Podcasts about research resources

In this episode, Ben and Kate discuss the transition process for the U.S. President and the U.S. Congress. Included in the discussion is the Presidential Transition Act of 1963 and general information regarding this law.Research/Resources: "Presidential Transition Act of 1963”. Published in U.S. Government Publishing Office (GPO) website February 16, 2023 and available on https://www.govinfo.gov/content/pkg/COMPS-1612/pdf/COMPS-1612.pdf "Implementation of the 1963 Presidential Transition Act” by Paul C. Light. Published in Brookings website December 4, 2000 and available on https://www.brookings.edu/articles/implementation-of-the-1963-presidential-transition-act/"Presidential Transition Act: Provisions and Funding” summary by Henry B. Hogue. Published in Congressional Research Service website May 22, 2024 and available on https://crsreports.congress.gov/product/pdf/R/R46602"Presidential Transition Act Summary” by Troy Cribb. Published in Partnership for Public Service website March 13, 2024 and available on https://presidentialtransition.org/reports-publications/presidential-transition-act-summary/  "2024 Transition Timeline” by Center For Presidential Transition. Published in Partnership for Public Service website and available on https://presidentialtransition.org/transition-resources/transition-timeline/ "The Inaugural Oath”. Published in Library of Congress website and available on https://www.loc.gov/classroom-materials/inaugurations/an-orderly-transition/the-inaugural-oath/#:~:text=The%20president%20takes%20the%20oath,Supreme%20Court%20or%20another%20judge. "The 119th Congress begins today. Here's what to know for the 2025 session.” by Caitlin Yilek. Published in CBS News website January 3, 2025 and available on https://www.cbsnews.com/news/new-congress-2025-what-to-know/Check out our website at http://artofdiscussing.buzzsprout.com, on Facebook at Art of Discussing and on Instagram @artofdiscussing.Got a topic that you'd like to see discussed? Interested in being a guest on our show? Just want to reach out to share an opinion, experience, or resource? Leave us a comment below or contact us at info@artofdiscussing.com!! We'd love to hear from you! Keep Discussing!Music found on Pixabay. Song name: "Clear Your Mind" by Caffeine Creek Band"

In this episode, Ben and Kate discuss the presidential cabinet nomination process and current nominees for President Trump's second term cabinet. Research/Resources:  "Trump Cabinet confirmation status: Which nominees have been confirmed” by Parker Kaufmann, Humera Lodhi, Christopher L. Keller, and Sara Burnett. Published in AP News website January 18, 2025 and available on https://apnews.com/projects/trump-cabinet-confirmation-tracker/United States Senate: About Senate Rules https://www.senate.gov/about/powers-procedures/rules.htm United States Senate: About Executive Nominations Historical Overview https://www.senate.gov/about/powers-procedures/nominations/executive-nominations-overview.htm “Confirming the Cabinet: Historical Trends of Cabinet Secretary Confirmations Across the Last Five Presidential Administrations” by Chris Piper. Published in Center for Presidential Transition website January 16, 2025 and available on https://presidentialtransition.org/confirming-the-cabinet-historical-trends-of-cabinet-secretary-confirmations-across-the-last-five-presidential-administrations/ Check out our website at http://artofdiscussing.buzzsprout.com, on Facebook at Art of Discussing and on Instagram @artofdiscussing.Got a topic that you'd like to see discussed? Interested in being a guest on our show? Just want to reach out to share an opinion, experience, or resource? Leave us a comment below or contact us at info@artofdiscussing.com!! We'd love to hear from you! Keep Discussing!Music found on Pixabay. Song name: "Clear Your Mind" by Caffeine Creek Band"

The Michael J. Fox Foundation for Parkinson's Research established its Research Tools Program to address gaps in the field and common challenges surrounding the development of reagents and models that slowed the initial stages of promising research projects. In collaboration with many partners and stakeholders, the Research Tools Program helps ensure that scientists around the world have access to high-quality reagents, models, and more. These tools have been instrumental in launching novel research projects to better understand Parkinson's disease and to develop promising new treatment strategies. This episode features Dr. Nicole K. Polinski, Director of Research Resources at The Michael J. Fox Foundation for Parkinson's Research. In our conversation, she discusses her role in the organization, the wide variety of tools available through the Research Tools Program, and how academic and industry researchers can share their insights and feedback on current tools and future directions for tool development.This podcast is geared toward researchers and clinicians. If you live with Parkinson's or have a friend or family member with PD, listen to The Michael J. Fox Foundation Parkinson's Podcast. Hear from scientists, doctors and people with Parkinson's on different aspects of life with the disease as well as research toward treatment breakthroughs at https://www.michaeljfox.org/podcasts.

The Michael J. Fox Foundation for Parkinson's Research established its Research Tools Program to address gaps in the field and common challenges surrounding the development of reagents and models that slowed the initial stages of promising research projects. In collaboration with many partners and stakeholders, the Research Tools Program helps ensure that scientists around the world have access to high-quality reagents, models, and more. These tools have been instrumental in launching novel research projects to better understand Parkinson's disease and to develop promising new treatment strategies. This episode features Dr. Nicole K. Polinski, Director of Research Resources at The Michael J. Fox Foundation for Parkinson's Research. In our conversation, she discusses her role in the organization, the wide variety of tools available through the Research Tools Program, and how academic and industry researchers can share their insights and feedback on current tools and future directions for tool development.This podcast is geared toward researchers and clinicians. If you live with Parkinson's or have a friend or family member with PD, listen to The Michael J. Fox Foundation Parkinson's Podcast. Hear from scientists, doctors and people with Parkinson's on different aspects of life with the disease as well as research toward treatment breakthroughs at https://www.michaeljfox.org/podcasts.

In this episode we talk with Dr. Mark McConnell, Assistant Professor of Upland Birds at Mississippi State, about wildlife conservation in agricultural landscapes and his research into creating win-win solutions for wildlife and agricultural producers. We cover a variety of topics in this episode from reacting to Adam's new mustache, Mark's use of memes to help wildlife student engage with farmers, and using precision conservation to delivery economically targeted conservation.  Themes in the episode: meeting farmer where they are, building your conservation team, economics and Precision Agricultural/Conservation. Targeted Conservation Delivery, Economically Targeted Conservation, Wildlife-Friendly Farming Give us some feedback or potential topics you would like to here by filling out our listener survey: https://purdue.ca1.qualtrics.com/jfe/form/SV_5oteinFuEzFCDmm   Research & Resources discussed in the episode Research on who farmers trust when making decisions about agricultural practices - https://www.extension.purdue.edu/extmedia/FNR/fnr-488-w.pdf Personal outreach to landowners is vital to conservation program success (article about Lutter et al 2018 paper). https://www.sciencedaily.com/releases/2018/04/180405093305.htm Bridging the gap between conservation delivery and economics with precision agriculture (McConnell 2021) - https://wildlife.onlinelibrary.wiley.com/doi/full/10.1002/wsb.995 Economically targeting conservation practices to optimize conservation and net revenue using precision agriculture tools (Meng et al. 2022) - https://link.springer.com/article/10.1007/s11119-022-09890-7 Farming and the fate of nature (Green et al. 2005) - https://www.science.org/doi/10.1126/science.1106049 Wildlife-friendly farming benefits rare birds, bees and plants (Pywell et al. 2012) - https://pubmed.ncbi.nlm.nih.gov/22675140/ Crop Advisors as Conservation Intermediaries (Eanes et al. 2019) - https://www.sciencedirect.com/science/article/pii/S0264837718310238 Creating Environmentally Resilient Agriculture Landscapes Using Precision Agriculture Technology: An Economic Perspective (McConnell 2019) - https://pubs.acs.org/doi/abs/10.1021/bk-2019-1334.ch007 CRP Menu Tool - https://crpmenu.gri.msstate.edu/

Discover how to access therapy on a budget. Uncover free therapy resources and learn where to cultivate mindfulness without breaking the bank. Elevate your mental health journey with cost-effective strategies on this episode of Sex Positivity: Unfiltered. Don't miss out! Watch now and share your thoughts in the comments. Let's spark a conversation!

In this lite byte episode, Kate and Ben discuss the Army-Navy Game including history, past and future locations, wining statistics and predictions of who will win the 2023 game. Research/Resources: "Army vs. Navy - Gillette Stadium". Published in Gillette Stadium website and available on https://www.gillettestadium.com/army-vs-navy/"Why 2023 Army-Navy Game is Not In Philadelphia, how to watch, rivalry's history" by Tom Dougherty. Published in CBS News Philadelphia December 7, 2023 and available on https://www.cbsnews.com/philadelphia/news/2023-army-navy-game-why-not-in-philadelphia/ “Army-Navy Game”. Wikipedia the Free Encyclopedia, Wikimedia Foundation, December 12, 2023 and available on https://en.wikipedia.org/wiki/Army%E2%80%93Navy_Game Check out our website at http://artofdiscussing.buzzsprout.com, on Facebook at Art of Discussing and on Instagram @artofdiscussing.Got a topic that you'd like to see discussed? Interested in being a guest on our show? Just want to reach out to share an opinion, experience, or resource? Leave us a comment below or contact us at info@artofdiscussing.com!! We'd love to hear from you! Keep Discussing!Music found on Pixabay. Song name: "Clear Your Mind" by Caffeine Creek Band"

In this episode, Kate and Ben discuss October being Cybersecurity Awareness Month and ways to protect yourself and your information in the electronic and "smart" age.Research/Resources"America's Cyber Defense Agency". Published in Cybersecurity & Infrastructure Security Agency website and available on https://www.cisa.gov/ Check out our website at http://artofdiscussing.buzzsprout.com, on Facebook at Art of Discussing and on Instagram @artofdiscussing.Got a topic that you'd like to see discussed? Interested in being a guest on our show? Just want to reach out to share an opinion, experience, or resource? Leave us a comment below or contact us at info@artofdiscussing.com!! We'd love to hear from you! Keep Discussing!Music found on Pixabay. Song name: "Clear Your Mind" by Caffeine Creek Band"

Tracy Fink is the Director of Scientific Programs and Science and Policy Initiatives at IFT. She has more than 25 years of experience in leading food safety and logistics initiatives for the food industry, including with Schwan Food Co. and NSF International. In this episode of Food Safety Matters, we speak with Tracy [29:49] about: Tracy's work overseeing IFT's food safety programs, which focus on several strategic topics of interest Programming and discussions that will take place at the IFT FIRST conference in July, the theme of which will be “Innovation in a time of crisis: Can we future-proof the food system?” Industry concerns, like facility cleanliness, with the introduction of sesame as a major food allergen, and resources for industry provided and being developed by IFT IFT's commodity-specific video series to help industry comply with FDA's Food Traceability Final Rule (FSMA 204) How IFT's global membership and partnerships with international organizations contribute to strengthening food science and food safety on global and regional levels. News and Resources Following California's Example, New York State Bill Would Ban Five Most “Pervasive and Harmful” Chemical Food Additives [1:48]Bill Reintroduced to Congress Would Create FDA Office for Regularly Reassessing Safety of Chemicals in U.S. Food Supply [3:04]USDA-FSIS Updates Guidance for Salmonella Control in Swine Slaughter, Pork Processing Establishments [7:48]40 Percent of Retail Foodborne Illness Outbreaks Linked to Sick Employees, Says CDC [11:02]Appropriations Bill Reveals Congressional Priorities for FDA in FY 2024: Restructuring Foods Program, Listeria Action Levels, and More [16:56]FDA Finalizes Action Level of 10 ppb for Inorganic Arsenic in Apple Juice [17:49]Effort to Develop Early Mycotoxin Warning System for European Cereal Grains Underway [18:20] IFT IFT FIRST IFT Global Food Traceability Center (GFTC) IFT GFTC Commodity-Specific Videos (FSMA Traceability Rule Resources) Food Safety Insights Column, Bob Ferguson Food Safety Priorities—Your Thoughts on FDA's Proposed Reorganization [21:16] We Want to Hear from You! Please send us your questions and suggestions to podcast@food-safety.com

Episode Notes The United States saw over 44,300 deaths from guns in 2022. And as the last year has made painfully clear, Virginia is not immune. Our state has been rocked by the horrific shootings in Charlottesville, Chesapeake, and Newport News. But even so, almost no meaningful gun safety legislation passed the General Assembly in the 2023 session. House Bill 2387 established tax credits for people who purchase gun safety devices, but that was about it.  That's a departure from 2020 and 2021, when Democrats in the House and Senate passed a bevy of legislation aimed at reducing gun violence. Yet while those were important changes, there's still a long way to go.  So, what do Virginia's gun laws look like now? And what can be done to end gun violence in the state? To help answer those questions, we talk to Andrew Goddard, Legislative Director at the Virginia Center for Public Safety, and Brian Moran, who served as Virginia Secretary of Public Safety from 2014 to 2022. To learn more, check out the Virginia Center for Public Safety's Research Resources.

Discussion on using vertical files in genealogical libraries and archives

In this episode, Kate and Ben discuss the discovery of classified documents in unauthorized locations in possession of high level government officials including President Biden, former President Trump, and former Vice President Pence. Research/Resources:18 U.S. Code 1924 – Unauthorized removal and retention of classified documents or materials. Published in Cornell Law School and available on https://www.law.cornell.edu/uscode/text/18/1924What are classified documents? Explaining the levels, penalties for mishandling by Adela Sulliman and Perry Stein. Published in The Washington Post website January 24, 2023 and available on https://www.washingtonpost.com/politics/2023/01/13/classified-documents-explained-biden-trump/Check out our website at http://artofdiscussing.buzzsprout.com, on Facebook at Art of Discussing and on Instagram @artofdiscussing.Got a topic that you'd like to see discussed? Interested in being a guest on our show? Just want to reach out to share an opinion, experience, or resource? Leave us a comment below or contact us at info@artofdiscussing.com!! We'd love to hear from you! Keep Discussing!Music found on Pixabay. Song name: "Clear Your Mind" by Caffeine Creek Band"

Today we chat about the Satanic Panic, focusing on the daycare allegations and the vendetta against Dungeons and Dragons. Please be warned that there is a lot of talk about mental health, suicide, and child abuse allegations. It sadly comes with the territory of talking about the panic of the 70s and 80s. If you or anyone you know needs help please feel free to visit this site for international resources https://unitedgmh.org/support/ Globally we can help those in need of mental resources and make it ok to ask for help when needed without judgement. We also talk about people who are in prison when they are innocent; to help get them back into society please visit: https://innocenceproject.org/Research Resources: https://www.dicebreaker.com/games/dungeons-and-dragons-5e/feature/dnd-satanic-panichttps://www.bbc.com/news/magazine-26328105https://www.nytimes.com/2016/04/18/us/when-dungeons-dragons-set-off-a-moral-panic.htmlhttps://kuscholarworks.ku.edu/bitstream/handle/1808/29349/Wilson_2019_SeniorThesis.pdf;jsessionid=87C358D49D2DF0165B4E4ABE5DF1A777?sequence=1https://nerdist.com/article/how-dd-writers-fought-the-satanic-panic/https://podcasts.apple.com/ie/podcast/44-dungeons-dragons-and-the-satanic-panic/id1175072618?i=1000425739340https://variety.com/2022/tv/news/peacock-satanic-panic-series-dungeons-dragons-honor-among-thieves-1235334461/ Hosted on Acast. See acast.com/privacy for more information.

During this episode, Dr. Katie Strong, Associate Professor in the Department of Communication Sciences and Disorders and Director of the Strong Story Lab at Central Michigan University talks with Dr. Jackie Hinckley from Nova Southeastern University about stakeholder engaged research and Project BRIDGE.   Dr. Jackie Hinckley is Professor and Director of the Undergraduate Program at Nova Southeastern University. She is Board Certified in Neurogenic Communication Disorders by the Academy of Neurologic Communication Disorders and Sciences (ANCDS) and Fellow in Person-Centered Care. Dr. Hinckley is currently a Board Member of Aphasia Access and the National Aphasia Association. She is Executive Director Emeritus of Voices of Hope for Aphasia. She is Project Lead for Project BRIDGE, formerly funded by two PCORI Engagement Awards and now supported by NSU. She is the author of two books, Narrative-Based Practice in Speech-Language Pathology, and What Is It Like to Have a Communication Impairment?  Simulations for Family, Friends, and Caregivers. She is an Editor for The Qualitative Report, and on the Editorial Board of Topics in Stroke Rehabilitation and Journal of Interactional Research in Communication Disorders.        In this episode you will:  Learn about the importance of including people with aphasia and clinicians in the research process to make the research better. Find out what stakeholder engaged research is and its importance in developing relevant evidence for clinical practice Hear how Project BRIDGE has enhanced stakeholder engagement in research related to aphasia. Be empowered to embrace your own expertise and the expertise of your clients and their family members. KS: Jackie, Welcome back to the Aphasia Access Conversations Podcast. I believe you were first interviewed on our podcast in 2016 – Episode #2! We now have over 86 episodes that are available! Who knew the series would have such staying power. It's really amazing! Thanks for joining me today. I'm really excited about this conversation with you and having our listeners hear about what you've been up to lately and how that is impacting our clinical practice and the people with aphasia that we work with. JH: Well, thank you, Katie, for the introduction, and thank you to you and Aphasia Access for the opportunity to be on this podcast. I'm really excited to talk about these issues and talk about them with you. KS: Well, let's dig in. So, today's topic is “everyone's an expert”. How does that relate to our clinical work and our research?  JH: Well, you know, Carl Rogers, the famous psychologist said that we are the best experts on ourselves. And I think that we all have that thought in our minds, but it really hits at the core of person-centeredness. An expert is someone with authoritative knowledge. So that has two parts, the authority and the knowledge. And an expert comes about when people agree that an individual has high performance or high knowledge in an area. I think that the idea of person-centered care in our clinical work is that we acknowledge that our clients are the best experts on themselves. And I think most of us who are practicing speech pathologists would certainly acknowledge that and agree with that. But in reality, in a normal clinical process, it's actually kind of hard to do. Because the clinician is, by definition, an expert, and has a certain degree of authority in the clinical interaction. So, for example, clinicians need to do an assessment and a diagnosis. And the client really can't self-diagnose, so there's an issue of authority and knowledge from the point of view of the clinician. But now that authority tends to seep into other areas like goal setting, where really the client needs to bring forward their own expertise about themselves. When we continue to exercise authority over what the goal should be,  and yet, evidence shows that collaborative goal setting like goal attainment scaling significantly improves not just the immediate outcomes of therapy, but also how active the client is after they are discharged home. So, there's a tension around expertise. It has to shift back and forth during the clinical process. And a lot of times, it starts with the clinician having a lot of authority, but we have to know how to give our client that authority about themselves. So, it's only in the last decade or so that the idea of who's an expert and person-centeredness really has been applied to research.  For example, if we think about a traditional research process, the researcher reads the literature and identifies the knowledge gap comes up with the experiment or whatever study that can contribute to that gap. And the researcher determines the design, the method, the measurement, does the research, publishes it and gets it out in a way that the researcher basically is crossing their fingers is going to have the impact that they hoped for. The problem is that it this ignores who is going to be affected by the research. So, aphasia in, our specialty in our world here, is, is always existing in persons. It's not something that we can be that we can study in a petri dish. So anytime we do research that has to do with aphasia, we need to be acutely aware that we're creating knowledge that is going to actually affect somebody's life. And so maybe this knowledge is going to affect how the aphasia is assessed or treated, or what we do to support people with aphasia, but whatever it is, it's the lives of people with aphasia that are being affected by this research.  So, you know, let's step back a minute. And let's say I invented some new kitchen gadget, or a shoe or something, right. So. I'm the researcher of this new gadget. If I want to be successful in selling the product and having the product being used, I would have incorporated the views of people who might use it by trying out the products way before I ever try manufacturing and selling it because I need that feedback. I need to know if there are potential customers out there and whether they're actually going to use it.  And the same thing really applies to research. So, if I'm a researcher and I create a new research product (a.k.a = knowledge, or study to create knowledge). If I create some research product, but I'm not an expert user of that knowledge, in other words I'm a researcher who doesn't do assessments every day or treatment every day, then I run the very great risk that I'm creating a product that can't quite be used by the people was originally intended for. If we really embraced person-centeredness in research, then we would start by thinking about who are the people who are going to end up being affected by this research product or this research outcome. And we would incorporate people living with aphasia, and also clinicians into our research, and that would make the research better. KS: Powerful stuff! I remember the Disability Rights initiative using a slogan, “Nothing about us without us.” JH: Yes, that is a great slogan that has been around for a while. And that definitely reflects the idea of person-centeredness. And I think we need to remember that slogan and everything we do, whether it's our clinical practice, but also in our research. And that's a little bit of a new way of thinking about research. So, research is not just about the people with aphasia, sometimes it is, but a lot of times it's also about what are the best practices in clinical activities. So, we need to include both people with aphasia, their families, clinicians, maybe policymakers, other people who are really the stakeholders who are affected by the research products that we make, and they need to be involved in planning and doing the research and saying what kind of research would be most helpful. KS: I'm thinking a lot about researchers out there, Jackie, you and I included. We have clinical experience. So maybe they have a good idea of what clinicians need to know from research.  JH: You know, I have heard this from some people saying, “Well, I've been a clinician, so I know.” And maybe that's true. I think that people like you and I, who have been spent a good amount of time being clinicians in our past, probably are ahead of the game. In a sense, we might have a better sense of what we don't know, right? Because we've been out there doing it. But I will, in my opinion, I think researchers who aren't actively out in clinical settings, and they mostly aren't, still aren't quite totally up to date with the current challenges that are being faced by people. Anthony Bourdain, the celebrity chef said, “Just because I like sushi doesn't mean I can make sushi.” So, I think we may think that…but if we're not right in the thick of it, we may not know as much as we think. And we need to bring in the experts who actually do know what it's like to do that daily clinical work. KS: Point well taken. This leads us to the idea of stakeholder-engaged research. What is it? JH: The term stakeholder engaged research is an umbrella term. It covers a lot of different approaches to the idea of bringing in individuals who are going to be affected by the research to actually help can plan, conduct, and disseminate the research. So, there are various ways that stakeholders can be involved in research. They could be consultants, or they could be co-researchers, and full collaborators. In the case of a co-researcher, they help come up with research questions, help design the research, pick the outcome measure, help with data analysis, or interpretation, and even contribute to dissemination of the research results. We have found that people, family members, clinicians, other stakeholders, and people with aphasia can participate it fully as collaborators in all of these things if they so choose. KS: Amazing. I know there are a few examples of this kind of research in Ireland. For example, Ruth McMenamin …. and also, in Denmark Jytte Isaksen is doing interesting work, and of course there is Ciara Shiggins in Australia….what about in the US? JH: Yeah, so in other places, like in Europe, as you say, in Australia, I, you know, I think they've been a little ahead of the United States in terms of understanding that they need to bring in the people who are affected by research into the actual conducting of research. And that also brings up the point that I said, stakeholder engaged research is an umbrella term. There are many different terms and in some other countries, they also use different terms for this. But I'm using stakeholder engaged research here, because as you point out, it really is the term that's coming to the forefront here in the United States. So, in the United States, and in our all of our ASHA journals, we unfortunately have very few examples of stakeholder engaged research, where clients and family members are fully engaged collaborators are involved. There's only a handful of studies. So, it hasn't been a widely used approach in our field yet, but I think it's growing quickly. KS: What makes you think it will grow quickly? JH: There are three broad reasons why I think this is changing fast. First, I think the idea that people who are being affected by something – whether it be a policy, regulation, legislation – is taking a broader hold in certain areas of our lives. For example, in academics where we have student-centered learning. Second, research funding agencies in the United States are starting to value, and therefore reward with funding, research projects in which stakeholders play an important role and make a substantial contribution to the research project. The most important landmark in terms of funding agencies in the United States is the creation of the Patient-Centered Outcomes Research Institute, called PCORI. It was created as part of the Affordable Care Act in 2010 and it was charged with funding comparative effectiveness research – in other words, research that would help patients and clinicians what is the best treatment for them. Their slogan is “Research Done Differently”, and I think that captures that the research they are producing is not at all the kind of traditional research that we mentioned earlier. PCORI is funding all kinds of health research across many disciplines in innovative ways. This is really changing the landscape of research and research funding, because other funding agencies are starting to follow their lead. The third reason why I think stakeholder-engaged research will grow quickly in our field is the experience we've had with Project BRIDGE. KS: I've been a Regional Coordinator and also a member of a few research teams for Project BRIDGE. Honestly, it's been a gamechanger for me in how I think about approaching research. Can you tell us about how Project BRIDGE got started? JH: Sure. So, 10 years ago, I was at a conference called the Clinical Aphasiology Conference. And for anyone who's not familiar with that conference, until the last couple of years, the only people who could attend the conference were people who submitted presentations. So, this means the conference in that sense rather exclusive, and that the audience, the people who are present at the conference, were really only researchers. So, 10 years ago, I was at this conference, listening to three days of presentations, all about aphasia treatment and I suddenly realized that we're all researchers talking to other researchers about aphasia treatment, but no one at the conference was either using the treatment as a clinician or receiving the treatment as a client. So, I said to some of the folks at the meeting, “There should be some people with aphasia at this conference. We're talking about their treatment.” And the response I got 10 years ago was, “Well, they don't really belong here.” The timing of that was one year after PCORI, became really active and started funding initiatives.  Around the same time, we had done a project with the Sarasota Aphasia Community Group, which is a fabulous group, if anyone needs a referral in that area. They run themselves. The group is really great. We asked their members to come up with ideas about what research they think would be important. We talked to them about research, and we set them off. So, they were off on their own and we did not interfere with this. They had their own group meetings and came up with the research ideas. So, they came up with 22 ideas.  Now most of their research, and by the way, these were really good questions. And most of them, you know, were formulated pretty close to how we would normally formulate research questions. I mean, they did a fabulous job with very little information about research. Most of their research questions were about the best treatment for different kinds of language issues. For example, “What's the best treatment for being able to produce sentences?” But then they came up with some really special questions that I don't think that you or I even despite all of our clinical experience, and our research experience, I'm not sure we would come up with these questions.  For example, they wanted to know, “How can the speech pathologist engage the person with aphasia, not just do rote exercises, but rather connect with the aphasic as a personality, tailor the therapy to the individual needs?” KS: Wow, that's mind blowing. And that's 10 years ago, right?  JH: Yeah, yeah, maybe even more than that. And by the way, I said aphasic. I'm reading what they wrote, so I just wanted to let everyone know that those are their words. Another question they came up with was, “What is the effect on the person with aphasia if they do not like their speech pathologist? or ‘The speech pathologist doesn't understand the patient's needs or doesn't customize the therapy towards them?'” Wow. I think as clinicians, we probably know, in our hearts that when we don't have a good match in terms the rapport between the clinician and client, it probably doesn't go that well. It's not the best outcome. We all know this. But we don't know very much about it from a research point of view. And then another question they came up with was “What makes a speech pathologist excellent?” These are from their point of view. It was just people with aphasia and family members coming up with these questions. KS: Wow, well I'm certain that I wouldn't be able to come up with those types of questions. They are so meaningful and important. They really get right down to what's important, don't they? JH: Yeah. I'm really pleased that we were able to publish that paper with the founders of the Sarasota Aphasia Community Group. They were co-authors. They were equal collaborators with us in the project. That was published in 2014.  And then two years later, in 2016, we submitted a proposal to PCORI, when I was the Executive Director of Voices of Hope for Aphasia. And although that first proposal was not funded, we got great feedback. When I read the feedback, I thought, you know, if we make this actually a little bit bigger, maybe it's going to be successful, which is not always the way you go. But we partnered with the University of South Florida. So, it was Voices of Hope for Aphasia and University of South Florida. And that was funded, and that proposal created Project BRIDGE.  The first two years of funding allowed us to create a working conference. The goal was to bring together people with aphasia, family members, clinicians, and researchers to form collaborative research teams. One challenge with this kind of work and you know, it's this is not just in the world of aphasia, this is any health domain that uses this kind of stakeholder engaged research. So, one challenge is that researchers know about how to do research but other people who aren't researchers don't know so much about research. On the other hand, researchers are not experts on daily clinical processes, nor are they experts on living with aphasia. So, we created some video trainings, and some of them were for people with aphasia and family members to learn more about the research process, and some were for researchers about communication supports role dynamics, and plain language. Because, you know, most researchers have never been trained in doing this kind of collaborative research. So that conference was held in October 2018. And after a two-day meeting, 11 research teams were formed. And you were there, Katie. KS: Yes! Project BRIDGE was a career changing experience for me. I had invited two of our Lansing Area Aphasia Support Group members, Chris and Ruby, to join me, and we flew down to Florida together. I think from that beginning of travelling together to a conference set a stage for something different. Actually, Chris's sister, who lived in Florida joined us at the conference too. None of us really knew what to expect, but from the very beginning, we all knew this was different. At the conference, I remember just having my mind blown that there were over 100 people attending the conference- many who had aphasia or were family members whose lives were impacted by aphasia. One of my favorite parts was when we were in our teams, I had a team about storytelling and aphasia, and everyone was brainstorming on research questions. The training, the collaboration, the energy, it was really impactful. I'd love for you to tell our listeners more about Project BRIDGE. JH: So, after that conference, we were very happy that these research teams were formed and there was so much energy. And I want to say that, you know, from the very beginning, before we even got funding, we had an advisory team that was made up of people with aphasia, families, clinicians, and researchers. And so, after the conference and a little bit of follow up with our teams. The whole advisory team was so excited, and we there was so much momentum, and we knew we wanted to keep Project BRIDGE going.  So, we applied for a second round of funding from PCORI. And with the second round of funding, we created what we call a research incubator. And we were able to create four regional centers around the United States because we knew there are many people who wanted to participate, but who cannot travel across country to a conference. So, we started Project BRIDGE as a research incubator in January 2020. Our mission was to train 48 people with aphasia, family members, clinicians, and researchers on stakeholder engaged research and get them connected to a collaborative multistakeholder research team. Katie, you are one of the regional coordinators in Michigan yourself for the Midwest, so you know how busy we got! KS: Oh yes, busy is an understatement. Suma Devanga from Western Michigan University and I were the Midwest Bridge Regional Coordinators. We had so much interest we just kept meeting with various stakeholders, holding trainings, connecting people with research teams. Definitely Project BRIDGE was the place to be!  JH: All the regional centers were very busy. At the end of two years, we had three times as many people sign up to participate than we planned, and we trained 25% more people than we planned. Many more stakeholder-engaged research teams have been formed, and they're studying topics like the effects of yoga on aphasia. The yoga team actually started in the original 2018 conference. And, you know, check it out, maybe we can share some links to a couple of their publications, because it's a very productive team. KS: Absolutely , we'll put we'll put the links to that and some of the other things you've mentioned in the show notes.  JH: Great. Another team that has been influenced by Project BRIDGE is aphasia games for health. There's more than one team now working on mental health interventions for people with aphasia. We also have a couple of teams working on different aspects of friendship and aphasia. One team is a collaborative team working on how to run aphasia groups. I mean, isn't that great? Get the people with aphasia to run a study on the best way to run the aphasia groups, right? It makes total sense.  We've got lots of teams working, and we've had several different presentations at various conferences. And, you know, please stay tuned in the coming months and, and years, because more and more the work will get to a point where it'll be out in different publications.  When I look back at the work that we did with the Sarasota Aphasia Group, and the questions that they came up with, I'm so overjoyed that many more of them are now being addressed because people with aphasia, care partners, clinicians are being involved in not just coming up with the questions but planning and actually doing the research. KS: Powerful stuff! This is all very exciting. But there must be some challenges…  JH: Definitely, there's definitely challenges. First of all, you know, most researchers who are active today have not been trained in this kind of research. They were not trained in their doctoral program, to sit down with people who have expertise in a completely different area. They may have been trained to collaborate with people who are more or less like them. But that is a very different game. So, one thing that I think we'd like to do in the future is help foster the incorporation of the skills needed to do this kind of research into doctoral training programs. When we talk to researchers who have gotten into this, like you. We find that this is a recommendation that many people come up with. Another challenge of this kind of work is that it takes more time. It is time consuming. It takes time to involve people who come from a different background. And it doesn't matter if they are people with aphasia, a community partner, whoever they are, when they have a different background, then an academic researcher, that's going to take more time, and it's really, truly an investment. That is an issue for this kind of work. Another challenge or risk is as there are more incentives for in involving stakeholders of different types into the research process, there's always a risk of tokenism. So, if that starts becoming rewarded in some way, like through funding, then there's a risk that, you know, stakeholders are up serving on advisory boards, so it looks like they're involved, but they're not really, truly collaborators or really involved. So that is a risk I think that we're going to run, especially in the future.  But you know, honestly, I think that's a risk that we run in our clinical work, too. Sometimes we don't mean to be to be tokenistic. But I think when we ask our clients a general question, like, “What would you like to work on in therapy?” You know, our heart is there, we want to involve the client. But that's a question that the client is not really prepared to answer in that form. Most of our clients, probably, they never been in therapy, they don't know what therapy is in the first place. They don't even know how to start thinking about that question. If we don't take extra steps to seek out their perspective, and what's important to them, that that's a little bit tokenism too. You know, we don't mean it to be, but it really kind of is, I think. We need to ask specific questions; we need to use tools that we have. For example, Aphasia Access now has the Life Interests and Values cards, which is a fabulous way of getting the idea of clients' priorities for therapy, in an aphasia friendly way. I think the other thing for clinicians for our clinical work is when we do ask questions of our clients, and they give us the answer, I think we have to do a better job at taking them at their word. Because I think sometimes, if the answer is not quite what we think it should be, or we're a little surprised by the answer, we're very likely to attribute insight, problem solving issues, motivation, issues, whatever it is, into that client's response, when perhaps, that that is their answer for them. And you know, they are the experts on themselves.   KS: Yes, that's such great perspective and food for thought. I think we really need to listen and embrace what our clients put forth with ideas for how to work on goal areas and be open to receiving the goals and the ideas that they that they have. Even if it takes us a little off road from where we typically go. How can we help them explore and develop and operationalize their ideas? And I think it is challenging, it's new territory for us as clinicians and research but I think once we're open to this, I mean, honestly, sky's the limit. And the cool thing is that we as researchers get to learn and grow alongside our clients as well. Jackie, this has been such a thoughtful and great conversation. The time has just flown by. But as we wrap up today, do you have any final thoughts? JH: Well, you know, a lot of times we hear people say, “I'm no expert”, and Project BRIDGE has really taught me and showed all of us involved I think that a few things. Clinicians might not feel like experts around researchers, but they are experts about what they do and the clinical process. People with aphasia and care partners probably don't feel they don't feel like experts around researchers or clinicians, but in point of fact they are experts about themselves and their own lives and, and what's important, and what we can best do to fit into those priorities. So, I think that we've learned from Project BRIDGE that a researcher or a clinician who exudes cultural humility. You know, we might not feel like experts in front of clinicians or people with aphasia and care partners. So, I think we need to acknowledge, we're all experts on ourselves and our little corner of the world, what we do all day, and other people are experts on other things. And hopefully, we don't impose that onto other people and that we can just collaborate with each other.  When some kind of research is going on, that might potentially affect something that a clinician routinely does, or how a person with aphasia is living, or the kind of therapy they're going to get, etc. We need to be willing to step up and contribute to a collaborative team. You know, probably not every kind of research in the world is a perfect fit for this kind of stakeholder engaged research. But a lot of what we do in aphasia, I think, and especially things that are important to members of Aphasia Access, would be better, more effective and more efficiently done with a collaborative team. We need everyone's expertise to change things for the better. When we do this kind of collaborative research, it speeds up how fast the research gets used in practice settings. So, it benefits people faster, because it's more effective. So, we need people to be aware of this and get involved. Project BRIDGE, fortunately, is now supported by Nova Southeastern University. So, it's not going away just because the funding ended in this year. And we are continuing to help people, whether they be researchers, clinicians, people with communication disabilities, or family members to get going on stakeholder engaged research. We still have our video trainings, And, coming soon, we'll be offering customized research team trainings. I invite everyone to please check out our website, www.projectbridge.online  You can sign up for our newsletter and we post various resources that are helpful tools. KS: Thanks, Jackie. I'll be sure to put all of your contact information and Project BRIDGE as well as some articles on stakeholder engaged research in the show notes. Thank you, Jackie. you've given us lots of food for thought and inspiration for action during the conversation. But I also just want to say, thank you for your forward thinking and helping us in the world of aphasia get on this stakeholder engaged research train. Project BRIDGE is a great conduit for who knows what's to come. JH: Well, thank you, Katie. And, and thanks again, for this opportunity to talk about this effort. You know, there's so many people around the United States who are participating in this, I could have spent the whole podcast just probably listing their names, but that might not be too engaging. KS: It's a big posse, Project BRIDGE! JH: It's very big. Broadly, I definitely want to acknowledge them, even though I can't acknowledge everyone by name. Everyone's doing such exciting work and people are finding their own paths through this, which is what we need. I didn't say it earlier, but the idea of incorporating people living with communication disabilities into the research really springs out of my own personal experience with disability and in life. And it's such a privilege for me to meld my personal experience into things that hopefully will help others too. So, thank you very much. On behalf of Aphasia Access, we thank you for listening to this episode of the Aphasia Access Conversations Podcast. For more information on Aphasia Access and to access our growing library of materials go to www.aphasiaaccess.org If you have an idea for a future podcast topic email us at info@aphasiaaccess.org. Thanks again for your ongoing support of Aphasia Access.   Resources Referenced in Episode Project BRIDGE www.projectbridge.online  Email: flaaphasia@gmail.com Twitter @ProjectBridge3 Facebook @bridgeresearch  Instagram @projectbridge2  Dr. Jackie Hinckley - Jh988@nova.edu   PCORI Engagement Resources: https://www.pcori.org/engagement/engagement-resources  Project BRIDGE (and resources) on PCORI: https://www.pcori.org/research-results/2020/building-bigger-bridge-research-incubator-network-pcor-communication-disabilities  Project BRIDGE Published Abstract: https://www.frontiersin.org/10.3389/conf.fnhum.2019.01.00030/event_abstract    Examples of Stakeholder Engaged Research Project with Sarasota Aphasia Community Group:  https://www.tandfonline.com/doi/full/10.3109/09638288.2013.829528  Team Yoga - 1: https://pubs.asha.org/doi/10.1044/2020_PERSP-20-00028  Team Yoga  - 2: https://pubmed.ncbi.nlm.nih.gov/34797684/  Aphasia Games for Health: https://www.aphasiagamesforhealth.com/    Canadian Institutes of Health Research Patient Engagement in Research Resources https://cihr-irsc.gc.ca/e/51916.html  Ethics in Patient Involvement: Hersh, Israel, & Shiggins 2021 https://www.tandfonline.com/doi/full/10.1080/02687038.2021.1896870    Goal Setting Resources for Aphasia Live Interests Values Cards (LIV! Cards) https://www.aphasiaaccess.org/livcards/ 

This week on the show we take our first foray into an incredibly important pillar of the long term care of art: how we document, catalog, and care for archives. Our guest Farris Wahbeh is the Benjamin and Irma Weiss Director of Research Resources at the Whitney Museum of American Art. Farris' role is quite unique in the sense that he oversees and serves as a central hub for all of the various teams that manage information at the Whitney: the archives, library, collections documentation – it is a rather unique and interdisciplinary role for a museum. In our chat we'll explore Farris' decades of experience working in incredibly interesting art archives, and how the Whitney integrates archives and documentation into their care of their collection of over 800 highly complex time-based media artworks.Links from the conversation with Farris> The Whitney Museum of American Art: https://whitney.org> David Tudor's archives at the Getty: https://www.getty.edu/research/tools/guides_bibliographies/david_tudor/index.html> The Center for Intuitive and Outsider Art: https://www.art.org/Join the conversation:https://twitter.com/ArtObsolescencehttps://www.instagram.com/artobsolescence/Support artistsArt and Obsolescence is a non-profit podcast, sponsored by the New York Foundation for the Arts, and we are committed to equitably supporting artists that come on the show. Help support our work by making a tax deductible gift through NYFA here: https://www.artandobsolescence.com/donate

We know that research resources are often limited, and Dr. DeDecker emphasizes the importance of allocating these resources appropriately, according to priorities, and how this study will add value to pig production. What other tips could we add?

