflammation, are confirmed to be associated with greater disease severity and newly shown to be preliminarily associated with blood-brain barrier disruption.

About the author

Neuro Doc Gnanapavan

10 comments

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  • Does microglia attack antibody-marked target? I agree that the general OCB status may be not related to rim lesions but I think that it could be possible that some lesions are triggered by some of the antibodies making part of the OCBs. It would be interesting to see in biological samples what kind of antibodies are there compared with the OCB pool

    • The antibodies in OCBs could be stimulating microglia via their Fc receptors, a process that is not dependent on specificity to any CNS antigen, convincing evidence for which continues to be elusive, which after decades of looking is, I suggest, telling.

      • There is an enzyme that is capable of breaking IgGs just above the hinge region. One could pick an IgG pool, treat with the enzyme, purify Fc by protein A affinity and then add Fc purified to brain tissue in presence of immune cells and see what happens. I don’t know if this is enough as proof.

  • “Their presence on MRI scans is felt to represent iron rich microglial inflammation in the brain occurring in a subset of individuals. Pathologically iron rims reflect slowly expanding chronically active MS lesions”

    I assume this process is the hot microglia that Prof G used to refer to and Paramagnetic Rim Lesions are SELs.

    But what comes first? Does the peripheral immune system launch and attack (relapse) causing a focal lesion and then microglia get involved and eat away at the rim of this lesion, or it it the other way round ie microglia start eating away at brain tissue (?virus) and then the peripheral immune system gets involved?

    I really don’t know what the researchers working in MS pathology do! When I was diagnosed the big story was about some Australian MS researchers (?Prineas and Barnett). They found (a young MSer who had died after a bad relapse) that lesions had formed, but there were no peripheral immune cells present. This finding was big news c.early 200s, but all went quiet.

    • Microglia play a wide role in the brain from supportive to immune. They may not necessarily focus around lesions – only some MS lesions have this. Their phenotype also is difficult to categorise so to a large extent have been ignored for a while but again interest has grown. My suspicion is there is a spectrum in MS that varies from person to person and autopsy studies mainly capture the young catastrophic cases and the old ones.

  • NDG,

    Thanks for your post.

    How might (i) BTK inhibitors and (ii) the drug being used on the Sizomus trial impact on SELs? Is the aim to stop the microglia from expanding the lesions and causing tissue loss?

    • Yes you’re correct but it’s difficult to know which one you’re looking at microglia or astrocytes. Some say S100B is a better microglial marker, and then there’s TREM2 in some eyes it’s microglial in others it’s a macrophage marker!

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