Ms frontiers handbook 2015

Sofi tel London, Heathrow 29-30 June 2015

MS Frontiers 2015

Bringing the research community together to beat MS12 CPD credits available #MSFrontiers

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BI-PAN-0389. Date of preparation: May 2015

MS Frontiers programme

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03 Contents

04 Welcome

06 Conference programme

12 Biographies

23 Presentation abstracts

36 Poster abstracts

97 Sponsor information

100 Notes

Contents

4

Welcome

A warm welcome to MS Frontiers 2015

At the MS Society we place great value on research

because every day we see the impact it can have on

the lives of people with MS. Since 1956, we have invested

over £150 million of today’s money in research, and

today we remain the biggest charitable funder of

MS research in the UK.

The spectrum of MS research spans many different

disciplines and involves a wide range of dedicated

researchers, neurologists, clinicians and allied health professionals.

The purpose of MS Frontiers is to bring these experts from across the

world together to speak on MS research, present their latest work,

share ideas and discuss key challenges.

In my role as Chairman of the MS Society I’ve had the opportunity to

see fi rst-hand the dedication and commitment the research community

shows to people affected by MS and to the MS Society.

In 2013 we announced the results of our extensive research priority

setting partnership. Working with the Association of British Neurologists,

the UK MS Nurses Association and the MS Therapy Centres, and guided

by the James Lind Alliance, we established the top 10 research questions

important to people affected by MS and healthcare professionals.

This puts people affected by MS at the absolute centre of our research

programme, guiding our own funding priorities as well as infl uencing

other research funding bodies.

Finding treatments that are effective to slow, stop or reverse the accumulation

of disability associated with MS is our number one research priority and

this is a goal that is also shared by the global MS community. The Progressive

MS Alliance brings together MS charities from around the world to lead a

new collaboration to speed up the development of treatments for people

with progressive forms of MS. We are proud to be a founding partner

of this Alliance.

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MS Frontiers programmeWelcome

There have been many exciting research breakthroughs in recent years and

we want to see this momentum increase to ensure that progress in research

continues to accelerate. We also want to ensure that research discoveries are

translated into effective treatments for people with MS as soon as possible.

That is why we launched our Stop MS Appeal, aiming to raise more than

£100 million for MS research over ten years, more than doubling our

current level of investment.

I hope that MS Frontiers 2015 will stimulate opportunities to network, learn

about the latest fi ndings in MS research and share your own fi ndings.

We look forward to working with you in years to come, together ensuring

that ground-breaking research can change millions of people’s lives.

This is an incredibly exciting time for MS research. With new knowledge

gained, new projects funded and many clinical trials ongoing, real

breakthroughs are on the horizon. I would like to take this opportunity

to thank you for your help, hard work, interest, and support.

With best wishes,

Hilary Sears

Chairman

MS Society

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Conference programme

Monday 29 June 201509:30-10:30 Registration & refreshments

10:30-10:50 Opening address Arora 1+2 Michelle Mitchell, Chief Executive, MS Society Nick Rijke, Executive Director of Policy and Research, MS Society

10:50-12:30 Plenaries Arora 1+2 Chair: Stuart Nixon, MBE, person with MS and MS Society Ambassador

Neuroprotection: prospects and emerging insights Dr Raj Kapoor, National Hospital for Neurology and Neurosurgery, London

Shared decision making in MS: a multi-cultural perspective Dr Alessandra Solari, Istituto Neurologico C. Besta, Italy

12:30-13:30 Lunch

13:30-15:30 Parallel sessions

A. Mechanisms of progression Arora 1+2 Chair: Prof Charles ffrench-Constant, University of Edinburgh

Invited Speakers: Dr Mark Kotter, University of Cambridge No title available Dr Don Mahad, University of Edinburgh Mitochondria and progressive MS Dr Julia Edgar, University of Glasgow Axonal dysfunction in dys- and demyelinating models: a potential role for the injured oligodendrocyte

Speakers selected from abstracts: Marie Dittmer, Queen’s University Belfast Dr Gareth Pryce, Barts and the London school of Medicine & Dentistry, QMUL Mario Amatruda, University College London

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B. Towards personalising Arora 3 treatment and care Chair: Prof Sue Pavitt, University of Leeds

Invited Speakers: Prof Paul Matthews, Imperial College London Towards personalising treatment and care for people with MS Dr Ana Manzano and Dr Hilary Bekker, University of Leeds Making informed decisions about disease modifying treatments Prof Stephen Sawcer, University of Cambridge New directions for MS genetics

Speakers selected from abstracts: Dr Wallace Brownlee, Queen Square MS Centre Alison Thomson, Queen Mary, University of London

C. Rehabilitation – London Suite New innovations and technology Chair: Prof Alan Thompson, University College London

Invited Speakers: Dr Lorna Paul, University of Glasgow Web-based physiotherapy for people affected by Multiple Sclerosis Dr Darryl Charles, University of Ulster Playful and Gameful Exercise Hilary Gunn, Plymouth University Value for effort in balance exercise programmes – challenges and opportunities Dr Sarah Thomas, Bournemouth University Enhancing adherence to behavioural interventions – the role of psychology Prof Diego Centonze, University of Tor Vergata, Rome The neurobiological basis of rehabilitation in MS

Speakers selected from abstracts: Rachel Goodwin, University of Nottingham Thomas Welton, University of Nottingham

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D. Modifi able risk factors for MS Paris Suite Chair: Prof Gavin Giovannoni, Barts and The London School of Medicine and Dentistry Invited Speakers: Dr Johan Öckinger, Karolinska Institute, Sweden Lung-specifi c immune activation in smokers and non-smokers diagnosed with multiple sclerosis Julia Pakpoor, University of Oxford Sex hormones, obesity and multiple sclerosis risk Cary James, Terrence Higgins Trust No title available

Speakers selected from abstracts: Dr Anne Astier, University of Edinburgh Elena Morandi, University of Nottingham