Ufo research resources, part 1, Blogs I like.Blogs covered here : Bad ufos by Robert Scheaffer : https://badufos.blogspot.com/UFO watchdog blog : http://ufowatchdog.blogspot.com/SUPERHIDEF : https://superhidef.blogspot.com/Fair use statement : This video uses clips from various sources which are used under fair use for purposes of comedic parody, education and or commentary. Use of these clips is allowable by law and is considered fair use.Comic disclosure out of context episode shared :https://www.youtube.com/watch?v=-yzxRlBJHPUThis video is produced by Spectral International, LLC.Follow Steven Cambian on twitter : @stevencambianJoin our Patreon : https://www.patreon.com/stevencambianDonate by paypal : Send a paypal to TRUTHSEEKERSHOW@GMAIL.COM Any amount you wish.Please include your chatroom user id, and any message you would like me to read on air. We read every paypal message we are sent and thank every person who sends any paypal support. Kari helps with graphics and show production. Buy her a coffee for helping out!Please buy her a coffee for helping out! https://www.buymeacoffee.com/outofcontextcwBuy me a coffee (A beer actually!) :https://www.buymeacoffee.com/truthseekersListen to the audio podcast : https://www.spreaker.com/user/14526799Email us : TRUTHSEEKERSHOW@GMAIL.COM#UFOTWITTER #CRYPTO #DAVIDWILCOCK #UFO #DISCLOSURE #ANCIENTALIENS #SSP #SECRETSPACEPROGRAM #TRUTHSEEKERS #STEVENCAMBIAN #ANJALI #AREA51 #ALIENS #BOBLAZAR #GEORGEKNAPP #JOHNLEAR #S4 #AREA51COVERUP #WEAPONIZEYOURCURIOUSITY #UAPREPORT #MYSTERYWIRE #ALIENBASE #F2B #JIMMYCHURCH #DAVIDWILCOCK #ANCIENTALIENS #EDGARCAYCE

Research Resources You Should Know About - SolutionsWatch - The Corbett Report www.corbettreport.com/ The Corbett Report is an independent, listener-supported alternative news source. It operates on the principle of open source intelligence and provides podcasts, interviews, articles and videos about breaking news and important issues from 9/11 Truth and false flag terror to the Big Brother police state, eugenics, geopolitics, the central banking fraud and more. The Corbett Report is edited, webmastered, written, produced and hosted by James Corbett. James Corbett has been living and working in Japan since 2004. He started The Corbett Report website in 2007 as an outlet for independent critical analysis of politics, society, history, and economics. Since then he has written, recorded and edited thousands of hours of audio and video media for the website, including a podcast and several regular online video series. He is the lead editorial writer for The International Forecaster, the e-newsletter created by the late Bob Chapman. His work has been carried online by a wide variety of websites and his videos have garnered over 50,000,000 views on YouTube alone. His satirical piece on the discrepancies in the official account of September 11th, “9/11: A Conspiracy Theory” was posted to the web on September 11, 2011 and has so far been viewed nearly 3 million times. For more information about Corbett and his background, please listen to Episode 163 of The Corbett Report podcast, Meet James Corbett: Episode 163 – Meet James Corbett Broc West has been the Video Editor of The Corbett Report since December 2014. He currently lives in Southern Vietnam. Twitter: @brocwest Audio taken from: https://www.corbettreport.com/research-resources-you-should-know-about-solutionswatch/

Market research is essential. Whether you're about to start a business or launch a new product, feature, or location. You must ascertain that the opportunity for your idea or product exists. This episode is also available as a multimedia blog post: https://evansonmarketing.com/2020/11/18/useful-marketing-research-resources/

In this episode, we go into the sufficiency of the living and active Word of God, and we also chat about how the enneagram falls short of being anything helpful. Research Resources: http://www.christiananswersforthenewage.org/Articles_Enneagram2.aspx http://www.christiananswersforthenewage.org/Articles_Enneagram.html https://awordfitlyspoken.life/podcast/top-7-reasons-the-enneagram-is-unbiblical/ https://www.facebook.com/DoreenVirtueForJesus/videos/proof-that-the-enneagram-is-new-age-occult-deception/543354266335237/ https://youtu.be/pFkYsry9njY https://youtu.be/rqh4XTDVboc Contact us at abidethepodcast@gmail.com or on Instagram @abidepodcast --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/abide-podcast/support

Research is an integral part of a pharmacist’s professional development.  Listen in as ASHP’s Gina Luchen and ASHP Foundation’s Barbara Nussbaum share resources, training and grant opportunities offered by ASHP and ASHP Foundation.  The information presented during the podcast reflects solely the opinions of the presenter.  The information and materials are not, and are not intended as, a comprehensive source of drug information on this topic. The contents of the podcast have not been reviewed by ASHP, and should neither be interpreted as the official policies of ASHP, nor an endorsement of any product(s), nor should they be considered as a substitute for the professional judgment of the pharmacist or physician. 

Dr Suzanne Bartlett-Hackenmiller, MD, started out as an OB/GYN but found she consistently wanted to ‘take it outside’- not common for a women’s health doctor doing pelvic exams. The outdoors continued to call to her as she raised her autistic spectrum son and was solace during and after losing her husband to cancer. It wasn’t until she found Shinrin Yoku, the Japanese Art of Forest Bathing, however, that her understanding of the true power of nature became clear. Her book, The Outdoor Adventurer’s Guide to Forest Bathing, exemplifies her unique approach to nature as medicine, be it a wilderness adventure, a plantain growing through a crack in the sidewalk, or a house plant. It includes resources (see below!) and invitations for Forest Bathing exercises like Pleasures of Presence, Sit Spot & Tea Ceremony with explanations and pictures of common, safe and local herbs. Dr Bartlett-Hackenmiller also insightfully recognizes that while outdoor adventure like hiking, biking and skiing have been for white people as of late, it's critical to decolonize our collective experience of wilderness in all directions, meaning recognizing the indigenous presence (historical, current and future) as well as being intentionally welcoming to People of Color and those with disabilities out into nature (or just getting out of their way). Throughout, Dr Bartlett-Hackenmiller weaves through the research that reflects nature as a true fourth pillar of health (diet, sleep, exercise, nature), pulling kernels out of her new one-hour open-access webinar on nature as medicine. Listen in; even better- go outside & listen as you move! Resources: Dr Suzanne Bartlett-Hackenmiller's website: https://integrativeinitiative.com/ Book link: Outdoor Adventurer's Guide to Forest Bathing: https://www.elliottbaybook.com/book/9781493042029 Blog 1hr CME on nature: https://parkrxamerica.org/continuing-education/ Association of Nature & Forest Therapy: https://www.natureandforesttherapy.org/ AllTrails App to find trails locally: https://www.alltrails.com/ ParksRx.com: https://parkrxamerica.org/ NativeLands app for finding your local names for places: https://apps.apple.com/us/app/native-land/id1194356597 Forest Bathing international: http://www.forestbathinginternational.org/ SHIFT: Shaping How we Invest For Tomorrow: https://shiftjh.org/

Guest Bio: J. Scott Yaruss is a professor of Communicative Sciences and Disorders, a practicing speech-language pathologist with more than 25 years of clinical experience, and a board-certified specialist in fluency disorders. He joined the faculty of  MSU in 2017, with the overarching goal helping speech-language pathologists improve their ability to provide meaningful and lasting support for people who live with stuttering. Yaruss has published more than 85 peer-reviewed articles, as well as more than 110 other articles, chapters, and books about stuttering. He has given hundreds of continuing education workshops, seminars, and other presentations at local, national, and international conferences. He has also served in various posts for the American Speech-Language-Hearing Association's Special Interest Group for Fluency Disorders and on the Board of Directors of the National Stuttering Association. He has been active in the stuttering self-help community for more 20 years. Prior to coming to MSU, Yaruss was at the University of Pittsburgh and Children's Hospital of Pittsburgh, where he led the Stuttering Center of Western Pennsylvania. He  holds a bachelor's degree in linguistics and psychology from the University of California Berkeley, and a master's and doctorate in speech-language pathology from Syracuse University. While at the University of Pittsburgh, he was recognized with the School of Health and Rehabilitation Sciences Dean's Distinguished Teaching Award. In 2011, he co-founded Stuttering Therapy Resources (https://www.StutteringTherapyResources.com), a specialty publishing company focused on providing practical materials for helping speech-language pathologists help those who stutter. Key publications include: School-Age Stuttering Therapy: A Practical Guide, Early Childhood Stuttering Therapy: A Practical Guide, Minimizing Bullying for Children Who Stutter, and the Overall Assessment of the Speaker's Experience of Stuttering (OASES), a comprehensive instrument used around the world to measure the adverse impact of stuttering on people's lives. In this episode Scott and Uri discuss: - Latest research findings in neuroscience, genetics, pharmacology and more. - Future directions, in research and clinical care for people who stutter - Advice for students and up-and-coming speech-language pathologists - Hopes for what we can do in the coming years  Links: https://www.StutteringTherapyResources.com School-Age Stuttering Therapy: A Practical Guide,  Host Bio: Uri Schneider, M.A. CCC -SLP passionately explores and develops practical ways for us to create our own success story. Delivering personalized experiences of communication care informed by leading professionals and influencers, Uri is re-imagining the next-level of speech-language therapy for people to benefit in real life. Uri Schneider, M.A. CCC -SLP is co-founder and leader at Schneider Speech Pathology and faculty at the University of California, Riverside School of Medicine. For more, visit www.schneiderspeech.com    

Did you know that NCATS issued over 45 patents in eighteen months? Listen as Lisa and guest, Lili Portilla, discuss the different parts of NIH, what NCATS is and what it does, and their work with small businesses and much more on this episode of Tech Transfer IP. Lili is the Director of Strategic Alliances of the National Center for Advancing Translational Sciences, also known as NCATS at the National Institutes of Health. Lili has worked in the areas of strategic alliances, technology transfer at NIH since 1999, joining NCATS in December 2011. Before coming to NCATS, Lili served as Senior Advisor to the Director of National Center for Research Resources and as the Director of the Office of Technology Transfer and Development at the National Heart, Lung, and Blood Institute. Lili discusses the functions her office performs, how NCATS is structured, and the most prominent programs that NIH is focused on. She speaks about NIH's data enclave and how it can help physicians with COVID-19 procedures, their work with rare diseases, and the data directory they have to connect people that have been diagnosed with others like themselves. Listen as Lili shares the BrIDGS Program and what it does, and other services her office provides. Lili discusses how the SBIR and STTR are structured and the clinical research management tools that NCATS funds. Listen as Lili speaks about the challenges her office faces, and how much she loves her job, especially now during the pandemic. In This Episode: [02:31] Welcome to the show, Lili! [02:51] Lili shares her journey to tech transfer and what led her to NIH. [04:50] Lili speaks about how much she loves working at NIH and the different parts. [05:55] Lili discusses what the NCATS center is and what it does. [07:33] Lili speaks about the functions that her office performs and their work with small businesses. [08:46] Listen as Lili shares how NCATS is structured. [12:23] Lili discusses some of their most prominent programs that NIH focuses on. [16:22] NIH's data enclave is a resource that allows physicians to see how to treat COVID-19. [17:09] Lili shares their focus on rare diseases; they have a directory for people to connect with people who have been diagnosed with rare diseases. [20:05] Lili speaks about some internal programs they have now. [22:19] She talks about the BrIDGS program that helped launch 13 INDs. [26:06] Lili shares some additional services her office provides. [28:16] They had 45 patents issued over 18 months. [29:54] Lili speaks about some interesting information about their patent portfolio. [31:45] With COVID, they have done some agreements that were finalized in two days. [33:55] Lisa points out that if they didn't have good relationships with people, they wouldn't have repeat customers. [35:18] Lili speaks about how SBIR and STTR are structured. [38:41] Lisa speaks about the difficulty of finding an animal model. [40:23] NCATS also funds clinical research management tools. [42:38] Lili shares how NCATS engages with women entrepreneurs in the program. [44:19] Lili discusses how NCATS will take part in the Applicant Assistance Program. [46:11] Lili says that being an SBIR or STTR grantee comes with resources that they can apply to. [48:26] Lili shares some of her office's biggest challenges. [51:26] How challenging is it to have to pivot anytime day today? [52:29] Lili speaks about how much her job means to her, especially now with the pandemic. [54:35] Lisa talks about how important the organizations are when there are situations like we are facing now. [56:07] If you had three wishes, what would those wishes be for your office? [58:27] Lili, thank you so much for being on the show! Find Lili: NIH NCATS  

The world is currently going through the strangest thing that any of us will likely face in our lives. And there's a ton of fear and anxiety and doom and gloom that comes along with a worldwide pandemic, of course. But in this episode, happiness expert and author Jennifer Moss gives us incredible, tangible advice on how to navigate through this uncertainty with less guilt. But also to accept the many stages of grief that we may be moving through right now, no matter what form the emotion may be taking.  It's ok to not be thriving right now, but we don't have to completely sink either.  *This episode was adapted from a Facebook LIVE that was recorded on March 26th, 2020 (if you want to see the video, here it is: https://www.youtube.com/watch?v=c6uLz2hRdqo) List of Resource Suggestions from this episode: HERO GEN – https://hero-generation.com/covid19/ Global Happiness Council Access here: http://www.happinesscouncil.org/ The Global Happiness Council (GHC) produces the Global Happiness and Well-Being Policy Report with the goal of informing policy around Positive Education initiatives, Happy Cities, Societal Well-being Interventions, and more. The site also includes videos and past reports, which are presented at World Governance Summits in a bid to shape legal and governmental frameworks through science-based findings. The GHC also carries out research into personal happiness and Positive Organizations. About Positive Psychology: Blogs and News Greater Good Magazine Access here: https://greatergood.berkeley.edu/ This is UC Berkeley’s digital magazine of science-based insights on well-being, gratitude, happiness, and more. Here you’ll find podcasts, videos, exercises, resources, and quizzes, along with articles that cover positive psychology themes in current affairs. Positive Psychology News Access here: https://positivepsychologynews.com/ This is written and curated by MAPP graduates and coaches, this site is a wealth of information on courses and resources. It’s regularly updated with book reviews, webinars, conference information, and is also a good place to find more background on PP through articles and a few nice frameworks. The Psychology of Wellbeing (A positive psychology blog by MAPP graduate and author Jeremy McCarthy) Access here: http://psychologyofwellbeing.com/ Jeremy McCarthy’s blog is actually an endearing mix of personal reflections on and news about positive psychology news. Here, the author applies positive psychology to wellbeing—holistic wellbeing, with a focus on spas and the hospitality industry. It includes transcripts from talks and relevant research on wellness. The Happiness Institute Blog Access here: http://www.thehappinessinstitute.com/blog/ Dr. Tim Sharp is an Adjunct Professor in Positive Psychology at the University of Technology, Sydney. On the Happiness Institute Blog, he curates and writes articles on positive psychology topics like stress, self-care, happiness, and mental health. There are plenty of links to academic articles with more information. The How of Happiness (A positive psychology blog by Dr. Sonja Lyubomirsky) Access here: https://www.psychologytoday.com/intl/blog/how-happiness Author Sonja Lyubomirski’s blog covers the science behind what is potentially the most popular positive psychology topic—happiness—from a scientific perspective. She is a Templeton Positive Psychology Prize winner and Professor of Psychology at the University of California, Riverside. The Good Life (A positive psychology blog by Dr. Christopher Peterson) Access here:https://www.psychologytoday.com/us/blog/the-good-life Christopher Peterson is frequently cited as the author of A Primer in Positive Psychology and has been an editor at The Journal of Positive Psychology. His Good Life Blog is not frequently updated but is full of opinions and insights on topics like happiness, life satisfaction, and books that are worth reading. Deeper Learning/Research: Upenn Positive Psychology Center Access here: https://www.positivepsychology.org (also available at https://ppc.sas.upenn.edu/) This is the University of Pennsylvania’s official Positive Psychology Center webpage. Dr. Martin Seligman, one of the founding fathers of Positive Psychology, is the director of this Center. On this site, you’ll find the latest of the University’s programs, an overview of UPenn’s research in various PP fields, and a wealth of resources such as questionnaires and further links to external bodies for therapists. VIA Institute on Character Access here: https://www.viacharacter.org/www/ This is the official site for the VIA Character Strengths Survey. The non-profit VIA Institute also provides a character strengths list and information about how to interpret the results of their assessment. There are resources for professional practitioners and quite a wealth of research findings, including survey data, full-text articles, fact sheets, and a blog that is updated weekly. The Jubilee Centre for Character and Virtues Access here: https://www.jubileecentre.ac.uk/ The University of Birmingham’s Jubilee Centre is involved in research projects aimed at understanding how character, values, and virtues contribute to human flourishing. At the link above, you’ll find more pages for learning about these projects, and multimedia resources for learning, as well as a nice blog on virtues. In the Library section, there is a further database of articles with numerous open access options. Science of Generosity Access here: https://generosityresearch.nd.edu/ This website from the University of Notre Dame has a Research Resources section which includes links to survey data and even the related questionnaire items that have been used in studies on generosity. Users who are hoping not to dig into hard data will also find reports, literature, and working papers in the same section. The Science of Generosity site also includes background on the Science of Generosity initiative and an overview of its current projects. Compassion: Stanford Medicine Center for Compassion and Altruism Research and Education Access here: https://ccare.stanford.edu/ Stanford’s Center for Compassion and Altruism Research and Education (CCARE) is committed to researching how ‘positive qualities of the human mind‘ benefit society and individuals. These include techniques and approaches for fostering compassion and its promotion in schools and institutions. On this page, CCARE features some of its own research, a database of other curated academic articles, and resources such as articles and overviews from past events. CompassionLab Access here: https://www.compassionlab.com/ CompassionLab is run by organizational researchers, with a goal of encouraging the use of compassion in professional contexts such as leadership and employee engagement. This site includes presentations, journal articles, book chapters, and links to other theory- and practice-related sites on Positive Organizations. Yale Center for Emotional Intelligence Access here:http://ei.yale.edu The Yale Center for Emotional Intelligence is a well-known source of academic information, research, and tools. It is behind the development of the RULER approach, a Social and Emotional Learning (SEL) framework with potential and demonstrated applications in professional development and education. The Center site thus provides background information on EI for educators, coaches, and therapists alike—here, you can access research on the Center’s science-based RULER approach. It also offers ample RULER documentation and emotional intelligence case studies. Consortium for Research on Emotional Intelligence in Organizations Access here:http://www.eiconsortium.org The EI Consortium seeks to progress research into, and practical applications of, emotional intelligence. This website contains a good collection of the publications and news about EI in business settings and leadership, as well as information on dissertations, book chapters, and emotional intelligence questionnaires. It’s a comprehensive source for anyone looking to research EI closely.  Gratitude: Emmons Lab Access here:https://emmons.faculty.ucdavis.edu/ Here is Dr. Emmons’ own research website, which provides some background into his work on the Youth Gratitude Project (YGP) with Giacomo Bono and Jeffrey Foh. It includes a list of relevant positive psychology publications on gratitude and links back to other webpages related to the YGP.  Flourishing: Authentic Happiness Access here: https://www.authentichappiness.sas.upenn.edu Another UPenn resource that links the user to books, questionnaires, projects and initiatives, academic research, blog posts, and news on happiness as a positive psychology topic. It is full of useful resources for teachers, therapists, and researchers, including videos, study opportunities, and training. Institute for the Study of Human Flourishing Access here: https://www.ou.edu/flourish This University of Oklahoma Institute was created to advance the study of human flourishing, further the scientific study of virtue, and engage with the community to promote flourishing. Here, you can easily find online and downloadable resources, including courses and relevant links for parents.  Global Happiness: International Research Associates for Happy Societies Access here: http://www.happysociety.org/ International Research Associates for Happy Societies is a non-profit, independent organization; IRAH started in 1995 as a network for individuals and organizations interested in happiness and promoting well-being in society. The site itself is in English, though it also includes links to publications in Thai and English. Here, you’ll find news on IRAH’s past activities and links to related sites. It is very much related to happiness in society and features some background on IRAH projects in developing communities. International Society for Quality of Life Studies Access here:http://www.isqols.org/ Founded in 1995, the ISQOLS goal is to advance research into happiness, well-being, and quality of life. ISQOLS hosts an annual conference on Quality of Life and publishes an official journal on the same, Applied Research in Quality of Life. Their official page includes a range of videos, webinars, access to their bibliographic database, and information about events. Happiness Economics and Interpersonal Relations Access here: http://www.heirs.it/ HEIR combines economic and positive psychology in its research, which focuses on understanding how individual relationships relate to societal happiness and subjective well-being. The team applies economic theory to the positive psychology topics of SWB and interpersonal relationships, and hosts workshops however, the site itself is not designed to be a source of literature or tools. Harvard University Center for Health and Happiness Access here: https://www.hsph.harvard.edu/health-happiness/ The Center for Health and Happiness at Harvard shares recent publications on topics like positive interventions, well-being, optimism, and health. The official site features links for students and researchers and also provides happiness resources and tools for use in a variety of different contexts. At this site, you can also find out more on the Center’s Seminar Series page, or watch seminar recordings from past events. OECD Better Life Index Access here: http://www.oecdbetterlifeindex.org/ In 2013, the OECD released its Guidelines on Measuring Subjective Well-being, to encourage a more holistic approach to studying SWB. These subjective indicators include constructs such as Life Satisfaction and Work-Life Balance, and the OECD considers them alongside objective measures of well-being on a national scale. This link will take you to the global country data that exists to date. According to the OECD, these statistics are being updated as different countries create more assessments of subjective well-being.  Mindfulness: UCLA Mindful Awareness Research Center Access here: https://www.uclahealth.org/marc/ MARC carries out education and research to encourage mindful awareness for well-being. The Center provides workshops, tools, and classes for the public and publishes studies on its site. These cover mindfulness topics such as MBSR, mindful awareness practices in education and the elderly, and also provide a little background on upcoming publications.  Education: International Positive Education Network Access here: https://ipen-festival.com/what IPEN has an extensive online learning library of resources for schools and educators. You’ll find articles, activities, handouts, worksheets, lesson plans, case studies, and downloadables such as posters for use in class. The link above takes you to a sister site which will lead you to the main site (currently under maintenance). On the site, you’ll see a map of where the IPEN community is distributed across the world and there is also considerable background materials about Positive Education. Positive Education Schools Association Access here: https://www.pesa.edu.au/ PESA is an Australian peak body dedicated to encouraging evidence-based approaches to well-being. The PESA site is a source of information on events, with a calendar of summits and conferences. Practitioners and educators can find out more about PESA’s state chapters to access support and resources for teachers and schools. The Positive Psychology Project: Character Strengths Access here: https://posproject.org/character-strengths/ This is an official page for research and resources on the 24 Positive Psychology Strengths identified by Drs Chris Peterson and Martin Seligman. The mission of the Positive Psychology Project is to train and equip educators and schools for helping children become their best selves through their strengths. The Resources section, therefore, includes playbooks, videos, character strengths, PPTs, and lesson plans for users to download. Character Lab Access here: https://characterlab.org/ A non-profit organization centered on Positive Education, Character Lab was set up by Angela Duckworth, UPenn’s Christopher H. Browne Distinguished Professor of Psychology, and two educators, Dave Levin and Dominic Randolph. Character Lab provides strategy playbooks for schools and educators, including the Kindness Playbook, Social Intelligence Playbook, and Gratitude Playbook. These also offer downloadable worksheets and links to further supporting research. Positive Emotions and Psychophysiology Laboratory Access here: http://peplab.web.unc.edu/research/ The University of North Carolina’s PEP lab promotes and conducts research into how positive emotions impact on their health, social behavior, thinking, and physiology. Its research page provides a link to the Lab’s publications and outlines various positive psychology theories of emotion. These include frameworks, articles, and ‘read more’ material on hypotheses in the field. Workplace: Center for Positive Organizations Access here: https://www.bus.umich.edu/positive In 2010, the Ross School of Business-based Center was awarded the Joanne Martin Trailblazer award for its work in Positive Organizational research. Here you’ll find Positive Organizational studies and scholarship on the topic, along with teaching resources, research, and tools for professionals. There are also links to talks in the Center’s Speaker Series and events listed, including conferences and Positive Research incubators. APA Center for Organizational Excellence Access here: http://www.apaexcellence.org/ Psychologically healthy workplaces are the goal of this APA Center. Here, employees, leaders, and psychologists will find tips for putting Positive Organizational theory into practice. As well as articles and tools for employers, there are also events and awards for companies. Resilience: The Resilience Research Centre Access here: http://www.resilienceresearch.org/ This is Dalhousie University’s Center for Research, the research featured on this site approaches resilience as a contextually- and culturally-embedded concept. Resources available on this site include tools, methods videos, publications, and approaches. The Resilience Research Centre (RRC) also offers case studies, workshops, and evaluations—the latter being initiatives that integrate some RRC measures in action. Master Resilience Training Skills Access here: https://www.usar.army.mil/MRT/ This page gives an official overview of the US Army’s Master Resilience Training (MRT) skills and competencies. This gives some background and detail on the approaches used in MRT to develop resilience in soldiers and their families, such as Energy Management, Problem Solving, and Real-Time Resilience. Harvard University Resilience Consortium Access here: https://resilienceconsortium.bsc.harvard.edu/ This Harvard University site presents a huge array of resources on research for students, educators, and individuals. You can browse resources by type or topic to find assessments, frameworks, interventions, handouts, and research on resilience. Or, you can watch videos, read the blog, listen to podcasts, or learn about the events that the Consortium supports.   Positive Psychology Research: Articles and Journals If you are looking for a list of peer-reviewed academic journals and special issues on the topic, hopefully, the following will be of help: The Journal of Positive Psychology: http://www.tandf.co.uk/journals/titles/17439760.asp Journal of Happiness Studies: https://link.springer.com/journal/10902 Emotion: https://www.apa.org/pubs/journals/emo/ Journal of Positive Psychology and Wellbeing: https://www.journalppw.com/php/JPPW International Journal of Applied Positive Psychology: https://www.springer.com/psychology/journal/41042 Journal of Wellbeing Assessment: https://www.springer.com/social+sciences/wellbeing+&+quality-of-life/journal/41543 Journal of Applied Positive Psychology: https://www.org/ Applied Research in Quality of Life: https://link.springer.com/journal/11482 The British Psychological Society (2003 Special Issue): https://thepsychologist.bps.uk/volume-16/edition-3/positive-psychology-special-issue American Psychologist (2002 Special Issue): https://www.apa.org/pubs/journals/special/4015501   Find out more about Jennifer: Website: https://www.jennifer-moss.com/ Twitter: https://twitter.com/JenLeighMoss Instagram: https://www.instagram.com/jleighmoss/ LinkedIn: https://www.linkedin.com/in/jenleighmoss/

Improving our relationship with radiologists can sound like a daunting task, but it's one that is crucial to what we do as speech-language pathologists. On this week's episode of Swallow Your Pride, the incredible Lauren Hermann discusses this very topic - how to improve our relationship with radiologists (in turn, helping us provide our patients with better care!) She covers ways to improve your expertise, build rapport, and resources to use when the episode ends. Tune in to learn more and get the show notes here: bit.ly/SYPpodcast123 - and Don't forget to take the survey (as mentioned in this episode!) which you can do with this link: http://bit.ly/slpradsurvey To share your thoughts: - Join the MedSLP Newbies Facebook group- Share this episode on Facebook or Twitter To help out the show: - Leave a review on iTunes. Your comments help me immensely and I just might read it on the show! - Contribute at patreon.com/swallowyourpride Download Ep. 123 Show Notes! This Month’s Featured Affiliates: If you like our work, support us on Patreon for as little as a dollar a month! Previous Next Previous Next

Fifty-years-ago, the sugar industry funded research that downplayed the risks of sugar and highlighted the hazards of fat. Forty-years-ago, high fructose corn syrup  (HFCS) started trickling into our food supply. Most people didn't know what HFCS was. So began the confusion about what is sugar and what sugars are healthy. When I decided to tackle the subject of sugar, one of the most surprising statistics I found out is that 99% of  toddlers ages 12 to 18 months are downing 5-7 teaspoons of added sugar a day.  Not only that, the average sugar consumption for adults is 25 teaspoons a day. Well over the recommended amounts.  Since the discovery of high fructose corn syrup, the American consumption of fructose jumped from 37 grams per day in the 1970s to a record high of 62 grams per day in 2000. So where is all this added sugar coming from? Here is an example. A 20 oz soft drink contains about 16 teaspoons of high fructose corn syrup, and an energy drink can hold over 50 grams of high fructose corn syrup. Salad dressings, ketchup, fruit drinks and even bread can have a large amounts of sugar. And most people have no idea they are consuming this much-added sugar. In today’s podcast, we break down the truth about sugar, and how it impacts our health. We also examine natural sugars and their role in a healthy diet. We also discuss why sugar may not be vegan due to its questionable infiltration. Resources: A List of Bone Char Free Sugar Companies Thanks for listening. Please follow me on Instagram@ordinaryvegan and please join our health and wellness community on Facebook, over 310,000 strong. I am devoted to keeping you healthy, and as many of you know, I began creating my own line ofCBD oilmade from hemp to assist you. CBD Oil(cannabidiol) is a naturally occurring compound found in the flowers of the hemp plant. A plant with a rich history as medicine going back thousands of years. I choose to provide CBD oilto our community because I wanted to make sure you received the safest and most reliable CBD oil on the market. Because I believe that the phytochemicals in CBD can help optimize human health no matter what your particular ailment may be. Hope my CBD oil can help you. To learn more about the power of CBD oil, listen toPodcast #30 – Everything You Need To Know About CBD Oil. Or visit our FAQ page. Thanks to this week’s sponsor - Blinkist. Go to Blinkist for your free seven-day trial. Til next time Research Resources: https://ordinaryvegan.net/vegansugar/ https://www.sciencedaily.com/releases/2017/10/171013103623.htm https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783224/ https://genome.duke.edu/news/mon-04302018-1349/cancer-cells-adapt-gorge-sugar-liver https://en.wikipedia.org/wiki/Sugar

Today I talk about the common Spanish contractions: al, del, conmigo, contigo and consigo. And in the process, we also learn some random history. :) Episode produced by © 2019 Language Answers, Ltd. Shout out to Women In Language Conference and Links: https://www.womeninlanguage.com The Fluent Show: Inside the Women in Language Conference: 12 Guests Tell All. (https://www.fluent.show/126) Research Resources used for/in this Episode: SpanishDict.com, “Consigo” - https://www.spanishdict.com/translate/consigo Quora.com, “In Spanish grammar, if you are talking formally (usted) do you use contigo or consigo?” - https://www.quora.com/In-Spanish-grammar-if-you-are-talking-formally-usted-do-you-use-contigo-or-consigo Jstor.org, “Excessive Analogical Change as an Impetus for Lexical Loss; Old Spanish Connusco, Convusco” by Joel Rini / Charlottesville -https://www.jstor.org/stable/pdf/27940047.pdf?seq=1#page _scan_tab_contents Gramática española blog, July 15, 2014, “Conmigo, Contigo y Consigo” by Eleonora Castelli - http://elblogdegramatica.blogspot .com/2014/07/conmigo-contigo-y-consigo.html Castellano Actual, August 20, 2012, “Conmigo, Contigo y Consigo” - http://udep.edu.pe/castellanoactual/conmigo-contigo-y-consigo/ Rael Academia Española, Diccionario, “Consigo” - https://dle.rae.es/?id=AQ1fBRU Woodward Spanish, “Contractions – AL-DEL: Spanish Grammar Rules,” https://www.spanish.cl/grammar-rules/contractions-al-del.htm Lawless Spanish, Free Spanish Lessons, “Spanish Contractions – Las contracciones” by Laura K. Lawless, https://www.lawlessspanish.com/grammar/contractions/

In this episode, the Spinsters take on one of the Big Three Horror Icons, Freddy Krueger. We discuss this iconic boogeyman and have an analysis of the women of the series as Final Girls as representative in movies 1 through 5 of the Elm Street series. Enjoy and welcome to our dark side... Intro Music: Robeast by Dance with the Dead Artwork by: Jess Hrycyk Editing work by Jessica and Blair McDonald. Research Resources can be found at https://www.spinstersofhorror.com/the-spinster-s-library

For our November episode, the Spinsters take on the ever controversial sub-genre: Rape/Revenge. Is it feminist or filth? The movies up for discussion are the classic I Spit on Your Grave (1978) and the newly released M.F.A(2017) Enjoy and welcome to our dark side.. Intro Music: Robeast by Dance with the Dead Artwork by: Jess Hrycyk Editing work by Jessica and Blair McDonald. Research Resources can be found at https://www.spinstersofhorror.com/the-spinster-s-library

For our October episode, the ladies will talk all about Witches in Horror by exploring the Good/Bad Witch Dichotomy and the elements of female empowerment and persecution. This will be explored in the two films, The Autopsy of Jane Doe (2016) and Romero's Season of the Witch (1973). Enjoy and welcome to our dark side.. Intro Music: Robeast by Dance with the Dead Artwork by: Jess Hrycyk Editing work by Jessica and Blair McDonald. Research Resources can be found at https://www.spinstersofhorror.com/the-spinster-s-library

For our September episode, the Spinsters talk about vampires and try to answer the question as to why we are all so drawn to them. Why have we sexualized and fantasized about vampires since their premiere in Bram Stoker’s novel, Dracula? The films we will be discussing are Interview with the Vampire (1994) and The Hunger (1983). Enjoy and welcome to our dark side.. Intro Music: Robeast by Dance with the Dead Artwork by: Jess Hrycyk Editing work by Jessica and Blair McDonald. Research Resources can be found at https://www.spinstersofhorror.com/the-spinster-s-library

The month of August is 90s horror month for the Spinsters of Horror! A decade close to our hearts and one we have been excited about getting into. There are two movies that we believe are the quintessential horror movies of the 90s: Scream and the Blair Witch Projectr. Enjoy and welcome to our dark side.. Intro Music: Robeast by Dance with the Dead Artwork by: Jess Hrycyk Editing work by Jessica and Blair McDonald. Research Resources can be found at https://www.spinstersofhorror.com/the-spinster-s-library

Welcome to I Spit on your Podcast brought to you by the Spinsters of Horror, Jessica and Kelly. For our inaugural episode, we introduce ourselves, this wonderful and brand new project, and discuss the origins of women in horror. Enjoy and welcome to our dark side... Intro Music: Robeast by Dance with the Dead Artwork by: Jess Hrycyk Editing work by Jessica and Blair McDonald. Research Resources can be found at https://www.spinstersofhorror.com/the-spinster-s-library

Welcome to episode #1! I give you a quick run-down of why I think this podcast is necessary. You’ll also get 4 resources to use when you’re doing your own fitness and nutrition research, and 8 questions to ask yourself to evaluate said research.

