Remyelination: do we need it?

Are we being hoodwinked by the remyelination zealots? #MSBlog #MSResearch

” I get a sense that you are frustrated with my sceptical, and at times cynical, position on remyelination in MS. The reasons are captured in this study below of alemtuzumab and the MRI metric called MTR. MTR is a marker of tissue integrity and correlates with myelin in pathological studies (see Schmierer et al below) . Interestingly, single MS lesion MTR changes are being used as the exploratory outcome to test remyelination strategies in MS. If remyelination treatments work they will improve the MTR of individual lesions better than control treatments or placebo.”

“Interestingly when you treat MS early and effectively, for example with alemtuzumab, the majority of MSers stabilise or improve and this is associated with stabilisation of the MTR ratio below (Button et al., below). In other words the brain is capable of repair provided you suppress inflammation early enough to allow it to recover. If you wait too long and too much damage has occurred, i.e. loss of axons and neurones, it may be too late to have an impact. You need surviving demyelinated axons to repair. Is there an in-between state, i.e. before too much damage has occurred so that remyelination will have an effect? That is the question some of the remyelination studies are trying to answer. But to do these studies without addressing the inflammation that drives MS is futile; any new myelin will simply get damages by ongoing inflammation. This is why we need to build up treatment strategies one  on top of the other; i.e. anti-inflammatories to stop MS, neuroprotection to maximise survival of damaged axons so that they can be remyelinated, remyelination strategies to help stimulate remyelination of the surviving axons and finally neurorestoration to restore pathways that have lost too many axons.”

“The million, or billion, dollar question is do we need to stimulate remyelination? In most studies done in inflammatory models remyelination is the norm. Stop inflammation and remyelination occurs. The one caveat is ageing; older animals remyelinate slower than younger animals, but they still remyelinate. So may be we need an anti-ageing strategy rather than a remyelination strategy?”

“In conclusion, I remain to be convinced that remyelination is a problem in MS, hence I am not sure the trials will be positive. However, until we do the experiments we won’t know. What I do know is if you treat MS early and effectively you don’t need to to worry about remyelination; we therefore should focus on what we know. Treat early, treat effectively; a simple message but a large number of MSologists are yet to adopt this treatment philosophy in anticipation of repairing the damage in the future.”

Button et al. Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab. Mult Scler. 2013 Feb;19(2):241-4.

The magnetization transfer ratio reflects the integrity of tissue structure, including myelination and axonal density. Mean magnetization transfer ratio fell in 18 untreated patients with multiple sclerosis both in normal appearing grey (-0.25 pu/year, p < 0.001) and white matter (-0.12 pu/year, p = 0.004). Conversely, mean magnetization transfer ratio was stable in 20 alemtuzumab-treated patients (grey matter: -0.01 pu/year, p = 0.87; white matter: -0.02 pu/year, p = 0.51). The gradient difference in grey matter was 0.25 pu/year (p < 0.001) after age-adjustment. These data suggest that in multiple sclerosis alemtuzumab protects against tissue damage in normal-appearing grey matter, perhaps by preventing new lesion formation.

Schmierer et al. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol. 2004 Sep;56(3):407-15.

Several quantitative magnetic resonance (MR) measures are used to investigate multiple sclerosis (MS) in vivo. Precise quantitative investigation of the histopathological correlates of such measures has, to date, been limited. This study investigates the relationship of quantitative measures of myelin content, axonal density, and gliosis with quantitative MR measures in postmortem (PM) MS tissue. MR imaging (MRI) was performed on a 1.5T scanner and T1-relaxation time (T1-RT) and magnetization transfer ratio (MTR) maps were acquired in fresh PM brain of 20 MS subjects. Myelin content, axonal counts, and the extent of gliosis all were quantified using morphometric and digital imaging techniques. MRI and pathological data were in most cases coregistered using stereotactic navigation. Using multiple regression analysis, we detected significant correlations between myelin content (Tr(myelin)) and MTR (r = -0.84, p < 0.001) and myelin content and axonal count (-0.80, p < 0.001); MTRcorrelated with T1-RT (r = -0.79, p < 0.001). No association was detected between the extent of gliosis and either MR measure. MTR was significantly higher in remyelinated than demyelinated lesions (means: 30.0 [standard deviation, 2.9] vs 23.8 [standard deviation, 4.3], p = 0.008). In conclusion, MTR is affected by myelin content in MS white matter.

CoI: multiple

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.


  • Thanks for taking the time to respond. I've made some of the comments on this issue. I'm mid 40s, male, and received my first infusion of Alemtuzumab 9 years ago. No relapses and stable EDSS. However, I'm 3 on EDSS – damage caused by earlier relapses. As you can imagine, I'm keen to explore any chance of some repair (even an improvement of 1 EDSS). Otherwise – I just need to accept that I'm stuck with what I have. Remyelination trials e.g. Anti-lingo antibody, work being done at Cambridge, work being done by Dr Moses Rodriguez are things I am watching closely. I am hoping the results may prove your view wrong, but have to accept that you may be right. Is Team G doing any repair work?

    • Re: "Is Team G doing any repair work?"

      We are doing neuroprotection work, but are working on soluble biomarkers to monitor repair.

  • Well, isn't it so that with age the immune response changes ( fewer relapses, less "active" disease), but the damage accumulates and the remyelination is less effective.
    So yes, treatments are needed early on to stop damage caused by inflammation, but once the transition to progressive form is there something to enhance remyelination would be of benefit?

  • It seems that even in remyelinated axons, changes occur that may ultimately lead to the death of the axon. It is more important to ensure remyelinated axons are not subject to further neurodegeneration instead of assuming once remyelination occurs all is well.

    "In summary, based on the changes in axonal mitochondria following demyelination and remyelination, the potential impact of a mitochondrial defect or an energy deficient state is likely to be greatest for demyelinated axons and greater for remyelinated than myelinated axons in multiple sclerosis. Thus, protection of mitochondria within neurons and axons within the CNS may be beneficial in multiple sclerosis even when remyelination is achieved."

  • Prof G,
    if post-alemz remyelination takes place and is effective, should we see latency improvements on patients VEPs? This should be simple to verify, much simpler then MRI measurements, why no studies on this?

    • Re: "VEPs"

      I am not sure why nobody has studied this. The current optic neuritis paradigm uses acute attack patients and this is a hard study to do.

  • I assume myelination in development would have to be simulated in patients with demyelinating diseases such as MS (i.e. the environment in the CNS in the diseased state would need to be restored for endogenous remyelination to occur). I think remyelination strategies are trying to recreate this. But is dampening inflammation enough to achieve the goal? Do inflammatory molecules control NPC differentiation into functioning oligos? What is the relationship between LINGO-1 expression and inflammation? Lots of questions for neuroimmunologists

    • See 29 July 2014 post on lentivirus shRNA anti lingo suppression of lingo transcript. It seems EAE model up regulates lingo-1 expression. If one can limit inflammation then lingo may be down regulated and repair by oligos can take place.

By Prof G



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