How demyelinated are my MS lesions?

H

Barts-MS rose-tinted-odometer: ★★★★★ (Vermillion Monday code #E34234)

There are very few what I call really deep-thinkers in MS research and Danny Reich is one of them. This paper from his group is so simple in its inception and execution; it is a fine example of seeing the woods for the trees. They use a relatively simple MRI technique to interrogate MS lesions to classify them as being remyelinated,  demyelinated or mixed. 

Using an MRI sequence they classify MS brains lesions as being “long-T1,” “short-T1,” and “mixed-T1”, which correspond to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively. Neat? You bet it is neat. Demyelination, rather than axon loss, dominantly contributed to initial T1 prolongation, which is a metric from the TI relaxation time* on imaging. 

*T1 is the so-called longitudinal relaxation time and is the time constant that determines the rate at which excited protons return to equilibrium. It is a measure of the time taken for spinning protons to realign with the external magnetic field.

Short-T1 or remyelinated lesions were most common in the deep white matter, whereas long-T1/demyelinated and mixed-T1/demyelinated-remyelinated lesions were more common in lesions next to the cortex (juxtacortical) and ventricles (periventricular) and were much more likely to have paramagnetic or iron rims suggesting chronic inflammation. The latter are the so-called slowly expanding lesions that are one of the drivers of smouldering MS. 

Please note older age at the time of lesion formation meant less remyelination, which is another reminder that as you get older your recovery mechanisms fail. 

The question is whether or not this simple technique can be used as an outcome measure in trials and/or to profile pwMS for remyelination studies. There is little reason to load remyelination trials with patients who are not going to be able to respond to remyelination treatments. What about using this technique as a prognostic tool? Is there a biological reason, apart from age, why some pwMS remyelinate and others don’t? 

Could this technique be used to supplement evoked potentials to assess whether or not a condition is demyelinating, i.e. as an aid to help make a diagnosis of MS? 

You know a paper is good when it leaves you asking more questions than it answers. 

Kolb et al. 7T MRI Differetiates Remyelinated from Demyelinated Multiple Sclerosis Lesions. Ann Neurol. 2021 Aug 14. 

Objective: To noninvasively assess myelin status in chronic white matter lesions of multiple sclerosis (MS), we developed and evaluated a simple classification scheme based on T1 relaxation time maps derived from 7-tesla postmortem and in vivo MRI.

Methods: Using the MP2RAGE MRI sequence, we classified 36 lesions from 4 postmortem MS brains as “long-T1,” “short-T1,” and “mixed-T1” by visual comparison to neocortex. Within these groups, we compared T1 times to histologically derived measures of myelin and axons. We performed similar analysis of 235 chronic lesions with known date of onset in 25 MS cases in vivo and in a validation cohort of 222 lesions from 66 MS cases, investigating associations with clinical and radiological outcomes.

Results: Postmortem, lesions classified qualitatively as long-T1, short-T1, and mixed-T1 corresponded to fully demyelinated, fully remyelinated, and mixed demyelinated/remyelinated lesions, respectively (p ≤ 0.001). Demyelination (rather than axon loss) dominantly contributed to initial T1 prolongation. We observed lesions with similar characteristics in vivo, allowing manual classification with substantial interrater and excellent intrarater reliability. Short-T1 lesions were most common in the deep white matter, whereas long-T1 and mixed-T1 lesions were prevalent in the juxtacortical and periventricular white matter (p = 0.02) and were much more likely to have paramagnetic rims suggesting chronic inflammation (p < 0.001). Older age at the time of lesion formation portended less remyelination (p = 0.007).

Interpretation: 7-tesla T1 mapping with MP2RAGE, a clinically available MRI method, allows qualitative and quantitative classification of chronic MS lesions according to myelin content, rendering straightforward the tracking of lesional myelination changes over time.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

Twitter   /  LinkedIn  /  Medium

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

17 comments

  • “You know a paper is good when it leaves you asking more questions than it answers.”

    I’d argue that this has been the Achilles heel of MS research. It’s almost as if no one dare provide a definitive answer to any of the key questions that have been floating around for the last 40 or so years (EBV’s role, inside out or outside in, do relapses result in smouldering MS or are relapses a response to smouldering MS…….). I suppose definitive answers and effective treatments against the “real MS” will be the equivalent of turkeys voting for Christmas – no more international conferences, advisory roles on pharma trials…

    Remyelination had its annus horribilis last year – Bexarotene, anti-lingo anti-body, high dose biotin. I can’t see pharma getting their fingers burned again. And we must remember that if the axon is gone, there’s nothing to remyelinate!

