Multiple Sclerosis Discovery -- Episode 35 with Dr. Daniel Reich

[intro music]   Hello, and welcome to Episode Thirty-Five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Daniel Reich, an expert in MS neuroradiology. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Every week somewhere between 30 and 100 scientific papers related to MS are published in the peer-reviewed literature. And every Friday MSDF lists them all. You can find this week’s list, as well as three years’ worth of past lists by clicking on the Papers tab at the top of every MSDF page. In addition to listing the new papers, we also have a section containing classic papers in the field, along with commentary about what makes them classic. We’d love it if you’d like to suggest a classic paper we haven’t yet listed, and we’d love it even more if you’d like to contribute commentary. Please send your suggestions to editor at msdiscovery.org.   In addition to detailed original reports on new research, MSDF also curates MS-related news from around the Internet in a series of news briefs we call Research Roundups. In our latest Research Roundup, we reported on a second case of progressive multifocal leukoencephalopathy in a patient taking fingolimod. We mentioned a new trial of mesenchymal stem cells that will soon begin recruiting people in Canada with relapsing or progressive MS. And we pointed out that while scientific research was a favorite choice of America’s 50 biggest philanthropists last year, no neurological disease benefitted directly from the $1.6 billion they contributed. If you happen to have one of those folks on speed dial, we hope you’ll put in a good word for MS research. You can find our Research Roundups by clicking on News and Future Directions and then on News Briefs.   If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation, even if you’re not a billionaire. MSDF is run by a small team of reporters and editors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussions and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.   [transition music]   Now to the interview. Dr. Daniel Reich directs the Translational Neuroradiology Unit in the National Institute of Neurological Disorders and Stroke, part of NIH. In his practice as a neuroradiologist, he cares for patients with multiple sclerosis and other neurological diseases, and he also leads several clinical studies. Research in Dr. Reich’s lab focuses on the use of advanced MRI techniques to understand the sources of disability in multiple sclerosis and on ways of adapting those techniques for use in research trials and patient care. Dr. Reich is also a member of MSDF’s scientific advisory board. Science Journalist Carol Morton caught up with Dr. Reich at the recent Keystone meeting on Neuroinflammation in Diseases of the Central Nervous System in Taos, New Mexico.   Interviewer – Carol Morton Can you tell us the value of MRI in multiple sclerosis?   Interviewee – Daniel Reich The way I see it, MRI has tremendous value in multiple sclerosis in three major ways. One is in the clinic, one is in clinical trials, and the third is really for understanding the biology of the disease; it’s an incredibly powerful tool for that. And in my own evolution as a clinician and researcher in multiple sclerosis, I’ve really moved my thinking a lot from kind of using MRI diagnostically or thinking about how we might develop markers of the disease to look at in clinical trials to really the third part, which is trying to understand the disease using the MRI, or sometimes as I call it, the MRIcroscope.   Because really it is, in a way, a scientific tool to look at aspects of the disease that we can’t access either because we can’t study the brain tissue or the spinal cord tissue directly, and because it’s really much more sensitive than doing clinical evaluations in neurology. So one of the interesting things that came out from early MRI studies in the 1990s, many of them done at the NIH long before I got there where they started doing MRIs every month on people even before the era of disease-modifying therapy, was that new plaques that appeared in the brain occurred roughly ten times more frequently than new symptoms appeared in the form of relapses.   MSDF Ten times?   Dr. Reich Ten times, or maybe even more. But that was with the sensitivity of the techniques that were available then, that was the number that was found. What that’s telling you, of course, is that there’s a lot of subclinical disease activity that’s going on that we can completely miss if we are just doing examinations or asking patients to report their symptoms.   MSDF Have there been eras of MRI use in MS and where are we now with it? And that could be in clinical trials and biology.   Dr. Reich We’ve made a lot of progress, I think, in all three areas. The MRI is absolutely the most important paraclinical tool for making the diagnosis of MS. And since the newest generation of diagnostic criteria were established, the McDonald Criteria, MRI has really formed the centerpiece of those. So in somebody who is having symptoms that may be due to multiple sclerosis, the MRI is absolutely the most important test that can be done. And, in fact, it’s now evolved to the point where the diagnosis can be made based on a single MRI at one time in many cases in somebody who comes in with the appropriate clinical symptoms.   MSDF A new challenge confronts the whole MS community in developing therapies and monitoring outcomes of interventions for progressive MS.   