15:30-17:30 Poster session with refreshments

16:00-17:00 Workshop

The changing MS treatment landscape Arora 1+2 Chair: Michelle Mitchell, Chief Executive, MS Society Prof Neil Scolding, University of Bristol Nick Rijke, Executive Director of Policy and Research, MS Society Dr Nikos Evangelou, University of Nottingham Prof Alasdair Coles, University of Cambridge Dr Jacqueline Palace, University of Oxford

17:30-18:30 Debate session Are stem cells the next frontier Arora 1+2 in MS treatment? Chair: Prof Siddharthan Chandran, University of Edinburgh Prof Gianvito Martino, San Raffaele Hospital, Milan Prof Gavin Giovannoni, Barts and The London School of Medicine and Dentistry Prof Alasdair Coles, University of Cambridge

19:00-20:00 Drinks reception

20:00 Conference dinner


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Tuesday 30 June 201508:00-09:00 UK MS Clinical Trials Network breakfast meeting: Designing a next generation clinical trial Meeting open to all delegates.

Speakers: MS Society Prof Sue Pavitt, University of Leeds

09:00-09:30 Registration & refreshments

09:30-11:30 Parallel sessions

A. Are we seeing better? Arora 1+2 New imaging methods and biomarkers

Chair: Prof David Miller, Institute of Neurology, University College London

Invited speakers: Prof Olga Ciccarelli, University College London New spinal cord imaging techniques Prof Gavin Giovannoni, Barts and the London School of Medicine and Dentistry Update on CSF biomarkers of disease activity and progression Dr Nikos Evangelou, University of Nottingham High fi eld MRI. What can we learn about MS?

Speakers selected from abstracts: Francesco Grussu, Queen Square MS Centre, UCL Institute of Neurology Emilia Padgett, University of Nottingham Dr Roberta Magliozzi, Imperial College London, Division of Brain Sciences

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B. The many facets of fatigue Arora 3 Chair: Dr Jeremy Chataway, National Hospital for Neurology and Neurosurgery, London

Invited speakers: Dr Don Mahad, University of Edinburgh Performance related fatigue in multiple sclerosis Prof Tom Mercer, Queen Margaret University Edinburgh Exercising infl uence on MS-related Fatigue: what do we really know? Prof Alison Wearden, University of Manchester Understanding and managing chronic fatigue syndrome (CFS): similarities and differences with fatigue in other conditions Vicky Slingsby, MS Specialist Occupational Therapist, Dorset Healthcare The practicalities of delivering fatigue management interventions Prof John Saxton, Northumbria University The EXIMS trial – impact on MS fatigue and lessons learned

C. Using big data to improve London Suite health and social care Chair: Prof Sue Pavitt, University of Leeds Invited speakers: Prof David Ford, Swansea University The UK MS Register: A platform for enquiry and research. Dr Peter Connick, University of Edinburgh FutureMS: Clinical, laboratory, and genomic predictors of disease activity in people with newly diagnosed relapsing onset multiple sclerosis: an observational cohort study David Davis, NHS England No title available Holly Dorning, Research Analyst, Nuffi eld Trust No title available Speakers selected from abstracts: Dr Paul Mattison, Scottish National MS Register Steering Group Rod Middleton, Swansea University

11:30-11:45 Refreshments

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12:00-13:00 Ian McDonald Memorial Lecture Arora 1+2 Insights from imaging multiple sclerosis Prof David Miller, University College London Chair: Prof Alastair Compston

13:00-14:00 Lunch

14:50-15:40 Plenaries Arora 1+2 Chair: Nick Rijke, Executive Director of Policy and Research, MS Society

Cognitive rehabilitation in multiple sclerosis: Looking back and moving forward Dr Roshan das Nair, University of Nottingham

Microglia: A reintroduction Dr Richard Ransohoff, Biogen

15:40-16:00 Close of conference


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Biographies

Speaker biographiesMichelle Mitchell is an experienced CEO and Trustee. She is committed to social justice and equality. Michelle started her working life as a special adviser to an MP and has held senior roles at Age UK and Age Concern. Michelle is passionate about driving lasting change in order to improve the lives of people who use health and social care services including people who are affected by multiple sclerosis. Michelle has led pioneering, high profi le campaigns and driven policy change in a number of critical areas including social care funding, which have resulted in fundamental improvements for those in later life. She was also part of the team that led the merger of Age Concern and Help the Aged and launched Age UK. Michelle has been a trustee of the Young Women’s Trust, and the Chair of Fawcett Society. She currently holds trusteeships at Kings Fund, and MS International Federation and is a director of Power to Change. Michelle is a mother to two young children and dedicated fundraiser and is training for the London Marathon 2016. Michelle has overseen the transformation of the MS Society to match its new ambitious strategy which is focussed on making real progress in MS treatments, research, care and support, and helping people affected by MS take control of their lives.

Nick Rijke was delighted to join the MS Society as Director of Policy and Research in January 2012. The opportunity to bring my eclectic experience to bear on MS, given my long standing connection to the condition, was a welcome challenge. Previously I have worked in the private, public and third sectors, mainly specialising in communications, public policy and public affairs, but also covering medical and social research, NHS improvement programmes and, if you go back to the 1980s, my early career was in investment banking. Organisations I have worked for in the past include the National Osteoporosis Society, the Environment Agency, the Local Government Association, the House of Commons and Kleinwort Benson. Outside of work I devote time to my now ageing Labrador and to better understanding various branches of history.

Stuart Nixon – After starting his career as a nurse, Stuart now works part-time in management at the Aneurin Bevan University Health board. Stuart has lived with MS for over 30 years and has used a wheelchair for 15 of those, but this is not the whole story. He is now an Ambassador of the MS Society, having been Vice Chair, Trustee and a volunteer for over 20 years. Having been a member of the MSS Research Strategy Committee Stuart is committed to the development of research. To prove this, in 2013 Stuart completed a 60km Challenge around London called ‘StuStepsUp’ raising over £70,000 for Research into MS. At the 2013 MS Awards Stuart was presented with the MSS Life-time Achievement Award for his work with, and commitment to, the MS Community and in the 2014 New Year’s Honours Stuart received an MBE for ‘Services to People with MS’. Stuart would describe himself as “the luckiest man he knows”, and this comes from being married to Marie and having two great sons Sean and Killian.