This week, we're chewing into M.T. Anderson’s Feed, in perhaps our most harrowing future yet because WE ARE SO CLOSE TO LIVING IT. Foregoing personal updates in favor of exploring and rectifying Caitlin’s total lack of understanding about video games and Bridget’s affection for Spyro, we then delve deep into the meat of Anderson’s richly developed world. Only we almost immediately get distracted by other books we’ve read and tales of schoolday horrors from yesteryear. This one is a forest of tangents, guys, but I promise we cover the best of the book under that ol’ canopy. Plus, a more robust definition of our weekly sweetie and a deep dive into integrated tech in the research section. Join us, won’t you?   Research Resources: https://www.npr.org/programs/invisibilia/385792677/our-computers-ourselves https://www.nbcnews.com/think/amp/ncna816886 https://techcrunch.com/2017/09/08/meet-the-tech-company-that-wants-to-make-you-even-more-addicted-to-your-phone/ https://www.1843magazine.com/features/the-scientists-who-make-apps-addictive

Dr. James O. Hill is a Professor of Pediatrics & Medicine, and Director of the Colorado Nutrition Obesity Research Center. Dr. Hill’s research examines factors that contribute to obesity and factors that are important in reducing obesity. He is a co-founder of the National Weight Control Registry and co-author of the book State of Slim: Fix Your Metabolism and Drop 20 Pounds in 8 Weeks on the Colorado Diet. Dr. Hill shares his insight and learnings from his work, along with the newly published research study: The Beef WISE Study: Beef’s Role in Weight Improvement, Satisfaction, and Energy. This research was conducted at the University of Colorado and adds to the growing body of evidence demonstrating lean beef can contribute to a healthy weight loss diet. Funding for this research was provided by a grant from the National Heart, Lung and Blood Institute, the National Center for Research Resources and the National Institute of Diabetes and Digestive and Kidney Diseases, Colorado Nutrition Obesity Research Center, and the Beef Checkoff. For the full show notes and resources visit www.SoundBitesRD.com

Many students come to us looking for a “rah rah” environment in their college—or convinced that a sports culture will negatively impact their college experience. We'll be discussing the impact of sports on campus culture, including how to determine if a school has it. In other segments, it's time for this year's group of seniors to make some final decisions about the college they will attend next year. For many (most?), one major factor in this process will be cost. In this week's Office Hours, we're looking at how to include finances in your decision making process. Your future self will thank you! Finally, we'll recommend some resources for researching answers to your college admissions questions.

Many students come to us looking for a “rah rah” environment in their college—or convinced that a sports culture will negatively impact their college experience. We'll be discussing the impact of sports on campus culture, including how to determine if a school has it. In other segments, it's time for this year's group of seniors to make some final decisions about the college they will attend next year. For many (most?), one major factor in this process will be cost. In this week's Office Hours, we're looking at how to include finances in your decision making process. Your future self will thank you! Finally, we'll recommend some resources for researching answers to your college admissions questions.

[intro music] Host – Dan Keller Hello, and welcome to Episode Sixty-One of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller. In this podcast, Dr. Yanming Wang of Case Western Reserve University in Cleveland, Ohio, discusses a solution to the vexing problem of how to track changes in myelin in the brain and spinal cord, a measurement believed to be especially important for new candidate drugs to restore this insulating sheathing around axons. First, here are some new items in the MS Discovery Forum. A new data visualization showcases the collaborations among authors who published papers reporting the results of clinical trials in progressive forms of multiple sclerosis in the last 30 years. You can find the network map on msdiscovery.org under “Research Resources.” You can mouse over circles in the graphic to find researchers' names. Click and drag the circles to animate the map and reveal connections. In research news, a Swedish team took the first steps toward finding potential disease markers in the immune cells of asymptomatic people with MS and with seasonal allergies. The study pinpointed three key proteins that may transform normally protective T cells into ones that attack myelin in the case of MS. The three proteins are transcription factors, which glom on to DNA and control which genes turn on and off. According to data from genome studies, the proteins are more common in genetic regions associated with disease, strengthening the case for their role in MS. Finally, the three proteins act differently in people with immune-related diseases, including multiple sclerosis, according to tests on blood samples. Ultimately, the researchers want to learn if they can detect multiple sclerosis and other autoimmune conditions much earlier. [transition music] And now to our interview. MSDF caught up with Dr. Yanming Wang last month at the 2015 World Congress of Neurology meeting in Santiago, Chile. We discussed his solution to what has been a missing link in MS research and practice; that is, how to image myelin -- not just lesions on an MRI, but how to tag the substance itself using a biomarker for molecular imaging called M-E-D-A-S, or "mee-das." Going beyond diagnosis, Dr. Wang told us it may eventually allow clinicians to get a better handle on disease progression and efficacy of treatments. Interviewer – Dan Keller You had referred to molecular imaging of myelin as the missing link. Why is this the missing link? Interviewee – Yanming Wang Because molecular imaging has really transformed how we practice medicine today, and it has become a standard care for virtually many neurological diseases. However, in multiple sclerosis, there's still no effective imaging technique in place that can help physicians to monitor not just for diagnosis, but also to monitor the disease progression. MSDF And would this be useful also in monitoring potential therapies? Dr. Wang Exactly. There's a lack of imaging technique that allow people to monitor the drug efficacy, particularly for those drugs that try to repair the myelin damage in the CNS. MSDF How would this differ from MRI imaging, what you see there, versus having a radioactive biomarker? Dr. Wang Currently, MRI is the commonly used imaging modality in MS, however MRI provides only anatomical information and also detect brain lesions. However, those lesions detected on MRI are not specific for myelin pathology. MSDF You do have a compound now, [11C]MeDAS, which would be specific for myelin. Is that right, is it very specific for myelin? Dr. Wang Exactly. It's very specific for myelin, because the advantage it has over MRI is that that is truly a molecular imaging modality which uses myelin-specific radiotracers that allow to quantitatively monitor the myelin damage and myelin distribution in the brain. So for this reason, we developed a specific radiotracer that can selectively bind to myelin with high affinity, so that we could directly image the myelin distribution. MSDF How quickly does it reach the CNS and you can image? Dr. Wang It takes minutes, literally, for the radiotracer to penetrate the BBB and enter the brain, and then the whole process takes only 60 minutes. MSDF Can you briefly describe your rat model where you're using lysolecithin as an MS model, and then what you did with your marker? Dr. Wang Lysolecithin model is an established model of focal demyelination in the brain, so we used that model to test our compounds to monitor the demyelination and remyelination. So after injection of MeDAS, the compounds could readily enter the brain and selectively bind to the myelin. And then at the peak of the disease, which is a peak of the demyelination, the brain uptake of the compounds is lowest, versus when the brain is recovered, then the brain uptake of the compounds is increased. So this demonstrated the in vivo specificity of the radiotracer for myelin. MSDF And you can image myelin on the way down and on the way up; you have this hepatocyte growth factor which causes some remyelination? Dr. Wang Right, exactly. In collaboration with my colleague, Bob Miller. So we'd use this imaging modality to see if we can monitor the drug efficacy for remyelination. So we'd give this HGF, which is a growth factor that promotes remyelination, and then we could use this imaging technique just to monitor the increase of remyelination after the drug treatment. MSDF Everything right now is in animals. Do you have plans for any human trials? Dr. Wang Yes, we are working on this paperwork required by FDA to put these compounds in humans. MSDF Is the compound so far nontoxic; it's diamino stilbene, is that right? Does it have any estrogenic effects or other toxic effects? Dr. Wang No. We have done systematic toxicity studies and there's any adverse effects in animal models so far. MSDF What do you see as the clinical utility of this if it enters the human realm? Dr. Wang It's going to be a very powerful tool for diagnosis and prognosis, and also particularly for evaluation of drug efficacy. As you know, currently pharmaceutical companies and academic investigators are all trying to develop new drugs that can repair myelin damage in order to restore the biological functions. However, there's a lack of imaging tools in place that allow them to monitor such myelin repair therapies, and this could provide the missing link for this endeavor. MSDF Does PET imaging with this compound correlate at all with what's seen on MRI, especially in a kinetic sense following time course? Dr. Wang Well, yes. In the wonderful publication in Annual Neurology a couple years ago, we did demonstrate that this PET imaging technique can be used as an imaging marker that correlates with the disease progression in terms of the severity of the symptoms in animal models, in the EAE models. The EAE rat, for example, its appearance, the relapsing or remitting stage, and that we could use this imaging marker to correlate nicely with the symptoms. And this is one of important application if we put this into clinical use. MSDF Is this compound the end-all and be-all, or are you developing others, or have some gone by the wayside for various reasons? Dr. Wang This compound, and also this imaging technique, could be used not just only in MS, but can also be used in many other neurological diseases, such as Alzheimer's disease, spinal cord injury, and stroke, for example, because all of these neurological diseases are associated to some degree with the myelin damage. MSDF Have we missed anything important, anything to add? Dr. Wang Again, I think the imaging technique, particularly molecular imaging technique based on positron emission tomography, is lagged behind in the field of neurological diseases because of the complexities of the brain and the lack of molecular probes that could advance our understanding, also facilitate the drug discovery. MSDF I appreciate it. Thank you. Dr. Wang Oh, thank you very much then. [transition music] MSDF Thank you for listening to Episode Sixty-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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit 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 editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller. [outro music]

[intro music]Host – Dan KellerHello, and welcome to Episode Fifty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.This week’s podcast features Dr. Jonathan Kipnis, who discusses his recent discovery of lymphatic vessels in the meninges. But first, here are some new items in the MS Discovery Forum.According to our curated list of the latest scientific articles related to MS, 34 such articles were published between August 21st and 28th. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This week, we’ve added 6 pieces of information about alemtuzumab and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.The MSDF team is looking forward to attending next month’s ECTRIMS meeting in Barcelona, Spain. If you, too, will be at the conference and would like to meet with us – or if you’re interested in being interviewed about your research for a future podcast – please email us at editor@msdiscovery.org.[transition music]And now to Part 1 of our interview with Dr. Jonathan Kipnis, Professor of Neuroscience and Director of the Center for Brain Immunology and Glia at the University of Virginia in Charlottesville. His group recently published in Nature their discovery and characterization of lymphatic vessels in the meninges. Interviewer – Dan KellerYou've described in this paper about meningeal lymphatics, the novel but actually more conventional path for cerebrospinal fluid drainage from the CNS than I guess had been thought of before; it's sort of conventional as revolutionary. Can you tell me what you found and what led you to look?Interviewee – Jonathan KipnisYes, so we've been interested in the role of meningeal immune system for quite some time, and we've shown that changes in meningeal immunity could impact brain after a CNS injury, or also for normal brain function. So, for example, mice that have impaired meningeal immunity would show cognitive deficits and would show some little bit more prone to stress and other phenotypes. So we've been very interested in understanding how meningeal immunity is being regulated. So the assumption was at some point that there is no immune cells in the brain, which is true, except for microglial which reside in the brain and compose 10% of the brain cells, but there is no peripheral immune cells within the brain. But in very nearby areas, which is the surroundings of the brain – the choroid plexus, the meninges, and the CSF – that's where actually there are immune cells, and there are all types of immune cells. And so we have been very interested to understand how the cells are getting in and getting out. Through the use of parabiotic mice, we demonstrated last year, we showed that immune population of the meninges is not static; the cells are being repopulated, and about 50% of T cells, for example, is being exchanged within about 10 days, and major exchange between the CSF or the meninges with the deep cervical lymph nodes. So nothing was really new, we just sort of established things maybe more solid way. Those cells can get in while still nobody understands very well how they get in; we'll assume they get in through the meningeal vasculature, which is probably true. But then how do they get out, or what happens with cells after they get to the CNS? Well, the assumptions were, well, they either die, magically disappear, or crawl under the nose through the cribriform plate and into the deep cervical lymph nodes through the nasal mucosa. They were okay explanations, but in our systems we did not find any of it to be sufficiently explaining what's going on in this really fast and pretty dramatic exchange of the immune system within the meningeal spaces. So when we just looking at it a bit closer, and it is very, very well established that there is lymphatic drainage from the CNS, so this needs to be remembered. So people in many labs have shown that if you put stuff in the brain – which stuff I mean proteins – if you put proteins or antigens in the brain, whether it's in the parenchyma or in the meninges or in the CSF, you will find those proteins, and you will find immune response to these proteins in the deep cervical lymph nodes.The question is, of course, how do they get there? And the path which was described just did not work in our hands, and so I was lucky to get a very, very talented postdoc, Antoine Louveau, at the lab. He realized that for us to understand how things get in and out, the only way to do it is to do live imaging and also to do a whole mount of the entire meninges. And I think that's when it was a breakthrough point. So Antoine laid out the entire meninges and was looking for location of the immune cells. And he said let's see where I see maximum accumulation of the immune cells, and then let's see how these places will change when we expose mouse to, for example, stress, learning, or EAE inflammation, viral infection, or whatever, let's see how these areas of dense immune population will change. And so he realized that there is a lot of immune activity around the major sinuses in the meninges, and then he saw that there are immune cells which are in the vascular structures which were not blood vessels. And I think that was the turning point. And I said, okay, if the cells are within the vasculature which is not blood vasculature, what would it be? Well, so I went to colleagues here and said what do you label lymphatic vessels with? And they didn't understand why would you want to label for lymphatic vessels, because they don't work with the brain. And so we labeled a lymphatic marker and we saw the vessels, which were lining the major sinuses and going all the way along them. So that's a very long answer to your very simple question.MSDFAnd Antoine Louveau's technique here that was the key to it was doing in situ fixation so he could get the meninges out intact?Dr. KipnisTo let's assume the meninges came out intact on the brain, and let's assume we had this beautiful staining. Let's say we did the coronal staining, and let's say we're labeling for lymphatic vessels. So you can imagine that what you'll see is at the border of the brain you will see a dot; you will see maybe three dots because there are three vessels going along the sinuses. And when you see a dot, you never take a dot seriously in immunohistochemistry. Now that we know that this dot represents the vessel, then we can actually go back and do those coronal sections and look at it. But back then only by seeing the whole meninges mounted as one on a slide, and by seeing those vessels there, I mean that's when we knew. And so to us it was obvious this is something that absolutely went under-noticed. And this technique of whole-mount meninges, I think, was absolutely crucial. MSDFDid he find these vessels in all layers of the meninges, or any specific ones?Dr. KipnisNo, no. Major lymphatic vessels are following the superior sagittal and the transverse sinuses, which is in the dura. So all the blood from the brain is being – at least in mice. In humans it goes a little bit different, but also through the sinuses, although sinuses are located so not all the blood in the human brain goes through the parasagittal sinus, but in the mouse brain all the blood goes through the sinuses in the dura. So major sinuses through which all the blood is being collected from the brain, and then goes out there. And so along those sinuses we find the lymphatic vessels, so they are sitting in the dura. MSDFAnd this system also has been found in humans?Dr. KipnisWell, that's a good question. You know, it's very hard to obtain high-quality human samples from the dura, because nobody really cares about this area. So we were lucky in the triple operation of Bea Lopes, who's a really great neuropathologist here at UV; she was able to give us, I think, nine samples from patients of dura of the sinus; these were all fixed in formalin. So we looked at those, and as you can imagine, the sinus in the human is huge, so obviously compared to a mouse. So in two out of nine, we were able to identify vessels that looked like meningeal vessels, but I think it warrants much deeper and much farther investigation to be able to say, yes, here they are. But if you ask me personally, why wouldn't they be? Why would mice have them and humans won't have them. So I think it's a matter of identifying their location and the best markers to use for them, but I think they should be there again. In two out of the nine samples, we were able to demonstrate that this is something that looks very, very good. MSDFAnd you did immunohistochemistry on these to show the lymphatic properties and not general blood circulatory vasculature properties, either in the mice or human?Dr. KipnisOh, yes. So in the mice we identified the characteristics of those vessels really, really well. You know, nothing is perfect, that every marker on mouse markers are expressed by different cells, so you need here to provide a series of markers and to demonstrate that this is also indeed the real lymphatic cells. So we stained for LYVE1 and we showed beautiful staining with LYVE1, also with macrophages. And those are vascular structures and they came out to be macrophages. But one of the major transcription factors that will define lymphatic and endothelial cells is a Prox1. So we demonstrated two ways of Prox1; one is transgenic mouse and the other is staining for Prox1. And we also did two other molecules. One is a Podoplanin which is expressed in tissue lymphatics, and these vessels are expressive. And the other molecule, she is very interesting. It's a receptor for VEGF3, VEGF-C. And this receptor is first on the lymphatic and endothelial cells. In the periphery, lymphatic and endothelial cells will respond to recombinant VEGF-C and will expand. So what we did here, we also injected a recombinant VEGF-C and we showed these vessels expanding. So we know now that the receptor is actually functional in the vessels, but also we now can expand the vessels. Whether it will impact any neurological disease, we don't know, but at least we have the capability to do so. And then we also identified them by flow cytometry. We took samples from skin and from diaphragm where lymphatics are very, very well defined, and using the exact same antibodies we did also flow cytometry on our meningeal samples. And we show that the cells look exactly like they look from the skin and from the diaphragm; of course, the numbers are much smaller. So I think in terms of their calculation in a mouse, we are very convinced.Now for humans it's more difficult. Like I said, the sample was in formalin and it's very hard to work with those samples, and, again, the area is huge to go through. So we were able in humans to get two markers to work; one was LYVE1 and the other was Podoplanin. We could not make Prox1 to work, I think it's a problem with the antibody and not with the vessel or potentially with the tissue as well. And these vessels would not label for some other markers, which would be characteristic of, for example, macrophages. So we were able to attack on them two out of four markers that would potentially allow for him to see. But we are now trying to identify those vessels by other means in humans as well, and I think flow cytometry may be the way to go. MSDFNow you've shown that these lymphatic vessels drain into the deep cervical lymph nodes, and it looks like you've also been able to rule out drainage through the cribriform plate back into the cervical lymph nodes. Is that true? Dr. KipnisI'm glad you bring this up, this is very important. So if you think of CSF, CSF is composed of several things. So we have the liquid itself, we have the macromolecules within the CSF, and then we have the immune cells within the CSF. So I don't think there is anybody would argue against liquid being drained through the cribriform plate and through the granulation; this is funny to argue. And obviously we are not claiming anything until we're absolutely sure; there is beautiful works from many, many labs showing that. But for the macromolecules and for the immune cells, the path which was proposed through the cribriform plate most probably if it's not a wrong one, it's probably not the major one. [transition music]Thank you for listening to Episode Fifty-Three 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. 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 editor@msdiscovery.org.[outro music]

[intro music]Host – Dan Keller Hello, and welcome to Episode Fifty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.This week’s podcast features Dr. David Tabby, who discusses the incidence of headache in MS. But first, here are some new items in the MS Discovery Forum.According to our curated list of the latest scientific articles related to MS, 53 such articles were published between August 14 and 21. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers. We’ve made some recent updates to our Funding Opportunities and our Meetings and Events listings, both of which can be found under our Professional Resources tab. Be sure to take a look at a newly-posted funding announcement entitled, “National MS Society: Health Care Delivery and Policy Research Contracts.” If you know of any meetings, events, or funding opportunities that are missing from our lists, please email us at editor@msdiscovery.org so that we can include them. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week, we’ve added one new trial and 15 other pieces of information. The drugs with important additions are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and ofatumumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline. [transition music]And now to the interview. Dr. David Tabby is an adult general practice neurologist, with a subspecialty in multiple sclerosis, in Bala Cynwyd, Pennsylvania. He was formerly associated with Drexel University College of Medicine in Philadelphia where he carried out the study on headache and MS that we discussed.Interviewer – Dan Keller Could you just tell me what the aim was? I think you were looking the variables affecting headache occurrence in MS patients.Interviewee – David Tabby Well, to be perfectly frank about that, my business manager had noted that many of my MS patients also had migraine, and she asked what’s going on with that. So we did a cursory review and found that close to 50% of my MS patients also had migraine. So that prompted the survey in a more formal fashion.MSDFWhom did you look at, and what were some of the variables you looked at?Dr. TabbyWell, we looked at everyone who was willing to answer a survey. And we wanted to include some typical migraine variables like frequency and intensity and triggers and age of onset and duration at that time and which came first, MS or migraine.MSDFAnd what were some of the major findings?Dr. TabbyI think our biggest contribution was that it seemed that we could correlate exacerbations with increase in headache, which I don’t think was known before that. Sometimes headache a little bit before the exacerbation, and sometimes exacerbation first, then with headache. But that raised the question about the role of inflammation in both headache and MS exacerbations. You know, I don’t think one is the cause of the other, but they’re clearly related.MSDFWhat about migraine with aura or without? Are there differences in the MS presentations or symptoms or relations in time?Dr. TabbyWe didn’t have a lot of migraine with aura patients. That’s only about 20% of the migraine population anyway. We didn’t have a big enough number to make any kind of association that would be distinguishing migraine with or the migraine without aura.MSDFDo you have a proposed mechanism in mind how these two may be linked – mechanism of migraine, mechanism of MS?Dr. TabbyI don’t think there’s a lot of work about what the immune system’s role is in migraine, but stress affects the immune system. My patients tell me that a particularly stressful event can seem to precipitate an exacerbation, and, no big secret, that stress can precipitate a migraine.MSDFFatigue can be a trigger, and obviously, that’s a large proportion of MS patients have it. So do you think there may be a link there, one triggering the other?Dr. Tabby90% of MS patients will complain of fatigue at some point, and I think that’s clearly got something to do with it. So anyone with migraine will tell you that when they overdo it and get overtired, they get a migraine.Interviewer – Dan KellerI think I saw something in the paper was talking about metalloproteinases in the CNS and leakiness of vessels and allowing either antigens out or T cells in. Does that have any legs or where does that idea come from?Dr. TabbyThat idea came from a paper that we found in our literature review of the basic pathophysiology of an MS exacerbation that matrix metalloproteinases have to be activated first, to increase vascular permeability of the CNS. Migraine was thought, at one time, to be a primarily vascular issue. It’s not. It’s primarily a neurochemical issue that affects the vasculature, but results in dramatic changes in blood vessel permeability. There’s a kind of leakage of fluid around blood vessels, which helps make them more sensitive.MSDFThere’s also a component of calcium flux in migraine. Would that have any effect on the immune system? There’s calcineurin inhibitors that are immunosuppressants, so I’m wondering if calcium in itself – could be an imbalance be a stimulant?Dr. TabbyThe role of calcium in modulating neural function can’t be overstated. I’m not ready to give you an exact mechanism of how that might function.MSDFPatients with migraine supposedly have more symptomatic clinical course of MS. Do you have any numbers there? What did you find?Dr. TabbyWe weren’t a longitudinal study. We’re really just a snapshot kind of picture to determine, you know, a relationship now. That was another one of our hypotheses that the worse headache you had the worse MS you were going to have. Our take-home message from the paper was MS doctors should be very aggressive about addressing migraine symptoms in their patients, because we think that it could have an effect in long-term prognosis in MS. And it’s not just the patient complaining about, oh, I have a really bad headache. There is a relationship. It’s been known for many years. I mean, you might have seen in our bibliography that some of the papers went back to the 1960s about the relationship with headache and MS. So, just to reiterate, migraine prophylactic therapy, migraine abortive therapy is important in the context of treating MS.MSDFCan pre-existing migraine before the MS diagnosis give you any clue as to being a risk factor in itself?Dr. TabbyThat’s an excellent point. We didn’t have a big enough group to come to that conclusion, but 12% of Americans have migraine – 18% of women, 6% of men. Less than 1% of the population has MS. Something else has to be happening.MSDFAlso, I guess you found that people with stabbing pain had more acute MS exacerbations than if they had other more throbbing kinds of pain.Dr. TabbyWell, we were just using that as an indicator of severity of the headache. Stabbing’s not a typical word used to describe migraine. We gave choices. We just didn’t leave it open-ended. We gave some example words for their responses to the survey to tick off. Yes, stabbing was one of them, and there was a correlation between the ones who said stabbing and worse exacerbation.MSDFSome of the patients you surveyed did not have pre-existing migraine, only after their MS diagnosis. Do you think that migraine is something that one should investigate whether they actually may be in a prodrome of MS, if they present late - develop migraine late in life – later in life?Dr. TabbyIn our world, pretty much everyone with a bad headache who sees a doctor about it, at some point is going to get some sort of imaging study of the brain. It might be a CAT scan, in which case there might not be enough information. But if it’s an MRI, there’s a good chance of seeing high-signal lesions scattered through the white matter. They may be real small and not particularly typical of MS. But not uncommonly, they’ll see a pattern that looks really quite like MS. And you examine the patient, and you don’t find anything that’s consistent with MS. You do a history, and you don’t find any symptoms that are consistent with MS. So this is the sort of thing you just file away and see what happens. I don’t think anyone would suggest that treatment for MS should be started at that point. There’s an entity that’s finally gotten a name, called radiologically isolated syndrome, which people get MRIs of their brain for some reason – head trauma, headache, anything really – and the pattern looks really quite like MS, but there’s no clinical support of MS. So same thing; we don’t forget about these people. You recheck their MRIs at some point in the future. You look for new lesions or enhancing lesions. I think the latest statistic is somewhere around 50% of them are eventually going to present as having multiple sclerosis.MSDFWould each entity be treated or each condition be treated as if it existed in isolation? Or do they complicate the management of the other?Dr. TabbyMy approach has been to treat them independently. Just follow the basic principles of headache treatment for the headache and the basic principles for MS treatment and adjustments of therapy and symptomatic therapy for MS. I would not suggest some interlinked therapy system.MSDFBut something like interferon and possibly other drugs may cause exacerbation of headache. Would that lead to noncompliance of the MS treatment or would you switch drugs or how do you handle that?Dr. TabbyThat doesn’t necessarily involve the headache issue. I think someone who has bad headaches on interferon who’s not taking their medicine, you know, you might try to fix it – fix the headache that is. But you’re probably fighting an uphill battle when that patient has negative associations with taking their medicine. I still tend to think of these two things as related but separate.MSDFSo what’s the big take-home message for a physician?Dr. TabbyReally just about treating migraine aggressively in their MS patients, and keeping in mind that we work very hard to preserve function to reduce the accumulation of disability, with drugs and other sorts of interventions. But intervening for migraine may be just one other way to reduce the burden of disability in the future, for your patients.[transition music]MSDFThank you for listening to Episode Fifty-Two 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. 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 editor@msdiscovery.org. [outro music]