Dr. Reich Yes. So how might MRI play a role in assessing therapies for progressive MS? That is a huge challenge. It’s a challenge I would say the majority of my colleagues in the imaging field in MS are working on; what can you measure with MRI that might be the equivalent of new plaque development for the progressive MS question? And it’s, in my view, quite unresolved. The most studied markers that have behind them the weight of evidence to date is brain volume changes – how much brain is there – which can be assessed with MRI and is being done routinely in clinical trials now. I think how exactly that’s being done, which parts of the brain to look at – grey matter, white matter, specific portions of the brain like the thalamus – remains an open question.   What quantitative analysis tools should you use to make the measurements from the images? How you set up the scanner? All of this is still being worked out. That idea of measuring brain volume and seeing whether therapies may slow the rate of brain volume loss appears to be relatively promising. But even with that, proof of concept early trials to see whether a therapy might work are still much larger and much longer than the proof of concept trials that work for assessing new therapies to reduce the number of plaques.   MSDF By how much longer?   Dr. Reich They usually are two years or so at the minimum and they would involve on the order of 100 to 150 patients. Contrast that to four to six months with 10 to 15 patients and you can see how many more therapies can be tested with the shorter, smaller approach. So, in fact, in our lab, one of the things we’ve been thinking about a lot is how we may shorten that. And in the context of progressive multiple sclerosis, I think that’s not clear how to do. However, a lot of the biological processes that are occurring in progressive multiple sclerosis, there’s now a lot of evidence that they also occur very early in the disease, perhaps even before somebody has their first symptoms. So these brain atrophy processes, I think that’s been quite well established.   But you can also ask the question of whether brain tissue repair. Parts of the brain that have been demyelinated that requires remyelination that occurs early in the disease and it may be relevant for progressive phases of the disease as well, or for people who have primary progressive MS. And so we’ve been thinking a lot about how to look at these early plaques that develop early in the disease and use imaging of those plaques to see how they repair in order to test new therapies coming down the block that may promote remyelination or protect brain tissue that’s undergoing inflammation and demyelination from more extensive destruction. And we think, based on the some of the work we’ve done that is going to be published next week, that we can design trials that are, again, very short – six months or so with 10 to 20 patients, 15 to 20 patients – that may be able to assess that. And, of course, we’ll need to understand whether success in such a trial would predict whether that therapy would work in larger trials of progressive MS.   MSDF Are there other challenges with MRI and related to multiple sclerosis?   Dr. Reich Sure. From the point of view of doing clinical trials that are generalizable to large groups of patients that are able to be implemented at multiple sites, we need to understand how to standardize our techniques better. I’ve been involved with an effort recently to develop a group of cooperating investigators in North America similar to our older, more venerable brothers and sisters in Europe who have been working together on imaging for 20 years or so in the MAGNIMS Consortium. Our group which is called the North American Imaging in Multiple Sclerosis Cooperative – or NAIMS – is really very interested in trying to understand how we can standardize high-end approaches that may be very effective for testing new therapies that may be useful for assessing tissue or repair. With this consortium, the NAIMS Consortium, we’ve been very interested in developing standardized protocols that could be useful for assessing in a multicenter way, whether new therapies that are designed to repair or protect brain tissue and spinal cord tissue work. So we’ve been working very hard to do that, and we hope that once a study can be done in multiple sites, it can often be done much more efficiently.   From a diagnostic point of view, the types of MRIs that are done at all different centers may be equally good for just assessing, for example, whether plaques are present in the brain of somebody who is being worked-up for multiple sclerosis. But if you have to take the next step to quantify that and to submit those results to statistical analysis, then you really need a lot more homogeneity. It’s not actually clear how much homogeneity you need, how much narratization you need, that’s an open question. Does it need to be exactly the same, or does it need to be approximately the same, or really do we need to understand the differences between what is done at one site versus what is done at the other?   The last area in which I think MRI is incredibly valuable and offers something that no other technique really can is the ability to study the spatiotemporal dynamics of the disease. MS is, of course, a disease that affects people young and that they carry with them for their entire life, so it can last 40, 50, 60, 70 years in some cases. And I think we all know that the disease changes a lot during that period, and it changes as people are changing and as they age, and you can’t take pieces of the brain or spinal cord and study it under the microscope. I mentioned already that clinical evaluation is less sensitive than the MRI for picking up these changes, so only with the MRI can you understand how things change and where they’re changing in the brain.   