    Prof G – I dare you to write a paper that actually answer/s a question/s. What about “how EBV causes and drives MS and how it can be stopped”. In the paper you can’t use phrases like “further research is required”.

    • I like your response. It reminds me of the interrogation of Colonel Jessup in the film “A Few Good Men”

      Col. jessup “you want answers!?”

      Lt. Caffey “I want the truth!”

      Col. Jessup “You can’t handle the truth!”

      Or in this case the truth is still elusive but makes for good debate😊

      • We have the answer to relapses (focal inflammation) and just need an answer to progression. MSers want one thing – not to become disabled. Prof Stephen Hauser thinks we are near to solving both halves of MS:

        https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiyzNnOgrbyAhWONcAKHXQyCaEQFnoECAIQAQ&url=https%3A%2F%2Fwww.youtube.com%2Fwatch%3Fv%3D-1PCcdB12BE&usg=AOvVaw3bZpazJeUogrH1kl3NP8-2

        This view is shared by many other eminent MSologists. But we need a sense of urgency to push this over the line. Wouldn’t it be nice in 5 year’s time for a newly diagnosed MSer to be offered a BTK inhibitor and a remyelination agent to stop MS in its tracks, or a progressive MSer to be offered a BTK inhibitor, a neuro-protective agent, and a remyelination agent?

        • BTK inhibitors are a good step forward. We need more and bigger trials of antivirals targeting EBV in multiple sclerosis. We need more of us pushing the idea forward to reach the next level of treatments available for all forms of MS. Can I ask Anon what sort of career do you have ( scientist, entrepreneur ) ?

          • Apologies – I forgot to mention anti-virals. If trials use the right ones at the right dosage, I’m convinced they’ll have an impact on progression / tissue damage.

            My career was varied, but a core requirement was questioning the status quo and identifying better ways of achieving the required outcome. Too much MS research is underpowered and EAE wasted decades / millions of pounds. EBV will be shown to kick off and drive MS and treatments which control it (anti-viral, HAART, therapies which kill B cells hiding in the CNS) will change the lives of MSers. We just need a research team prepared to put together the evidence and test therapies which prove it.

    • >In the paper you can’t use phrases like “further research is required”.
      It’s almost a joke how the conclusion of nearly every MS research paper includes the phrase “further research is required.” If you haven’t managed to prove or disprove your hypothesis maybe your research isn’t ready for publication.

    • “Prof G – I dare you to write a paper that actually answer/s a question/s. What about “how EBV causes and drives MS and how it can be stopped”. In the paper you can’t use phrases like “further research is required”.

      These are the best papers on EBV and MS/autoimmune…is this where Prof G got his EBV theory..?
      This is the therapy https://clinicaltrials.gov/ct2/show/NCT03283826

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270541/

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292561/

      • There is also another different person called anonymous that left a comment. I am not related to that comment. Good question, I believe Professor Gavin had the idea for EBV many years ago through different research papers accumulating over the years.

  • Every paper published using 7T magnet technology for studying MRI lesions of brain/cord (mostly brain, of course, for obvious reasons) in MS deserves to be lauded. The problem, however for those who do NOT have (EVEN at the University level and with fellowship trained neurologists in MS) the 7T MRI magnet at their disposal is that they are left to lick their lips in anticipation, as it were, because they can only hope to get some action one day, perhaps, while the ‘big players’ have it all, now.

    To make the playing field even, federal governments must install a 7T MRI (11 million, the a few years ago, when I checked) in EVERY American university (at least one in each state) and then see how research flows. Well, don’t you want to be more inclusive and not confine these ‘discoveries’ to a select few, particularly so since the FDA has approved 7T MRIs for clinical use/research about 6-7 years ago and everyone should have access to such cutting edge patient related tools ? Deeds, not words, matter.

  • What Tesla is the average scanner in a general or teaching hospital? Is it that T7 scanners are just much more expensive and therefore out of the reach of the NHS?

  • Thank you, Gavin, for your kind words about our paper. But I assure you that the deep thinking here is that of Hadar Kolb (the paper’s first author), now a consultant neurologist at the Tel Aviv Sourasky Medical Center in Israel.

    I should also note that we are testing to see whether a similar approach to differentiating demyelinated and remyelinated lesions is possible on 3-tesla MRI scanners that are more widely available. Stay tuned!

By Prof G

Translate

Categories

Recent Posts

Recent Comments

Archives