13

Biographies

Raj Kapoor is a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, and Reader in Neurology at University College London. He graduated from the University of Oxford, and then completed his postgraduate medical training in London. After a period of basic research on neuronal physiology with Rodolfo Llinas at NYU Medical Center, and in the University Laboratory of Physiology in Oxford, he returned to London to complete his neurological training at the National Hospital with Ian McDonald. His research has since focused on the pathophysiology and treatment of demyelinating diseases, specifi cally on mechanisms of neuronal injury and consequent proof of concept trials of neuroprotection with lamotrigine in secondary progressive MS and with phenytoin in optic neuritis. Dr Kapoor also sits on the Scientifi c Steering Committee of the Progressive MS Alliance, and on the Coordinating Committee of the MS Outcome Assessments Consortium.

Alessandra Solari – Head of the Unit of Neuroepidemiology, Foundation Neurological Institute C. Besta. Dr Solari graduated (summa cum laude) and specialized in neurology (summa cum laude) at the School of Medicine of the University of Parma, Italy. Her main area of research is the validation of instruments and outcome measures (chiefl y patient-reported outcome measures, PROs) for clinical, epidemiologic, and quality of care studies in neurological diseases, particularly multiple sclerosis (MS). Other main interests are: the design and conduction of randomised controlled trials (RCT) on complex interventions; and shared decision making. PROs: Dr Solari validated linguistically several questionnaires into Italian (e.g. the 54-item MS Quality of Life, MSQOL-54; the Chicago Multiscale Depression Inventory, CMDI) and coordinated multi-lingual adaptations (e.g. of the Control Preference Scale, CPS). Dr Solari’s team produced the MS knowledge questionnaire (MSKQ) for patients and their signifi cant others, now available in 8 languages, and COSM, a questionnaire on satisfaction with communication of the MS diagnosis. RCT on complex interventions: The most recent projects are the “Sapere Migliora” information aid for newly diagnosed MS patients, and the Palliative Network for Severely Affected Adults with MS in Italy (PeNSAMI) study, on a home-based palliative care service.Shared decision-making: Dr. Solari leads with Prof. Chris Heesen (University of Hamburg) a collaborative project on MS patients empowering and on improving the skills of health professionals caring for them (www.automsproject.org).

Charles ffrench-Constant graduated MA MB, BChir in Medicine from Cambridge in 1980, gaining MRCP in 1984 following posts at the Hammersmith and UCH. He then joined Martin Raff’s lab at UCL as a PhD student, followed by postdocs at MIT with Richard Hynes and Cambridge with Chris Wyllie. He was a Junior Group Leader position in the Wellcome/CRC (now Gurdon) Institute at Cambridge from 1991-1996, becoming a University Lecturer/Consultant at Addenbrookes Hospital, Cambridge from 1996 and Chair in Neurological Genetics at Cambridge from 1999. During this time he was funded by Wellcome Trust Senior and Research Leave Fellowships. He took up his present appointment as Chair of Medical Neurology and co-director of the MS Centre at the University of Edinburgh in 2007, becoming Director of the MRC Centre for Regenerative Medicine in 2011 and Director of Edinburgh Neuroscience in 2013. His research focuses on the biology of myelin formation and repair in the brain with the aim of discovering novel therapies in multiple sclerosis based on the activation and recruitment of endogenous stem and precursor cells.

14

Biographies

Mark Kotter – no biography available

Don Mahad – I am a Scottish Senior Clinical Fellow interested in MS. My research focus is on mitochondria and we are exploring its role in progressive MS. The studies include assessment of post-mortem tissue, development of models that adequately capture the mitochondrial changes described in progressive MS and identifying potential therapeutic targets for progressive MS.

Julia Edgar did her PhD in developmental neuroscience at the University of Edinburgh, under the supervision of Dr David Price. In 1998 she moved to the University of Glasgow where she worked under the supervision of Professor Ian Griffi ths. She was awarded a Multiple Sclerosis Society Junior Fellowship in 2005 and became a lecturer at the University of Glasgow in 2009. Her work aims to understand the role of the oligodendrocyte in supporting the function and integrity of the myelinated axon.

Sue Pavitt is Chair of the UK Multiple Sclerosis Society’s Clinical Trials Network and in establishing the infrastructure to facilitate clinical trials and translational research within the MS network. She studied her PhD in Human Cancer Genetics at University College London and has had a high profi le career in human genetics working with Professor Sir Walter Bodmer, FRS. She went onto University of California, San Francisco USA and was involved in establishing the Human Genome Centre. She returned to the University of Oxford as a Senior Fellow in 1992. In 1998 the academic focus of her career changed to applied health research; she was appointed as the Founding Director of TayRen establishing the premier Scottish multidisciplinary Primary Care Research network. She worked at the University of Manchester in translational research and Cochrane reviews. In 2007 she was appointed as Divisional Director at the Clinical Trials Research Unit, University of Leeds; leading a large portfolio of trials. The clinical trials she designs typically include translational research, are multidisciplinary, tailored to address unmet health needs and place patient public involvement (PPI) central to maximises the likelihood of delivering tangible patient benefi t and advances in healthcare that are important to needs of patients. She continues to work on clinical trials and translation including MS-SMART a drug repurposing trial in Secondary Progressive MS.