[intro music] Host – Dan Keller Hello, and welcome to Episode Fifty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features Dr. Luke Lairson of Scripps Research Institute, who discusses discovery of small molecules to induce remyelination and, in particular, some muscarinic receptor antagonists currently approved for other indications. But first, here are some new items in the MS Discovery Forum. According to our curated list of the latest scientific articles related to MS, 114 such articles were published in the first two weeks of August. We selected a few of these articles as our Editor’s Picks. One is a longitudinal study of gray matter lesions and cortical atrophy in MS published in PLOS ONE. The investigators obtained MRIs at baseline and five years later from subjects with clinically isolated syndrome, early and late relapsing-remitting MS, and secondary progressive MS, and examined lesion placement and cortical thinning in the different disease subtypes. To see this publication and the other articles we selected, go to msdiscovery.org and click on Papers. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 1 new trial, we updated information on 2 other trials, and we added 12 other pieces of information. The drugs with important additions and changes are ATX-MS-1467, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, and interferon beta-1b. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline. [transition music] And now to the interview. Dr. Luke Lairson is an assistant professor at the Scripps Research Institute and a principal investigator at Calibr, the California Institute for Biomedical Research, in La Jolla. We spoke at the research institute. Interviewer – Dan Keller Dr. Lairson, we're talking about the potential for remyelination. And your institution is taking a very systematic and maybe novel approach. Can you describe how you're going about looking at possible ways to induce remyelination? Interviewee – Luke Lairson Sure. So we're using a phenotypic assays to look for small molecules that selectively induce the differentiation of the precursor cell population which is required for remyelination, which are the so called oligodendrocyte precursor cells or OPCs. We developed imaging-based assays where we could look for small molecules that selectively induce that differentiation phenotype. MSDF And how are you going about screening compounds, and what is your institute set up to do? Dr. Lairson So at Scripps and Calibr we have the capacity to screen on a million compound scale capacity to look at molecules. In this particular assay, we do it in a 3D four-well format, which limits us to screening collections on the scale of hundreds of thousands. And to date, we've screened about 200,000 compounds with this assay. MSDF In terms of multiple sclerosis, what are you looking at now? Dr. Lairson From our preliminary screen of our collection of bioactive compounds, including FDA-approved drugs and drugs in late-stage clinical development, we identified a series of compounds for which OPC differentiation had not been previously reported, which are muscarinic receptor antagonists, which are clinically approved drugs and which work in the central nervous system. And we demonstrated a number of these compounds work in two different rodent models of remyelination in MS. And we're currently developing these as a lead class of compounds as a combination therapy when combined with existing immunosuppressant drugs, including Gilenya. MSDF What compounds have you focused on most? There's a multitude of approved antimuscarinic agents. Dr. Lairson Right. So this is actually a a critical point. So we identified a number of compounds which had antimuscarinic activity, which were active in our OPC differentiation assay. We used pharmacology to demonstrate that the antagonism of M1 or M3 receptor subtype is a required component of the mechanism of these drugs. However, we think that there's a second target, and it's a dual mechanism action through which these drugs are acting, which we're currently trying to elucidate what that second target is to fully characterize the mechanism. That second target actually provides the opportunity to identify compounds that have a potential to have a better therapeutic index in vivo. So the lead compound we published was benztropine. Jonah Chan's lab at UCSF later showed that clemastine also works, which was in our paper, as well. So these are drugs that have been demonstrated to work in vivo. What we did after we published that is we then looked at every compound that we could get our hands on that had antimuscarinic activity – specifically targeting M1/M3 receptor subtypes – and then characterized their activity in the OPC differentiation assay and, as well as profiling their potency on the M1/M3 receptor subtypes, with the goal of looking for compounds that have an optimal therapeutic index in terms of on-target toxicity. So benztropine induces OPC differentiation in the low micromolar range, but it antagonizes M1 and M3 receptors in the low nanomolar range so there's a discrepancy there. And we think that the on-target toxicity of antimuscarinic activity is going to limit the therapeutic potential of these drugs. We've since identified other FDA-approved drugs for which that index is improved and we compounds with approximately 100-fold improvement in therapeutic index, which we've demonstrated in the EAE model are active. And we're currently evaluating them in combination with immunosuppressant drugs to identify an optimal combination, which could well be benztropine or clemastine but may be another FDA-approved drug. MSDF You're at very early stage in terms of clinical utility of these things in MS. But is there any way to separate out the negative antimuscarinic effects that affect people taking drugs for overactive bladder and various other things from their therapeutic effect? Or is it really intrinsic to attacking that receptor? Dr. Lairson That's the key point. So we do think that it's that on-target toxicity which is going to potentially limit this class of compound, which is why we're looking for these other compounds and where we have an improved therapeutic index of inducing remyelination versus antagonizing those receptor subtypes. And likely this class of drugs – and any class of drugs that induces remyelination – is going to have to be used in combination with immunosuppressant drugs. It will require a careful clinical evaluation to figure out which combination will be the most effective and what doses will be safe. MSDF But you also have been doing T-cell assays I take it in looking at benztropine in your work. So what goes on with immune modulation? Is there any effect there? Dr. Lairson So we did extensive studies with benztropine to evaluate its activity in not just T-cell biology but also macrophage biology both in vitro and in vivo. And we found benztropine had no affect on in vitro or in vivo T cell numbers or activity in terms of cytokine production. It has no affect on macrophage polarization in vitro or in vivo, including looking at spinal cords of animals. We don't think that it's acting through a peripheral immune system effect. We can't rule out an important concept that came out at a recent meeting was we need to look at the affect of these compounds on microglial cell activation in the brain and also in astrocyte activation. MSDF So it looks like it's a pure remyelination effect at this point and not really an immunosuppressive effect, which would argue for having to use it in conjunction with today's drugs for MS. Dr. Lairson Correct, that's our current reasoning, yeah. MSDF Have you looked at other models other than cuprizone? Dr. Lairson Yeah, we looked at the EAE…PLP-induced EAE model of relapsing-remitting MS, and we've looked at the MOG model of progressive MS and the cuprizone model. Yeah, those are the models we've looked at to date. MSDF With similar results? Dr. Lairson The compounds we've evaluated have all been active in in those models. MSDF Do you have an idea of the mechanism of action how this is actually working in the oligodendrocyte precursor cells? Dr. Lairson Downstream of the muscarinic receptor…so as I said, based on pharmacology, these classes of compounds – these neurotransmitter receptor modulating agents – are notoriously pleiotropic in that they had multiple receptor subtypes in the brain. So benztropine, for example, it hits nicotine and histamine receptors in this dopamine reuptake inhibitor in addition to being an antimuscarinic. We've shown that those activities are not responsible for inducing OPC differentiation. However, as I said, we've identified multiple compounds that do inhibit muscarinic receptors – specifically receptor subtypes 1 and 3 – that do not induce OPC differentiation. So we think there's a second target; we're actively trying to identify what that second target and downstream mechanism is. MSDF Do you think the same compound would attack both targets, or are you going to need to give multiple compounds to hit multiple targets very selectively as I would think would be the hope? Dr. Lairson The existing compounds we have the argument is that they are hitting both of these targets to induce the differentiation. In that, there's a number of compounds that do hit the M1/M3 receptors that do not induce differentiation, which argue that you need both. The compounds we've identified fortuitously hit both of the necessary targets. MSDF In the antimuscarinic field, often the goal is to be very selective and limit activity at different receptors, but it sounds like you want some overlap here. Dr. Lairson Exactly. We've also initiated some medicinal chemistry where we're trying to see if we can dial in potency for the second target. So we know if benztropine is active on muscarinic and low nanomolar can we improve its potency in the OPC assay by dialing in potency on that second target? MSDF By modifying the molecule? Dr. Lairson Yeah, so making analogs of existing active antimuscarinic agents and then evaluating their activity in the OPC differentiation assay, as well as evaluate their antimuscarinic activity. MSDF Are you hoping that the same active part of the molecule hits both receptors, or have you ever considered making a bifunctional molecule that would be best at both receptors? Dr. Lairson If we knew what the other receptor was, we could potentially address that, or you could argue a bifunctional versus having two unique compounds so it would be you'd have to evaluate that in vivo I think, yeah. The other argument for moving away from this is that as soon as you make a change to that compound it's no longer an approved drug, and you have to go through the rigor of bringing that to the clinic. MSDF Now in your screening, you're using a lot of drugs – a lot of compounds at this point – that have already passed phase 1 screening or phase 1 clinical testing, and this has shown safety. Does that speed up do you think the approval process if these things look active? Dr. Lairson It does. So UCSF has actually initiated a phase 2 trial to evaluate clemastine in MS. So they were able to immediately proceed from a screening result to a clinical trial because it's an approved drug. MSDF And just about Calibr, your institute. You have full facilities for taking this from screening up to what stage? Dr. Lairson Up to the rodent proof of concept stage. So we have a high throughput screening facility, as I mentioned, and then we have a medicinal chemistry group, a pharmacology group where we can do pharmacokinetics in-house and then in core biology. So we take it to the rodent proof of concept. MSDF Do you do any synthetic chemistry, or this is all screening of existing molecules? Dr. Lairson Yeah, we do significant amount of synthetic chemistry so we have a group of 20 chemists – medicinal chemists – that are making analogs. And we do a significant amount of contract research to get compounds and analogs made. MSDF What have we missed, or what do you think is important to add, if anything? Dr. Lairson The other aspect of our program is we've identified novel compounds for which their mechanism of action is unclear. So we've identified multiple scaffolds. We've focused on three of those, which have been subjected to medicinal chemistry optimization. So we identified screening hits, which we were unable to evaluate in the rodent models due to their pharmacokinetic property. But we've now identified analogs of those compounds which are potent in the OPC assay, in which we can achieve reasonable levels in the brain. So we're currently evaluating those in these preclinical rodent models. And once we demonstrate efficacy there, we'll then go and evaluate their mechanism of action. MSDF You test these compounds first in a phenotypic sense to see if they actually do something that you want done. And then you trace it back to mechanism of action? Dr. Lairson Correct. That's our general approach for a lot of assays. So rather than looking at a validated, biochemical target, typically we'll just look for small molecules that induce the cell fate decision that we're interested in. For me, personally, it's the most interesting part of the project is I’m figuring out how those compounds that we rule out known mechanisms how they're actually acting. So we do the mass spec-based proteomics to figure out the specific protein target. And then we use standard cellular molecular biology techniques to elucidate the downstream mechanism of action. MSDF So I suppose the phenotype you're looking for in the case of this research we've been discussing is remyelination. How do you look for that activity? Dr. Lairson The remyelination activity in vitro? We use a co-culture assay, which we collaborate with Rusty Gage at Salk where we pre-differentiate neurons in a dish and then co-culture with our oligodendrocyte precursors plus or minus drug and then look at the ability of those drugs to enhance the rate of myelination of co-cultured axons. MSDF And you just stain the cells in vitro looking for myelin production or myelin basic protein? Dr. Lairson Exactly, yeah. So we just look at myelin basic protein co-localization with axon. MSDF Very good. I appreciate it, thanks. Dr. Lairson Absolutely. Thanks very much for your interest. [transition music] MSDF Thank you for listening to Episode Fifty-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. 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 editor@msdiscovery.org. [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Fifty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. David Tabby, who discusses the use of balance vests in people with MS. But first here are some new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 65 such articles were published last week. We selected one of these articles as an Editor’s Pick. It’s a large case-control study in the European Journal of Clinical Investigation demonstrating that MS is associated with more than a six-fold increase in the risk of venous thromboembolism. To see this week’s articles, go to msdiscovery.org and click on Papers.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of July, we added 6 new trials, we updated information on 6 other trials, and we added 56 other pieces of information. The drugs with important additions and changes are alemtuzumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, GNbAC1, interferon beta-1a, interferon beta-1b, masitinib, natalizumab, rituximab, RPC1063, and teriflunomide. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   And now to the interview. Dr. David Tabby is an adult general practice neurologist with a subspecialty in multiple sclerosis in Bala Cynwyd, Pennsylvania. He was formerly associated with Drexel University College of Medicine. We spoke about balance vests for people with conditions that impair their balance. He first describes what the vest is.   Interviewee – David Tabby       The balance vest looks like a bulletproof vest; it's a black nylon vest that's worn over the torso like a typical vest. And it was discovered by accident, I suppose, by a physical therapist from California called Cindy Horn who was treating people with Parkinson's disease, and she was troubled by the fact that these people tended to be forward-flexed at the hip and walk like they're looking at the floor. So she wondered if she put some weights on their back, if she could tip them more upright. And she did that and it worked, but she also discovered that people had better balance. Falls is a major cause of morbidity and even mortality in Parkinson's disease, so this was big.   So the next step was that she developed a system to figure out how to maximize the weighting of the torso, consisting of perturbations – pushes really – of the shoulders forward or back or side to side, twisting the pelvis and seeing the rebound to that, and figuring out by trial and error a way of using weights to dampen those oscillations really. She worked on it for years; this process started about 15 years ago, I think, maybe more than that now. And then she realized that there were other people besides Parkinson's patients who could benefit from it. Multiple sclerosis patients turned out to be a big one, but other types of people with cerebellar disorders, and ataxias, and even peripheral neuropathy; if the problem was balance, it seemed like the balance vest could make a difference.   Interviewer – Dan Keller           What about for vestibular dysfunction, maybe those 20% of people who shaking their head doesn't fix the problem?   Dr. Tabby I don't think we have a lot of data on vestibular patients, but that's important. It's not exactly the topic of this talk, but we've had some really great results in post-concussive injury. My theory on this is that kind of everything doesn't work right after concussion, you have to think consciously about all these things that used to be automatic, including walking. And if you imagine that you only have a finite supply of mental energy to expend on different tasks, if you're expending a lot of that on balancing, there's not as much left for thinking and talking and other normal cognitive tasks. So we've seen unexpectedly some significant improvements in cognitive function from people who had concurrent balance disorders freeing up, if you will, their cognitive reserve to do what it's supposed to do instead of worry about why you're not falling over.   MSDF Is there a proposed mechanism here; is it only dampening oscillations or is there some sort of perceptual thing that it's enhancing, or how's it working?   Dr. Tabby This is not known, there are only theories at this point. I had started on a study while I was still at Drexel with the Department of Physical Therapy who had built a device for measuring sitting balance; you know, taking the entire lower extremity out of the equation. It's basically like a chair without legs on a half dome. So if you don't have a disorder, in fairly short order you can teach yourself how to sit on the chair and not fall over. It sits on a very sensitive pressure plate, and then you can measure how much deviation there is from the exact center point. Your feet are strapped so you can't move them around, and you're supposed to hold your arms over your chest, so you have your torso and head to move around. Then you try to do certain exercise. You're looking at a screen that has a big circle on it and you're supposed to roll your center of gravity forward maybe to 3 o'clock on a clock face, and 6 o'clock, and 9 o'clock, and go back to the center, and you can see how much progress you're making.   And we had started on an experiment to put the balance vest on people and see if they did better with the balance vest with the lower extremity, you know, taken out of the equation. We didn't collect enough data to make a conclusion about that. I think it's really fascinating, though, because if you carry your cell phone in your shirt pocket, doesn't that change the vector forces about your torso, but somehow we don't seem to fall over over that. Maybe it does change things but it's not big enough to notice. We need a lot of research into determining what the exact mechanism of action is for the vest, because there's a lot of question marks about it right now.   MSDF So how do they fit this vest, adjust it? How long does it take?   Dr. Tabby An experienced physical therapist can do a good fitting probably in 30 to 45 minutes, sometimes a little longer than that depending on how severe the problem is. We generally video the patient before, during, and after of some more objective confirmation of the changes. There are tests both in standing still and also walking. We would like to bring some more quantification into that process about ways to get data about walking, like a pressure plate that you walk over and times the interval between heel strikes and variability from the center line, but that's all in the future. It's been very just pragmatic right now. Patients almost always leave from their fitting session knowing that they could balance and walk much better than when they came in, and they're all anxious to get their permanent vest soon. It's accomplished with quarter pound and half pound weights, and to be honest, I don't know how to do it; I didn't get trained, so I don't know exactly all the principles involved, you know, where you put the weight, how far from the midline you put the weight. Do you put it up high on the torso, do you put it low on the torso?   MSDF So counting the weights and the vest, how much extra weight is a patient carrying around, and does that become a burden?   Dr. Tabby We don't use more than 2 lbs of weight, and then the vest itself is about 2 lbs. Now we're also working on a t-shirt or an undershirt, a close-fitting athletic-type shirt that we can incorporate the weights right into that. That's really nice because it can be worn under any clothing at all, and the complaint about it being hot won't be as relevant. It does not include a lumbar brace, as this standard brace does. A lot of patients like the brace, though, they think that that contributes somewhat to the sense of balance that they get.   MSDF For an MS patient – and I realize they vary a lot in their disability – is it fairly easy to put this on once they have it?   Dr. Tabby Some might require help. It zippers and tightens up with Velcro straps, so it takes some coordination to get it on.   MSDF Is there any residual effect? I mean, you said they have an immediate effect, but once they take it off is there any benefit or do they always have to wear it?   Dr. Tabby I'm so glad you asked that, because a lot of patients find that they can wear it intensively for two or three days and then not wear it for a day or two and still have carryover benefit. Exactly how that works, I'm not sure either, but that's what they say.   MSDF You've used this with patients. How many in your practice have been trying it?   Dr. Tabby We have over a hundred in the last five or six years.   MSDF Is there any downside?   Dr. Tabby You have to change your wardrobe. I'm kidding a little bit, but I do have a patient… You know, the vest comes in every shade of black that you want, so she changed her wardrobe to only include black so the vest doesn't look strange. You know, if you wear big, loose clothing, you could probably have it under something and it might not be obvious. You know, the fashion sense is an issue, the weight by the end of the day and the temperature.   MSDF Sounds like those are all things that can be worked out sort of cosmetically; color and different fabric eventually or something.   Dr. Tabby Yes.   MSDF Have you done any of the research on this, or you've just been using it? I see there's actually a fair bit published about it.   Dr. Tabby We have a trial that we're working out the kinks of now. We wanted to do a trial with other medications that might help with walking; I'm not sure it's going to be feasible to do that, but just accumulating other types of data that doesn't exist right now, like great systems for measuring body position and movement with small wearable sensors on the body, as well as pressure plates on the floor that you can walk along a pathway. We'd like to do more specific research in specific conditions. Of course, my interest is mainly in MS, but I know I've been able to help other patients with it. You know, it's important if this therapy is going to help more people, that there be as much published as possible that shows that this is a real phenomenon; it's worthy of patients' and physicians' attention.   [transition music]   Thank you for listening to Episode Fifty 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 editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. Hugh Rosen of the Scripps Research Institute. But first here are some new items in the MS Discovery Forum.   If you’re an MS researcher, you may want to keep an eye on our Bulletin Board section, where we post a variety of news items that may be of interest. One of the items we posted this week is directly related to Dr. Rosen’s work. It’s a notice that a phase 3 trial of a sphingosine 1-phosphate receptor modulator called RPC1063 has started recruiting twelve hundred patients with relapsing remitting MS in the US. RPC1063 had its origins in Dr. Rosen’s lab.   We also recently added a notice of another clinical trial to the Bulletin Board. That one’s a phase 2 trial of oral laquinimod in primary progressive MS. And a third new Bulletin Board announcement is a request for information from the Patient Centered Outcomes Research Institute to identify patient registries and research groups with established cohorts of patients for potential collaborative research opportunities on comparative effectiveness research in MS treatment.   To read any of these announcements, go to msdiscovery.org and click first on Professional Resources and then on Bulletin Board. And if you have an announcement you think may be of interest to MS researchers, please send it to editor@msdiscovery.org. We won’t post purely promotional press releases, but if we judge the notice to be of general interest, we’ll be happy to post it at no charge.   In other news, it was a relatively slow week in published MS research. According to our curated list of the latest scientific articles related to MS, only 22 such articles were published last week. Typically at least 40 MS-related peer-reviewed articles are published weekly, and we’ve seen some weeks with more than a hundred. To see the weekly lists going back to March 2012, go to msdiscovery.org and click on Papers.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 2 new trials and 7 other pieces of information. The drugs with important additions are dalfampridine, fingolimod, masitinib, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Hugh Rosen studies chemical and biological approaches to the molecular mechanisms regulating lymphocyte trafficking. I met with him in his office at the Scripps Research Institute in La Jolla, California.   Interviewer – Dan Keller We're talking about mostly new compounds, S1P1 receptor compounds; the prototype now I suppose is fingolimod. What's in development and do they appear to offer advantages?   Interviewee – Hugh Rosen So, firstly, let me disclose that I am a cofounder of a biotechnology company called Receptos that has licensed an S1PR1 agonist from the Scripps Research Institute, so I have and my institution have a significant interest in this particular field.   Sphingosine 1-phosphate receptors act in a number of ways to modulate immune tissue damages in both autoimmune diseases and in viral infections. They've proven to be particularly efficacious in multiple sclerosis. Gilenya, of course discovered by Yoshitomi in Japan and developed by Novartis, has proven to be a clinically useful compound in the treatment of relapsing-remitting multiple sclerosis. And it appears to do so, at least in part, by altering the ability of lymphocytes to recirculate, and thus lymphocytes to reach the target tissues where they, in fact, produce demyelinating damage to the white matter of the central nervous system, and then the signs and symptoms of multiple sclerosis. So clearly these are useful compounds.   Gilenya, of course, is not a selective small molecule, it is an agonist of four of the five high affinity receptors for sphingosine 1-phosphate – S1P1, 3, 4, and 5 – and some of the associated side effects may be attributable in part to activity of Gilenya on other receptors like the S1P3 receptor that are not required for modulation in the treatment of multiple sclerosis.   MSDF I see that it's referred to as an immunomodulator, not necessarily referred to as a receptor agonist. Does it not have pure agonist effect? Does it have any effects either because of the other receptors or at that same S1P1 receptor?   Dr. Rosen No. In fact, Gilenya when phosphorylated is a full agonist of the sphingosine 1-phosphate receptors, and the newer compounds that are much more selective are also agonists of the sphingosine 1-phosphate 1 receptor. And some of the effects on them for cyto-mediated by downmodulation of the receptor, but I don't use the term modulators or immunomodulators because of the activity on the sphingolipid receptors per se, I use the term immunomodulator because of some of the unique advantages that we've demonstrated in model systems and in man about altering the activity of the sphingosine 1 receptor, because one of the beauties of immunomodulation is to blunt the immune response that causes collateral damage to the tissues whilst leaving sufficient of the immune response intact to allow protection from opportunistic pathogens – bacteria, viruses, and yeasts.   So one of the most striking features that we found – and these have been in some experiments done as a collaboration between my laboratory and the laboratory of Professor Michael Oldstone here at Scripps – has been in the area of influenza; pandemic influenza causes significant collateral tissue damage by having an overactive immune response. What we show is that the sphingosine 1-phosphate 1 receptor blunts that immune response and blunts the amplification of cytokines and chemokines so that you protect from the collateral tissue damage, but you leave intact the ability to mount protective, sterilizing T cell and B cell immunity to the virus. So you can eradicate the virus, sterilize it, you can provide a long-term memory both on the T-lymphocyte side as well as on the antibody side; there's class switching, there's affinity maturation, there are good protective immunity that is produced, and all this while blunting the immune response.   This is the Holy Grail as we think about treating patients, because the window for patients with autoimmune diseases like multiple sclerosis is that window between effective blunting of the immune response and the prevention of deleterious opportunistic infections that can have life-threatening consequences. So one of the advantages that I suspect we will see over time is that the sphingosine 1-phosphate agonists will prove to be particularly well-tolerated and have a wide window between the ability to limit tissue damage and progression of RRMS, and the need to protect patients from intercurrent infections or subclinical infections that become expressed later.   MSDF Do the other sphingosine 1-phosphate receptors interfere with lymphocyte trafficking also, or do they have other effects which nonselective ligands would then induce these adverse effects through them, or do they also have some effect in terms of trafficking?   Dr. Rosen They don't have significant effects on lymphocyte trafficking the way that S1PR1 does, both from the chemical approaches and the genetic evidence. S1P1 is clearly a toggle switch for lymphocyte trafficking. S1P2 is involved in the maintenance of hearing and in the function of vascular smooth muscle, so it regulates blood pressure. S1P3 is involved in cardiac contractility and also in the control of coronary artery caliber and the control of the airways, so S1P3 agonism is not a useful thing, it's actually quite deleterious. S1P4 and 5 have really no rate-limiting functions, at least of which I am aware, so there may be some redundancy and may not play a critical role in the modulation of health and disease.   MSDF Do you see compounds coming along which will be more selective and therefore not lead to the adverse effects so much? And if so, are these compounds chemically similar or do they have different structures to attach to the receptor, the S1P1?   Dr. Rosen These are clearly different structures, they're structurally very distinct from Gilenya and from each other. Novartis have a backup called siponimod. Actelion had a compound but it's only being used in psoriasis called ponesimod. Receptos has a compound now known as ozanimod – formerly known as RPC1063 – that is in two phase 3 studies for relapsing-remitting multiple sclerosis, a two-year study called RADIANCE and a one-year study called SUNBEAM, both of which are enrolling twelve hundred patients each.   MSDF And the RADIANCE trial results looked pretty good; I mean, you had 85, 90% effects at 12 to 24 weeks or even at a year in terms of relapse rate. Does this look like the next compound to emerge?   Dr. Rosen I think it's likely that ozanimod will be the next compound to be submitted for the regulatory process here in the United States and probably in Europe as well. The pleasing thing about the phase 2 data for ozanimod was, in fact, both the strong efficacy signal and a very well-tolerated safety profile; in fact the adverse effect profile of ozanimod and placebo were, in fact, indistinguishable and overlapping in the phase 2 studies. In addition, this very well-tolerated, favorable safety profile has been replicated in a highly successful phase 2 study in ulcerative colitis called TOUCHSTONE that was released recently. So clearly this is a mechanism of immunomodulation that could well prove to be useful for relapsing-remitting multiple sclerosis, but also in a range of other autoimmune diseases where treatments are hard to come by.   MSDF Even with Gilenya, I think there have been reports of a couple of cases of progressive multifocal leukoencephalopathy, so it gives a nice balance between immune surveillance and inhibiting T cell trafficking, but it seems like not a perfect balance. Does it look like that margin will be narrowed in the future with other compounds?   Dr. Rosen It's possible that it will be. I think the critical point to bear in mind is that real-world experience in tens of thousands of patients with hundreds of thousands of patient-years is really ultimately what is required to define these very rare events that on occasions do occur, and preexisting treatments with other immune-modifying agents such as Tysabri, for instance, may predispose to issues being seen later with PML. And I think that we always have to say that long-term patient experience and physician comfort are ultimately the best guides to the risk-benefit ratio.   MSDF I think you've identified something like four compounds in development, those are some that I had seen. Are there others, or these are really the ones to focus on at this point for people to keep an eye on?   Dr. Rosen There may well be others that are further behind. There have been a number of others that have had safety signals, particularly liver enzyme elevations, and significant first-dose cardiac effects. Arena have a compound that has recently completed a phase 1 multiple-dosing study and will go on to phase 2. So, you know, there are additional compounds and there will be additional compounds. Ultimately, patients do best when the best compounds appear, and the only way one knows that is to test them in man over the long-haul and define that risk-benefits for patients. And, you know, these multiple efforts really reflect the fact that a field has advanced, and that advancing field really does improve through intelligent intervention our ability to offer patients a better set of choices and a better set of long-term outcomes, which is what we're all about.   MSDF We're still focusing here on RRMS, none of this applies to the progressive phase. Is there anything coming along there?   Dr. Rosen You know, there's been one trial in primary-progressive; this was the Gilenya trial which didn't meet its endpoints. It may be that the mechanisms in rapidly progressive MS are a little different and that we don't yet, I think, understand the pathogenesis of that rather different presentation. So I'm not aware of a good alternate approaches to that, but that doesn't mean that the understanding isn't there for that to happen over time, it simply means that I'm not yet aware of it.   MSDF Finally, in secondary-progressive MS, we can understand what's going on, what led to it; if you limit relapses, that's good. But does it look like primary and secondary really may be overlapping but not the same disease?   Dr. Rosen I think there may be balances of pathogenesis where you can intervene more easily in some than in others. Clearly the sphingosine 1-phosphate agonists work particularly well by inhibiting the movement of lymphocytes into the brain. The movement of lymphocytes from the perivascular cuff into the parenchyma, into the white matter, where the demyelination proceeds. However, in parallel in multiple sclerosis, there are also events where there is collateral damage to neurons; we see axonal severing, we see elements of neuronal loss. Certainly with the sphingosine 1-phosphate agonists, there is some evidence that there is a diminution of cortical thinning over time with treatment, and that may be a really good thing.   I think that the neurodegenerative components is one that is hard to get a handle on right now, and that I think that these differences will become more obvious with early treatments of the immunopathology of multiple sclerosis. And that may well separate the autoimmune inflammatory damage and its sequelae from neurodegenerative mechanisms that may be entrained, and I think we will learn a lot from looking at those subsets of patients over time, particularly as more, better, and earlier treatment modalities allow the avoidance of significant damage in most patients.   MSDF Is there anything important we've missed or you'd like to add?   Dr. Rosen You know, I think for all of us who try to work at this interface of therapeutics, we do so because disease is, in fact, personal. We all know patients, we've all seen the multigenerational impact and depredations of multiple sclerosis on friends and family. And I think this is the very strong underlying motivator that drives us as scientists and as physician scientists to really try and bear in mind that the basic mechanisms and the basic therapeutic approaches that we pursue ultimately need a safe and effective human face to change the lives of patients in a positive way.   MSDF Very good. Thank you.   [transition music]   Thank you for listening to Episode Forty-nine 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 editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Forty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. Bruce Cree on the EPIC, CLIMB, and SUMMIT clinical trials in MS. But first here are some new items in the MS Discovery Forum.   We're very happy to report that MSDF has received three generous grants that will allow us to continue our mission: to focus attention on what is known and not yet known about MS and related conditions in a way that builds bridges among different disciplines. Genzyme has given us two grants. One will allow us to continue producing this weekly podcast for another year, and the other will allow us to develop an additional 12 monthly data visualizations. And Biogen has given us a grant for general operating support. None of these grants will interfere with our editorial freedom, and you can continue to count on MSDF to be an independent source of unbiased MS news.   A conference in Cambridge, Massachusetts several weeks ago sponsored by Orion Bionetworks outlined the progress and challenges in turning computational modeling into actionable knowledge in MS and other brain disorders. Allison Provost, who is Orion’s scientific program manager, has written a blog post describing the parts of the conference of particular interest to MS researchers. You can find her post by going to msdiscovery.org and clicking first on News and Future Directions and then on Blogs.   According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected three of those papers as Editors’ Picks. Two of them are comprehensive review articles: one on biomarkers in MS and the other on MS immunogenetics. The third is an evidence-based consensus guideline on the use of MRI in MS diagnosis.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 1 new trial, we updated information on 3 other trials, and we added 13 other pieces of information.  The drugs with important additions and changes are alemtuzumab, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab, and rituximab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to the interview. Dr. Bruce Cree is a neurologist at the University of California, San Francisco. MSDF Executive Editor, Bob Finn, caught up with Dr. Cree in his office at UCSF’s Mission Bay Campus shortly after a departmental seminar entitled “An EPIC CLIMB to the SUMMIT.”    Interviewer – Bob Finn Dr. Cree, welcome.   Interviewee – Bruce Cree Thank you.   MSDF Now EPIC, CLIMB, and SUMMIT are acronyms for three MS clinical studies. So first, what's EPIC, what's CLIMB, what's SUMMIT?   Dr. Cree Great question. So the EPIC study is a long-term observational study now in its 11th year at UC San Francisco. It's a a cohort study of multiple sclerosis patients who have been followed annually for the last 11 years. And this cohort initially had about 517 participants, and now – in its 11th year – we have about 91% of those patients coming back for ongoing assessments. The assessments include annual MRI scans, as well as clinical assessments and the blood draws for biomarker studies.   The CLIMB study is a similar related study that was developed independently at the Brigham and Women’s Children's Hospital in Boston under the directorship there of Howard Weiner. And it is also a long-term followup study. And now, after about seven years, that study has some 217 patients who have been retained out of the original cohort.    SUMMIT is the idea of bringing together long-term, well-curated observational cohorts from multiple sites. And the first iteration of SUMMIT will involve investigators from Basal, Amsterdam, UCSF, and Harvard who will merge together their long-term observational cohorts into a larger study. And the hope here is that we will obtain greater statistical power and be able to answer some of the more pressing questions about MS therapeutics, outcome measures, and utility of both conventional and nonconventional MRI in assisting with the diagnosis and management of patients.   MSDF So in the EPIC study, I'm struck by the fact that you've been able to retain 91% of your patients after 11 years; whereas in the CLIMB study they've lost 90% of their patients in just 7 years. How do you account for that difference?   Dr. Cree The EPIC study has had a great amount of support for long-term followup and subject retention. And we've gone to great lengths to keep our participants interested in the study and wanting to come back. And we have a terrific group of study coordinators who work day and night to maintain contact with our patients, inform them about why it's important for them to participate in the study. And we've even done outreach where we've gone to people's homes to perform evaluations in their homes where they were too ill to come in, as happens with multiple sclerosis as people develop more advanced disability. So we have very good retention as a consequence of the hard efforts made on behalf of the overall study by the coordinators and other members of the team.    MSDF Now you've used several measures of disease progression in the EPIC study, as have others in other studies. There's the EDSS, there's the MSFC, and there are several other measures. But let's talk about the EDSS first. That's probably the most commonly used measures, and it's also the one that people seem to love to hate.    Dr. Cree Yes.   MSDF Can you tell me about the EDSS and what its advantages and disadvantages are?   Dr. Cree Yeah, so the Expanded Disability Status Scale of Kurtzke is an ingenious scale that was really intended to describe where patients are at during the course of their lifespan. And it's a 10-point scale with half-point increment changes after the score of 1. And this scale has been adopted for use as the disability outcome measure in all MS clinical trials. The scale has a fair amount of inter-rater variability, which makes it challenging to administer. Because anytime you have a scale where there's a fair amount of variability it gets harder to interpret change. We did look at the EDSS systematically and looked at change over the first few years in the study and used that as a predictor for long-term disability transitions. We also looked at harder endpoints in the EDSS such as the time it takes for patients to go from no systems, disease onset, to the time where they require a cane to ambulate.    You mentioned the MSFC, the Multiple Sclerosis Functional Composite. This is a set of scales that were developed for use in multiple sclerosis that included the Timed 25-Foot Walk, which is a measurement of how fast somebody can walk 25 feet. That is clinically relevant because the speed at which somebody walks correlates quite well with the distance they can walk. So the faster you can walk 25 feet the longer you can walk. The 9-Hole Peg Test is a test of upper arm coordination and function. And the Paced Auditory Serial Addition Test is a test of cognitive function that measures specifically the tension and processing speed.    So we looked at these things, and we set up thresholds based on other clinical work that were considered to be clinically meaningful changes. So with respect to the Timed 25-Foot Walk and 9-Hole Peg Test, we were looking for a 20% worsening in function over the course of the trial. And with respect to the Paced Auditory Serial Addition Test – or PASAT – we were looking at the reliable change index for that outcome. And so these have been validated outcomes that are related to actual disability.   So we looked at all of these measures. And what we found was that when we looked at our relapsing MS patients about half of the patients experienced worsening in terms of EDSS change over 10 years. For the patients who had progressive multiple sclerosis, about 70% of them worsened. And then for these more stringent measures with respect to the MSFC components, we found lower proportions of patients with relapsing MS in secondary progressive or primary progressive disease had worsening in those outcomes, as well. So those were our endpoints for the study; they're clinical endpoints.   MSDF One of the things I noticed in your talk was that there was a great deal of overlap between the EDSS and the overall MSFC score; whereas there wasn't much overlap between the individual components of the MSFC score. What is the significance of that?   Dr. Cree Well the EDSS is itself a composite measure, and people tend to forget that. Especially earlier on in the scores that go from 0 to about 4, there you have 6 functional scale scores that contribute to the overall EDSS. That includes assessment of vision, brain stem function, motor function, sensory function, cerebellar function, bowel and bladder function, and cerebral function. And those separate functional scale scores are scored independently and then are summarized into an EDSS score between 0 and 4. After that, the EDSS score becomes really much more of an assessment of how far patients can walk until they have hit the major disability milestones of an EDSS of 6, which is walking with a cane, 6.5 a walker, 7 a wheelchair, or 8 bed bound.    MSDF So why is there a lot of overlap between EDSS and MSFC but not so much overlap between the components of MSFC?   Dr. Cree So when you look at the MSFC, you have two measures to the MSFC that are looking at motor function: the 9-Hole Peg Test and the Timed 25-Foot Walk. They can also be measures of cerebellar function. Both of things are very well measured in the EDSS by the functional scale scores for pyramidal and cerebellar function. The PASAT is not as well measured in the EDSS, although we have a cerebral functional scale score it's not a very precise measure, and there's a weakness associated with EDSS. Whereas in the MSFC, it's a very precise measurement.    When we look at the individual MSFC scores themselves, you can have patients who worsen in terms of walking, patients who worsen in terms of arm function, and patients who worsen in terms of cognitive function. And there is some degree of overlap in those three domains but not complete. And that just underscores how MS will affect different individuals differently. Some people have more ambulatory impairment, other people have more upper limb function impairment, and still other people have more cognitive impairment.   MSDF You made an interesting analogy to rheumatology in the treatment MS: the question of whether you should treat to no evidence of disease activity. I wonder if you can talk about that analogy and the NEDA, or no evidence of disease activity, goal.   Dr. Cree Sure. So in rheumatology in the 1990s, the discussion at that time had to do with how to treat rheumatoid arthritis. And this concept was advanced, which was a treat-to-target approach. The idea of using increasingly effective therapies to silence and suppress any evidence of active rheumatoid arthritis. And this strategy turned out to be extremely effective in treatment of rheumatoid arthritis. And instead of waiting for people to develop more disability, initiation of early highly effective treatments and really suppressing all joint inflammation became the current standard of therapy. And this has resulted in significant improvements in long-term disability in patients who are living with rheumatoid arthritis.    So taking that example and extending it to the field of multiple sclerosis, the idea here is that you have evidence of active multiple sclerosis on MRI scans such as gad-enhancing lesions and new T2 lesions; and evidence of relapses, which are clinical manifestation of acute inflammation; and disability progression, which is looking at the EDSS score and saying okay well if we have a combined measure that looks all of these things, and we try to suppress disease activity perhaps we're going to wind up with better outcomes. And so, this metric of no evident disease activity is defined as no evidence of relapses, no evidence of disability progression by the EDSS, and no evidence of MRI disease activity.    And it was originally developed in the context of clinical trials; specifically the pivotal trial of the natalizumab versus placebo study. And a certain proportion of patients in that study met this criteria of no evidence of disease activity. Subsequently, with more recent trials, other compounds have also been looked at and compared to their placebo or active comparator controls. And in each of these studies, you can see differences between treatments with respect to the proportion of patients with no evident disease activity.    The field of MS today is considering use of no evident disease activity as a therapeutic strategy or goal so that one would escalate therapy to the point where you see no evident disease activity. And the hypothesis here is that if you are able to effectively reach no evident disease activity that that is similar to putting patients in remission or preventing further disability from occurring. So we were very interested to find out whether there was long-term prognostic value of this marker, no evident disease activity.    And so, within the EPIC study, we looked at no evident disease activity over the first two years of the trial, and there was a proportion of our patients from this study who met those criteria: who had no change in terms of disability, no change in terms of clinical relapses, and no evidence of active multiple sclerosis by MRI scan. And we thought that that group would have a better outcome overall than the rest of the cohort. To our surprise, we found that there was no predictive value of no evident disease activity on any of the clinical markers that we looked at for 10 years.    So these patients had exactly the same risk for disability progression as patients who had evidence of active multiple sclerosis. And this was very perplexing; we just didn't really understand why that would be the case until we really started to look at the impact of treatment and use of escalation therapy in our cohort. And I think that when you look at the influence of therapeutic intervention in multiple sclerosis the effect size of therapeutic intervention is so great that other markers of biological disease activity such as new lesions wind up being minimized by the therapeutic impact. And as a consequence, things that might have been predicted based on natural history studies – such as brain volume loss, new lesions – become less apparent as having clinical meaning over a 10-year period of time because of the dominant influence of therapeutic intervention.    With respect to the no evidence disease activity, one of the questions that I think needs to be answered is do we really have the best markers for this? And if we are going to use a treat-to-target approach, are the things that are currently being looked at in no evident disease activity the right things to look at? And there is now interest in looking at other markers, as well, looking in incorporating, for example, brain volume into the no evident disease activity. And it will remain to be determined whether other ways of looking at no evident disease activity wind up performing better as a long-term predictor.   MSDF So when you're confronted with an individual patient – a new patient early in their course of disease – every neurologist is confronted the question of whether you start them with an interferon and escalate as they progress, or whether you start them with a highly active therapy. How do you make that decision, and how does the evidence from EPIC inform that decision?   Dr. Cree That's a great question, and I think this is probably one of the most provocative aspects of this long-term study. In EPIC, we used the escalation strategy where we began with so called platform therapies; drugs that are used as disease-modifying therapies that have been around for a long time, specifically the interferons and glatiramer acetate. And in the event that patients experienced relapses or had other markers of worsening such as brain volume loss, many of those patients were escalated onto what we would consider to be high-potency therapies. Drugs like natalizumab or medications that are off-label but still used in treatment of multiple sclerosis like rituximab or cyclophosphamide.    So we used this escalation strategy in this cohort. And what we found was the following. Treatment escalation was not associated with improved outcomes. In fact, treatment escalation was associated with worse outcomes in some patients. Now, why would that be the case? Well there's probably a confounder there of the indication to treat so that the patients who were getting escalation therapy are doing worse, and so they get the escalation therapy. So what we don't know from this study is if those patient hadn't gotten escalation therapy how would they have fared? We can't answer that question. That would require a randomized controlled trial.    But what this study does provide is this provocative idea that perhaps escalation therapy was really too little too late. That we were identifying a group of people who were at high risk of disability progression, but we weren't really setting things back to restore them onto a normal pathway and certainly not to prevent long-term disability. And this raises the idea that perhaps we should be utilizing these higher-potency therapies earlier. Now, that type of approach – the maximal efficacy approach – doesn't have data yet to support its use, but there are a few provocative studies that suggest that high-potency therapy might be associated with better outcomes. And we have the recent results of the cladribine study in clinically isolated syndrome where we had the best data yet for use of a broad-spectrum immune suppressant in terms of venting, time to the next clinical or radiographic event in patients who have presented with a first demyelinating event. And that study out performed all prior trials in clinically isolated syndrome so raises the question should be using an aggressive therapy right from the get-go?   And then, we have the alemtuzumab pivotal trial where alemtuzumab was compared head-to-head versus interferon beta-1a twice weekly in newly diagnosed patients. And in that study, alemtuzumab also out performed interferon beta-1a on many of the short-term markers of inflammatory disease activity. And we recently saw long-term data with alemtuzumab indicating that those patient do really quite well over a four-year period of time. So actually midterm data.    So we have a few lines of evidence to suggest that perhaps we should be using these high-potency therapies earlier. What we don't know is the relative risk-to-benefit profile. Certainly these higher-potency therapies carry greater risk to the individual subjects who are treated with these medications. And what we ultimately have to determine is whether those risks at a population level are worth the potential benefits of using a greater potency therapy early on in the course of MS.    It's my opinion that it's unlikely that the pharmaceutical industry is going to answer this question for us definitively. This type of approach to compare escalation therapy to high-potency therapy or maximal efficacy therapy from the get-go will require quite a bit of time of followup – at least five years if not longer – and will require large studies. So it seems to me unlikely to be endorsed by the pharmaceutical industry. It also seems unlikely that it's going to be sponsored by national organizations such as the National Institute for Neurological Disease and Stroke because of the extremely high costs associated with this type of clinical trial.    So that raises the question how are we going to answer this pressing unmet and unanswered question? And I think observational studies such as EPIC will be able to do this when merged together with other long-term followup cohorts. Today we have treatments that we didn't have 10 years ago, for example, fingolimod, dimethyl fumarate, alemtuzumab. These medications are currently being used in clinical practice. And I think we should be responsible for aggregating data on the patient experience with these medications, putting it into a systematized process for analysis, and aggregating this type of data across multiple centers. And that really is the goal of SUMMIT, which is going to involve pooling together our patient experience with our existing cohort, as well as new cohorts from UCSF, from Harvard, from Basal, from Amsterdam, and hopefully from many other MS centers as well. And then, with that pooled data, we'll hopefully be able to answer this question in a meaningful way.    MSDF Well, Dr. Cree, thank you very much.    Dr. Cree My pleasure.    [transition music]   MSDF Thank you for listening to Episode Forty-eight 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 editor@msdiscovery.org.   [outro music]      

