In Part 1 of this podcast, Robert Zivadinov MD, PhD, Professor of Neurology, Professor of Biomedical Informatics, Department of Neurology, Jacobs School of Medicine and Biomedical Science, University at Buffalo, Buffalo, New York discusses his presentations at the Consortium for Multiple Sclerosis Centers Annual Meeting titled Detecting Demyelination and Remyelination by MRI in the CNS and Imaging Remyelination in Clinical Trials of Multiple Sclerosis.

In the upcoming Part 2, Dr Zicandinov continues explaining detecting demyelination and remyelination beyond magnetic resonance imaging (MRI).

Read the Transcript:

Dr Robert Zivadinov:  Hi, everybody. This is Robert Zivadinov. I'm a Professor of Neurology at the University of Buffalo. I direct two centers. One, the Buffalo Neuroimaging Analysis Center. The other one is the Center for Biomedical Imaging with Clinical Translational Science Institute.

I have directed this remyelination and repair course at the recent Consortium for Multiple Sclerosis Centers meeting, where we discussed a number of areas pertinent to remyelination and repair of MS.

One thing that has to be said upfront is that myelin really is the fundamental part of wrapping around the axons and allowing nerve signals to be conducted.

When for any reason this membrane is damaged, the oligodendrocytes, the cells in the CNS, are trying to somehow replace the damaged myelin. There are several reasons why this sometimes is not successful. One is because there are inhibitory factors for the oligodendrocytes to repair the myelin. The other is because there are not a sufficient number of oligodendrocytes to repair the myelin, or some other reasons.

The ultimate effect is that the nerve signal is going to go slower to these myelin sheets, jumping from one node of the Ranvier to the other. Therefore, in which axons it's happening throughout the body, the function is going to be altered.

What has been discussed has been the factors that lead to these oligodendrocytes, this function. Based on the mechanisms, how this is happening and inhibitory factors that can contribute to this, there is a number of different mechanistic pathways how the remyelination can be stimulated.

As a result of this, there are many different angles how the remyelination therapies can be developed. The key beyond the just treatments for MS is how we conduct the status. Clearly, there are preclinical and clinical models of remyelination in MS.

It has been discussed. What are the most feasible preclinical models? These are clear with the experimental autoimmune encephalomyelitis or EAE. Some virus models. Most in the last decade, toxin models have been used, including cuprizone, a copper chelator, lysolecithin, or lysophosphatidylcholine. In vitro assays of oligodendrocytes and neuron co-cultures are useful.

In terms of clinical models, one model that's very pertinent to studying remyelination is optic nerve model, which can be acute and chronic. Many trials that have been done in the past use this model.

Certainly, the relapses in the relapsing and progressive stage can be also used as a model. Others are based on imaging biomarkers. This was the central part of the course. In particular, MRI, positron emission tomography, and some visual imaging biomarkers have been discussed, which I will enter in a little bit detail in a minute.

The other markers are clinical. As the studies are getting approved by FDA, so far we don't have a remyelination therapy approved by FDA, more clinical biomarkers will be needed. Beyond the models, how to start the remyelination, it's very important to also talk about the design of the studies.

Clearly, you need to identify whether some of these drugs may, in a very short term, show to be useful to be studied in larger studies. That's why short-term studies of three to six months are needed.

In general, the studies are parallel group, which means placebo control, or they can be crossover, which means that a patient gets a treatment, real treatment for some time, let's say three months, followed by crossover to placebo. On the other hand, the placebo in the first months, in the second part of the study, get a real treatment.

You can really see how in both treatment arms, the things are changing. There could be pre-therapeutic round periods. We follow the patients for some time before the drug is introduced and then after it's introduced. Then the adaptive designs.

The ultimate goal of this remyelination therapies are to improve pre-existing disability, or to prevent subsequent disability worsening. Certainly, to improve the pre-existing disability would be a major goal, especially as the patients are getting into progressive stage because that would mean reversal of the dysfunction.

There are not established guidelines for approval of remyelination therapies with FDA. They usually require clinical outcomes, including expanded visibility start to scale change. Most recently, walking hand function, and cognitive processing speed outcomes have been added.

This usually requires a long time. Maybe three to five years, which is very challenging for conducting these studies. That's one of the reasons why some of the trials that we've seen have failed. In particular, regarding the MRI imaging, it has been discussed that the most promising measures currently are magnetization transfer ratio and diffusion tensor imaging.

This, over the last 15, 20 years, went through many iterations. First, second, third, and fourth generation outcomes. Now, on the modern scanners, you can get very sophisticated measures like myelin water fraction and axonal water fraction, and obtain a g-ratio from those with very high sensitivity and specificity for myelin changes in a short period of time.