Paul Matthews is the Edmond and Lily Safra Chair of Translational Neuroscience and Therapeutics and Head of the Division of Brain Sciences in the Department of Medicine of Imperial College, London, where he is lead for the public-private consortium, OPTIMISE, for collaboration between Biogen and multiple UK MS centres for development of a data capture and management tool for improved pharmacovigilance and development approaches for stratifi ed medicine in multiple sclerosis. He was founding Director of the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain and, after leaving Oxford, became a Vice President in Pharmaceuticals for GlaxoSmithKline, where he led a medicines development team for MS. Matthews is the Imperial College Health Trust BRC Theme Leader for Neurosciences and on the Executive of the College virtual Institute for Translational Medicine and Therapeutics. He also serves in several external clinical research leadership roles including Chair of the Imaging Work Group for the UK Biobank and UK representative for the Interim Board of Euro-Bioimaging. He was a member of the MS Society Research Strategy Group (2009-12) and Strategy Advisory Board (2006-8). In 1997 Matthews was made a Fellow by Special Election in St Edmund Hall, Oxford, in 2008 he was awarded an OBE for services to neuroscience and, in 2014, he was elected as a Fellow of the Academy of Medical Sciences.

15

Biographies

Hilary Bekker is an Associate Professor in Psychology and Medicine at the School of Medicine – University of Leeds with teaching responsibilities to the undergraduate medical degree. Her research uses decision science, health psychology, and applied health research to investigate people’s decision making about healthcare, and to design, implement and evaluate interventions supporting people’s informed decision making between options. In collaboration with health professionals and patients, she has designed over 40 patient decision aids in paper and web formats for research and use in UK health services (e.g. http://sdm.rightcare.nhs.uk/pda/). She has published over 70 articles including systematic reviews of interventions facilitating informed decision making in healthcare, randomised controlled trials of patient decision aids, and surveys investigating patient and professional treatment choices in varied health contexts (chronic kidney disease, obstetrics and gynaecology, screening and immunisation, cancer and trial participation). She is part of the International Patient Decision Aids Standards (IPDAS) collaboration, and internationally recognised as an advisor on shared and informed decision making research and practice.

Ana Manzano is a Lecturer in Health and Social Policy at the Centre for Health Technologies and Social Practice, University of Leeds (United Kingdom). She is a social research methodologist with expertise in applied health research. Her specialist area is the evaluation of complex applied healthcare interventions using mixed methods (qualitative and quantitative approach). She is interested in the relationship between research methods, evidence and policy making in healthcare, and in the involvement of patient perspectives into the evaluation of complex interventions. Dr Manzano has undertaken research aimed at improving the management of pain and secondary effects of aggressive treatment in patients with advanced illnesses through better understanding the profi le of prescribing.

Stephen Sawcer is Professor of Neurological Genetics at the University of Cambridge and an Honorary Consultant Neurologist at Addenbrooke’s Hospital. He has a BSc in Physics from Liverpool University and did his undergraduate medical training at Birmingham University. After becoming MRCP in 1991 and FRCP in 2010. His PhD (A linkage genome screen in multiple sclerosis, 1997) was undertaken at the University of Cambridge, supervised by Professor Alastair Compston and Professor Peter Goodfellow. Professor Sawcer has worked on the genetics of multiple sclerosis for more than 20 years with a main focus on genomewide approaches. He is a member of the International Multiple Sclerosis Genetics Consortium (IMSGC) and the Wellcome Trust Case Control Consortium (WTCCC).

Alan Thompson is Dean of the Faculty of Brain Sciences at University College London, Garfi eld Weston Professor of Clinical Neurology and Neurorehabilitation at the UCL Institute of Neurology, a consultant neurologist at the National Hospital for Neurology and Neurosurgery, Queen Square, and Chair of the Neuroscience Programme at the UCLP Academic Health Sciences Centre. His main area of expertise is in demyelinating disease, particularly the diagnosis, evaluation, and management of multiple sclerosis (MS), focusing on the pathological mechanisms that underpin neurological disability and recovery using structural and functional imaging. He has published extensively in high-impact peer-reviewed journals. Professor Thompson is chair of the Scientifi c Committee of the International Progressive MS Alliance, Chairman of the International Medical and Scientifi c Board of the Multiple Sclerosis International Federation (MSIF), a Senior Investigator for the National Institute for Health Research, Editor-in-Chief for Multiple Sclerosis Journal, and a Guarantor of Brain. He received his undergraduate and postgraduate degrees from Trinity College Dublin, and an honorary doctorate from Hasselt University, Belgium.

16

Biographies

Lorna Paul is a physiotherapist and Reader in Rehabilitation at the University of Glasgow. Lorna has been involved in MS research for over 15 years and is particularly interested in the use of technology to support the rehabilitation of people with long term conditions. Lorna has published many papers in the fi eld of neurological rehabilitation and is currently leading the WEBPAMS study (WEB based physiotherapy for People Affected by MS), funded by the MS Society. Lorna is a member of the National Neurological Advisory Group for MS in Scotland and was previously a member of the MS Society Grant Review Panel (Care and Symptom Management).

Darryl Charles is based at Ulster University in Northern Ireland where he specialises in computer games and emerging technologies. His research background is in computational intelligence and he has applied this expertise to both serious and commercial games. His research involves intelligent interactive storytelling, machine learning, user profi ling, and streaming cloud games. Since beginning his research in 1998 he has had over 80 papers published in peer reviewed journals and conferences and supervised a dozen PhD students to completion. His recent research has focused mainly on health technologies and creating games with natural user interfaces to support and motivate people to engage with exercise and rehabilitation.

Hilary Gunn is a physiotherapist who originally trained in Birmingham, UK. Her clinical career has focussed on working with adults with neurological problems (many of whom had MS) in a variety of settings including in-patients, out patients and in the community. Her last post also combined this role with a caseload of older people’s rehabilitation - where she developed something of an obsession with falls and falls management. Hilary moved into academia in 2005, working with under-graduate and post graduate physiotherapy students and other Allied Health Professionals. She recently completed her PhD which combines her two clinical interests of MS and falls management - with the original (somewhat naïve) aim of fi nding out ‘why people with MS fall and what we can do about it’! This work included an observational study of falls risk factors (n=150), 2 systematic reviews and a nominal group study (n=36). All of the studies undertaken to date have had a strong service user focus, involving people with MS and professionals throughout. The output of this work is a model for an MS specifi c falls intervention programme – which has been developed to meet the key aims of addressing modifi able risk factors, supporting user engagement and maximising clinical application within the UK health setting. She now aims to continue this work by undertaking feasibility testing prior to a full-scale evaluation study.