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second part of a two-part interview with Dr. Hans Lassmann, who discusses oxidative stress as a mechanism of tissue injury in progressive MS. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 56 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One of them includes revised guidelines from the Association of British Neurologists on prescribing disease-modifying treatments for MS. The other describes an international consensus on diagnostic criteria for neuromyelitis optica and related disorders.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of June, we added 10 new trials, we updated information on 6 other trials, and we’ve added 67 other pieces of information. The drugs with important additions and changes are alemtuzumab, cladribine, cyclophosphamide, daclizumab, dalfampridine, dimethyl fumarate, fingolimod, glatiramer acetate, idebenone, interferon beta-1a, interferon beta-1b, laquinimod, rituximab, natalizumab, and ocrelizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to our interview with Dr. Hans Lassmann of the Medical University of Vienna in Austria. Last week we spoke about biomarkers, and this week we’ll discuss oxidative stress as a mechanism of tissue injury in progressive MS.   Interviewer – Dan Keller What's interesting there at this point?   Interviewee – Hans Lassmann The big problem in multiple sclerosis is that we have very good therapies for the early stage of multiple sclerosis, and they all interfere with the inflammation and the immune system. But when the patients have reached a progressive stage of the disease, then all these therapies are currently noneffective. So the key points were to define what are actually the mechanisms of inflammation and tissue injury in the progressive stage of multiple sclerosis, and there are still a lot of open questions. It is clear that even in the progressive stage there is an inflammatory process, and this inflammatory process is associated with active tissue damage. From that certainly we cannot definitely conclude that the inflammatory process drives the tissue damage; however, it's clearly associated.   Now, we were then very interested to see what are the mechanisms of tissue injury. And this involves, first of all, studies on the nature of the inflammatory process. And here what we found is that in the progressive stage of multiple sclerosis the inflammatory reaction is predominantly hidden within the central nervous system behind a repaired blood-brain barrier. So that means this inflammatory process is no longer really under control of the peripheral immune system. And also, the therapies which we have currently mainly interfere with immune functions in the periphery, and they have actually very little access to an inflammatory process which is taking place within the central nervous system.   So that means that new drugs have to be developed and tested which actually exert an antiinflammatory or some neuroprotective action directly within the central nervous system. And there are now a number of the large companies fully engaged in this process, and there are new candidates coming up, which will have to be tested in proper clinical trials in patients with progressive MS.   The second question, which we have mainly addressed during the last year, was the mechanisms how the tissue damage is induced. And in this regard, we concentrated on cortical lesions in multiple sclerosis, which are very, very specific for the disease. And we compared in gene expression studies these cortical lesions not only with normal controls but also with inflammatory controls. And we used here a disease which has very similar inflammatory infiltrates, as you see in multiple sclerosis brain, but doesn't lead to the MS typical demyelination, and this is tuberculous meningitis. And then we also used as a control for neurodegeneration Alzheimer's disease just to see what is a reaction in gene expression due to degeneration of neurons.   And when we did that, actually it was interesting to see that there were relatively few genes which were specifically changed in their expression in multiple sclerosis patients in comparison to these other disease controls. And these genes were, in part, associated with inflammatory processes. A large part of the genes were associated with a more or less single pathway of tissue injury, which includes oxidative injury leading to mitochondrial injury and its secondary consequences. And then, there were also some genes involved which were MS specifically related to tissue regenerative processes.   We have then looked in further detail, and it now turns out that this cascade of oxidative injury leading to mitochondrial dysfunction and with that to a state of energy deficiency is actually one of the major driving forces of neurodegeneration in the progressive stage of multiple sclerosis. So this oxidative injury is, in part, driven by the inflammatory process. But it is also augmented by factors which are related to age of the patients and to the accumulation of lesion burden due to the chronic disease.   So here the central portion is the activation of microglial cells which can, on the one hand, be activated in the inflammatory process, but they also get activated when tissue is damaged due to completely different causes. And they also get activated just simply in an aging process. And in this respect, then they get activated in a pro-oxidative form. And then, the tissue injury can further be propagated through additional age-related changes, including, for instance, the accumulation of iron in the central nervous system and also obviously the chronic microglia activation due to retrograded and anterograde degeneration when lesions already present within the central nervous system.   MSDF Are the microglia just overdoing what they normally would be expected to do? I mean macrophages use oxidative systems to get rid of pathogens.   Dr. Lassmann Yeah, this is absolutely true. That is a key element of microphage and microglia function. And this is exaggerated in both the aging process, as well as in the chronic inflammatory state like multiple sclerosis. The question only remains what is really driving this massive microglia activation in MS, which is even more and more pronounced than even in very severe other inflammatory diseases of the central nervous system.   MSDF Can you identify or has anyone identified factors that disappear with aging or are increased with aging that may lead to this state?   Dr. Lassmann That is also not really very clear now. I think one interesting aspect is that this massive microglia activation in the direction of oxidative stress you don't really see in rodents and even not in primate experimental models; you see it in humans. And the reason for that is not completely clear, but it may very well be that environmental factors actually play a major role. I think one of the major differences between humans and these experimental animals is that the experimental animals are genetically very homogenous; they are generally inbred strains. And the second is that they are kept under a very constant pathogen-free environment. And this is very different in a human situation, and these animals also have a very … standardized diet. Now this is completely different in human situations, and there are certainly many factors, including peripheral infections but also including diet changes, and many other factors can actually have an influence on microglia in the central nervous system.   MSDF And experimental animals also have optimized diets; people have figured out the nutrients they need I suppose. They're getting a good diet compared to people who knows how everybody is eating these days.   Dr. Lassmann Yes, that's absolutely the case. They have a standardized diet, and they certainly are not exposed to very much of the fats, for instance, which we take into when we eat fat pork meat.   MSDF Do any of the antiinflammatory agents modify the course? Things like lipoxygenase inhibitors and things like that? Not necessarily NSAIDs but now that you bring up fats?   Dr. Lassmann I think there is certainly an aspect behind that is that lifestyle control certainly has a beneficial effect. One can just see that in a way that environmental lifestyle factors, which actually also increase the risk for vascular injury or other things, will be certainly deleterious in a patient with progressive multiple sclerosis where the brain is already damaged due to the original disease process and where the functional reserve capacity of the brain is already partially exhausted. So in that case, even minor changes – which are related to lifestyle or aging – will have a more dramatic effect in such a brain than in a normal aging brain.   MSDF Finally, circling back to something you said at the beginning, in progressive MS I think you said that the immune system the cells have now entered the brain, but the blood-brain barrier has – once again – become a real barrier. So do you really have an immune response running autonomously in the brain no longer subject to any sort of peripheral control?   Dr. Lassmann Yeah, this is certainly a very important open question. We know that the inflammatory cells are present within the central nervous system in the progressive stage and that they are associated with the degenerative processes and the demyelination. We know currently very little about the exact phenotype and functional activation of the inflammatory cells within the central nervous system. This is actually a large research project, which is running currently in my lab, to try to define exactly the functional polarization of the cells within the MS lesions and to determine their activation state, their proliferation rate, and so on.   What we can say from our preliminary data on that is that they are present, they are in part activated. They also express certain transcription factors, which would be associated with a proinflammatory state in the central nervous system. However, overall all these changes are relatively small in comparison to an acute, for instance, virus-induced inflammatory process in the brain. So it seems to be that there is a slow and low-grade activation state which, however, could be completely sufficient to drive the degenerative process in the patients. But that is not the final answer yet.   [transition music]   MSDF Thank you for listening to Episode Forty-seven 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 editor@msdiscovery.org.   [outro music]      

Hello, and welcome to Episode Forty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the first part of a two-part interview with Dr. Hans Lassmann, who discusses biomarkers in multiple sclerosis. But first, here are some of the new items in the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 61 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, on the prevalence of pain in MS, found that around two-thirds of MS patients experience pain, and this symptom is associated with disability, depression, and especially anxiety. The other editor’s pick is a study of a toxin produced by Clostridium perfringens, a common bacterium often found in the gut that produces an MS-like disease in sheep. This epsilon toxin selectively kills oligodendrocytes while preserving all other neural elements.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 2 new trials and 5 other pieces of information. The drugs with important additions are dalfampridine, dimethyl fumarate, and fingolimod. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Hans Lassmann of the Medical University of Vienna in Austria, is one of the most prolific and highly respected MS researchers in the world. In this first part of a two part interview, Dr. Lassmann discusses biomarkers in MS and related conditions such as neuromyelitis optica and how the two conditions may differ important for therapy.   Interviewer – Dan Keller Let’s talk about new markers in MS or differentiating conditions from MS. What’s coming along, and what do we know now?   Interviewee – Hans Lassmann Well, there has been a very important development during the last years. And this was the technical development of assays which can really identify pathogenic autoantibodies which can modify the inflammatory process in the central nervous system. The major trick behind was that these assays are, in essence, based on cells which are transfected with the respective antigen, and so they express the respective antigen on the surface of the cell. And one can now identify those autoantibodies which really bind to the surface of the cell and are pathogenic, in comparison to those antibodies which recognize epitopes, for instance, within the cells, which cannot be reached by the antibodies in the in vivo situation, and which, therefore, are not pathogenic.   MSDF Can you give me some examples of these kinds of antibodies?   Dr. Lassmann So the first antibody which was the antibody against aquaporin 4, which has been shown to be associated with neuromyelitis optica, at least with a large fraction of patients with neuromyelitis optica. And this antibody then was very well characterized, and it turned out that it is directed against aquaporin 4, which is a water channel in astrocytes. And when patients have these antibodies on the background of an inflammatory disease in the central nervous system, these antibodies can reach their astrocytic targets and destroy the astrocytes, which then leads to secondary demyelination and neurodegeneration.   Having these antibodies, it was then possible to define the clinical spectrum of the disease, and it turned out that it is very strictly associated with neuromyelitis optica, but that the spectrum of the disease is broader than only affecting the spinal cord and the optic nerve. So these patients actually have also lesions in other regions of the brain. But they are still different from those lesions which you see multiple sclerosis.   It was then also possible to define the clinical spectrum of the disease. And, again, differences to multiple sclerosis became very clear. And, finally, it was also possible to then look in these patients with these aquaporin 4 antibodies how they respond to the current treatment strategies which have been established for multiple sclerosis. And it turned out that several of the key therapies for multiple sclerosis, including interferons but also natalizumab or fingolimod, can actually make the disease worse in patients with neuromyelitis optica.   So that was the first example that a disease which has originally been defined as a disease in the spectrum of multiple sclerosis has emerged as a separate and distinguishable disease which requires also different treatment in the patients.   MSDF It seems like neuromyelitis optica has components of autoimmune disease. So why do these compounds that work in MS potentially make the condition worse in NMO?   Dr. Lassmann This is currently not yet clear. One possibility is that the action of pathogenic antibodies makes the difference. The immune mechanisms are certainly different in a purely T-cell mediated disease, in comparison to disease which is mediated by a combination of T-cells and antibodies. And that could possibly explain why differences are seen.   There is another possibility is that some of these drugs actually stimulate the B-cell response or increase the B-cell response in the peripheral blood, and with that possibly also the antibody response. So, in that case, the T-cell mediated inflammation would be suppressed, but the antibody-mediated effects would be enhanced. And that could certainly also play a role. But these are, at the present moment, not proven.   MSDF But even in MS there’s evidence for B-cell trafficking and B-cell participation, but it seems to be less important or am I off base?   Dr. Lassmann No, this is a very interesting question. There is clearly a B-cell component in multiple sclerosis, and it has also been shown that depleting B-cells, for instance, with an antibody against CD20 can actually have a very good therapeutic effect in multiple sclerosis. However, we have to keep in mind that B-cells not only produce antibodies, but they have also other immunological functions. So one function, for instance, is that they help the T-cells, for instance, by very efficient antigen presentation. So by eliminating B-cells, you get also a decrease of the T-cell response. But this is not only one possibility. There are other possibilities that B-lymphocytes actually can also produce cytokines – proinflammatory cytokines – which may directly act on the tissue and damage the tissue independent from antibodies.   MSDF Getting back to NMO, if someone tests negative for antibody, but has clinical signs, does that rule out NMO or are you just not detecting antibodies or is it always required or not?   Dr. Lassmann So it rules out an aquaporin 4 antibody associated form of NMO, but a fraction of NMO patients – it’s around between 10 and 20% – which have a clinical presentation of NMO, but have no antibodies against aquaporin 4. There is currently very much effort to define what is the mechanism in these patients. And it turned out that a fraction of these aquaporin 4 antibody-negative NMO patients actually have antibodies against myelin oligodendrocyte glycoprotein.   And this leads, actually now, to a second type of disease which can be separated from multiple sclerosis. These are patients with high titers of pathogenic antibodies against myelin oligodendrocyte glycoprotein. Now, again, these patients, when you look at them at pathology, you would clearly define the disease as multiple sclerosis because they have inflammation, and they have very selective primary demyelination. And this is different from what you see in NMO where the astrocyte pathology is the earliest event. But in those patients with the MOG antibodies, its demyelination sort of hallmark, actually, of multiple sclerosis…of the disease process in multiple sclerosis.   However, when you now analyze these patients with mock antibodies, clinically you see that the clinical presentation is different from the classical presentation of multiple sclerosis patients. These antibodies are, for instance, frequent in children with inflammatory demyelinating disease of a spectrum of acute disseminated encephalomyelitis or relapsing disseminated encephalomyelitis or even patients with a disease similar to relapsing, remitting multiple sclerosis. This is in children.   In adults, you find these antibodies in a fraction of NMO patients. But there are also other patients who have a disease which is more similar to what is seen in multiple sclerosis, with the exception that they have relatively large and aggressive lesions, and also that they have, relatively frequently, lesions in the brain stem such as, for instance, the pons or the medulla oblongata. And, again, it seems to be that here a new disease entity appears which can be separated from multiple sclerosis.   Regarding therapy of these patients, we don’t have yet the data which we need to have. It can be speculated that the therapeutic response may possibly be more similar to those patients with NMO in comparison to the classical MS patients, but to know that we would have to have much larger cohorts of patients who have been treated with the different regimes.   MSDF Do some of these do worse on the typical MS treatments such as natalizumab or fingolimod?   Dr. Lassmann These data currently are not yet existing. It’s also because, due to these possible problems related to NMO, generally now, patients with mock-antibody-associated diseases are more likely to be treated with global immunosuppression or with rituximab, so the anti-CD20 antibody. And clinicians are very reluctant to use these therapies which have been shown to make disease worse in NMO in these mock patients. So we don’t have the data, currently.   MSDF Are there separate etiologies, does it look like here, the MOG versus classical MS?   Dr. Lassmann This comes to the important question about the etiology of MS in general. We have to admit that we don’t know what is the real etiology of multiple sclerosis. It is thought to be an autoimmune disease, but this is not finally proven. It may also be associated with infections – Epstein-Barr virus infection is, for instance, one possible example. And there are certainly other theories also, which discuss completely different mechanisms of disease pathogenesis in multiple sclerosis. It is clearly that all these diseases, including NMO, mock antibody associated disease, and MS are chronic inflammatory diseases. But what drives the inflammation is currently not yet known.   MSDF Is it possible there’s an initial insult to oligodendrocytes which then sort of precipitate a chain reaction cascade?   Dr. Lassmann This is also one of the theories which is put forward, but one has to say that with a bit caution, because there are experimental models where you can actually destroy oligodendrocytes in the central nervous system which do not lead to an autoimmune disease which is somehow related or similar to multiple sclerosis.   MSDF Anything interesting or important to add on the subject, in this context?   Dr. Lassmann I think what is now of interesting new research line is to search for additional autoantibodies in the population of multiple sclerosis patients. There are indications from pathology that there are certainly more patients who may have pathogenic autoantibodies, in comparison to those patients which now can be identified as NMO or mock-autoantibody-associated disease. There is a relatively recent study suggesting that another channel, a potassium channel on oligodendrocytes and astrocytes, the KIR4.1 channel, may also be a target for pathogenic autoantibodies in multiple sclerosis. Here, however, we are still in the very early stage because the test systems are not yet fully reproducible. And we will see in the future whether this antibody association with the KIR4.1 antibody really holds true in MS patients. And if that’s the case, what patients are they and whether they differ in any way in their clinical presentation or also response to therapy.   MSDF Is there a way to survey patients and essentially see what commonalities they have in antibody reactivity, and zero in on it that way, looking at a wide array of antibodies in various patients and seeing if they have reactivities in common?   Dr. Lassmann I think this is valid as a second step. But there is another alternative strategy which is now very well established also for other diseases, including paraneoplastic diseases or other autoimmune diseases. In that case, one can actually take the sera of the patients, and there are now new technologies developed where you can put these sera, for instance, on brain sections – normal brain sections – of either humans or animals and test whether they bind to specific structures.   This has been tried for nearly 30 years now, but only recently, new technologies became available which make that in a much more specific way. And this has been very successful in identifying new diseases which are associated with antibodies against a variety of neurotransmitter receptors or ion channels. So they certainly, in general, have not the spectrum of multiple sclerosis. They may have epilepsy. They may have psychosis. They may have motor neuron diseases, other things. But, on the other hand, the same technique can also be used to identify in multiple sclerosis patients whether some of them have actually antibodies which bind to brain tissue. And when that is established, one can actually then isolate the specific protein with the antibodies out of the brain tissue, and then, with modern molecular biology technology, can identify the antigen.   This is a strategy which has very nicely and very successfully shown for other diseases. And this was also, in principle, the strategy how people found evidence for these, for instance, KIR4.1 antibodies and also for the NMO antibodies.   MSDF Finally, do you envision being able to develop specific treatments if you find out specific autoantibodies or causes of some of these conditions?   Dr. Lassmann It may very well be. I think there are two dimensions on that. The one dimension is that such patients have pathogenic autoantibodies, and that certainly will have implications for therapy. That means that you will try to block the pathogenic action of the antibodies in general. In that case, it doesn’t make a difference whether the antibody is now directed against a neuron or against an astrocyte or against an oligodendrocyte. And this is a strategy which is actually now already approached in many different conditions, and neuromyelitis optica certainly is a disease where this is relatively advanced in this respect.   Now, the other possibility would be to try to find therapies which are then counteracting specifically the destruction of the particular cells which contain the antigen. So it can very well be that, for instance, an antibody against a neurotransmitter receptor will have a different implication on neuronal function, in comparison to an antibody against an astrocyte or an oligodendrocyte. Here, if these are just blocking antibodies and not antibodies which destroy the tissue, one can actually then try also symptomatic therapies with interfering with these channels directly.   MSDF Is there any thought towards trying to induce tolerance or clonal deletion of the pathogenic clones?   Dr. Lassmann This is obviously the dream of immunologists, and it would be extremely attractive. And it works extremely well in inbred mouse models with a very well-defined disease induction process. The strategy is very dangerous in a genetically heterogeneous population and also in a disease process which may be induced by different mechanisms. So, in that case, the big danger is that this tolerizing strategy in certain patients, for instance, with a certain histocompatibility genetics, actually is counterproductive and increases the immune response. And this is actually a problem which is very, very difficult to solve, in the aim of translating this mouse data into humans.   [transition music]   Thank you for listening to Episode Forty-six 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 editor@msdiscovery.org.   [outro music]    

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-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 Dr. Simon Hametner, who discusses the role of iron in multiple sclerosis. But first, here are some of the new items on the MS Discovery Forum.   According to our curated list of the latest scientific articles related to MS, 59 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One, published in Nature Reviews Neurology proposes a definition of aggressive multiple sclerosis as well as a treatment algorithm. The other editor’s pick, published in the journal Neurology, reports on a randomized, placebo-controlled study on patients switching from natalizumab to fingolimod, concluding that shorter washout periods may be better.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 3 new trials, we updated information on 2 other trials, and we added 9 other pieces of information. The drugs with important additions and changes are daclizumab, dimethyl fumarate, fingolimod, interferon beta-1a, laquinimod, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Simon Hametner works with Hans Lassmann at the Medical University of Vienna in Austria. We spoke about iron accumulation in MS in cells of the central nervous system and what iron may be doing.   Interviewer – Dan Keller Let's talk about iron and neurodegeneration. What specifically are you looking at?   Interviewee – Simon Hametner We are looking at the formalin-fixed, paraffin-embedded brain tissue from multiple sclerosis patients and controls, and we're looking, for example, at iron in these tissues. We're also looking now at proteins which are engaged in the management of iron in these tissues, for example, now.   MSDF What are you finding different in MS patients that you don't see in healthy people?   Dr. Hametner So we see iron accumulation, for example, in microglia and macrophages in MS, which are related to MS lesions. There are, for example, some MS lesions which have macrophages around those lesions, and we don't see much of iron in macrophages and microglia in healthy control tissue. We also see iron loss in multiple sclerosis because the iron is normally stored in oligodendrocytes in the controls. And this is also the case for MS, but in MS we also see a loss of this iron in the oligodendrocytes, especially at the oligodendrocytes which are closed to MS lesions.   MSDF Do you know the mechanism of why you're seeing these differences in iron?   Dr. Hametner We are now performing the research to find about these mechanisms. We have some prior indications, for example, hephaestin upregulation on oligodendrocytes in the vicinity of the lesions, but these data were not so straightforward. We are now also looking for ferroportin; ferroportin is an iron exporter of glial cells, it's actually ubiquitously expressed in mammalian cells. And all the glial cells also can express ferroportin, and we found it also in the oligodendrocytes; we now undertake this research. We think that oligodendrocytes really upregulate ferroportin and hephaestin in order to export iron.   MSDF Is the iron detrimental?   Dr. Hametner It depends. We don't think that it is, per se, detrimental; we see loads of iron in the deep grey matter nuclei and it seems that the brain can handle that quite well. But if there is even a minor amount of iron in the extracellular space even in the ferrous form – because iron normally is stored in the ferric and the trivalent form in ferritin – but if we see even minor amounts in the ferrous form, then it might be detrimental at very low amounts actually.   MSDF Is this a result or a marker of what's going on, or does it really contribute somehow to the disease?   Dr. Hametner This is a very interesting question. We think that iron really colocalizes or is found and accumulated at sites where things are going on with these lesions which accumulate iron in the microglia and macrophages around them. On the other hand, you can detect it very nicely with magnetic resonance imaging today. So we think that on the one hand it does play a role in the disease pathogenesis, and on the other hand we think that we can detect really these sites of iron accumulation, for example, around MS lesions.   MSDF Are you doing this only on fixed patient tissue, or do you have animal models of this; how are you exploring it?   Dr. Hametner We have this fixed material on the MS, and I think it's really important to also characterize the human material in very detail to perform all the necessary analysis to characterize what's going on in the human tissue. But, of course, as you mentioned animal models, it's very important to look at the EAE models. And collaboration partners have done that from McGill University in Montreal, Juan Zarruk and Sam David, and we are collaborating with them. And actually now they have been looking at some iron transporters and we are looking at exactly the same iron transporters now in the MS tissue. And they have found it in the same cell types, these iron transporters, in the EAE model being upregulated in the course of EAE as we see now in the MS tissues actually. So we really look for confirmation also from animal models from our collaboration partners.   MSDF And does this work with various kinds of animal models, or is it restricted to the EAE?   Dr. Hametner This survey has now been performed on the EAE, so it is a mock EAE actually and that they have performed a relapsing-remitting mock EAE in the chronic EAE model, and they have characterized those proteins, but they also do spinal cord injury models and they have performed a very interesting experiment on iron-loading in macrophages in the course of spinal cord injury where the iron gets into the macrophages possibly from a hemoglobin source from erythrocytes in the traumatic lesional tissue. And we think that regardless of the source of iron, it has these detrimental effects in the macrophages and triggers them to have a pre-inflammatory – or so to speak, M1 state – and are detrimental to the surrounding tissue.   MSDF This is macrophages or also microglia?   Dr. Hametner So in the spinal cord injury model, it was mainly macrophages. In the acute phases of the EAE at the peak of the disease, it was also mainly macrophages, but later they also found iron in the animal model within microglia, as we do also in MS. We have these early lesions where there are a bunch of macrophages in these classical active lesions, and these are mainly macrophages, and if they are iron-loaded, it is in the macrophages. But for the later lesions for these chronic active lesions which have this iron ring around the lesion, we find it also within macrophages but also microglia.   MSDF So does this change the oxidative environment inside the macrophage?   Dr. Hametner That's a good question. We think that it does change something with the macrophages because they seem to die. So we have these dying macrophages in the EAE model, as they have observed it, but in the MS we saw this dystrophic microglia at the lesion edge. So these are microglia which are highly iron-loaded probably for some time, and they have these nice processes. And if these processes get those beads and the process fragmentation and these process budding and blips in the processes, we call them senescent or that dystrophic microglia. And we have indications that this is really related to the iron load of this microglia. And then they get diminished towards the inactive centers of the lesion. So we think that at the edge of chronic active or slowly expanding MS lesions, these get iron-loaded in microglia and they don't handle it quite well, and then they die and get diminished towards the inactive centers.   MSDF So when they die, do they release this and is it affecting other cells?   Dr. Hametner We believe so. We think more or less that it is necessarily released into the extracellular space if an iron-loaded cells just dies by necrosis, or apoptosis, or something in between. So it is just released into the extracellular space. It has to be taken up by other cells; for example, other microglia, or other macrophages, or even astrocytes; it seems that it is really liberated. But, of course, it is hard to say whether iron within a specific microglia has been acquired by some other microglia which has died, or by some oligodendrocyte which has died, or even another source. But the fact is although we are sure that they have really accumulated lots of iron, and given actually the concentration of iron in these microglia and the surrounding tissue, we do think that there must be other sources than only oligodendrocytes by which iron gets into these microglia.   MSDF Where do you go from here? What do you see the steps in the research?   Dr. Hametner  I think it is necessary to characterize these rings around lesions which have these iron-loaded microglia and macrophages, to characterize at which disease phases these rings occur, and, of course, this is very interesting because you can use it in vivo. Because one of the things we are really sure is that we can image iron within microglia at the lesion edge of those lesions very nicely at 7 Tesla of magnetic resonance imaging; we are very sure that this is iron then within microglia and macrophages. And if we can relate pathologically the disease mechanisms or the degenerative actions going on in these lesions to the presence of iron, we then can also relate our in vivo findings from MRI with the things which are going on there, like neural degeneration and demyelination, for example.   MSDF Do you find that the iron-sensitive MRI imaging correlates with duration of the disease or stage or clinical condition?   Dr. Hametner Yes, we think so from our pathological material. So we think that in the progressive stage of MS, there are these lesions which are the slowly-expanding lesions, and they have these chronic activity, chronic demyelinating activity at the lesion edge. And we think it's a typical feature of progressive MS. It remains to be determined whether this also holds true in vivo. If you make an MRI, an iron-sensitive MRI, and you look for iron rings around MS lesions, for example, by susceptibility-weighted imaging or by quantitative susceptibility mapping or even Ultrastar imaging, if you look at these iron rings around lesions, it remains to be determined at which disease phase is, because in the pathological material we have more of the chronic cases and we have very few relapsing-remitting. So we cannot say what's really going on in the relapsing-remitting disease because we don't have this material pathologically.   MSDF Right, you would have to find people in various stages who probably died from something else; they're not going to be advanced MS patients at that point. Is there some relationship of your findings to the idea of oxidative stress?   Dr. Hametner Yes, we have these overactivity for malondialdehyde or E06, which is this antibody against oxidized phospholipids, and we have found actually by working performed partly in this lab that there is a higher activity for oxidative stress of various glial cells in the lesions. But as for the microglial degeneration, we did not see so many microglia being positive for these markers. So the microglia, they seem to die, but we only have these morphological features of dystrophic or senescent microglia actually from the pathological side. On adjacent side, if you stain for iron and you stain for oxidized phospholipids, you see partly that there is a 1:1 colocalization. But we don’t see these always actually.   I think what's really clear is that there is lots of oxidative stress in MS lesions, but even in early MS lesions which on iron stainings don't have so much iron, because on these early lesions we actually see predominant iron loss. If you have a very highly active MS lesion in the early stages, you see iron loss, and you will see also oxidative damage there. So there is also other factors leading to oxidative stress, like NADPH oxidase, for example, the p22phox, the functional subunit of NADPH oxidase, which we have shown in this lab that it is upregulated on macrophages and microglia, but also in the absence of iron.   MSDF What tips the balance between loss and iron accumulation?   Dr. Hametner That's an interesting question, actually a complicated one. You're right, we see on the one hand iron loss, and we see iron accumulation. So in the early stages, we see iron loss around MS lesions, in the MS lesions, because oligodendrocytes try to get rid of their intracellular iron possibly to prevent the iron efflux or iron liberation, which is uncontrolled if there is demyelination and oligodendrocyte degeneration actually. So we think that inflammation in the early phases of the disease leads to this efflux, which we think also involves not only oligodendrocytes, but also astrocytes. So we now think actually that oligodendrocytes probably efflux the iron towards astrocytes, and those astrocytes then might efflux it towards the periphery even. So I think inflammation is an obvious candidate to trigger this upregulation of iron efflux mechanisms.   I think what drives the iron accumulation within the microglia at the lesion edges is a different story. We think that these are two unrelated processes. On the one hand you have these iron loss mechanisms, the iron efflux mechanisms from the oligos leading to iron loss in early MS lesions, and this seems to be a protective phenomenon; this is, so to speak, a protective reaction of the glial cells against oxidative stress. But in later lesions, in chronic active lesions with this iron accumulation within microglia and macrophages, and we don't think that they are really correlated. So we think these are two distinct processes going on in MS, probably even in two distinct phases of the disease.   MSDF Is there anything interesting to add?   Dr. Hametner I think the really crucial question is now to find out about the source of iron for microglia and macrophages, and even to find out about the source of iron for the oligodendrocytes. We are not so sure whether this is really transferrin-bound iron entering the brain and being loaded in oligodendrocytes, as you find it in control tissue, control brains. And we don't think that this is only this iron from the oligodendrocytes which is then loaded into the microglia and macrophages; we think there are additional sources possibly from the vasculature.   MSDF Very good, thank you.   [transition music]   Thank you for listening to Episode Forty-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 editor@msdiscovery.org.   [outro music]  

[intro music]   Hello, and welcome to Episode Forty-Three 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. May Han, who discusses issues related to following patients with clinically isolated syndrome. But first, here are some new items on the MS Discovery Forum.   We recently posted an article on a surprisingly strong association between a certain gene variant and non-response to interferon beta in people with RRMS. The study is a meta-analysis of three independent cohorts in Italy, France, and the U.S., and it comes from the labs of Philip De Jager and Filippo Boneschi. You’ll find this article by clicking first on News & Future Directions and then on New Findings.   This past week we published the latest in our series of data visualizations. This month’s visualization is a series of word clouds illustrating how key terms in the MS clinical-trial literature have changed between 1993 and 2014. To find this visualization, first click on Research Resources, then on Data Visualizations, and then on Word Cloud.   According to our curated list of the latest scientific articles related to MS, 30 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s study of the association between depressive symptoms and walking ability in people with RRMS.   Are you attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis this week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.   [transition music]   Now to the interview. Dr. May Han is an assistant professor in Neurology and Neurological Sciences at Stanford University. I spoke with her about following patients with clinically isolated syndrome, as well as her approach to patients with MS across the course of their disease. But first, she addressed some unmet needs in MS.   Interviewer – Dan Keller Dr. Han, you told me that we’re good at the diagnosis of MS in general, but still there’s a vast area that we don’t know about. What are some of those unmet needs?   Interviewee – May Han So it’s been over 150 years since Charcot first described multiple sclerosis, and I have to say that we have come a long way in understanding and treating this disease. But as you have mentioned, there are still areas where we have no idea, there are gaps in our understanding of this disease. One of these areas that is clinically very relevant and is very challenging is in the day and age where we have a dozen disease-modifying therapies for MS patients, and yet we don’t have a good way, a scientific way of selecting the most effective therapy for a particular patient is what I find quite challenging in the clinics.   MSDF What gives you clues or how do you approach this essentially algorithm of deciding where to begin and how to move on to other medications if the first one’s not working well?   Dr. Han Currently, of course, we follow the guidelines. So for any relapsing-remitting patients, our logic is to go for the safest medication that we think are going to be most effective, which means we go with the first-line therapies. So we have the convention ABC drugs such as beta-interferon family of therapies and glatiramer acetate, plus the newer oral medications such as Tecfidera and fingolimod or Gilenya that we use for the first-line therapy; not a whole lot of science in choosing these medications for a particular patient, but what we would do is initially we would educate the patient about these disease-modifying therapies and then select the medication together with the patient to see what would be most appropriate and the patient could be most compliant for a particular medication.   To give you an example, certain patients have aversion to needles, in which case we go with the oral medications. We also have in mind what the preference of the patient, such as whether they could be able to follow it through for years on end with a particular medication. Ideally, we would like to have zero relapses or MRI activity when a patient is on a disease-modifying therapy, but as we all know none of these medications are 100% foolproof, and they can still have some degree of MRI activity or infrequent relapses on this medication. However, if a patient is clearly not responding to a therapy either in terms of not being compliant, being intolerant to the mode of administration, or if they’re having worsening disease activity, we would decide to go on to stronger medications or second-line of therapy.   MSDF Do you initially discuss a plan of action, a stepwise pattern of medication prescribing, or do you wait until something needs to be changed to bring it up with patients?   Dr. Han That is a very good question. I’m sure it varies among clinicians, but, however, I would like to paint the picture to the patient the best that I can. So, let’s say for example, if a patient who is a newly-diagnosed MS patient who has very few MRI lesions, I would discuss with them what the most appropriate medication could be. We would decide a medication and we would also give them an outline of what the followup plan would be and when we would be deciding to switch to a different therapy, and if so, which medications would be most likely appropriate for them, and also how we would monitor them. So by doing this, it gives the patient a better picture of their path and what to watch out for, and in my experience we have a better outcome with these patients.   MSDF Do you find that once you achieve success in limiting relapses and lesions that the medication is fairly stable for a long time, or do you have to have an armamentarium that you keep moving through?   Dr. Han So my model if a patient is responding to a medication, unless they have other side effects or reasons to switch, I would like to get the most mileage out of the medication as much as I can for a particular patient. However, if a patient, for example, has JC virus positivity, in which case even if they’re responding to Tysabri really well, there is a cutoff time point where we have to sit down and consider whether this patient should be switched onto a different medication to prevent the development of opportunistic brain inflammation such as PML, in which case what the next medication would be. And so we would sit down and talk the pros and cons; this conversation was started even before the patient was started on medication, but that would be the checkpoint.   MSDF I suppose another aspect is do medications start to fail patients even after a long period of stability, or do they usually continue to be stable if the medication is working for some period of time?   Dr. Han This is also a very pertinent question. MS patients, as we know, is very heterogeneous. Some of the patients, if they are stable on a medication, they would continue to do well on a medication for several years up to decades. However, some patients would have an initial improvement or stabilization of their disease, however in the later stages they would have worsening disease. And it is really unclear whether because their disease per se is getting worse or whether their body is rejecting the medication secondary to the immune response. And that is also one area that we should do research on to better understand this condition.   MSDF When you say reject the medication, are you actually referring to an immune rejection such as with, say, interferon; I would think it would be less likely they would actually mount an immune response to a small molecule. Am I clear on that or not?   Dr. Han I think we have quite a lot of information in terms of beta interferon therapies, because we clearly know that patients do tend to develop antibodies against beta interferon, especially the therapy. However, even that we don’t really know if all those antibodies are attacking the drug or whether they are just there. So just by finding the antibody alone is not enough to say that the patient is not responding to it; I think we need to use it hand-in-hand with the clinical response as well as the MRI activity.   Getting to the second part of your question whether there’ll be less intolerance or rejection to the therapy if it were small molecules, but I don’t think we understand at the cellular or molecular level. For small molecules there could be receptor down-regulation, there could be availability or cellular sequestration, or even the prodrug being converted to an active drug, or how the breakdown process occurs. So when a patient does not respond anymore to a medication, we just know that the clinical response is worse, and we don’t really know whether it is because the disease activity has worsened or other aspects, pharmacodynamic or kinetic aspects of the system has changed in such a way that they no longer respond. So, again, we do need to do more research to have a better understanding.   MSDF You have called it MS comes in many different flavors. Have you found that any medications are particularly good for different constellations of symptoms, or is everything about equal no matter how they present?   Dr. Han Very good question as well. I think in the experimental models people know that MS, or central system autoimmunity, can have a bias towards one type of inflammation as opposed to the other. For example, some would say that certain medications are better to treat Th1 as opposed to the Th17 type of inflammation, however in human beings there’s no clear-cut Th1 MS or Th17 MS. I don’t think people have done enough studies to clearly decipher the immune profiles of patients. So the answer is we don’t know.   MSDF Finally, let’s talk about the need for biomarkers especially very early in the disease when someone’s presenting with CIS which may or may not become MS. Where does that stand and how acute is the need?   Dr. Han The need is there, especially if you look at it from a patient who just had an initial attack. If you tell them that we don’t really know whether this is a one-time thing or whether you’re going to develop MS, and we’ll have to wait and see for three-plus years. So for these three years, the patient’s life is very much consumed by the “is it going to be MS” kind of question. And it does affect their physical-mental wellbeing as well as their quality of life.   I think we’ve come a long way with the advancement of the MRI studies in such a way that if a patient has MRI lesions together with the first-time attack, we could almost clearly say that this is going to blossom into MS. However, for patients who are radiographically clean and who just had one episode, it would be very, very helpful to have some kind of blood biomarkers to predict whether this could be a single event or whether it could be a central nervous system inflammatory disorder.   MSDF You picked three years as a period of waiting, watching. Are they out of the woods after that, or how late can it blossom into full MS?   Dr. Han It’s always a bell-shaped curve. There are patients who would declare themselves sooner than three years, there are also patients who would take several years before they have the second attack. I have one patient who had an initial attack of optic neuritis and nine years later she had the second attack. During that period, she had had MRI scans for three years which were clean. So, I guess, one is never completely out of the woods, but at the same time it is also not prudent to perform unnecessary tests on a patient.   So I think we have to focus on what is the safety net and pick a period of time, but at the same time it is very important to educate a patient to symptoms to watch out for, how to get help, and to work very closely with the primary care physician or a neurologist so in case the symptoms show up they will not be ignored or delayed to receiving treatment.   MSDF Is there anything we’ve missed or is important to add? I’m sure it’s a gigantic field, but is there anything glaring that should be added?   Dr. Han I would like to encourage people in the field to also focus on the secondary-progressive stage of MS. We know that relapsing-remitting MS patients with or without therapy eventually would end up having secondary-progressive MS, so it’ll be really important to decipher whether during the secondary-progressive stage there is no inflammation but only the early neurodegeneration, or how the immune system and the central nervous system interact and how we can change it, or at least modulate it, to either delay or to prevent neurodegeneration. The third area that I think is very important is to try to understand the regenerative aspects of the central nervous system.   As I have given you the example, if we have two patients who have had similar lesion burden or even lesions that are approximately the same in similar areas, a patient can be severely devastated, neurologically devastated, whereas the other may have minimal neurologic deficits. And we would always say that it depends on the brain reserve, or neural reserve, but we don’t quite know what it is. Is it the stem cells, is it the nervous system being more resistant to insult and how the immune system interacts with it? And I think this is also a big area that we should focus on, of course, to prevent further damage, but also once the damage is done to limit the damage and perhaps to regenerate it. And I think that people always have within themselves the ability to heal.   MSDF Good, thank you.   Dr. Han Thank you.   [transition music]   Thank you for listening to Episode Forty-Three 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 editor@msdiscovery.org.    [outro music]

