Multiple Sclerosis Discovery -- Episode 21 with Dr. Paul Matthews

[intro music]   Host – Dan Keller Hello, and welcome to Episode Twenty-one 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 Dr. Paul Matthews about imaging in multiple sclerosis. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   We recently reported on a draft of a review released by the Agency for Healthcare and Research Quality about discontinuing disease-modifying therapies in patients with MS. Though the report’s main conclusion was that little evidence is available to assess the risks and benefits of discontinuing therapies, several MS groups came together to criticize the report during the open comment period. Groups like the National MS Society and Medical Partners 4 MS raised concerns that the review was not conducted properly and that insurance providers may use it as justification to reduce coverage of DMTs for MS. The AHRQ told Multiple Sclerosis Discovery Forum that they would consider the comments carefully and make any necessary revisions.   MSDF’s parent organization, the Accelerated Cure Project, is launching a new research resource called iConquer MS. Hollie Schmidt, Vice President of Scientific Operations at the Accelerated Cure Project, recently wrote a blog post explaining that the new initiative aims to take data and biosamples from 20,000 people with MS and make them open-access to researchers. We want your input about what you may want to do with such a resource. If you’re interested, go to the blogs section of MS Discovery Forum under the “News and Future Directions” tab and click on the blog post titled, “Invitation to Share Your Thoughts on a New MS Research Resource.”   Our list of meetings and events is ever-growing. We’ve posted multiple meetings of all shapes and sizes sprinkled throughout 2015 and even into 2016. And if you know of a meeting that’s not yet listed, please do submit what information you have. We’ll take care of the rest. Just go to “Meetings and Events” under the “Professional Resources” tab on our website and click on the “submit new item” button to tell us about your event. We’re even willing to list local departmental seminars and journal clubs.   [transition music]   Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. He met with MSDF to talk shop about imaging in MS.   Interviewer – Dan Keller Welcome, Professor Matthews. What do you see now as new modalities or new ways of doing imaging, and what’s coming along?   Interviewee - Paul Matthews Thanks, Dan. Imaging continues to reinvent itself in areas particularly like MS. Magnetic resonance is becoming more and more powerful with use of particularly multiband techniques, allowing multiple coils to be used to accelerate the imaging process, and because of that being able to collect much more data to enhance particularly diffusion images. So, for example, within the Human Connectome Project, development of new multiband techniques has accelerated imaging to the point where very high resolution diffusion tensor images can be acquired in spaces of 15-20 minutes. The implications of this for MS are that we can begin to develop powerful approaches to expression of the diffusion tensor information in terms of diffusion parallel to the fibers, perpendicular to the fibers, and free diffusion that is anisotropic. This means that potentially we’re going to be able to separate out free-water contributions from those contributions arising from myelin and axonal loss, providing a very powerful complement to magnetization transfer images.   A second area of major development in magnetic resonance is the increased use of ultra-high field systems at 7T, and potentially higher, for applications in MS. The first advantage this has brought is for increased spatial resolution that can be used to begin to image cortical lesions with a really impressively enhanced sensitivity. The second area has been new kinds of contrast. The high magnetic fields allow new susceptibility-weighted contrast to be generated which provides a powerful way of visualizing vessels. It’s very clearly defining the vessels at the center of most of the inflammatory lesions, helping a little bit with differential diagnosis, but even more importantly helping us understand what the microvascular architecture is in and around lesions.   A second potential advantage of the ultra-high field is simply increasing the sensitivity of MR for applications in magnetic resonance spectroscopy. We’ve known for a long time that signals from myo-inositol can help us understand glial components of inflammatory lesions, but there’s increasing interest in applying this kind of tool to measurements of glutathione, to provide indices related to reactive oxygen species generation, and potentially also to measuring excitotoxic neurotransmitters such as glutamate.   In a completely different space, positron emission tomography (PET) has begun to play a renewed kind of role in MS. I’ve always been a little bit disappointed that more wasn’t done with it over the last decade or so since pioneering studies that demonstrated that assessments of energy metabolism based on simply the fluorodeoxyglucose signal not only discriminated people with MS from healthy volunteers, but, more importantly, began to show discrimination between different stages of the disease and a relationship to cognitive impairment, with potentially reversible components with treatment. Now, that still is an area of potential work.   