Sarah Thomas is Deputy Director of the Bournemouth University Clinical Research Unit and a National Institute for Health Research (NIHR) Research Design Service (RDS) Consultant. Her background is in psychology and she has over 10 years’ experience in health services research. She is particularly interested in the application of psychological approaches to the management of long term conditions and the development and pragmatic evaluation of complex interventions. Sarah led the development of a fatigue management programme (FACETS) for people with MS that incorporates cognitive behavioural approaches and that was evaluated in a MS Society funded national multi-centre randomised controlled trial (ISRCTN76517470). The MS Society has subsequently supported its roll-out in the UK via one day training events for health professionals. Sarah, along with a multi-disciplinary team, has recently completed a MS Society funded study to develop and pilot a physiotherapist supported home-based Nintendo Wii™ intervention (‘Mii-vitaliSe’) to increase activity levels and wellbeing in people with MS (ISRCTN49286846).

17

Biographies

Diego Centonze is Associate Professor of Neurology at the University of Rome Tor Vergata and Head of the UOSD Multiple Sclerosis Clinical and Research Center at Tor Vergata Hospital. He leads the Laboratory for non-invasive brain stimulation at Tor Vergata Hospital, the Experimental Neurology Laboratory at Tor Vergata University and the Neuroimmunology and Synaptic Plasticity Laboratory at Fondazione Santa Lucia in Rome. His major clinical interest involves the evaluation of new drugs for the treatment of MS. His research interests are related to the role of synaptic transmission and plasticity in the pathophysiology of Multiple Sclerosis and of its experimental model, and to the physiology of the endocannabinoid system and its involvement in infl ammatory neurodegenerative diseases. Prof. Centonze graduated in Medicine at the University of Rome La Sapienza in 1994, specialised in Neurology in 1999 and in Psychiatry in 2006 at the University of Rome Tor Vergata. He obtained his PhD in Rehabilitation Medicine in 2012. He is Principal Investigator of many phase II, III and IV national and international trials with new therapeutic agents for MS. Prof. Centonze is author of around 280 peer-reviewed papers published in international journals of Neuroscience, Neurology and Psychiatry.

Gavin Giovannoni was appointed to the Chair of Neurology, Barts and The London School of Medicine and Dentistry, in November 2006. He did his undergraduate medical training in South Africa. He moved to the Institute of Neurology, Queen Square, in 1993 to do a PhD in Neuroimmunology. His clinical interests are multiple sclerosis and other infl ammatory disorders of the central nervous system. His current research is focused on Epstein Barr virus as a possible cause of multiple sclerosis and progressive MS.

Johan Öckinger, PhD, is a researcher at the Respiratory Medicine Unit, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. He received his MSc in biomedicine and his PhD in experimental neuroscience from Karolinska Institutet. Öckinger’s doctoral thesis described the genetic regulation of infl ammatory mediators in MS and EAE. As a postdoctoral fellow at Harvard School of Public Health, department of Genetics and Complex Diseases he investigated the cellular mechanisms of immune regulation, in particular the activation of infl ammasomes in macrophages. His current work is focused on the immune activation induced by cigarette smoke exposure, and in particular the role of smoking in development of MS and other autoimmune diseases.

Julia Pakpoor is currently a fi nal year medical student at the University of Oxford, from where she has also obtained a BA in Medical Sciences (neuroscience option) upon intercalating. She will take up a clinical academic training post on the Academic Foundation Programme in Oxford from August 2015. She has been actively engaged in multiple sclerosis (MS) research for the past four years and her work has yielded numerous publications and international presentations. She has a particularly keen interest in risk factors of the disease. More specifi cally, her current focus lies in aiming to elucidate the role of sex hormones on the demographic profi le and aetio-pathogenesis of MS, and the resulting potential implications for the development of new prevention and/or treatment strategies.

Cary James – no biography available

18

Biographies

Neil Scolding trained in neurology in Cardiff, Cambridge (Addenbrooke’s), and London (National Hospital for Neurology); he was a Consultant and Lecturer in Cambridge before coming to Bristol in 1999 as foundation chairholder of the Burden Professorship of Clinical Neurosciences. His clinical interests and research centre on clinical and biological aspects of MS and related infl ammatory neurological diseases, and on developing and trialling adult stem cell repair treatments. He has published various research papers and three Neurology textbooks, some relating to laboratory-based research, others on diseases characterised by brain or spine infl ammation, including in particular MS. He is currently a Guarantor of the neurology journal Brain, and a member of the editorial board of several other neurology journals. He is a member of Council of the Association of British Neurologists (ABN), Chairs the ABN’s MS Section, and is a past Secretary of the UK Neurology Specialty Advisory Committee of the Royal College of Physicians/JCHMT, as an Executive Committee member of the European Council for Treatment and Research in Multiple Sclerosis (ECTRIMS), as a past member of the MRC Neurosciences and Mental Health Panel, of the UK national bioethics committee, ESBAC, and of the UoA4 2014 REF panel. He is currently also Chairman of the Anscombe Centre for Healthcare Ethics.

Nikos Evangelou is Clinical Associate Professor of Neurology and Head of Service for Neurology at Nottingham University Hospital. His neurology training took place in Oxford and Nottingham. He was awarded his DPhil in Oxford for his research on axonal loss in multiple sclerosis and he continues to be research active in MS. His research team explore neuroimaging methods to diagnose MS earlier with accuracy and better ways to use high and ultra-high fi eld MRI techniques to understand the development of physical disability, and other symptoms in MS. He participates in a number of clinical trials and is a member of the Clinical Trials Network and the grant review body of the MS Society.