[intro music]   Hello, and welcome to Episode Forty-Two 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. Lawrence Steinman, who discusses a surprising result involving amyloid, a molecule typically associated with destruction in Alzheimer’s disease, in an animal model of MS.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 1 new trial and 16 other pieces of information. The drugs with important additions are dimethyl fumarate, daclizumab, glatiramer acetate, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s a meta-analysis of epidemiological studies of neuromyelitis optica, also called NMO or Devic’s disease. The conclusion of the meta-analysis is that there’s a high level of heterogeneity among the 9 studies that met the inclusion criteria. The prevalence of NMO in the studies ranged from 0.51 per hundred thousand in Cuba to 4.4 per hundred thousand in southern Denmark.   Will you be attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis next week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.   [transition music]   Now to the interview. I spoke with Dr. Lawrence Steinman, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, who has a new twist on amyloid, this time in MS.   Interviewer – Dan Keller Dr. Steinman, you have proposed that amyloid can be a protective molecule as well as what’s commonly viewed as a destructive molecule. How did you come upon this?   Interviewee – Lawrence Steinman We came about it serendipitously or by accident. I had a graduate student and I thought I would give that student some low-hanging fruit, and the low-hanging fruit was to take the conventional animal model that we use for multiple sclerosis called experimental autoimmune encephalomyelitis – EAE. And when she put in these long peptides from an infamous protein named amyloid beta – A-beta – she put it into the animals with EAE at the time they were paralyzed, and I thought well, these are molecules that cause even more inflammation in the central nervous system, so they should make the disease worse, or perhaps they’ll have no effect and then we’ll have to think of another project for her PhD. So the student, Jacqueline Grant, came back and said, “Well, I gave the A-beta peptides and the animals are all better, they’re walking around.” And I first reacted, no, you must have confused the cages, let’s do it again. And when we did it again there was the same result, so then we were off to the races.   There was a second reason besides the low-hanging fruit description. May Han, my colleague, and I had reported the proteomics of MS lesions; so we took well-defined MS lesions, May cut frozen sections and then removed the lesion area with a laser tool, and then we trypsinized, fragmented the proteins, and used a modern technique, mass spectroscopy, to get the proteome, a list of all the proteins in the lesions. So amyloid proteins such as amyloid precursor protein and cal protein are found in the lesions themselves, so I thought that that was a second opportunity, a second foundation for doing these experiments in EAE; let’s see what happens when we augment, if you will, a naturally occurring protein found in the lesion to see perhaps what it’s doing. But, again, my bias, based on the dominant theory in Alzheimer’s disease is that amyloid was going to cause harm in MS as well as Alzheimer’s.   MSDF In these experiments, the amyloid was injected IV so it seems to circulate, but does it get to the brain in these mouse EAE models?   Dr. Steinman Actually, it does not get to the brain. We’ve actually put it into the brain directly to see if it would spread throughout the brain, and in our hands the molecules we’re working with do not spread. Most of these experiments showing a prion-like spread of amyloid is done in animals that are overexpressing the amyloid proteins in the brain so that they’re sort of tilting the balance to enhance spread if it’s going to occur, but we don’t get these amyloid molecules into the brain when we inject them intravenously, nor do we spread them around when we injected them directly into the brain.   MSDF So if you’re injecting them peripherally, do you think that there is some direct effect, or do you think they’re acting through lymphocytes or other circulating cells?   Dr. Steinman Well, we now know that there are at least two mechanisms. One is that when we are injecting them peripherally, these amyloid-like molecules, they go to sites of inflammation and this could include sites of inflammation within the brain. But remember, they’re on the vascular side of the lesion. And they act in a way like molecular sponges. The amyloid molecule is very sticky; in fact, when you try to work with some of the amyloid molecules, they’re like bricks, they stick to the walls of test tubes, and more importantly, they stick to each other and form these long, brick-like fibrils.   So what they’re doing when we put them into the circulation is they’re sopping up many of the inflammatory mediators that appear in the circulation during inflammatory diseases, including inflammatory diseases of the brain. These inflammatory mediators include the complement proteins and some of the famous apolipoproteins that we’ve heard about in reference to Alzheimer’s, we’ve heard the most about apolipoprotein E. So these amyloid molecules, when they’re in the circulation, actually stick and take away, precipitate away these inflammatory mediators. So I call it a molecular sponge.   There’s another set of mechanisms that we’re learning about that we’re able to use these amyloid proteins to do a couple of things to lymphocytes. One, it sets up a type 1 interferon response in lymphocytes. So the amyloid fibrils are a known trigger for the production of type 1 interferon, and type 1 interferon is actually beneficial for neuroinflammation; we have approved drugs. It’s doing another thing that we’re on the verge of publishing, but I’ll sort of give the headline without too many details; it’s setting up a type of lymphocyte that has a more regulatory function. So these are all rather unexpected roles for amyloid proteins.   MSDF And you have done adoptive transfer of some of these lymphocytes and find similar effects?   Dr. Steinman Yes. And the adoptive transfer experiments are very interesting. When we set up the system to produce a lot of type 1 interferon after we give an amyloid fibril, if the type of disease is what’s called the Th17 disease, the increased beta interferon actually worsens that, and if we create a disease that is called T-helper 1 – Th1 – then the type 1 interferon is beneficial. So we’ve engineered some amyloid structures so that they trigger less type 1 interferon, and when they trigger less type 1 interferon, then they work in both the Th1 and Th17 models. We published on that in the Journal of Experimental Medicine. But, again, even here with the type 1 interferon, the effect is nuanced and we can engineer these amyloid structures to be really beneficial and to take away the harm.   I wanted to say one thing, that clinicians and working scientists generally understand amyloid very well. Amyloid-beta that’s well known. Other amyloid proteins that people are, of course, familiar with are tau, prion protein, alpha-synuclein. But an amyloid structure is a general description of a protein that forms beta sheet, so the beta strand structure allows through hydrogen bonds the formation of what you should think of as a venetian blind, these monotonously parallel sheets that actually intercalate dyes, like Congo red or thioflavin T, so that when you shine polarized light on them they refract it in a polarized way. So we can make these structures, if you will, they’re organized nano particulars, to be more or less water-soluble, to be greater or lesser inducers of type 1 interferon. So there’s a whole armamentarium of very interesting amyloid structures that we can engineer to provide benefit in different situations.   Now what does this all mean for the Alzheimer’s hypothesis? And we’re doing an audio interview, so I’m sort of smiling wryly. I don’t want to get into that because we haven’t done the experiment in the amyloid-beta overproducing transgenic mice that have served as the model system to test whether various amyloid-lowering procedures will provide benefit, we just haven’t done that. And we’ve tried our particular approach in a number of other conditions ranging from stroke to EAE, as I said, to experimental heart attacks. And in the systems that we’ve studied, we see benefit.   MSDF But as a further proof of concept of what you have found in the protective effect of amyloid, you’ve looked at amyloid precursor protein knockout mice. Is that right?   Dr. Steinman Yes. Well, that’s a whole interesting story, and thanks for reminding me. So in a series of experiments that we have done and others have done, we first noticed that amyloid precursor protein knockout mice, they had worse EAE. Another person in Australia, Colin Masters, who’s actually one of the leaders in the field of Alzheimer’s research, looked at experimental head trauma, and in the amyloid precursor protein knockout mouse, they had a worse condition after head trauma that was alleviated by giving amyloid precursor protein in its soluble form. And then other people have shown that experimental encephalomyelitis is worse in prion knockout animals and in tau knockout animals.   We had been working with a protein called alpha-B crystallin, which is also an amyloid-forming protein, and we noticed that EAE was worse in the absence of alpha-B crystallin. So there’s a long series of experiments that loss of function, loss of the parent protein of these amyloid-producing molecules, leads to worsened inflammation, whether it’s EAE, head trauma, or somebody else did it in experimental heart attack. And we also did it in experimental stroke, so under a variety of conditions.   So this makes the argument even stronger, suggesting that amyloid structures when augmented can provide benefit and reduce inflammation, and when absent can actually exacerbate inflammation; so gain of function better, loss of function worse. So you have to look at the amyloid molecule as something that is not always harmful and pathologic. Whether it is the main culprit in Alzheimer’s, whether Alzheimer’s is an example of neuroinflammation, I leave it to people in that field because I really don’t want to take them on headlong at this point in time when we have all these fascinating results elsewhere. But I let the listeners draw their own conclusion based on the published work that I’m talking about, not only from my own lab but from other investigators all over the world.   One might want to think a little bit differently the next time one thinks about the deleterious effects of amyloid in Alzheimer’s, but I’m not going to be the one that takes on that massive scientific opinion, we’ll just have to see how it works out. I hope everyone’s been right over all these years because we certainly need some answers in that field. And if they are right, then we’ll have to integrate the kinds of things that we’re understanding about the role of amyloid proteins in other types of inflammatory conditions with a positive result in Alzheimer’s when it’s taken into the clinic. If it turns out that the experiments do not succeed in Alzheimer’s, then it will be easier to reconcile these different outcomes. But I think we’ll have to be patient; science doesn’t move as fast as some of us would like to have it move.   MSDF What was the time course of seeing a result by injecting the amyloid in your EAE models?   Dr. Steinman It’s very fast. When you inject the amyloid, it’s within 48 hours. If you stop giving the amyloid – we like to give it every day – if you stop giving it for a few days, the inflammation recurs, and that suggests that these amyloid structures are acting like a pharmaceutical. It’s not one of these situations that you sometimes see in science; you give the molecule once or twice and the disease goes away forever. This seems to be suppressing ongoing inflammation while it circulates, and when you take it away the effect is gone and the disease recurs, so that’s very interesting.   MSDF The effect seems to be too quick for remyelination to be occurring as the answer, but when you give it chronically do you see remyelination?   Dr. Steinman So far, we haven’t looked for long enough periods of time or with sensitive enough techniques. Your question triggers an experiment and we should really take a look at that. I would imagine that if you can abrogate inflammation that you’ll allow for remyelination if there’s anything left in the oligodendrocyte precursor to remyelinate itself, or if you need a little augmentation, it would be good to do a stem cell type of therapy under the protection of this kind of antiinflammatory approach.   MSDF Are you planning any early human trials?   Dr. Steinman Ha! I chuckle because this is a tough one to bring into the clinic. I’ve been funded by people who first scolded me for saying don’t take this too fast into the clinic, because I like to translate results. In this one, we’ll have to be more cautious than we might for other types of therapies.   MSDF Is there anything important to add?   Dr. Steinman I thought the questions were very comprehensive. And as you can see from where our matters stand now, there’s a lot of positive leads to pursue. And I think we’ll have to be cautious about translating in the fields of multiple sclerosis or stroke because of the infamy of the molecule I’m working with, but we’ll get there. Thank you.   MSDF Thank you.   [transition music]   Thank you for listening to Episode Forty-two 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 editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-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 Diego Cadavid, who discusses trials of anti-LINGO-1 in MS. But first, a few updates on the latest developments at MSDF.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 3 new trials and 11 other pieces of information.  The drugs with important additions are dalfampridine, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, naltrexone, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   According to our curated list of the latest scientific articles related to MS, 54 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected two of those papers as Editors’ Picks. One is a meta-analysis of mortality studies showing that excess mortality in MS relative to the general population has not changed over the past 50 years. In the other Editor’s Pick, Jagannadha Avasarala points out that 20% of patients who present with a symptom consistent with a diagnosis of clinically isolated syndrome do not meet radiological criteria on brain MRIs. Dr. Avasarala has contributed an essay to MSDF in which he discusses the consequences of this finding. To see his essay, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.   [transition music]   Now to the interview. Dr. Diego Cadavid works at Biogen Idec, a pharmaceutical company involved in MS therapeutics. Our executive editor, Bob Finn, caught up with him in Washington D.C. at the annual meeting of the American Academy of Neurology, where Dr. Cadavid presented results of a phase 2 trial of an anti-LINGO-1 antibody called BIIB033 in which the antibody appears to promote myelin repair in the human brain.   Interviewer – Robert Finn Dr. Cadavid, welcome.   Interviewee – Diego Cadavid Thank you, Bob, for having us.   MSDF First, what is anti-LINGO-1, and what does it target?   Dr. Cadavid Anti-LINGO-1 is an investigation and treatment for a myelin repair. It targets a protein called LINGO-1 expressed in the myelin forming cells that normally inhibits the production of myelin. By blocking LINGO-1, we believe healthy cells actually make myelin and at the same time help patients with demyelinating diseases like MS.   MSDF Tell me more about LINGO-1. Why this target makes sense in multiple sclerosis.   Dr. Cadavid Yeah, so LINGO-1 is an inhibitor of myelination. So MS is a demyelinating disease, and it's well established that the majority of patients once they lose myelin they actually are not capable of repairing it. And the question in the field has been why? It's becoming clear that it's not because of a lack of cells; the myelin forming cells are there, but they're not making myelin. So one of the leading hypothesis is that there is a blockade of the ability of these cells to make the myelin. Biogen – more than 10 years ago – was looking for a molecules that could mediate that inhibition, and that's when they found LINGO-1. And through a series of experiments in animal models and in vitro, they showed that when you block LINGO-1 these cells actually differentiate and make myelin. Here we are more than 10 years later reporting the first results of an efficacy trial of anti-LINGO in humans. That's the RENEW study in acute optic neuritis.   MSDF So tell me about the use of optic neuritis sort of as a model of MS.   Dr. Cadavid Yes, we chose acute optic neuritis as the first efficacy trial because, first of all, acute optic neuritis is how many of them, as patients, actually initially present. They're healthy, living in the community, and so then they lose vision in one eye due to acute optic neuritis. In fact, during their lifetime, most MS patients will develop acute optic neuritis, so it is very relevant to MS. But also because it's the one part of the brain that is readily accessible. Through the pupil, we can actually image the neurons of the optic nerve. And using electrophysiology and something called visual evoked potentials, we can very accurately measure the function of this neuronal pathway. So it is not only relevant to MS, we have really good tools to investigate not only the disease but what anti-LINGO-1 may be doing to help the patients.   MSDF But are there indications that anti-LINGO-1 has affects more centrally than the optic nerve?   Dr. Cadavid So the optic nerve – we call it a nerve, but it is really not a nerve – it's a part of the brain. So anti-LINGO-1 is actually a central molecule. What we mean? It's really expressed only in neurons and in the myelin forming cells; it's not expressed outside of the central nervous system. So all the effects of anti-LINGO-1 are believed to occur centrally.   MSDF Where is anti-LINGO-1 in the development process?   Dr. Cadavid We are in the middle of drug development process, Bob, I assume you're asking me. We are in the middle of phase 2. We just finished the first of the two phase 2 trials called RENEW. These are results we are communicating at the academy this year. We believe the RENEW trial results showed efficacy on the primary endpoint: recovery of latency of the visually evoked potential. And we believe this is the first evidence that blocking LINGO-1, in fact, is leading to remyelination in the human brain, first episode of acute optic neuritis. So it's only approved for biology. At the same time, we are running a larger study in MS patients both relapsing-remitting and secondary-progressive. It is a longer trial, 22 months. That trial is fully enroll, ongoing, and we are looking forward to the results next year. The results of both trials will inform on the next steps.   MSDF Is that a phase 2 trial, as well?   Dr. Cadavid Correct. It's the MS trial; it's called SYNERGY, and it's a phase 2 trial. It is dose ranging. Unlike RENEW in which we only tested one dose, in the MS trial – SYNERGY – we are testing several doses.   MSDF How is it administered?   Dr. Cadavid It is a monoclonal antibody given every four weeks by an intravenous infusion.   MSDF So you said that the results of this larger phase 2 trial will be available next year. Assuming that those results are favorable, what's the next step after that?   Dr. Cadavid The final phase of drug development is what we call phase 3, which is when we actually run definite trials where the primary endpoint it's some meaningful clinical endpoint. For example, improvement in disability, slowing of disease worsening. So those phase 3 trials are usually longer and larger, and if the primary endpoints are met and the safety and tolerability is adequate, we file hoping for drug approval and to make this therapy available to patients.   MSDF Four or five years?   Dr. Cadavid Phase 3 trials are usually longer, and we don't know until we're there. But yeah, these are a longer part of the drug development process.   MSDF Now assuming that the clinical trials do pan out – and maybe it's a little bit too early to ask this question, but I'm going to ask it anyway – how will anti-LINGO-1 be used? Is it going to be used early in the disease, late in the disease? The way other DMTs are used now continuously or to respond to a remission?   Dr. Cadavid Ultimately, it will come from the results from the trials. But if you think about demyelination, it is a core component of MS. All forms of MS – from very early to very late – have a loss of myelin. So as long as there is ongoing or preexisting loss of myelin, we believe there is a potential for a remyelinating therapy like anti-LINGO to help the patients.   MSDF Now you mentioned not only relapsing-remitting but secondary-progressive, and I'm sure you know there's a long history of things that have not worked well for progressive disease. Do you have a reason to believe that anti-LINGO-1 will be efficacious for progressive disease?   Dr. Cadavid So, Bob, it is true that there really no effective therapies in SPMS right now. It is an area that we are focusing on anti-LINGO because we know there is extensive demyelination in secondary-progressive MS. Interestingly, there is a lot of cortical demyelination with relative preservation of axons and neurons. So we believe that if this drug is capable of repairing the myelin we could actually be able to help patients with SPMS. The phase 2 program includes patients with SPMS, so we obviously are looking forward to the results from the ongoing phase 2 trials to help us make decisions on next steps.   MSDF Why not primary progressive?   Dr. Cadavid Primary progressive MS is also under consideration. Right now we have to focus. Obviously what we learned from secondary-progressive MS will also inform us as to pursue primary progressive MS. We are aware there is a high unmet need, and we keep those patients at heart too.   MSDF Just in terms of procedurally a technique why are you focusing on secondary-progressive before primary progressive?   Dr. Cadavid So there are some practical reasons. One of them is that SPMS is viewed as closer to relapsing-remitting MS relative to primary progressive MS. So in the phase 2 trial, we have to try to keep some focus on the population. If we spread too much, it may become more difficult to actually interpret the data. There is a strategic reason as SPMS is closer to RRMS than PPMS is.   MSDF Well, Dr. Cadavid, I've come to the end of my prepared questions. Is there anything I haven't asked that I should have asked or anything you'd like to add?   Dr. Cadavid I like to finish by saying that the results of the RENEW trial it's really the first time we have seen evidence from the human brain that it appears possible to repair the myelin. This is a very important step in the field. There is a lot of work to do. But it is encouraging news, and we are happy to share this with the community. And Biogen is very committed to MS and to help patients who are living with this chronic disabling condition. So we welcome the news, and we also are ready to embrace the following stages of drug development, which are obviously very challenging.   MSDF Well Dr. Cadavid, thank you very much.   Dr. Cadavid Thank you, Bob, was a pleasure.   [transition music]   MSDF Thank you for listening to Episode Forty-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 editor@msdiscovery.org.   [outro music]  

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty 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 Raj Kapoor who discusses a clinical trial of the epilepsy drug, phenytoin, for MS. But first, a few updates on the latest developments at MSDF.   We posted an essay by Dr. Katie Lidster of the National Centre for the Replacement, Refinement, & Reduction of Animals in Research, a U.K.-based scientific organization. In her essay, she points out that Dr. Kapoor’s phenytoin study was made possible by the prior development of a refined mouse model of MS that is more humane than experimental autoimmune encephalomyelitis, which results in paralysis. To find Dr. Lidster’s article, go to msdiscovery.org and click first on News and Future Directions and then on Essays and Opinions.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the month of April, we added 9 new trials, we updated information on 28 trials, and we've added 42 other pieces of information.  The drugs with important additions and changes are alemtuzumab; BAF312; BIIB033, which is also called anti-LINGO-1; daclizumab; dalfampridine; dimethyl fumarate; fingolimod; glatiramer acetate; interferon beta-1a; interferon beta-1b; laquinimod; mitoxantrone; natalizumab; phenytoin; rituximab; RPC1063; and teriflunomide. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   According to our curated list of the latest scientific articles related to MS, 42 such articles were published last week. We selected two of them as Editors’ Picks. One is a review of the role of microRNA in MS. The other is an analysis of the cost of MS drugs in the U.S. This study reports several startling facts. For example, first-generation MS drugs, which cost $8000 to $11,000 annually when they were first released, now cost $60,000 a year. And disease-modifying therapies cost two to three times more in the in the US than in comparable countries. This study ties in nicely with our interview with Dr. Kapoor. Phenytoin has been off patent for many years and is dirt cheap. Good news for MS patients? Maybe not. Paradoxically, phenytoin’s low cost may mean that it will never be fully developed for use in MS. To see our curated list of recently published papers, go to msdiscovery.org and click on Papers.   [transition music]   Now to the interview. Dr. Raj Kapoor is a neurologist at the National Hospital for Neurology and Neurosurgery in London, England.   Interviewer – Robert Finn Hello, this is Bob Finn. I'm at the American Academy of Neurology meeting Washington, D.C., and I'm talking with Dr. Ray Kapoor, who's presenting a very interesting study on a trial of phenytoin – also called Dilantin – in optic neuritis. Dr. Kapoor, welcome. So my first question is why phenytoin and why optic neuritis?   Interviewee – Raj Kapoor So phenytoin we use because it works as a sodium channel blocker, and this is based on years of experience and validation in animal models over the years about how neuroprotection could be achieved in MS. And it turns out that sodium channels are quite important for neurodegeneration in the setting of inflammation. And work in London that we've done, work in Yale has validated animal models that say that if you block sodium channels you can achieve neuroprotection. So why phenytoin? Well that comes down to why optic neuritis? We wanted to test sodium channel blockade in a relapse. And optic neuritis has a lot of advantages because you can study the visual system in so many ways. So why phenytoin? Because we think there's a window of opportunity, and a relapse degeneration occurs pretty rapidly. You need to treat quickly to switch off the mechanisms of neurodegeneration. And phenytoin has the advantage that we can load it very quickly and achieve therapeutic levels. So we have here a model of neuroinflammation and neurodegeneration, which we can study using multiple techniques. And we have a drug that we can load and inhibit those mechanisms quickly.   MSDF I find it fascinating that optic neuritis, which is one of the many symptoms of multiple sclerosis, can be used as a model for multiple sclerosis itself.   Dr. Kapoor The important thing there is it's part of the model. And the key is that we have – in MS – two processes going on. We have inflammation flaring up and leading to relapses like optic neuritis; and then, there is perhaps an allied or even a second process going on, which is the slow grumbling degeneration that leads to progression of disability. Now, we've studied both, but what we're focusing on in this study is that acute process that leads to relapses, you know, attacks which occur from time to time. I mean they're quite important in themselves because they don't always recover. We know that with every attack – even if there's apparent recovery – there is underlying damage to the nervous system. So to protect the nerves in any case is self-serving; it's a good idea. But what we are hoping is that this may even be a key to preventing progression, and that would really be a worthwhile target.   MSDF So you say you chose phenytoin because of its effects as a sodium blocker. What's the connection between sodium and neurodegeneration?   Dr. Kapoor What we found many years ago was that in areas of inflammation there can be nerve damage. And the inflammation drives nerve damage through a number of pathways, but one of them is that it actually indirect leads to sodium accumulation inside the nerve fiber, the axons. This has been well worked out in ischemia, as well. So sodium enters axons; it can't leave through the normal sodium pump because they're metabolically inhibited by the inflammation itself. And the sodium exchanges with calcium. So there's a sodium/calcium exchange in the membrane of nerve cells, and if you load them with sodium then sodium has to get out and gets out by driving the influx of calcium, and that's dangerous; that kills axons. So the whole process can be inhibited by inhibiting sodium entry. Now there's another thing that's very important, which is in acute inflammation one of the things that drives it is microglia, activated microglia release chemicals such as nitric oxide, which in themselves drive the whole inflammatory damaging cascade. But it turns out – and this is work from Yale – that actually the microglia themselves have sodium channels, and that their functioning can be inhibited by inhibiting those same channel. So what phenytoin is doing is it's actually inhibiting not only the cascade that damages the axons but is actually inhibiting the cells which are driving the inflammation and causing the damage in the first place.   MSDF Now, is there any indication that phenytoin may be working in this way more centrally than the optic nerve?   Dr. Kapoor It's very unlikely because the mechanism that we've testes is really something well characterized as inflammation within the optic nerve. And we are measuring the damage and the effects of treatment by actually imaging the retina looking at retrograde degeneration from the optic nerve lesion. So I think it's very unlikely given the timescale – you know, we're treating within a couple of weeks of onset, we're having a readout within six months – that it's doing anything other than what we're asking of it, which is a readout of what's going on in the optic nerve and retina.   MSDF If I understand you correctly, even if this is working exactly the way you want it to be, it's not going to be doing anything for people with central damage. Is that correct?   Dr. Kapoor Well I think the thing to understand here is it may do in MS where damage is happening everywhere. This is really a proof of concept. We've tried our very best to isolate the damaging process and to work out whether the theory works. So yes, there may be more general implications, and we think there probably are. But it's important to note that really what we're doing here is choosing a very clearly defined model to test the hypothesis.   MSDF Now one of the advantages of phenytoin is that it's generic; it's dirt cheap. But is that a liability, as well?   Dr. Kapoor Yeah, this is a very important point. So we're talking here about this whole issue of repurposing drugs. And we think that there may be many different drugs on the shelf which may have a role in treating diseases like MS. Now for us that was an advantage. This is an investigator led study, and it was funded by charitable means from the National MS Society and UK MS Society. So that's an advantage because the drug is really cheap. But of course, in terms of development, the commercial reality is that there's very little money in this. And so to take this further, it makes it harder not to have a drug that makes money.   MSDF So what's the solution to that problem?   Dr. Kapoor We don't know. I mean there are lots of ways that we're taking this forward. I mean you may know that there is a thing called the Progressive MS Alliance, which is an international body of MS societies, which is trying to work its way through questions exactly like this establishing industry relations. And it may be that they're a scope for industry to step in. And governments step in sometimes. I mean in the U.K. we have a trial running at the moment which is using funds from government to do a moderately sized Phase 2/Phase 3 trial of neuroprotection. So I think, actually, this all depends on the results. If the results are good, then we hope that either through industry or through government or, indeed, through charitable means there may be a way through. Just to get back to your question, I think that, you know, repurposing is a problem because clearly the commercial angle is far less prominent.   MSDF Is one possible solution to find a drug that's still under patent?   Dr. Kapoor Indeed, that would be a remarkable thing to do. But of course, a trial in the beginning would then need commercial collaboration. But certainly that's an angle.   MSDF So assuming that your research is confirmed and extended and phenytoin proves to be truly neuroprotective, when in the course of MS is it likely to be useful?   Dr. Kapoor So by definition, phenytoin is going to be useful for relapses. The idea that relapses sometimes leave damage and that a drug like phenytoin or phenytoin itself prevents some of that damage speaks for itself. The real question, though, comes down to whether progressive MS is also driven by similar mechanisms. We did a trial of lamotrigine, which is another sodium channel blocking anticonvulsant, and published the results about five years ago now. And that trial was reportedly negative for its primary outcome, which was brain atrophy; could we reduce the rate of loss of brain volume. I suppose what we've done is to go back to that trial and look at positive signals there because after all the question is do sodium channel blockers prevent progressive MS or prevent progression? And in fact, it turns out that there was some remarkable positive signals in that trial. So I have the knowledge that phenytoin should be useful for relapsing MS. But I also have a hunch that it may be useful for progressive MS, as well.   MSDF Now there's a flipside to the fact that phenytoin is so easily available, and that is that physicians listening to this podcast or to other news reports may consider prescribing it off-label. How would you counsel somebody considering that?   Dr. Kapoor I think it's difficult for somebody to use phenytoin in that way because the way the trial was designed was to treat people in a very narrow window after the onset of a relapse. Now people may say well, you know, the next time I see a patient who has a relapse, you know, can't walk or the vision is affected I will immediately prescribe phenytoin. The difficulty I have there is that this remains a very attractive study but hasn't proved the point. And phenytoin is not without its side effects. You know, I'm always somebody who's evidence led, and so I would counsel against using drugs without even further evidence. This is one Phase 2 study after all. I think the temptation will be there nevertheless.   MSDF And if a physician falls to that temptation, what should he or she look for?   Dr. Kapoor Well again, this is the point. We have shown a concept works. You know, we have shown that phenytoin, by a number of measures, prevents nerve damage. I think the difficulty – and I need to be very clear about this – is that with acute optic neuritis where vision generally recovers we didn't see better recovery with phenytoin. So again, perhaps another answer is that if I treat somebody with a relapse with phenytoin I'm not really sure that I may be protecting nerves, but am I producing a better outcome? So that may be another reason to say let's wait for a better drug or a better trial.   MSDF That's a very good point. So is there anything I haven't asked that I should have asked, or anything you'd like to add?   Dr. Kapoor No, I think that really the way I want to convey the result is that it's a robust result. I mean what I'll be presenting is that on a number of measures the drug worked. I think it worked with a modest amount of success. I see this is opening a door. I don't see this as the final answer to a problem. You know, if you think about it, we've been looking for a long time for a neuroprotective drug in MS and a strategy. And I think this is opening a door, which I think needs to be opened a lot wider.   MSDF Dr. Kapoor, thank you very much.   Dr. Kapoor Thank you.    [transition music]   MSDF Thank you for listening to Episode Forty 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 editor@msdiscovery.org.   [outro music]          