In that context, I think people have been going along one of two pathways for how to use MRI to understand the biology of the disease. On the one hand, people have been using the physics of MRI to build really complicated models of how different types of tissue changes – demyelination, inflammation, atrophy – could affect the pictures we take, and that’s been a very interesting but quite complicated effort and the results have been a little bit hard to interpret. The other approach is to take advantage of the rapidly evolving technical changes in MRI acquisitions to really just learn how to take higher and higher resolution pictures.   And I think that’s the bias that we have in our group, that’s the approach we’re taking where we think that as we begin to hone in on really fine features of structures of the brain, whether it be the cerebral cortex or the spinal cord or the brain stem or the cerebellum, we’ll begin to see things that will help to bridge this divide between what people can do in the lab with really fancy molecular techniques with what they can do in the clinical with MRI. And so that’s really where we’ve been spending a lot of our effort using very powerful MRI machines – 7 Tesla – using very advanced antennas – we call them coils – in MRI to really get high-sensitivity images.   Changing the way we tune the magnet to focus on things that we think are interesting. For example, one of the areas we’ve been studying quite intensively recently is inflammation in the meninges in the coverings of the brain, which we think from the pathological data are quite relevant to the disease. We have a way now that we’ve described of assessing at least some of that inflammation in MS, and we’ve been following up on that. So I think the potential of MRI as a biological tool, even after 30 years of work on it, is really largely untapped.   MSDF Are there things that the MRI can’t do right now that you really want it to do?   Dr. Reich Oh, absolutely. You know, MRI is based on the physics of how protons behave in a strong magnetic field and when those protons which are largely in water are aligned when they go into a magnetic field. And we can perturb that alignment, and then it relaxes back into the equilibrium state. And the rates at which that happen depend on where these protons are located, and that’s what allows us to see the tissue. And I go into that because it just illustrates that we’re not looking at T cells and B cells and microglia and axons and oligodendrocytes, we’re looking at the physics of protons in a magnetic field.   I would, of course, love to have a technique that combines the exquisite submillimeter spatial resolution of MRI with specificity for these various cell types or biological processes that are going on. And a lot of people have been working on this, but to date that doesn’t really exist. And part of the reason for that is because the biological processes don’t occur in isolation. Lots of different things happen with inflammation – water moves around – and so it may actually not be possible to do that, but people are still working in that. So that’s a great challenge is to figure out how we could specifically assess inflammation, myelination, axonal health with imaging. But I don’t think that precludes us, again, from using the imaging either to help with the diagnosis, to assess new therapies, or to really observe and build stories about how the biology is working in the disease.   MSDF What’s happening in the cutting-edge of MS neuroradiology?   Dr. Reich I think the most exciting development in MRI and multiple sclerosis is the ability to look with greater and greater precision at what’s going on in the brain and spinal cord, and how that changes over time. And that is being made possible by really rapid advances in the technology. I think that will no doubt translate into the ability to better assess the course of an individual person’s disease, whether they’re responding to therapies, either immunomodulatory therapies that current exist or the reparative or protective therapies that will hopefully come online soon. And I think that’s tremendously exciting.   MSDF Do you also collaborate with people in other specialty areas in the course of your work?   Dr. Reich Yeah. Personally, I have many collaborations. I have collaborations with pathologists, I have collaborations with immunologists, with clinicians, with virologists, with other imagers. So for my work which really depends on understanding the intersection between the imaging we do and the biology of the disease, those collaborations are critical. Through our NAIMS Cooperative, the imaging group in North America that we’ve recently started, we’re hoping really to develop very powerful interactions among groups that have a lot of expertise in how to do imaging in multiple sclerosis.   So in addition to the standardization work, we’re very much hoping to be able to share techniques that we develop. And we’ve established a platform in which that is happening. We’re also hoping to use this cooperative group to sort of cross-pollinate the various labs to use it as a training forum so that the next generation of people interested in imaging and MS will, number one, get to know each other, but also learn from labs in which they don’t spend all their time. So it has a multipartite mission which hopefully will really drive the field forward.   MSDF Well, thank you for sharing your thoughts on MRI and MS with MSDF.   Dr. Reich It’s my pleasure.   [transition music]   Thank you for listening to Episode Thirty-Five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].    [outro music]