Alasdair Coles has been a University Lecturer in Clinical Neuroimmunology and a Consultant Neurologist since 2004. He is a Medical Advisor to the MS Society. Since 1993 Alasdair has been involved in the development of alemtuzumab as a treatment for multiple sclerosis. His team in Cambridge is currently testing the ability of keratinocyte growth factor to promote thymic lymphopoiesis and so prevent autoimmunity after alemtuzumab, in a MRC-funded clinical trial. The team is also developing a trial of a potential remyelinating therapy in multiple sclerosis.

Jacqueline Palace is a consultant neurologist in Oxford and honorary senior clinical lecturer for Oxford University. She leads the Oxford Multiple Sclerosis group and runs a national service for congenital myasthenia and jointly a UK neuromyelitis optica service. Her MS service comprises a regional clinical service and a clinical research group. Research interests include clinical treatment trials, immunological studies and imaging studies on neurodegeneration and its detection and association with infl ammation. She is a UK lead for the National Risk Sharing Scheme which assessed the long-term effectiveness for disease modifying agents in multiple sclerosis.

Siddharthan Chandran is MacDonald Professor of Neurology, Director of the Centre for Clinical Brain Sciences at the University of Edinburgh. He trained in medicine at Southampton University, subsequently undertaking neurology training at the National Hospital for Neurology and Neurosurgery, London, and Cambridge. Ph.D in developmental neurobiology from the University of Cambridge (2000). His previous appointments have included Consultant Neurologist, University Lecturer and Fellow of Kings College at the University of Cambridge. In addition, to specialist research clinics in MS & MND, his lab works in the emerging discipline of regenerative neurology using MND and MS as disease models to study glial-neuronal cross-talk.

19

MS Frontiers programmeBiographies

Gianvito Martino received his Medical Degree in 1987 from the University of Pavia (Italy) where he completed his residency in Neurology in 1991. In 1990, he was a Visiting Scientist at the Department of Neurology of the Karolinska Institute (Stockholm, Sweden) and, from 1991 to 1992, he held the position of Research Associate at the Department of Neurology of the University of Chicago (Chicago, IL, USA). From 1992 to 2008, he worked fi rst as Senior Scientist and then as Director of the Neuroimmunology Unit of the San Raffaele Scientifi c Institute in Milan (Italy) where, from 2008, he acts as Director of the Division of Neuroscience. From 2009 to 2012, he served as President of the Italian Neuroimmunology Society (AINI) and, from 2012 to 2014, as President of the International Society of Neuroimmunology (ISNI). In 2000, he founded the European School of Neuroimmunology (ESNI) and, since then, he has been acting as scientifi c coordinator of the school. In 2009, he has been appointed Honorary Professor at the School of Medicine and Dentistry at Queen Mary University of London. He is co-author of more than 250 original articles and book chapters. His scientifi c interests range from the elucidation of the pathogenic mechanisms of immune-mediated central nervous system disorders to the development of gene and stem cell-based therapies for the treatment of these disorders.

David Miller is Emeritus Professor of Clinical Neurology at the Institute of Neurology, University College London. His major clinical and research interests, spanning more than 30 years, are based on multiple sclerosis. He works in a multidisciplinary research group supported by peer-reviewed grant funding that investigates magnetic resonance applications with the aims to improve diagnosis, identify prognostic markers, understand disease mechanisms and monitor new treatments in MS. He has published extensively in the fi eld, has been a recipient of the Sobek Prize (2005) and Dystel Prize (2009) for MS research, is a fellow of the Academy of Medical Sciences and the current Vice President of ECTRIMS.

Olga Ciccarelli is Professor of Neurology at the Institute of Neurology, University College London. Her research aims to understand the mechanisms of damage and recovery in the central nervous system in patients with multiple sclerosis. She runs multiple sclerosis specialist and diagnostic clinics. She has more than 110 publications in peer reviewed journals, she supervises PhD students and had received grant funding from charities and research councils over the years. She serves as Associate Editor of Neurology, leading on the neuroimmunology and neuroinfections portfolio.

Jeremy Chataway – After qualifying in medicine at Cambridge and Oxford Universities, and general medical training in London, he specialised in Neurology over an 8 year period with posts in Edinburgh, Cambridge and London. He was awarded a PhD from Cambridge University in genetic epidemiology of multiple sclerosis and took up his post as a consultant Neurologist in 2001. He is the MS clinical lead at the National Hospital for Neurology and Neurosurgery, Queen Square. He has a major interest in clinical trial work involving novel agents and advanced trial design eg, the MS-STAT and MS-SMART trials in secondary progressive MS. He sits on the UK MS Society Grant Review Panel for Care and Services Research; UK MS Society Clinical Trials Network Steering Group (where he Chairs the Fatigue management working party) and National Institute of Clinical Excellence (NICE) 2014 MS Guideline Development Group.

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Tom Mercer is the Professor of Clinical Exercise Physiology and Rehabilitation and at Queen Margaret University, Edinburgh. He is a member of the Multiple Sclerosis Society’s Clinical Trial Network, a member of the MS Society’s Fatigue working group and is also a Fellow of the British Association of Sport and Exercise Science (BASES). He also co-chairs the United Kingdom Kidney Research Consortium’s Exercise Clinical Study Group, is a member of British Renal Society “Exercise Rehabilitation” steering group and former elected Vice-chair of the European Association of Rehabilitation in Chronic Kidney Disease. Professor Mercer’s exercise rehabilitation research has been supported by a number of sources including the NIHR HTA programme, the Chief Scientist’s Offi ce, NHS Health Scotland, various charities (e.g. MS Society and British Kidney Patients Association) as well as industry (Ortho Biotech, Amgen, Boehringer-Mannheim). His recent work has begun to address the role of non-pharmacological therapies (assistive technologies, such as functional electrical stimulation, and exercise) in extending physical performance capability (e.g. walking) and managing activity of daily living related fatigue in pwMS. He is co-directing, along with Dr Marietta van der Linden, a programme of research exploring the independent and/or interactive infl uences of exercise and FES on motor fatigability in pwMS.