[intro music]   Host – Dan Keller Hello, and welcome to Episode Thirty-Nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features the second part of our interview with Joseph Berger of the University of Pennsylvania. But to begin, a couple of updates.   Last week we told you about our Drug-Development Pipeline, which includes continually updated information on 44 investigational agents for MS. Since last week’s podcast we added two new trials, we updated information on 10 other trials, and we added 10 other pieces of information. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and phenytoin. To find information on all 44 compounds, visit msdicovery.org and click first on Research Resources and then on Drug-Development Pipeline   Two weeks ago we described how we curate a weekly list of all newly published scientific papers on MS and related disorders. Last Friday’s list included 53 papers. We selected two of them as Editor’s Picks: One is a Cochrane meta-analysis of dimethyl fumarate – trade name Tecfidera – for treating MS. The other is a study from Paul Tesar’s group at Case Western Reserve University. That study, which appeared in Nature, is entitled “Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.” To find the full weekly list and the Editor’s Picks, click on the Papers tab at msdiscovery.org.   [transition music]   Now to the interview. Dr. Joseph Berger is a professor of neurology at the Hospital of the University of Pennsylvania. In part one of his interview we talked about risk of progressive multifocal leukoencephalopathy. This week, Dr. Berger discusses diagnostic dilemmas in MS.   Interviewer – Dan Keller Dr. Berger, how do these present, and what are some of them?   Interviewee – Joseph Berger They’re legion, actually. There are a lot of different diseases that can look very much like multiple sclerosis both in terms of the history and physical examination as well as in terms of the radiographic findings. And the question is, do you want to avoid treatment that is not very helpful and expensive? You know, once you’ve made a diagnosis of multiple sclerosis you tend to put the patient on a disease-modifying therapy that they would remain on for the rest of their lives. And there’s an expense and some risk depending on what you put them on, associated with that. Secondly, there are diseases that, if you miss the diagnosis, these are diseases that can be aggressive in and of their own right, and if you’ve misdiagnosed it there’s a concern that disease may go on and create its own problems for the patient. So there are a variety of reasons why you want to ensure that what you’re dealing with is truly MS and not one of the MS mimics.   Among the common MS mimics, one that we’ve had increasing experience with in the recent past, is neuromyelitis optica. So, neuromyelitis optica was a disease that we lumped together with multiple sclerosis, but we’ve realized recently that not only is the pathogenesis different than multiple sclerosis, it being a humoral immune disorder, but that the therapies that we employ for multiple sclerosis may actually aggravate neuromyelitis optica. So that’s a common concern and one of the reasons why we frequently obtain neuromyelitis optica antibodies in patients, particularly when they present with optic neuritis or transverse myelitis, and certainly when they present with both of them.   MSDF That would be aquaporin-4 antibodies?   Dr. Berger That’s correct. It’s an aquaporin-4 antibody, but not everybody with neuromyelitis optica has the aquaporin-4 antibody that’s demonstrable. A certain percentage of them have what appears to be an anti-MAG antibody, and others we simply don’t know what the antigen is. And that’s being worked out. So there’s this whole spectrum of neuromyelitis optica that you certainly want to sort out from multiple sclerosis. But there are also a wide variety of other illnesses that can look like multiple sclerosis. In fact, if you take any broad classification of diseases – infection, vascular, neoplastic, toxic, metabolic, genetic, etc. – if you do that and say, are there diseases in these categories that can appear like multiple sclerosis and be mistaken for multiple sclerosis, there are. So every single one of these broad categories can have within it a disease that can be mistaken for multiple sclerosis.   MSDF Would they be mistaken for multiple sclerosis on many measures or mainly signs and symptoms or is it radiologic on imaging? How do you sort out this kind of gamish of different diseases and how they present, and really nailing down an MS diagnosis, not even considering a diagnosis of what else it could be?   Dr. Berger So it can be enormously difficult to do so. And I’ll give you some examples from my own practice. I have, for instance, seen individuals with a disorder called hereditary spastic paraparesis where you were unaware of their hereditary nature of their disease. And the patient has come in with a progressive myelopathy. And you say, well, could this be primary progressive multiple sclerosis? And could be extraordinarily difficult to sort out, particularly if they don’t have common mutations, and they don’t have a family history. And you say, well, which is it? The spinal fluid can be very helpful in that regard.   The MRIs can be very helpful in that regard, but not always. I’ve seen individuals who’ve had vascular disease where the MRI abnormalities have looked very much like multiple sclerosis. They’ve had recurrent episodes of neurologic symptoms be it numbness or weakness or visual problems, and it be mistake for MS. I’ve seen individuals with intravascular lymphoma, a rare disease, but one where they’ve presented with both clinical picture and MRI that looks very much like multiple sclerosis.   Although we have good diagnostic criteria, there is no single test that tells you that this is MS. But there are times when all of us, even the very best clinicians, scratch our heads when a patient’s reappeared in the office; nothing new has happened to him. Ten years have elapsed, and you say to yourself, did they really have multiple sclerosis? So, again, it’s a matter of comprehensive history and physical; the appropriate radiographic studies; looking at the spinal fluid when that’s indicated; and doing the appropriate laboratory studies to rule out things that may mimic multiple sclerosis.   MSDF Is that why there is a diagnosis of CIS? If it never returns, then it was CIS?   Dr. Berger I guess one could say that, but I use the term CIS to mean the very first episode of multiple sclerosis. So when I label somebody with CIS, I already believe that they have multiple sclerosis. I think that if they have CIS in the absence of any radiographic findings, I’d be unlikely to label them CIS. CIS to me is in the continuum of MS, so you have CIS, relapsing/remitting multiple sclerosis, secondary progressive multiple sclerosis. So that’s how I use the term.   MSDF Can you definitely rule in or rule out multiple sclerosis?   Dr. Berger I think that there are probably rare instances where people fulfill all the criteria for multiple sclerosis. And at the time of autopsy you say, how about that? That wasn’t multiple sclerosis. There’s an old expression in medicine that you can never be a 100% certain. You can never have a 100% certainty. So I think that you do the best you can. And I think that probably the rate’s 99% or better, but in these people fulfilling the criteria that have been established. However, you can never be entirely certain.   And it is not that uncommon in my practice, and I’ve been practicing medicine nearly 40 years, where an individual has presented the office after a long hiatus. And the chart is unavailable to me, and they come in with a diagnosis of multiple sclerosis, and I say, who made the diagnosis of multiple sclerosis in you? And they go, you did, Dr. Berger. So I think go down to the cave where they keep the charts that are over seven years old only to find out that they had all the criteria for multiple sclerosis; that they had oligoclonal bands, and they had hyperintense signal abnormalities on their MRI, and they had relapsing symptoms, but, you know, over the course of the last 10 years they’ve had little. And you scratch your head and say, geeze I wonder if this is truly MS?   There are probably people who carry this diagnosis, and there’s literature on it, that carry it incorrectly.   MSDF Those criteria, even though it never turned out to be MS, satisfied a diagnosis of MS. When you see something like radiologically isolated syndrome, do you work it up for MS, or only once it presents later does it become MS?   Dr. Berger This is a very difficult question, and we see this with some regularity, that is, the individual that has hit his head in a car accident or developed a headache that somebody’s decided to do an MRI on. And they come in with an MRI that looks all the world like a patient with multiple sclerosis, yet they have no symptoms and no signs on physical examination that is suggestive of multiple sclerosis. And the question then becomes, what do you do with them?   There’s currently a study in which that question is being addressed. However, I will tell you what I do, currently. I do look for multiple sclerosis. I look for lesions in their spinal cords because I think that if they have that, the prognosis can’t be good, and I would likely start somebody with lesions in their spinal cord, who I’m convinced has MS, on a disease-modifying drug.   I look their spinal fluid. And I look at their spinal fluid for oligoclonal bands, and, if I see that, I’m increasingly convinced that that’s what we’re dealing with. And I would be inclined to treat those people as well. Now whether I’m doing the right thing or not, I don’t know, but for others in whom there are no spinal cord lesions, there are no signs or symptoms, and the spinal fluid is pristine, I’ve elected to wait. That is not necessarily the consensus among the MS community. That’s simply how I practice, currently.   MSDF People don’t need oligoclonal bands to have MS, though, do they?   Dr. Berger No, not at all. So, we certainly see a fair number of people – and it depends on the study – who have pristine spinal fluids. That means no oligoclonal bands, no cells, no increased protein, no elevated myelin basic protein or IgGs who still have multiple sclerosis.   MSDF What about fatigue as an initial symptom of multiple sclerosis? A lot of people have fatigue – tiredness. Is there a way to differentiate the fatigue of multiple sclerosis from just being tired or a sleep apnea or an insomnia or they just don’t feel good?   Dr. Berger Well, I think your history is very helpful because the sleep deprivation and excessive daytime sleepiness is not the same as the fatigue that people with MS report. The fatigue that people with MS report is akin to the fatigue that one experiences when they have a viral illness. So when you have the flu you go, oh man, I just can’t get out of bed. I feel terrible. And that’s precisely what the people with multiple sclerosis have. And what’s so interesting is how common it is. So it’s been said to be the greatest cause of disability in the MS population. It’s an acceptable cause of disability; not blindness, not incoordination, not weakness, but fatigue.   And it’s curious, when I practiced in Kentucky, I had a number of patients who were wheelchair-bound, had very poor vision or had double vision because of paralysis ocular palsies, who went to work every single day. And then I had patients that looked as healthy as you and I, and they were on disability. And I said, well, why is it that you can’t work? They said, I’m just too fatigued. I can’t do anything. It’s affected everything.   So the fatigue is different, and getting back to the frequency of it, so in individuals who have been diagnosed with multiple sclerosis, and I was part of this study, if you look at large numbers of individuals diagnosed with MS or who are on disease-modifying drugs for MS and go back and look at their medical records prior to the time of the diagnosis, you will see that about a third of them had been labeled by their family physician or their internist as having one of two diagnoses: chronic fatigue syndrome or fatigue and malaise. They’re the only two diagnoses with fatigue in them that you could put into the ICD-9 classification.   So, this is striking that so many individuals have fatigue recognized, yet it’s an advance of their having any neurologic symptoms that were believed to be the consequence of multiple sclerosis. It’s not to say that they didn’t have them. You know, it might have been some transient numbness or transient tingling or slight weakness that went away that nobody ever thought was due to multiple sclerosis. So that we don’t know about. But what I can tell you is that prior to an established diagnosis of multiple sclerosis, roughly a third of individuals have been labeled by their family physicians with fatigue.   MSDF It’s interesting that you make the analogy between this sort of fatigue and that with a viral illness like the flu. Could this be a prodrome telling there’s an inflammatory process going on? I mean, is there interferon release or are there other mediators that seem to be unique to this kind of fatigue?   Dr. Berger I would like to think that that’s the case. I would like to think that this is due to the very same cytokines that cause the fatigue that’s associated with viral illness. That’s not been convincingly demonstrated, although it’s been proposed. I think it makes a lot of sense. Coming full circle, eventually, although most of my colleagues classify multiple sclerosis as an autoimmune disease, there must be a trigger for the autoimmune disease. And my own belief, coming to this from virological angles as opposed to coming at it from an immune angle, is that there’s probably some infectious origin.   One of the things that’s so striking is the association between Epstein-Barr virus and multiple sclerosis where virtually every adult patient with multiple sclerosis has evidence serologically of having been exposed to Epstein-Barr virus. Now I’m not saying that that’s necessarily the cause, but in some way it must contribute to the development of the disease perhaps in a way that low vitamin D levels contribute to the genesis of the disease.   MSDF Is there anything you’d like to add about diagnostic dilemmas or any kind of a mental framework for approaching this sort of thing, in nutshell?   Dr. Berger Yes. The one thing that I would say is never be too confident. Never be too confident. I found that my highest confidence levels were right before I took boards in neurology, which was a long time ago. And I thought I knew everything. And the more I practice neurology, the more humble I’ve become in terms of establishing diagnoses and selecting right therapies for patients. So I always have a healthy skepticism. I have a healthy skepticism of things that I feel certain about. And when patients represent to office I always question myself, particularly if there’s something that doesn’t fit with the diagnosis. And I think that that’s good advice to anybody practicing medicine.   MSDF Very good! Thank you.   Dr. Berger My pleasure.   [transition music]   Thank you for listening to Episode Thirty-Nine 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 editor@msdiscovery.org.   [outro music]

[intro music]   Hello, and welcome to Episode Thirty-Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features part one of a two-part interview with Joseph Berger of the University of Pennsylvania. But to begin, we’d like to tell you about MSDF’s Drug-Development Pipeline.   Twelve drugs are currently approved in the US for the treatment of MS, but there are many more drugs in various stages of clinical and pre-clinical development. We’re keeping daily track of 44 of them in our Drug Development Pipeline.   To visit the pipeline just go to msdiscovery.org and click on Research Resources, and then Drug-Development Pipeline. You’ll find a finely detailed, fully referenced, and easily searchable database of all 44 of those drugs. The database includes details on each drug candidate’s physiology, its progress through pre-clinical and clinical trials, and its regulatory and commercial status.   Science journalist Heather McDonald has managed this database since its inception, and she updates it continuously, whenever new information becomes available. In just the last week, for example, she added one new clinical trial to the database, she updated information on two other clinical trials, and she added 5 other pieces of information. The drugs with important additions and changes were dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and RPC1063.   [transition music]   Now to the interview. Dr. Joseph P Berger is a professor of neurology and Chief of the MS Division at the University of Pennsylvania in Philadelphia. In part one of our discussion with Dr. Berger, we’re talking about the risk of progressive multifocal leukoencephalopathy (PML), a rare but serious brain infection that occasionally arises in people being treated for multiple sclerosis.   Interviewer – Dan Keller The topic of quantifying risk and mitigating risk comes up with certain immunosuppressive drugs, notably natalizumab in MS but also with other drugs as well in other conditions. What are some of the confounding factors? Why is this not an easy thing to approach?   Interviewee – Joseph Berger Well, it’s not easy because it’s so unpredictable. Nobody would have thought that natalizumab would have uniquely predisposed to the development of progressive multifocal leukoencephalopathy. In fact, when natalizumab was introduced, if one would have attempted to predict what would have happened, you might have said, well, we’ll see a wide variety of opportunistic infections of the central nervous system, since this is a drug that prevents the neural immunosurveillance that is necessary to prevent these diseases from occurring. However, that’s not what we see. We don’t see the opportunistic infections of the central nervous system that we see in the AIDS patient; for instance, things like cryptococcal meningitis and toxoplasma and tuberculous meningitis, it simply doesn’t happen. What we see, on the other hand, is this unique increased risk for the development of progressive multifocal leukoencephalopathy. This was an entirely, in my mind, unpredictable event. I suspect that this is true of many of the other drugs that are now coming to market; that our experience with them is limited, they have what we think is a well-defined effect on the immune system – they’re not broadly immunosuppressant – yet our knowledge of the immune system is such that we don’t understand fully the downstream effects they have. And it’s only after we’ve used these drugs for a number of years do we have a comfort level with what sort of risks that are engendered by their use.   MSDF But it’s not unique to natalizumab; other drugs can induce this whether in neurologic conditions or even rheumatologic conditions. Is that right?   Dr. Berger Yes. In talking about PML, that is true that there are other drugs that carry black box warnings for the development of PML; however, there’s something unique about natalizumab and another drug that is somewhat related to it and now off the market called efalizumab, which was a drug which went by the name of Raptiva and was used for the treatment of psoriasis. So there are drugs that uniquely increase the risk of PML and there are those that marginally increase the risk of PML, and one shouldn’t conflate them. And though a drug carries a black box warning for PML, it doesn’t necessarily mean that the risk is the same as it is with another drug that may also carry such a warning.   And let me explain this a little further. If you look at natalizumab and you look at efalizumab, those are drugs that have been used for conditions that had never previously been associated with progressive multifocal leukoencephalopathy. So despite the fact… And natalizumab, as you know, is used in the treatment of MS and used in the treatment of inflammatory bowel disorders, in particular Crohn’s disease, efalizumab used in the treatment of psoriasis; these are autoimmune diseases. And prior to the availability of these compounds, we did some aggressive immunosuppressive therapies in the treatment of these diseases. We would treat them with drugs like Cytoxan and azathioprine and high-dose steroids; a wide variety of things were employed. Yet until the PML experience with natalizumab and efalizumab, we had never seen PML in the setting of multiple sclerosis, in the setting of inflammatory bowel disease, or in the setting of psoriasis. So that tells you that there’s something unique about the drugs that we’re using and that it’s not necessarily the underlying condition that is responsible.   The second is when you start the drug, you do not see PML develop immediately; it takes some time. So the experience with efalizumab was three or more years, the experience with natalizumab is typically 12 months; actually the vast majority of cases – over 80% - have been on natalizumab for 24 months, so they’re on the drug for a long time. The shortest latency from initiation to the development of PML has been a single case in which it developed within eight months; everything else is 12 or more months. So what is that telling you? That tells you that the drug is doing something fundamentally to overcome the barriers to the development of this disease and that it’s not simply opening up a gate and letting the horses out; it’s doing something to the pathobiology of the disease.   And then lastly, the incidence with which we see PML with natalizumab – and presumably with efalizumab, although the numbers were much smaller – is extraordinarily high in the appropriate context. So for natalizumab, the risk of developing PML, provided you’re on the drug for two years, you’ve seen prior immunosuppressive therapy, and you’re JC virus antibody-positive so that you have been exposed to the virus that causes this disease, if you have all three of those, your risk is on the order of 1 in 90 or thereabouts. That is a risk that is commensurate with what we see with HIV-associated PML, so it’s very, very high.   However, if one looks at these other drugs which I have called Class 2 agents in several papers now; drugs like rituximab, also a monoclonal antibody though directed against CD20, drugs like brentuximab vedotin or mycophenolate mofetil – which is CellCept – those drugs, too, carry black box warnings for the development of PML; however, the setting in which PML occurs with their use is almost always with a condition that already predisposes you to the development of PML. So with rituximab, for instance, it’s seen with lymphoproliferative disorders, or with transplantation, or with autoimmune diseases in which PML had already been described long before the use of rituximab for the condition. And the same is true with these other drugs.   The second is there’s no latency to the development of the disease, so this is strictly a stochastic event; you may start rituximab today and in two weeks’ time develop PML. There’s no way that somebody’s developed PML in two weeks’ time. What that indicates is that individual was predisposed to developing PML, that virus was already in their brain, it was percolating there, your immune system was suppressing it adequately so it wasn’t expressing itself. And now you’ve done something, you’ve tweaked it a bit and the PML is now expressing itself because you’ve introduced the drug, but the drug fundamentally is not changing the pathobiology of the disease.   Lastly, although we do not have good figures on this, but the best data that I have is that we’re talking about orders of magnitude lower risk with these other drugs. So rituximab, for instance, the risk is probably on the order of 1 in 30,000, or something to that effect. That compared to 1 in 90 when you have all the risk factors that I described with natalizumab. So we’re talking orders of magnitude difference. So I’d suggest that we avoid conflating these drugs when talking about PML risks, and I think that this is something that is generalizable for other risks; I mean, PML is just one risk, but we see other infections and other things that have occurred with other drugs that we’ve employed tweaking the immune system, and I don’t think that one should necessarily put all these drugs that cause these things in the same boat.   MSDF These drugs that are used in other conditions that do in themselves predispose to PML, when they’re used in MS which as a disease does not, on its own, predispose to PML, these same drugs – azathioprine, cyclophosphamide, mycophenolate – add to the risk when you give natalizumab?   Dr. Berger That’s what it looks like. So when Biogen looked at the data that they had available from the initial cases of natalizumab-associated PML, one of the risks that they identified was the increased risk of the development of PML in those individuals that had previously received immunosuppressive therapy. And it really didn’t seem to matter which immunosuppressive therapy it was, it was any immunosuppressive therapy. However, it may be different with the different immunotherapies, it’s simply that the numbers weren’t large enough for one to say that this was particularly associated with azathioprine. People in Europe like to use azathioprine often very early in the course of the disease, so they were seeing a bit more PML than we had seen in the United States at least initially. And it wouldn’t surprise me if there aren’t certain immunosuppressive agents that increase the risk significantly compared to others, but we simply don’t have that data. And what is known is that it really doesn’t matter, any of them can do that.   MSDF Without really having a firm understanding of the pathogenesis of PML – you know the risks but maybe not exactly why it’s occurring – how do you come up with a framework for mitigating risk; is it purely empiric?   Dr. Berger That’s an excellent question. So it turns out that this was a back-of-the-textbook disease; this was the disease that occurred very, very rarely. Between 1958 and 1984 in a review published by Ben Brooks and Deward Walker, there were only 230 cases that they were able to come up with; 1958, of course, is when the disease was first described. So this was a very, very rare disease until the AIDS pandemic where people developed some interest in it, and then it really became interesting when we saw it with natalizumab. And there’s been more resources put into the study of this disease since then, so that we do have a better understanding of the pathogenesis. But in identifying these risks, we’ve worked backwards; you know, we say, alright, what does natalizumab do? So why is it that we see this increased risk?   So in getting back to your question, we know that immunosurveilling the brain is important; so if you have a drug that prevents appropriate immunosurveillance of the central nervosus system, it should not surprise you that the risk of PML is increased. And we do think that the alpha-4 beta-1 integrin inhibition that occurs preventing the entry of JC virus-specific cytotoxic T lymphocytes into the brain is in a large measure – but not completely – contributing to the development of PML. We also know other things. For instance, the virus that we are likely infected with – and the infection occurs very early in our lives; seroepidemiologic studies indicate that most individuals that are infected are infected before the age of 20 – that that virus is a virus that is ubiquitous but incapable of growing effectively in glial tissues; it is a virus found in urine and found in the urinary tract, it’s found in kidney and renal pelvis and bladder, and it’s found in high concentrations in some people’s urine. That virus will not grow in the brain. So something has to happen to the virus.   Does natalizumab change that in some way? Well, we think it does. We think it does that by causing the release of immature B cells; these immature B cells can harbor JC virus, and that virus as these B cells mature there is an upregulation of transcriptional factors that transactivate the virus, it is occurring in a milieu that may uniquely predispose to a genetic rearrangement of the virus enabling it to become a form of the virus referred to as a prototype strain or a neurotropic strain that can grow in the brain. So we think that there are at least two very large barriers that prevent PML that are affected by natalizumab; there may be others. And as we investigate this disease further, our understanding may improve and these explanations I’m telling you will likely be expanded. And, in fact, it may be that some of the thoughts that we have are wrong, because the story with the B cells is actually somewhat hypothetical; there’s some preliminary evidence supportive of it, and that’s why I tell people that I’m fond of Ralph Waldo Emerson’s comment, that consistency is the hobgoblin of small minds. If I stand before you a year from today and tell you something different, it’s only because we’ve learned more about it.   MSDF So how do you mitigate risk and how do you get the point across to patients to let them make informed decisions with you?   Dr. Berger So this is difficult, but we lay the facts out to them. And the facts are that there is this risk of PML, the risk in individuals that are JC virus antibody-negative are very small, the product label puts the risk at less than 1 in a thousand; the belief is that it’s significantly less than that. The fact is that we do see individuals who are JC virus antibody-negative months before the development of PML – it’s rare but it occurs – and there have been studies, including my own, that have indicated that the antibody study doesn’t necessarily mean you’ve never been infected by the virus. So one shouldn’t conflate JC virus antibody negativity with never having been infected, but it is a very good marker for the development of PML, and it is one that needs to be monitored carefully at six month intervals.   So we lay out to the patients that if you’re antibody-negative your risk is infinitesimal and an acceptable risk, and that we monitor you carefully. The second is this is a disease that can be life-threatening, and if not life-threatening certainly severely debilitating – multiple sclerosis I’m talking about – and there are people that have very aggressive disease and will accept the risk of developing PML, knowing that the risk may be 1 in 100, but their risk of developing something that was going to leave them wheelchair-bound and totally disabled is very, very high, and they say I’d rather take the risk of the development of PML.   So we do know what the numbers are. There’s a table that’s been published and gets revised periodically that puts into it JC virus antibody positivity, duration of therapy broken up into 24-month epochs, and prior immunosuppressive use. So we know what the risks are; the highest are in individuals that are treated more than 24 months with the drug, are JC virus antibody-positive, and had previously received immunosuppressive therapies.   MSDF What about monitoring for signs and symptoms of PML if someone does choose to go on some of these drugs?   Dr. Berger Yes, so that’s very, very important. And we do have patients that even in the face of JC virus antibody positivity, we and the patient elect to continue them on the drug. And patients on natalizumab need to be monitored very carefully for the development of PML, and that is a combination of both clinical screening – there is a TOUCH program that queries for the development of symptoms that may be concordant with PML – unfortunately, you also see symptoms of that nature develop in MS patients, as well, so it’s sometimes difficult to tell whether it’s MS or PML – and at that point in time you definitely want to survey them with an MRI. And, in fact, many of us do MRIs at regular intervals in patients on Tysabri attempting to identify the disease – PML – when it is asymptomatic. And those people seem to do best; the prognosis both in terms of disability and in terms of survival is better when you pick the disease up while they’re still asymptomatic, and they have what one would refer to as radiographically isolated PML.   So it’s a combination of vigilance, asking the right questions, performing your physical examination, and obtaining period MRIs, and in those that are JC virus antibody-negative – or even the antibody-positive – repeating that study periodically. And the reason I say that repeating it periodically even in the positive patients is because what’s been demonstrated is that the higher your antibody titer, the greater the risk of developing PML. So there’s a threshold now that’s been identified and individuals above that range have a significantly higher risk of developing PML than individuals who are seropositive but below that level.   MSDF And just to clarify; the TOUCH program is the Tysabri Outreach Unified Commitment to Health? This is what you’re referring to in terms of monitoring for signs and symptoms of PML?   Dr. Berger That is correct. That is the risk mitigation strategy that is FDA-approved and that Biogen has implemented in an effort to decrease the likelihood of PML developing.   MSDF Very good, thank you.   Dr. Berger My pleasure.   [transition music]   Thank you for listening to Episode Thirty-Eight 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 editor@msdiscovery.org.    [outro music]

[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 editor@msdiscovery.org.    [outro music]

 [intro music]   Hello, and welcome to Episode Thirty-Four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features a follow-up interview from last week’s episode with Dr. Pierre-Antoine Gourraud. This week, we interview Dr. Jill Hollenbach about killer immunoglobulin-like receptors – or KIR – and their relationship with human leukocyte antigen and MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Take some time to check out our most recent data visualization on our website. Under the research resources tab, you can find a series of interactive data visualizations useful for MS researchers. Our most recent one organizes 142 ongoing clinical trials into an interactive bubble chart. We have another visualization on the natural history of MS symptoms. The interactive bar chart allows you to see the change of various symptom severity in MS over a 30-year period.   If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of full-time employees and a few regular contributors. 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 discussion 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. Jill Hollenbach is an assistant professor in the department of neurology at the University of California, San Francisco. She met with science journalist Cynthia McKelvey, to talk about KIR in MS.   Interviewer – Cynthia McKelvey Why don’t we start by introducing what KIR is, how it’s different from the potassium channel and what its relationship is to HLA.   Interviewee – Jill Hollenbach Well, KIR is an acronym, it stands for killer immunoglobulin-like receptor. These are receptors on the surface on the surface of natural killer cells. They use generally, not in every case, but use HLA as their ligand and they have either an activating or inhibitory effect on natural killer cells.   MSDF You mentioned in your talk earlier today at UCSF that they are difficult to study. Why is that?   Dr. Hollenbach Just in terms of their genetic architecture. KIR occupy a complex on chromosome 19, it’s a multigene complex. And so on any individual haplotype that’s one chromosome, an individual can have between 4 and 14 KIR genes. These genes are really recently evolved, and so they’ve kind of arisen in humans as a result of repeated events of recombination and gene duplication. So what that means is that one KIR gene often at the nucleotide level looks an awful lot like another KIR gene. And so we’ve had a lot of issues. A lot of the methodologies that are available right now in terms of sequencing, part of this has to do with a lack of human genome reference alignments, but there has been a lot of difficulty in examining these genes because they look so much like one another.   MSDF How does that relate to why they haven’t really seen them on genome-wide association studies?   Dr. Hollenbach There’s a couple of reasons why we don’t see them on genome-wide association studies. One is that, as I mentioned, there haven’t been a lot of good reference alignments, so as a result we don’t actually see a lot of SNP markers on most of the common platforms that are used for genome-wide association studies. And then the markers that are there are often lost to quality control, because we have a lot of gene content variation, which is kind of like a copy number variant. And so if we only see a result for one chromosome, for example, for a given SNP, that is not going to pass general quality control thresholds. And, of course, you have to recognize that when you’re doing these GWAS studies, you’re looking at a hundred thousand, five hundred thousand, a million markers, two and a half million markers, so you’re not going one-by-one and saying, well this KIR-1, we expect to only see one copy or that sort of thing. So it just gets thrown out in the mix with things that don’t pass QC.   MSDF How does KIR relate to multiple sclerosis specifically?   Dr. Hollenbach Well, we’re trying to figure that out. So there’s been a small number of studies examining KIR in multiple sclerosis, and what seems clear is that variation in the KIR does play a role in susceptibility to multiple sclerosis. It may play a role in progression; we’re just not sure. There’s not been enough work done to say definitely what’s going on, but there’s enough evidence to say that something is going on. And some of the work that I talked about in my talk today, an analysis of KIR variation along with HLA in an African-American MS cohort, a very large study population, it seems clear that there is some association of KIR variation with susceptibility or protection for multiple sclerosis.   MSDF Why study the African-American cohort? What does that tell us about MS in general?   Dr. Hollenbach We want to study them because they’re different from one another; so an African-American population is going to look very different genetically with respect to KIR and HLA from a European-American population. So we want to know two things. We want to know is there something different going on with these genes with respect to disease in these different populations, OR at the same time we want to know is something the same going on? And so we can learn something both from these commonalities and differences, and both can be really important in genetics. So if there’s something that is important that’s specific in the African-American population, we want to know that, and we can only find out by looking at a number of different ethnic groups.   MSDF Let’s talk a little bit more about interaction between KIR and the HLA ligand, and how that plays in with Bw4. And if we can define all of those things, too, that would be great.   Dr. Hollenbach Okay. Well, so KIR molecules, as I mentioned before, need to see something, they need to have a ligand on their target cell. We have both inhibitory receptors and activating receptors. The job of the NK cell is to perform immune surveillance. So NK cells kind of wander around the body, and what they’re looking for are cells that don’t look healthy. So what does that look like and what is an unhealthy cell? It’s a cell that is virally infected, it’s a tumor cell. Those are the two main things that NK cells are looking for. And it’s a really important function because they’re part of what we refer to as the innate immune system; it’s the first line of defense against these kind of unhealthy events.   And so what does an unhealthy cell look like? Well, one of the things that happens in both viral infection and tumors is downregulation of MHC class I. That’s what the KIR are looking for. So when an NK cell encounters a healthy cell, it will see HLA class I, it immediately recognizes this is self, this is healthy cell at least in terms of what I’m able to see as an NK cell, and it will move on and it won’t cause any damage to the cell after making contact between the KIR and that ligand.   On the other hand, if the KIR doesn’t see this HLA ligand, the inhibitory KIR, an activating KIR – and we’re still not completely sure what the activating KIR ligands are – but the activating KIR is also bound to something on the surface of this cell. If the activating KIR is bound but the inhibitory KIR is not, what happens is the NK cell is going to lyse that cell which is presumably unhealthy in some ways – tumor or viral infected.   Now HLA class I – actually all HLA molecules – have another primary really important role which is antigen presentation to T cells. Class I molecules present antigen to the CD8-positive T cells, and so that’s how these T cells perform their role in terms of the active immune response. KIRs see a different part of the HLA molecule than the T cell receptors, and so they see kind of this piece of the HLA class I molecule that’s kind of on the side of where the T cell receptors sit. And the variation that they see on that HLA class I molecule can kind of be defined by these broad categories based on the particular amino acid residues. And it’s generally just from two to four amino acid residues that determine whether or not a given KIR can see a given HLA class I molecule.   So one of these epitopes, as we call them – and if they were originally defined on a serological basis because specific antibodies could recognize them – so one of these epitopes is referred to as Bw4; these are epitopes that we mainly see on HLA-B molecules – not all – so depending on the population, human population, may be from 40 to 60 or 70% of HLA-B molecules will have this Bw4 epitope. Some HLA-A molecules also bear the Bw4 epitope. So that’s what some KIR molecules, specifically KIR3DL1, is seeing is Bw4.   The results of the study that I talked about today and what we saw is in this African-American multiple sclerosis cohort, individuals that have both 3DL1 and HLA alleles with the Bw4 epitope appear to be protected from multiple sclerosis. And so we see higher frequencies of this combination in our control population relative to patients. So that suggests a protective effect of that combination, 3DL1 plus Bw4.   MSDF Where do you see the research going from here?   Dr. Hollenbach Right now the data that we’re looking at is strictly in terms of carrying frequencies for these particular genes. So these genes are actually highly variable at the allele level, so any given gene like KIR3DL1 has many, many variants that are already known, and likely many variants that we haven’t identified yet because the technology has not been there. The technology is just about now caught up to the point where we are able to examine at the sequence level the variation within these specific KIR genes, and so I think that that’s really the next step. And we’re actually taking steps to start examining this cohort and others in terms of this fine-grained variation in the KIR genes.   MSDF Very good. Thanks.   [transition music]   Thank you for listening to Episode Thirty-Four 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 editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Thirty-Three 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. Pierre-Antoine Gourraud about the function of human leukocyte antigens and their role in MS. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Early in January, the journal Nature Reviews Neurology published a highlights issue of research advances in MS in 2014. The milestones included successful phase 2 trials for simvastatin in progressive MS, new clinical phenotype categories, and more. We summarized each of these advances, supplemented with interviews from some of the authors. Go to the “News and Future Directions” section of our website and click on “Top 8 MS Research Advances of 2014” to read it. And please do make use of our comment section, especially if you believe that we – and Nature Reviews Neurology – failed to list any equally important advances.   Dimethyl fumarate, also known as Tecfidera, may lower CD8-positive T cells in patients with MS, according to a new study out last week. This news follows an earlier story of a patient who died of complications from the rare brain infection, progressive multifocal leukoencephalopathy, or PML, after taking dimethyl fumarate. The drug is known to lower leukocyte levels, including lymphocytes, but many patients are able to maintain normal white cell counts while on the drug. This study showed that even patients with normal leukocyte counts may have dangerously low levels of CD8-positive T cells. These cells are involved in viral immunity, and lower levels of them may leave the gate open for opportunistic infections, such as JC virus, that causes PML.   If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of three full-time employees and a few regular contributors. 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 discussion 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. Pierre-Antoine Gourraud is the leader of the translational digital medicine group in the Department of Neurology at the University of California, San Francisco. He’s also a distinguished member of our scientific advisory board. He met with science writer, Cynthia McKelvey, to talk about human leukocyte antigen in MS.     Interviewer – Cynthia McKelvey Let’s begin by defining the major histocompatibility complex and human leukocyte antigen; what those are and how they relate to multiple sclerosis.   Interviewee – Pierre-Antoine Gourraud So the MHC, the major histocompatibility complex is one of the most important region of the genome. It’s 1000 of the genomes, 3.6 megabase, but it represent about 1% of the total number of genes. So a region that is very dense in genes that are very, very important in neurological functions. It’s also one of the most polymorphic region of the genome, which mean that there are many, many version, many diversity, a lot of alleles, as we call these different forms of a given gene for that particular region of the genome. Basically, it’s encode for or identity or genetic identity, and it has been studied a lot for transmutation. So for multiple sclerosis, since 1972 has been recognized that something in that region had to do with multiple sclerosis risks or the susceptibility; why people are getting multiple sclerosis whatever or not. So back in 1972, researchers realized that people carrying an HLA-DR2 type were actually more susceptible to multiple sclerosis. So doing that in a very simple and comparative manner, we took a bunch of people that have MS, a bunch of people that don’t have MS, and you just see that people that have MS tends to have more HLA-DR2. At that time, the HLAs so the genes that bears the immunity identity of [?] – very important for transmutation again – they were typed by serological techniques. So we were using antibodies to distinguish different types. Over the years, serology has been replaced by PCR-based technique, molecular techniques, and we are now doing HLA typing by sequencing. And for 30 years basically this result has been confirmed, and many additional findings we find the initial association between the MHC region and multiple sclerosis.   MSDF So you’re looking at a cohort of African American MS patients and comparing them to people of European descent with MS. And, you're seeing some differences in the major histocompatibility complexes with these. And how do those relate to MS? What are they telling you about the disease?   Dr. Gourraud You know, if we're stepping back a little bit, it's very important to get very large samples to do genetic studies. The more people we are looking at the easier the findings easy to find alleles. So UCSF and other groups in the world have been organizing to coordinate their effort in structuring the International Multiple Sclerosis Genetic Consortium, IMSGC, and we have been really, really successful in gathering large number of MS patients of European ancestry, as well as controls. Within that consortium, UCSF and Dr. Cree and Dr. Oksenberg, have been pushing an effort to coordinate as well African American cohort of MS patients. So we have been working on that, and for the past two to three years we have done a tremendous effort to actually type the HLA of these patients and these controls. And we have gathered more than about 1600 African American MS patients – and we are still collecting them – and roughly 2000 African American controls to do the comparison.   So the first thing we want to do is to see if we are confirming what we see in the European patients – and that is true – we have found  HLA-DRB1 15:01, 15:03 as a specific allele for African American. The HLA-DRB1 03:01 is also to some extent a risk allele in African American. And we also confirm that in the class I HLA-02:01 has a protective effect on MS. So, it's not necessarily obvious, because some of these alleles are actually not found in people of African ancestry, and they also have a much larger diversity. So we are starting to accumulate evidence showing that other alleles that are not present in the Europeans are associated with MS risk. And that’s a very important finding, because now we are in a position where we're going to find structural, functional commonalities between the African American alleles and the European alleles that are both associated to MS.   MSDF And where do you see the research going from here?   Dr. Gourraud So one also very important topic that's being working on both in Europeans and African American is trying not to consider HLA on its own, even if we have really put a lot of samples and money and effort in that, but also consider another very complex family of genes that interact with HLA. These are called KIR (K-I-R), and they are receptor at the cell surface of NK cells, the natural killer cells that have a very important role in immune regulation, and it has been reported that NK cells are actually present in the brain in active MS lesions. So we looked at these two system as potentially interacting to define the risk of MS. So we started typing also for these KIR genes in our African American to be able to study at the same time the MHC or the HLA genes, the KIR genes on a different region of the genome, and also the rest of the genome where we've used a simple marker called SNP.   MSDF That’s great. Thank you very much.   Dr. Gourraud You’re very welcome. Thank you.   [transition music]   Thank you for listening to Episode Thirty-Three 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 editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Thirty-Two 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. David Holtzman of Washington University in St. Louis about how a protein implicated in Alzheimer’s disease may also have a role in MS progression. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   We recently added a new data visualization to our growing collection. This one organizes every ongoing MS clinical trial—142 of them—into an interactive bubble chart. The size of each bubble represents the sample size of the trial, and the color indicates if the compound has been used to treat MS before. You can organize the chart 10 different ways, including by phase, compound, and sponsor. Go to the “Research Resources” section of our page and click on “data visualizations” to view it.   Yet another Phase 2 trial on autologous hematopoietic stem cell transplant was published last week. We reported on this trial’s results and how it was different from previous trials we covered. Like the last two studies we reported on, this current study yielded very encouraging results. To view all of the stem cell stories, go to the “news and future directions” section of our website and look for any story with an image of a mouse in a little white lab coat.   New research from the journal Neurology suggests that imaging measurements of the spinal cord and retina independently correlate to disability. Specifically, damage in the two structures was related to visual acuity and to the patient’s ability to discern vibration sensation. The authors suggested that clinicians may want to incorporate scans of the spinal cord and retina into their routine practice.   [transition music]   Now to the interview. Dr. David Holtzman is Chairman of the Department of Neurology at Washington University. He met with MSDF senior science journalist, Carol Cruzan Morton, at a recent Keystone meeting in Taos, New Mexico, to discuss how his work on apolipoprotein Ein Alzheimer's disease may be relevant to MS.   Interviewee – David Holtzman Most of my career has been focused on trying to understand the pathogenesis of Alzheimer's disease, as well as to develop better diagnostic and treatment methods. However, in doing that – in trying to study the science behind that disease – I've also worked a lot on how normal brain function might be related to not only Alzheimer's disease but just some of the proteins that are involved in both Alzheimer's disease and related disorders.   Interviewer – Carol Cruzan Morton We're at the Keystone meeting on neuroinflammation in Taos, New Mexico, and at the talk this morning you mentioned that there might be a connection between the ApoE and this protein involved in Alzheimer's and MS. Can you talk a little bit more about how that protein works normally in an Alzheimer's, and how you came to make that connection to multiple sclerosis?   Dr. Holtzman Sure. Apolipoprotein E first just in terms of a risk factor for Alzheimer's disease ApoE is present as a protein in all of our bodies. It's made in the brain; it's made by the liver; it's at very high levels in the bloodstream. ApoE plays a role in the bloodstream in transporting lipids around the body. It turns out, though, that if the only thing it did was to transport lipids in the blood then you would probably only need to produce it in the liver so that it was secreted into the blood. But interestingly, it's also produced in several other organs: the ovary, the testes, the brain, and a few other places. So in those other organs, it doesn't probably have exactly the same function that it does when it's made by the liver. But the form of the lipoprotein that's in the brain that ApoE is within is somewhat different than it is, for example, in the bloodstream. It's in what's called HDL or high-density lipoproteins in the brain.   MSDF That's a good thing, right?   Dr. Holtzman That's the good cholesterol. That's the good cholesterol in the blood. In the brain, it's not entirely clear what these HDL lipoprotein particles are really doing. So, for example, if ApoE is absent from the brain of a person, and there are people that have genetic mutations, they have no ApoE in their body…   MSDF Completely gone.   Dr. Holtzman Completely gone. And they have developed serious problems with cholesterol buildup in their arteries because they can't clear big lipoprotein particles from their blood, but their brain is okay, no problem. The people are born normal; brain is okay. And there are probably other proteins in the brain that may be able to takeover for its function in the brain; whereas in the blood that's not the case.   MSDF And when it goes wrong in Alzheimer's, what's happening…?   Dr. Holtzman So that's a different issue. So in Alzheimer's disease, there's no lack of ApoE. In humans, there's three different flavors of ApoE: ApoE2, ApoE3, or ApoE4. And there's a very, very subtle difference between the ApoE2, 3, and 4; just really, really small difference. So brain function in people that are of different ApoE types is normal when they're born and when they grow up and as adults. But for some reason – which we'll talk about in a moment – when people have the ApoE4 form of ApoE, it causes a higher risk for Alzheimer's disease probably because it's promoting the buildup of one of the proteins that's really important in causing Alzheimer's disease earlier. So this amyloid protein that builds up in Alzheimer's is strongly influenced by the form of ApoE that you produce. So if you make the E4 form, it's probably because amyloid doesn't get cleared away as well; it builds up earlier. And if you have the ApoE2 form, which is protective against Alzheimer's disease, it pushes out the development of amyloid deposition until very old ages, if ever. That may be something that's related to Alzheimer's disease that's distinct from what it might do in other diseases of the brain like MS, for example.   MSDF How did you make that connection to MS?   Dr. Holtzman Right. So over the years, there's been a number of scientists and physicians around the world who have studied the many possible functions of ApoE in the body. And for gosh it's been about 30 years or so, there's been reports that one of the things that ApoE does is to influence inflammatory cells: T cells, macrophages, etc.   MSDF All over the body or in the brain and spine?   Dr. Holtzman Yeah, in different locations actually. It's never been completely clear exactly what ApoE is doing to the immune system. A lot of studies individually show effects, but it's not entirely clear what it's doing. And so, I got interested in this personally a few years ago there was a prominent paper published suggesting that one of the things that ApoE does to the immune system outside the brain is to help present antigens to the immune system if they contain lipids. And so, that caught my attention because, one, ApoE carries lipids. And just naively I thought well if it helps present lipid antigens in multiple sclerosis the antigens that are being attacked generally are the lipid related antigens.   MSDF The myelin.   Dr. Holtzman The myelin, right, exactly. So I thought well that seems, you know, maybe there's something to this that one could study in relation to MS because of that.   MSDF And then how did you go about asking those question? Where did you start?   Dr. Holtzman Basically, I thought alright, well a lot of people who work on MS if they use animal studies use the model EAE. So we thought well some of my colleagues at Washington University have been using the EAE model for years – like many people have – and so we thought well the obvious experiment to try first is just compare animals that express ApoE in their body versus those that don't. And simply ask the question is there anything different about EAE in an animal that lacks ApoE or not? And so, first, we started working with Anne Cross and then later with Greg Wu together who are experts in using animal models of MS. And ultimately published findings showing – and a few other groups have worked on this, as well – showing that there appears to be decreased clinical severity of EAE in a slightly later onset of disease in animals that lack ApoE.   MSDF And what does that tell you…there might be a role or…?   Dr. Holtzman Obviously many other studies would need to be done to know if it has a role in human MS. But once we found that, particularly Greg's lab began to ask the question well if that's true what's the mechanism? If there is a mechanism that we could hone in on, is that something that seems logical based on what we actually know about ApoE already? And so, the things that kind of came out of our first series of studies was that – unlike what I initially had thought from this earlier paper – it doesn't appear that ApoE is modifying antigen presentation of cells or the ability of T cells to react against the brain. But something once T cells do get in the brain to attack myelin and other components, there's something about that ApoE is acting on at that point. It could be that it's involved in allowing the myelin to repair, or alternatively it could be that when T cells get into the brain and interact with other cells in the brain – like other immune cells like microglial cells or dendritic cells – that that interaction is altered by ApoE within the brain. That might make sense given that ApoE is highly expressed by macrophages outside the brain, and inside the brain it's highly expressed by what are called activated microglial cells. So kind of the macrophages of the brain. So that's where we kind of are now, and I think there's a lot more studies that could be done to really understand both that interaction as well as whether human ApoE causes the same effect that we saw in animals as mouse ApoE. Because they're not exactly the same; they're similar but not the same.   MSDF Is there other evidence connecting ApoE or its various forms with MS?   Dr. Holtzman There are human studies that have been done trying to ask the very simple questions of is the ApoE4, which is a risk factor for Alzheimer's, is that over represented in MS? Or is the ApoE2 form, which is under represented in Alzheimer's, is that protective against MS? And the studies on this some have suggested effects, some haven't. There's no clear answer. But I think if ApoE is involved in MS, it would be less likely to be involved in whether you get MS but more likely involved in the progression of the disease. And I know in the MS field one of the big areas now – now that there's so many studies and as well as treatments that have emerged that are quite effective at suppressing the initial phases of MS, the immune response phases – a lot the work is going into understanding this prolonged progressive phase of MS. And that's where ApoE could be important in sort of the repair and recovery of neurons and axons, for example. Because the fact it transports lipids between cells, maybe it has something to do with recovery of the brain after injury. And that's been speculated on for some time, although not as much work on that has been done in MS.   MSDF Has it been speculated on in MS or MS and Alzheimer's both or…?   Dr. Holtzman No, it's been speculated on after a variety of different brain injuries that it plays a role in redistributing lipids in the brain after injury, and that might be promoting recovery. So one possibility that still hasn't really been tested that I'm aware of in models of MS or in human MS is to whether that really happens for ApoE in the human brain or animal models.   MSDF Can that be tested now?   Dr. Holtzman Absolutely, absolutely. Those are some of the studies that I think are really critical as the next step.   MSDF Is it conceivable that the body of knowledge for Alzheimer's research on ApoE might yield a treatment for progressive MS?   Dr. Holtzman It's possible. I mean a lot of the understanding of what ApoE might be doing in the brain has really expanded because people have been studying Alzheimer's disease and its relationship with ApoE. So I can't imagine it wouldn't help with that because we've learned a lot so far.   MSDF Are there other treatments in the pipeline for Alzheimer's related to ApoE?   Dr. Holtzman There are. There's not too many things yet that have reached human trials, but there are groups trying to alter the level of ApoE in the brain or to alter its receptors in the brain as potential treatments for affecting Alzheimer's disease. So yeah, I mean those are the kind of things, as they advance, depending on what's found in regard to the relationship between ApoE and MS could be tried in MS. I don't see why not.   MSDF That's interesting. What else should I be asking?   Dr. Holtzman I think what scientifically what I think is really important to still sort out in this area is that when the innate immune cells of the brain – the microglial cells or even macrophages when they get into the brain – they produce tremendous levels of ApoE when that happens. And I think understanding what that protein is really doing in that setting could provide insight into future treatments. So that's what I think is really fascinating to try to understand.   MSDF Well if it happens in Alzheimer's, as well, it happens before the blood-brain barrier breaks down and then after it, it sounds like.   Dr. Holtzman Well, in MS, it's probably occurring after there's cell entry into the brain. But the upregulation of ApoE by these innate immune cells is much higher in MS than it is in Alzheimer's disease.   MSDF Oh, is that right?   Dr. Holtzman Yeah, yeah.   MSDF That's interesting. That's even more interesting.   Dr. Holtzman Yeah, I know. That's why it's really, really fascinating. I think one of the figures from the paper that we published last year from Greg's lab showed that the level of ApoE increasing in microglial cells versus similar cells that are present in the spleen of an animal is like 25 times higher in the setting of an EAE model than normal. So it's really, really high. Is it really doing anything, or is it just a byproduct? I suspect it probably is doing something. So that's what I think would be really interesting to figure out.   MSDF Thanks. Well I appreciate your taking time out at the Keystone meeting to talk with MS Discovery Forum.   Dr. Holtzman Yeah, it's great. Well good luck. MS is such a…the treatments that have been evolving are so exciting compared to Alzheimer's disease where we don't yet have good treatments. So I think there will be soon, but I think it's a great opportunity to even advance for ...   MSDF Is there a chance that the reverse could be true? That treatments existing for MS would be helpful in Alzheimer's?   Dr. Holtzman That's a good question. I don't know if any of the frequently used ones where you're preventing cell entry into the brain necessarily would be useful for Alzheimer's. But like one of the new drugs, Tecfidera, this oral medication does do some interesting things to cells in the brain that might be useful in a disease like Alzheimer's. So maybe there will be some things that we can translate.   MSDF I appreciate it. Thank you so much.   Dr. Holtzman Thank you.   [transition music]   Thank you for listening to Episode Thirty-Two 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 editor@msdiscovery.org.   [outro music]          

