Bruce Trapp on Identifying Myelocortical Multiple Sclerosis

Bruce Trapp, PhD, the Department Chair of Neurosciences at Cleveland Clinic

Bruce Trapp, PhD

Bruce Trapp, PhD, the Department Chair of Neurosciences at Cleveland Clinic, was a leading part of the group of researchers that recently identified a new subtype of multiple sclerosis (MS): myelocortical MS.

Currently indistinguishable from typical cases of the condition, the implications for therapeutic development and treatment abound, yet to be wholly understood. However, from the jump, this discovery has opened up an entirely new arena of research into the condition, as patients with myelocortical MS have a defining trait—no demyelination in the cerebral white matter of the brain.

Trapp spoke with NeurologyLive to provide some insight into the discovery, how it was made, and what the research team is looking into next.

NuerologyLive: What prompted this research? How was this discovery made?

Bruce Trapp, PhD: It started in the autopsy suite, many years ago that the pathological characteristic of MS is demyelination of brain white matter. When that happens, the white matter turns form white to tan, tannish brown in color. As you’re cutting an MS brain in autopsy, you can see the lesions. Really, this started when I was cutting a brain and I saw no lesions. The first thing that comes to mind is, is this MS? Our neurologists don’t get this wrong—it was MS, but it was also clear that they had no cerebral white matter demyelination. Again, we identified a patient—and a one-off wouldn’t do much—but we went back and continued to look, and we found out that these patients without cerebral white matter demyelination represented 12% of our autopsy program, so it’s a significant cohort.

They do have MS because they have spinal cord demyelination, and it’s hard to distinguish the spinal cord lesions from these patients from typical MS. They also had cortical lesions, subfield cortical lesions, therefore we termed this myelocortical MS—myelo for the spinal cord, cortical for where the lesions are.

What these patients gave us was a platform to investigate the effects of cerebral white matter demyelination on neuronal viability. In general, it’s assumed that neurodegeneration in MS is a consequence of demyelination, but now we have this cohort of MS patients that did not have cerebral white matter demyelination. What we did was match this cohort with 12 patients with typical MS, that is, patients with cerebral white matter demyelination. This match was based on age, sex, disability, MRI-protocol, and postmortem time—matched as closely as we could with our 100 brains.

We had the opportunity to look at neuronal density in the cortex, so we compared myelocortical to typical MS, the control brains. If cerebral white matter demyelination was causing neurodegeneration, we should see a greater neuronal loss in typical MS than in myelocortical, but in fact, what we found was the opposite. Compared to control brains, there was more neuronal loss in myelocortical MS. We looked at 5 cortical regions and looked at 3 layers in these 5 regions—these are the layers that project axons to the white matter projection neurons—and in myelocortical MS, 11 of 15 of those layers had decreased densities compared to control, whereas in typical MS only 5 out of the 15 had a decrease.

This was a surprising, and also a significant, observation because it supports the concept that neurodegeneration can be independent of demyelination. Now, historically, we thought that most of the degeneration in MS was caused by demyelination. The concept that they’re not connected is not novel—the imaging community, the MRI community, has been presenting data that supports that concept that brain atrophy precedes significant amounts of cerebral white matter demyelination as measured by MRI; that grey matter atrophy can occur early, before there’s much obvious demyelination, based on MRI. So, the concept isn’t novel, but to date there has been no pathological evidence that provides support for that. The myelocortical MS gave us a very nice platform for studying that.

What’s the next step? Does a way to distinguish these patients need to be identified?

BT: There are 2 things we’re proceeding [with]. One is that most of the clinical characteristics of these patients were done from chart review, and I think we’re in a new world now of clinically classifying MS patients, and going forward we may be able to distinguish between the 2—we’ll have to see. But I think we have a lot more work to do on the brains from these myelocortical patients that could give us some clues to how we could distinguish them from typical MS. One of the focuses is the MRI altered regions in the white matter. We cannot distinguish the myelocortical patient from the typical patient based on standard MRI analysis. That is, they look the same.

Of course, we were very interested—and in the paper, there is significant data on what’s causing the MRI changes in myelocortical MS—in cerebral white matter. Our analysis, if we look at the MRIs, the regions most severely affected are altered on T2, T1, and by magnetization transfer ratio (MTR). Historically, those regions are thought to be chronically demyelinated regions—black holes. Yet, here they are present in white matter that’s myelinated. We found 31 of these regions in the paper and we analyzed them histologically, they were all myelinated, but what we found is that their axons, their myelinated axons, were swollen. If you look at the sensitivity of the T1 and the MTR, they’re much more sensitive than T2. Those values are affected by free water. If you swell an axon, there’s an increase in free water, so our hypothesis right now is that the MRI changes are caused by axonal pathology.

Another interest in our lab from a scientific perspective is, is there a primary axonal degeneration or pathological process that’s occurring in the white matter? We’re very interested in looking into the neuronal degeneration in the cortex, molecularly, and then more detailed characterization of these swollen myelinated axons in the brain. It’s hopeful we’ll get some clues there, and maybe some identification of biomarkers. The whole field of biomarkers in MS has exploded with the neurofilament indication of neurodegeneration. That technology is going to advance and hopefully, the list of molecules in those types of platforms will increase and it’ll be possible that one could help distinguish myelocortical MS from typical MS.

Transcript edited for clarity.

REFERENCE

Trapp BT, Vignos M, Dudman J, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol. Epub August 21, 2018. doi:10.1016/ S1474-4422(18)30245-X.