Alison Wearden is Professor of Health Psychology at the University of Manchester and Director of the Manchester Centre for Health Psychology. After graduating in Psychology at the University of Manchester in 1977 Alison took a long detour via social work training and working as a Probation Offi cer, before returning to academic psychology as a researcher in 1993. She obtained her PhD in 2000 and at the same time was appointed Lecturer in Psychology at the University of Manchester, where she has spent her entire academic career becoming a Professor in 2011. She is currently co-Editor (with Professor David French) of the British Journal of Health Psychology. Alison is best known for her research in chronic fatigue syndrome, having conducted two large randomised controlled trials and published numerous other studies relating to the condition. She has also had a long-standing interest in interpersonal factors in illness, and is currently developing a programme of work on interpersonal infl uences on fatigue. Alison has published in leading medical and psychology journals such as the British Medical Journal, British Journal of Psychiatry, Journal of Consulting and Clinical Psychology, and Health Psychology.

Vicky Slingsby – MS Specialist Occupational Therapist working for the Dorset Multiple Sclerosis Service based at Poole Hospital NHS Foundation Trust. Predominantly working in the fi elds of fatigue management, cognition and vocation and has been part of the development, research trials and rolling out of FACETS (group fatigue management programme).

Biographies

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John Saxton is a Professor in Clinical Exercise Physiology and Head of the Department of Sport, Exercise and Rehabilitation at Northumbria University. He is a BASES Accredited Research Physiologist, member of the Physiological Society and has served on Council for the Society for Research in Rehabilitation. His research is focused on the role of exercise and other lifestyle factors in the prevention and management of long-term conditions. He has worked with a number of clinical populations, including people with multiple sclerosis, cancer patients and survivors, patients with peripheral vascular disease and chronic heart failure. As Principal Investigator or Co-Investigator his research has been supported by the Multiple Sclerosis Society, British Heart Foundation, Heart Research UK, Cancer Research UK, American Institute for Cancer Research, Prostate Cancer Charity, Health and Safety Executive and the Food Standards Agency. In 2011, he was editor of a book entitled “Exercise and chronic disease: an evidence-based approach”, published by Routledge, UK. His published clinical intervention studies have helped to build a solid evidence-base to support the use of exercise in the management of many age-related long-term conditions. Most importantly, his research has had a major impact on the quality of many patients’ lives.

David Ford is Professor of Health Informatics and leads the Health Informatics Group at College of Medicine in Swansea University, Wales, UK and directs the UK MS Register Project. David is Director of the Administrative Data Research Centre (ADRC) Wales, an £8 million investment by the Economic and Social Research Council (ESRC) as part of its Big Data initiative and is Deputy Director of the Centre for Improvement in Population Health through E-records Research (CIPHER), part of the MRC’s Farr Institute of Health Informatics Research. David is also Director of the eHealth Industries Innovation (ehi2) Centre, developing links between academia, the NHS, and business within the UK and internationally. He is also University Director of NHS Wales Informatics Research Laboratories, created through a collaboration between Swansea University and NHS Wales Informatics Service. David is joint lead of the SAIL Databank, an internationally recognised data linkage resource formed from a wide variety of routinely collected data from across Wales. David is a Fellow of the Royal Society for the Encouragement of the Arts, Manufactures and Commerce (FRSA) and past Chairman and a current Director of MediWales, a membership organisation representing the medical technology sector of Wales.

Peter Connick is currently a Wellcome Trust Postdoctoral Research Fellow and Honorary Consultant Neurologist at the University of Edinburgh, Anne Rowling Regenerative Neurology Clinic. His research interests include the application of stratifi ed (personalised) medicine in neurological diseases, and cognitive outcome development in multiple sclerosis. He trained in Cambridge, London, and Norwich before moving to Edinburgh.

David Davis – no biography available

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Roshan das Nair is a consultant clinical psychologist and honorary associate professor. His research focusses on applying psychological and neuropsychological theories and models to better understand and treat problems associated with long-term physical health conditions. He has worked in the fi eld of cognitive rehabilitation for over 10 years. With people with MS, he has investigated the experience of living with an unpredictable illness, social and family identity development following a diagnosis of MS, and the effectiveness of cognitive rehabilitation. He is the co-chief investigator of the Cognitive Rehabilitation of Attention and Memory in Multiple Sclerosis (CRAMMS) trial.

Richard M. Ransohoff served at the Cleveland Clinic as Director of the Neuroinfl ammation Research Center in the Lerner Research Institute (2005-14); a professor of molecular medicine at the Cleveland Clinic Lerner College of Medicine (from 2003, now adjunct); and a staff neurologist in the Mellen Center for MS Treatment and Research (1984-2014). Dr Ransohoff joined Biogen (Cambridge, MA) in 2014 as Senior Biogen Research Fellow, Neuroimmunology. Among his awards are a Physician’s Research Training Award from the American Cancer Society (1984-86); a Clinical Investigator Development Award from the National Institutes of Health (NIH; 1988-1993); the Harry Weaver Neuroscience Scholarship of the National MS Society (1987-1992); the John and Samuel Bard Medal in Science or Medicine (2002); the Cleveland Clinic Lerner Research Institute’s Award for Excellence in Science in 2006; and the Cleveland Clinic’s Scientifi c Achievement Award in Basic Science (2009). He was invited to give the FE Bennett Memorial Lecture to the American Neurological Association in 2009. He has been cited in Best Doctors in America for his expertise in the clinical care of patients with multiple sclerosis (MS). The American Academy of Neurology and the National Multiple Sclerosis Society awarded Dr Ransohoff the 2012 John Dystel Prize for MS Research. Dr Ransohoff served as regular member and chair on study sections of the NIH and NMSS and is currently a regular member of the CMBG Study Section. He is a member of the American Academy of Neurology, the American Neurological Association, and the American Association of Physicians and is a Fellow of the American Association for the Advancement of Science. He has written numerous book chapters, and edited fi ve books.