[intro music]   Host – Dan Keller Hello, happy new year, and welcome to Episode Twenty-Six 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 Tim Kennedy about remyelination and neural development. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   According to a new clinical trial, azathioprine, or AZA, may be as effective as interferon beta. The generic immunosuppressant was effective in both reducing relapses and reducing new brain lesions in the multicenter trial. This may not be surprising since the drug has been used off-label to treat MS for several decades. If trials continue to go well, AZA may become the go-to alternative for patients who can’t afford brand name interferons.   A pair of Canadian studies recently showed that both neurodegeneration and inflammation may start in the early stages of pediatric multiple sclerosis. One team found epitope spreading in the blood of children shortly after the onset of MS, suggesting a potential new diagnostic tool. Though children comprise only 2 to 10 percent of the MS population, data gleaned from them may provide insights into the disease as a whole.   If you enjoyed our end-of-the-year interview with Alan Alda and find MSDF to be helpful, please consider supporting us with a donation. We share Mr. Alda’s philosophy that closing the gaps between scientific disciplines is key to improving scientific progress. To make a donation, visit msdiscovery.org and click on the green “Support MSDF” button next to “Research Resources”.   [transition music]   Now to the interview. Tim Kennedy is a researcher at the Montreal Neurological Institute. He met with MSDF to talk about the role of certain molecules and receptors necessary for oligodendrocyte development, maintenance, and function and their implications for remyelination.   Interviewer – Dan Keller Welcome, Dr. Kennedy. Let's talk about the life of oligodendrocytes. These are important for myelination and probably play a role in remyelination. What is the life of an oligodendrocyte? How does it start out? And what does it react to?   Interviewee – Tim Kennedy Many labs around the world have been studying the life history of an oligodendrocyte and also the lineage of the cells and how they differentiate during normal development. One of the reasons for doing this is that oligodendrocyte precursor cells are present in the mature nervous system and almost certainly contribute to remyelination in demyelinating diseases like MS. Oligodendrocyte precursors are born in the early embryonic CNS, and from the very restricted regions where they're born they then migrate away to populate all of the regions of the mature CNS where myelin occurs. In the lab here, we've been very interested in the molecular cues that direct and influence oligodendrocyte precursor migration. These include a family of proteins called netrins that we work on. And receptors for netrin like a protein called DCC. DCC stands for deleted in colorectal cancer. It was originally identified in cancer, and we now know that it has a critical role in the central nervous system in the migration, maturation, and maintenance of myelin by mature oligodendrocytes.   MSDF Some of these molecules take on different functions as the oligodendrocytes mature. How do they react, or what do these molecules do over time?   Dr. Kennedy When an oligodendrocyte precursor is born, it makes the netrin receptor DCC, but it doesn't make netrin. What the cell does is it responds to netrin in the environment, and through DCC reacts to it, and the netrin directs the cells to migrate. It tells them to initially migrate away from the position where they're born and sends them in the direction of axon tracks that require myelination. In mature myelinating oligodendrocytes, one of the huge surprises we had is that both of these proteins are made. Now, both netrin and DCC are required for normal neural development. If we examine a conventional knockout mouse that lacks either netrin-1 or DCC, those mice die within a few hours of being born, and there's a massive disorganization of the nervous system. So these are essential for normal neural development. When we look at the mature nervous system, we see that every single oligodendrocyte, every single mature myelination oligodendrocyte, makes readily detectable levels of netrin-1 and also the receptor for netrin-1, DCC. And a very simple statement of the question that we wanted to answer is what's the point of that? Why do these cells make these proteins that are essential for normal neural development but make them in the adult nervous system? In every adult human that we encounter, every single person, we're making netrin-1 and DCC in our brains right now. So what's the point? One of the functions that we've recently identified is that DCC produced by oligodendrocytes is required for the maintenance of myelin. Now what that means is that initially when we looked at the distribution of netrin-1 and DCC in relation to myelin we see that they're enriched at paranodal junctions. Paranodes are at the ends of internodes that are the regions of compact myelin that wrap and insulate an axon. The paranodes are a specialization that's made by the oligo that then connects it and ties it down to the surface of the axon. The paranodes flank the node of Ranvier, which is the key point, the specialized region along an axon that regenerates the action potential. So if we think of the internode of compact myelin as the region where the oligodendrocyte insulates the axon and allows the action potential to jump from node to node, the paranodes are the specializations at the end that tie it down. Now, the paranode is where we see the netrin and DCC enriched. If we take away either netrin-1 or DCC from oligodendrocytes, what we see is that the paranodes begin to come apart. Now in a very recent publication, what we did was use a genetic trick called cre-lox recombination to selectively take DCC out of mature myelinating oligodendrocytes. In these mice, the mice develop perfectly normally, the nervous system develops normally, the myelin develops normally. But then, at two months of age, we induce the deletion of DCC only from oligodendrocytes. Now having taken DCC out of oligodendrocytes, what we see is that first the paranodal junctions start to come apart, and then as we let the mice age the compact myelin itself starts to become disorganized. Now, that's interesting because what we're able to document in these mice is a progressive disorganization of the myelin produced by the oligodendrocyte. The progression is interesting, obviously, because we believe that this has identified a new mechanism that maintains myelin, and we would then relate that to the progression of demyelinating disorders like multiple sclerosis. A consequence of having lost DCC is that the action potential conduction velocity in the nervous system is delayed, and when we look at the mice themselves – and look at their behavior, put them through behavioral tests – what we see is that they become uncoordinated and slower in their movements. So again, this would all be consistent with this disruption of the myelin along the axons in the central nervous system due to the loss of DCC. And it's an indication that DCC being made by oligodendrocytes is absolutely essential to maintain the appropriate organization of myelin.   MSDF That explains why myelin may become disorganized. Now, if there is a state in which it's already disorganized, which we look at someone with MS, is there any indication here how to remyelinate knowing what you now know about what's required for maintenance of myelin?   Dr. Kennedy Certainly. What's really exciting having found that DCC is essential to maintain myelin is that this is a new biochemical mechanism that is required to organize and maintain the structural paranodal junctions, and that that's critical for the integrity and the maintenance of compact myelin. Now, DCC is a transmembrane receptor, and every single component of the signal transduction pathway downstream of DCC is potentially a drug target that could be manipulated to enhance the maintenance of myelin. So this is a new biochemical mechanism that exists in oligodendrocytes that promotes myelin maintenance. And that has enormous potential for trying to encourage the persistence of myelin in demyelinating disease.   MSDF What about remyelination? I think you've said oligodendrocytes are born to myelinate. What's stopping them?   Dr. Kennedy If we go back to the oligodendrocyte precursor in early development, what our studies of the developing nervous demonstrated was that oligodendrocyte precursors are repelled by netrin-1. The normal function of netrin-1 in the early embryo is to drive oligodendrocyte precursors away from where they're born so that they can go out into the rest of the central nervous system, find axons that need to be myelinated and myelinate them. That indicates that in the early embryo netrin-1 is a repellent for these cells. Again, we recently reported that in human MS plaques netrin-1 is present in those plaques. Where that's likely coming from is from the wreckage of cells that have died in those plaques. So I had said that mature myelinating oligodendrocytes express netrin-1. When those cells die and when the myelin is lost, the debris from those cells remains behind and potentially even builds up in plaques. There are a number of inhibitors of oligodendrocyte precursor migration that we now know are present in human MS plaques. These include proteins like chondroitin sulfate proteoglycans, semaphorins, and now netrin. What that strongly suggests is that when oligodendrocyte precursors are migrating in the adult brain to sites of demyelination with the intention of remyelinating an axon that has been demyelinated these inhibitors will very likely prevent those cells from entering the plaque and doing what they were born to do, which is to remyelinate. A very exciting thing about MS research today is that we know that the brain contains stem cells that produce oligodendrocyte precursor cells that readily give birth to these cells. So all of us have oligodendrocyte precursor cells in our head. Those cells are born to myelinate. They will migrate towards plaques where demyelination has happened, and if they're allowed to enter the plaque find the axon that needs to be remyelinated. And if they can be encouraged to overcome whatever it is that is blocking them from remyelinating, potentially that aspect of MS remyelination could be encouraged to happen.   MSDF Do you have some ideas on how to overcome this blockage either clearing away the debris or making the oligodendrocytes insensitive to the inhibitors and the debris?   Dr. Kennedy Both of those approaches would be very appropriate. So encouraging the nervous system to clear away the debris we would predict that that would encourage remyelination to happen. In addition, although I said there were multiple inhibitors present in MS plaques – and those inhibitors have different receptors – downstream of those receptors it's very likely that common signal transduction mechanisms are engaged. So targeting those common signal transduction mechanisms inside the migrating oligodendrocyte precursor cell could very potentially nullify all of the inhibitors at once. If it was possible to turn off the sensitivity to those inhibitors, then we would predict that the cells would enter the plaque more readily, and more of the cells would then be able to encounter the axons that require remyelination, and we would obviously predict that that would promote remyelination happening.   MSDF What are some of the big questions now to look at, solve?   Dr. Kennedy The oligodendrocyte is an absolutely fascinating cell type. It's a highly specialized cell type, critically clinically important. We still understand very little about these cells. The mechanisms that I've been talking about that regulate the maintenance of myelin, those have only very recently been discovered. And I think it's extremely exciting that this type of thing is being found in oligodendrocytes. But these are still very mysterious cell types. I think the more we understand about the cell biology of the oligo the more we'll be able to target pathways in the biochemistry of oligodendrocytes to try and promote things like myelin maintenance and the ability to remyelinate. Being able to do those things and essentially manipulate these cells in specific ways, we can then overcome specific clinical issues.   MSDF Does this go beyond MS? Are there other conditions that it applies to?   Dr. Kennedy I think there are two things built into that question. One is that there are many diseases for which the cause either isn't clear – and MS would be in that category – or there are also diseases that have many different causes, but they may manifest in similar ways. So by understanding oligodendrocytes and being able to encourage oligodendrocytes to remyelinate, that could have broad applicability for treating the symptoms of many different forms of demyelinating disease irrespective of the cause of those diseases. Beyond that, as we come to better understand how cells move in the nervous system, how they migrate, how they form attachments, how they connect to each other, and how they maintain those connections, those kinds of insights are going to have broad applicability for all sorts of neurodegenerative diseases where the basic problem in the neurodegenerative disease is that the networks that are the nervous system are coming apart. And if we can encourage those networks to just stay together or rebuild themselves, then I think that again has broad applicability to many types of neurodegenerative diseases in the myelinating field and outside of myelination, as well.   MSDF It sounds like it may even have applicability to not only neurodegeneration but in development where you may have miswiring such as potentially an autism or something like that.   Dr. Kennedy Yeah. An exciting thing is that a lot of the mechanisms that I'm thinking about and we're thinking about in the lab is that the insights that got us working on myelin, that brought us to work on myelin really came from neural development and better understanding neural development; the studies of neural development identified proteins and gene families that have very, very potent actions in the nervous system. When we then looked at expression, we saw that they were expressed in the mature CNS, and that brought forth a whole other group of questions related to the function of the normal adult nervous system and also the degeneration of the adult nervous system in neurodegenerative disease. The exciting thing about that is that as we understand the molecular biology of the central nervous system better that's going to be applicable to development, to normal function, to enhanced function, and also promoting function in degenerative conditions.   MSDF I appreciate it. Thank you.   Dr. Kennedy You're very welcome.   [transition music]   Thank you for listening to Episode Twenty-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 editor@msdiscovery.org.   [outro music]          

[intro music]   Hello, and welcome to Episode Twenty-four 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 Professor Aksel Siva about asymptomatic MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   We just uploaded a new data visualization to our website. This one breaks down the design of MRI-related clinical trials in MS. It combines 88 trials conducted between 1998 and 2013 in a colorful, interactive dot plot. Each dot represents a point in time for a particular measurement, such as brain volume. You can sort trials by phase, and you can look at trials in aggregate or one at a time. To view this new visualization, go to the Data Viz section under the “Research Resources” tab and click on the top link.   Magnetic resonance imaging is a source of anxiety for many people with MS. Just getting into the machine is nerve-wracking, and waiting for the results is even scarier, says a recent study from PLOS One. The researchers conducting the study suggested that educating patients about MRIs might alleviate some of the dread. Even though MSer’s typically know a great deal about MRIs, understanding how to interpret their own results may help increase the bond of trust with their physicians, the researchers said. To read more about the study, visit our “News and Future Directions” section, and under “News Briefs” click on the article, “MRI Education May Benefit MSers.”   Have a burning question? A bone to pick? Something you want to get off your chest? Start a discussion! We invite you to participate in our discussion forums by making your own threads and commenting on others. Just click on the “Discussions” option under the “Forums” tab on our website to get started.   [transition music]   Now to the interview. Last week, we spoke with Professor Aksel Siva about radiologically isolated syndrome. This week he’ll be speaking to us about asymptomatic MS and approaches to medicine in Turkey.   Interviewer – Dan Keller Professor Siva, first of all, why is it MS if it’s asymptomatic?   Interviewee – Aksel Siva Well, that’s a very good question and very difficult. But now with the tools that we have in medicine, we probably diagnose people without developing the disease. And, again, if we look to some other neurological diseases, today we are now discussing whether we can really diagnose Alzheimer prior that the individual develop the disease with imaging, with biomarkers, and so on. So to see the same thing in MS, I think it’s not really something very different. The thing is that not all these people will develop the disease, so the way we have been trained as clinicians, to us it’s important to see clinical signs and symptoms.    But now we have to start seeing that not everybody will develop the disease even if they do have it biologically, morphologically, or whatever you name it, however you name it. And then when they develop, we know well that all people are not going to have the same course. So these individual differences based on genetic background, maybe environmental influence, or whatever, should put a light in the way we see individuals – not a disease, but the individual with the disease rather let’s to say than the disease affecting the individuals. So I think this concept of subclinical disease, which is not only for MS, should influence our practice or our approach to our patients, and also in understanding the diseases and how to manage them.    MSDF Can you tell me a little bit about some of the studies that show heightened susceptibility and that possibly invoke the idea of genetics or environment?   Professor Siva I don’t think that I am in a state of responding to this question, because this is not really my area of interest. But from the genetic studies, we know there are some people who have the susceptibility genes, some who have the protective genes, and also some genes that may probably affect the course and prognosis of the patients. But, again, to my knowledge, what we have today, the information we have, is not really unique for everybody. It’s also very heterogeneous. So we need more time, and I think that this time it’s not too far, and especially the Genetic Consortium in the US, their findings are going to bring a lot of new information in the very near future.     MSDF What about studies on twins or just siblings. Although it doesn’t really nail down whether it’s genetic or environmental, it does speak to heightened risk. What did those show? Who looked at them and what did they find?   Professor Siva Well, again, I’m not aware of really very new studies on twins; identical and non-identical twins, the risk is very different, it’s maybe 2 to 3% up to 5%, depending like if it’s Canada or France it changes. But when it is identical, it’s 25 to 30. To my knowledge, the Canada cohort went up to 37%, although this number, I guess, was not published, but we know this. So it’s about only one-third even in the highest identical twin studies. So the question is what happens to the two-thirds? Maybe some of them do have incidental lesions, but they don’t have the disease. What is the present state in this genetics or others, I’m not aware of.   MSDF Even siblings who show oligoclonal bands don’t necessarily have or get the disease, is that correct?   Professor Siva No, that’s correct. According to the Swedish study, these people did not have the disease. Maybe more important, there was a subsequent paper reported in the same cohort, they have looked in the CSF of these asymptomatic, or let’s say of these siblings with positive oligoclonal bands, and what they called immunopathic trait. They looked in some other issues, but let’s put it these people with positive oligoclonal bands and the immunopathic trait, and they have looked in some neuronal degeneration markers. And the sibling who had the disease had high levels, which shows that there was a CNS damage, and asymptomatic case it was normal. So that is very clear that, yes, if you get the disease you might have some, let’s say, the biological evidence of it together with CNS damage, whereas if you don’t get… you may have the same trait but not the disease, because you will not have CNS damage. And there might be some underlying mechanisms – immunogenetic, whatever – which controls the disease spread and clinical expression. So I think this is a major issue.    And in the Steffano study when he had studied, again, the relatives of people with MS who had lesions – these 4% or 10% of asymptomatic cases – he also looked in the normal-appearing white matter. And in the diseased individuals it was abnormal; whereas in the people who had just those, let’s say, T2 changes, the normal-appearing white matter was completely normal, which again shows us that the CNS damage is very, very limited in people who don’t get the disease. And from the early autopsy studies, again the people in whom the autopsy had shown brain lesions, they were mostly periventricular and probably in silent areas, and there was not widespread damage as we see in people who get the clinical disease.    MSDF It seems Turkey is a very good setting for looking at a lot of this, because people get a lot of MRIs.   Professor Siva That’s correct, that’s very correct, and that’s why we have so many cases. Today with contribution of another medical school from Ankara, Hacettepe Medical School, together now we have more than 86 RIS cases that we continue to follow up, some of who have converted now.    MSDF And RIS is radiological isolated syndrome. Do people pay for their MRIs, or why are they so apt to come in and get so many?   Professor Siva Not really, it’s reimbursed, mostly it’s reimbursed, or if they have their private insurance because, let’s say, physician is suspecting something. And I should also confess that in some hospitals – mainly state hospitals – there is an overload of patients. Let’s say neurologists in those institutions may not find time to listen and examine the patient as they should do. So in order not to miss something, even a patient who comes with a headache may get an MRI.   MSDF Is there a difference in Turkey of how you approach MS patients, or treat them, or follow them from in other countries that you’ve noticed?   Professor Siva Not really. It’s, I would say, very much the same. I have started our MS clinic in 1987 here, and today we have more than 7,000 registered patients, which is really quite a very large population. This doesn’t mean that we follow all the 7,000 and more patients because many of them had been referred for second opinions, but I would say we continue to see at least half of these people. And the way the practice is here is not any different than most major European and US centers. I had spent some time at Mayo many years ago and I had some of my other colleagues now who had spent some time. So it’s more or less the same. We have all the same drugs, most of them are reimbursed. So we have many alternatives for our MS patients, although there are some restrictions for reimbursement. We need to at least try the so-called injectables in order to go to orals, or, let’s say, the monoclonal antibody therapies, but almost all are available. And according to some rules, they are also reimbursed.    MSDF Are there good patient support services, psychosocial and other?   Professor Siva Not maybe so strong. That we may differ a bit from Europe and US. We do have Turkish MS Society where such services are tried to be provided, but that is not enough. We do have some MS Society chapters in some cities but not everywhere. But mostly the problem, I would say, is economical. All these services mostly are based on voluntary basis.   MSDF Do you think that patients react the same to their disease?   Professor Siva We do have some studies – psychologically, physically – and it’s at very similar to western theories. So actually Turks are Caucasians mostly, and therefore it’s what if we are going to call the western-type MS, that’s what we see here too.   MSDF Are there cultural differences in various parts of Turkey how people view their disease, or is it all about the same? I mean, Istanbul is really Europe, as you move farther east you get into more Asian and Middle Eastern.   Professor Siva I may say not really, because we get referrals from all around Turkey, and the behavior is not really much different. I should say either whether the patient is from Istanbul or from the east part of the country or the Mediterranean, it’s more or less the same.   MSDF  Anything important to add that we’ve missed or interesting topic points?   Professor Siva We have a large number of MS people in Turkey, probably prevalence rate is around 50 per 100,000 or more. There have been a number of prevalence studies, and this is about what we can really derive from all the studies – 50 or more even. But I have the impression that we are getting more and more MS in Turkey today, and more familial cases, which was not the case maybe 15 to 20 years ago.   MSDF Very good. Thanks a lot.   Professor Siva Thank you.   [transition music]   Thank you for listening to Episode Twenty-four 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 editor@msdiscovery.org.    [outro music]  

Hello, and welcome to Episode Eighteen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   The term “neuroscience” makes it very clear who is the star of the show—neurons. But over the past few years, glial cells have been elbowing their way in from supporting cast to stars in their own right. We recently reported a story about how oligodendrocytes need to make new myelin in order for mice to learn a new motor task effectively. The study demonstrated how glia are required in active learning, as well as highlighted the importance of targeting remyelination in new therapies for demyelinating disorders.   Finally, we recently added a new data visualization examining the differences in baseline characteristics of patients in 74 RRMS and CIS clinical trials. You can easily see how individual trials compare to the overall mean values of gender, age, Expanded Disability Status Scale score, the number of gadolinium enhancing lesions, and the volume of T2 lesions. To see the new data visualization, click on the “Data Visualizations” tab under “Research Resources,” and then click on “RRMS and CIS baseline characteristics.”       In terms of remyelination, what do we know now? Are there new thoughts about mechanisms and are there any compounds in development that would facilitate it? Interviewee—Samuel Ludwin           It is interesting that some of the drugs are either approved for other uses or they are older drugs or derivatives of older drugs that are now resurfacing in this arena. How do some of those work? Dr. Ludwin   It sounds like those have sort of general repair functions. I mean they are using estrogen or testing it in traumatic brain injury and things like that. Dr. Ludwin   Now I guess there is a difference between neuroprotection and remyelination. Some of these drugs do both or do they fall into separate categories? Dr. Ludwin   You hear much more in terms of reperfusion injury, the role of excitotoxicity, particularly glutamate. Does that also enter here or is this such a chronic process that you really don't have an accumulation of glutamate? Dr. Ludwin   On these topics, either compounds that look promising or the process of repair itself, what have we missed, or is there anything important to add? Dr. Ludwin   Very good, I appreciate it.

1) Dementia management quality measures and 2) Topic of the month: Multiple sclerosis therapy and treatment. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Jeff Burns interviews Dr. Amy Sanders about her paper on dementia management quality measures. Dr. Adam Numis is reading our e-Pearl of the week about Leber's hereditary optic neuropathy. In the next part of the podcast Dr. Mark Keegan interviews Dr. Alasdair Coles about alemtuzumab treatment of multiple sclerosis. The participants had nothing to disclose except Drs. Burns, Sanders, Numis, Keegan, and Coles.Dr. Jeff Burns serves on the editorial board for Journal of Alzheimer's Disease; receives royalties for the publications of Early diagnosis and treatment of mild cognitive impairment and Dementia: An atlas of investigation and diagnosis; is a consultant for PRA International and receives research support from the NIH, Alzheimer's Drug Discovery Foundation, Elan, Janssen Pharmaceuticals Inc., Wyeth, Pfizer Inc, Novartis Pharmaceuticals Ltd, Danone, Avid Radiopharmaceuticals, Merck Serono and for clinical trials.Dr. Sanders is a member of a federal advisory committee (MEDCAC); received honoraria for serving on peer-review panels from the CMMI and PCORI; and research support from the Einstein CTSA Grant from the National Center for Research Resources, a component of the NIH and NIH roadmap for Medical Research; loan repayment support from LRP/NIA. Dr. Numis serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Keegan serves as Chief Editor of eMedicine and receives research support from Terumo BCT.Dr. Coles is a co-editor of Advances in Clinical Neuroscience and Rehabilitation; serves on the scientific advisory board for the Multiple Sclerosis Society of GB & NI, International Society for Neuroimmunology, Genzyme Corporation steering committee, UK Advisory Board, Merck Serono; is a consultant and receives speakers' honoraria from Nil, Merck Serono, Genzyme Corporation, Bayer Schering Pharma; and has a patent for IL-21 as a marker of autoimmunity after alemtuzumab treatment.

Fran Devlin, Kim Glover and Lars Leon from the KU Libraries describe research resources available for online instructors and students.

From the flu to HIV, RNA viruses challenge our immune systems like no other infectious agent on the planet. RNA viruses provide unique insights into the patterns and processes of evolutionary change in real time. The study of viral evolution is especially topical given the growing awareness that emerging and re-emerging diseases (most of which are caused by RNA viruses) represent a major threat to public health. How do RNA viruses adapt and change, and how do our bodies respond? Why are diseases like HIV so difficult to predict and contain? In episode 35 of MicrobeWorld Video, Eddie Holmes, professor in Biology at Pennsylvania State University leads a discussion before a live audience at Busboys & Poets in Washington, D.C. on the genetics and evolution of RNA viruses and how we can combat them. The Dish was created by the Marian Koshland Science Museum and is made possible by a Science Education Partnership (SEPA) grant from the National Center for Research Resources, a component of the National Institutes of Health. This program was held in collaboration with the Proceedings of the National Academy of Sciences.

From the flu to HIV, RNA viruses challenge our immune systems like no other infectious agent on the planet. RNA viruses provide unique insights into the patterns and processes of evolutionary change in real time. The study of viral evolution is especially topical given the growing awareness that emerging and re-emerging diseases (most of which are caused by RNA viruses) represent a major threat to public health. How do RNA viruses adapt and change, and how do our bodies respond? Why are diseases like HIV so difficult to predict and contain? In episode 35 of MicrobeWorld Video, Eddie Holmes, professor in Biology at Pennsylvania State University leads a discussion before a live audience at Busboys & Poets in Washington, D.C. on the genetics and evolution of RNA viruses and how we can combat them. The Dish was created by the Marian Koshland Science Museum and is made possible by a Science Education Partnership (SEPA) grant from the National Center for Research Resources, a component of the National Institutes of Health. This program was held in collaboration with the Proceedings of the National Academy of Sciences.

From the flu to HIV, RNA viruses challenge our immune systems like no other infectious agent on the planet. RNA viruses provide unique insights into the patterns and processes of evolutionary change in real time. The study of viral evolution is especially topical given the growing awareness that emerging and re-emerging diseases (most of which are caused by RNA viruses) represent a major threat to public health. How do RNA viruses adapt and change, and how do our bodies respond? Why are diseases like HIV so difficult to predict and contain? In episode 35 of MicrobeWorld Video, Eddie Holmes, professor in Biology at Pennsylvania State University leads a discussion before a live audience at Busboys & Poets in Washington, D.C. on the genetics and evolution of RNA viruses and how we can combat them. The Dish was created by the Marian Koshland Science Museum and is made possible by a Science Education Partnership (SEPA) grant from the National Center for Research Resources, a component of the National Institutes of Health. This program was held in collaboration with the Proceedings of the National Academy of Sciences.