But more recently focus has shifted particularly to use of ligands that bind to the 18 kilodalton translocator protein which provides a marker of microglial inflammation in the brain. While it’s not entirely specific and with the caveat that we have little understanding of the relationship between the TSPO expression and the microglial phenotype, it clearly is highlighting some very interesting things. First, we found that the TSPO binding by ligands is increased multifocally in brains of people with MS; it’s increased multifocally in the white matter and in the grey matter. Moreover, increases in binding in both regions are related to degrees of disability; patients with higher disability show increased binding particularly in the cortex.   There’s emerging evidence, driven first by elegant preclinical studies done by the Finnish group and some human studies yet to be fully reported, that there are also strong treatment effects with powerful amino modulators. So because this provided us a window that is clearly giving us information distinct from that provided by T2 hyperintense lesions on MRI or by gadolinium enhancement on MRI, it promises a powerful adjunct.   And, finally, just to kind of round that idea out, it’s clear that it will be the combination of MR and PET that’s powerful rather than PET replacing MR in some way in our diagnostic or monitoring armamentarium for treatment. One manufacturer has already started supplying commercially integrated MRI-PET systems. Another manufacturer is expected to do so very soon, and potentially a third. This may become a platform for brain imaging that is very powerful for disorders like MS that have multifocal manifestations where the registration – the precise registration – between the MRI and the PET becomes important. Moreover, the potential to use dynamic MRI acquisitions where we’re just imaging very, very rapidly throughout the entire PET scanning period to follow the position of the head within the PET scanner may allow a new kind of precision of special resolution in the PET scan that allows MS studies where we rely on this very much to be done with far greater precision than it’s been possible in the past. So with these developments in MR, with the new radioligands in PET, and with this new technology for integrated MRI-PET, I think the brain imaging is off in incredibly new spaces.   Now I can’t close the discussion of imaging without at least making a mention of the revolution in applications of optical coherence tomography that have been conducted over the last five years in particular for MS. This is really exciting, too. It’s an inexpensive examination that can be performed very rapidly in any clinic that provides very high-resolution measures of optic nerve fiber layers, of multifocal edematous regions within the nerve fiber layer, all of which can provide measures to stage MS and its associated neurodegeneration, and potentially to usefully monitor it in assessing the progress of patients on treatments. It’s an exciting time for imaging.   Interviewer - MSDF Now just to clarify, this is optical coherence tomography of the retina and its surrounding structures.   Interviewee - Dr. Matthews Yeah, Dan, thanks for clarifying that. Absolutely. So it’s an eye examination, but it’s an adjunct because the retina is just an extension of what we study in the brain.   Interviewer - MSDF Either using metabolic markers or following metabolism with PET or something else, or using other ligands and markers, can you discern or image where remyelination is occurring?   Interviewee - Dr. Matthews So, of course, the world of PET is a big one because what we can observe changes with the type of radiotracer that we use. Recently, Yanming Wang, who I had the privilege of collaborating with at Case Western, published, I think, a really groundbreaking paper. Although it was a preclinical study, I think it shows the way we could be moving in this space. Using a novel radiotracer that he developed called MeDAS – MeDAS for short – this carbon positron-emitting isotope-incorporated tracer allows specific myelin proteins to be imaged, and thus provides a marker of myelin integrity in life. Yanming has shown how it can selectively image myelin, it can image both established myelin and new myelin being formed, and he demonstrated in a proof of concept study in rodents that the dynamics of demyelination and remyelination following therapeutic intervention can be followed, and moreover, that the therapeutic effect can be quantified relative to an untreated control group.   Really exciting and a potentially important adjunct to MTR or diffusion measurements in human studies. The trick of moving a tracer from preclinical studies into humans is not without some need for care, but because only microdoses of these tracers are used for the human imaging experiment, Yanming, myself, and colleagues believe we can make this transition rapidly. We’re watching closely to see what happens next.   Interviewer - MSDF Pretty good. I appreciate it.   Interviewee - Dr. Matthews Thanks, Dan.   [transition music]   Thank you for listening to Episode Twenty-one 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]