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Presentation abstracts

Monday 29 JunePlenary session

Neuroprotection: prospects and emerging insights

Dr Raj Kapoor National Hospital for Neurology and Neurosurgery, London

No abstract available

Shared decision making in MS: a multi-cultural perspective

Dr Alessandra Solari Istituto Neurologico C. Besta, Italy

Originally developed in family medicine, person-centred care has six dimensions: exploring illness experience as well as the disease, understanding the whole person, fi nding common ground, incorporating prevention and health promotion, enhancing the patient-physician relationship, and being realistic. Shared decision making (SDM) is a development of person-centred care applied to the patient-health provider dialogue. SDM goes beyond informed consent (which implies discussion of risks and benefi ts of each health care option, including the option of doing nothing), providing an opportunity for patients to select options consonant with their personal context, values and preferences. Thus, the SDM model incorporates the unique expertise of patients and physicians. Evidence-based, understandable information is at the core of this model.

In multiple sclerosis (MS) therapeutic options have expanded signifi cantly. Such options are not straightforward and patients have to evaluate complex information, and make diffi cult decisions, shortly after diagnosis. The European MS Platform’s Code on Good Practice (http://www.emsp.org/attachments/article/134/1code08.pdf) and the UK National Institute for Health and Clinical Excellence guidelines for MS diagnosis and management (http://www.nice.org.uk/nicemedia/live/10930/29199/29199.pdf) urge the provision of clear, concise, high-quality information from diagnosis onwards, to empower persons with MS to self-manage their disease as much as possible. This contrasts with the current reality of inadequate disease knowledge by MS patients and their signifi cant others, and limited SDM skills of MS physicians. Persons with MS confronted with an overwhelming amount of web-based information of variable quality and objectives, whereas well-developed information and decision aids are hardly ever implemented in routine care, and become rapidly obsolete. Data from the AutoMS study (https://www.automsproject.org) indicate differences in preference for participation in medical decisions across European countries, which might be due to variations in public investments and initiatives for patient and citizen empowerment.

Strategies to improve the communication and SDM skills of MS neurologists and other health professionals are needed: Equally important is the production of reliable and easily accessible/updated evidence summaries to be used in the clinical encounter.

24


Parallel sessions

A: Mechanisms of progression

Dr Mark KotterUniversity of Cambridge


Mitochondria and progressive MS.

Dr Don MahadUniversity of Edinburgh

Mitochondrial changes are now established in MS and apparent predominantly within the neuronal compartments. The majority of motor neurons harbor mitochondrial respiratory chain enzyme defects, which are likely to contribute to the excess of reactive oxygen species, calcium mishandling and energy failure within the central nervous system in progressive MS. In contrast, chronically demyelinated axons are abundant in functional mitochondria, which help protect the axons. These mitochondrial changes are not recapitulated in the established experimental disease models. We developed transgenic mice with neuron specifi c mitochondrial respiratory chin enzyme defects. Interestingly, the neurons with defective mitochondria survive for a signifi cant period before degeneration. The clinical phenotype during the pre-degenerative phase include motor fatigability and at a molecular level synaptic components are altered. Synaptic loss is the most striking neuropathological fi nding during the neurodegenerative phase. Mitochondrial changes within neurons are contribute to the clinical phenotype as well as axon degeneration in MS and targeting mitochondrial pathways is likely to offer therapeutic benefi t in progressive MS.

Axonal dysfunction in dys- and demyelinating models: a potential role for the injured oligodendrocyte

Dr Julia EdgarUniversity of Glasgow

In the central nervous system (CNS) oligodendrocytes synthesise the myelin sheath. Myelin speeds conduction of electrical impulses along the myelinated axon by promoting saltatory conduction. We and others have previously shown that myelin synthesis is not the only function of the oligodendrocyte. The myelinating cell also shapes the axon during development and supports the structure and function of the axon, independent of compact myelin itself. Using a functional axonal transport assay in vivo, we showed that the oligodendrocyte modulates fast axonal transport. Indeed, in mice defi cient in the myelin proteins proteolipid protein and DM20, retrograde and fast anterograde axonal transport are impaired, implying an axonal energy defi ciency. Recently, studies led by the Nave and Rothstein labs demonstrated that oligodendrocytes supply glycolytic products to myelinated axons to support oxidative phosphorylation in axonal mitochondria. Metabolites and the transporters that convey them across the glial membrane to the peri-axonal space reach the glial-axonal junction via the non-compact myelin (or myelinic channel) that provides continuity

25


between the oligodendrocyte cell body and the distal part of the oligodendrocyte process. We hypothesise that infl ammatory factors perturb the myelinic channel resulting in impairment of the supply of metabolites and/or their transporters to the glial-axonal junction, resulting in axonal energy insuffi ciency beneath the myelin sheath. Funding: Multiple Sclerosis Society UK

B: Towards personalising treatment and care

Towards personalising treatment and care for people with MS

Prof Paul MatthewsImperial College London

The course of MS varies widely between patients, as does response to current MS treatments (MST). Severity of disease varies amongst MS patients. Clinical course is determined by individual clinical and social history, as well as the genetic, environmental and immunological factors that contribute to the dynamics of neuropathological changes (the “psychobiology of treatment effectiveness”). Response to treatment also varies as each of the contributing factors can interact with pharmacology. Many are optimistic that inferences can be extended from a group, to an individual level, to enable informative combinations of clinical, imaging and soluble, genomic imaging data to have predictive potential people with MS. These advances, along with rapid growth in the range of new medicines for MS, their differential benefi ts and risks and cost barriers make stratifi cation of medicines for improved health outcomes in MS timely.

Stratifi ed medicine provides new opportunities for pharma, diagnostic and other healthcare industries given the increasingly crowded and diverse therapeutic market. The range of treatments for MS, their high costs of development and use and the disease heterogeneity together establish the promise and case for investment.

One element for addressing this challenge will be developing large databases of prospectively collected data from people with MS, relating individual characteristics to disease course and treatment response. While this has been done in research cohorts, there is an imperative for this effort to be linked to the delivery of care. An added benefi t will be that clinical effectiveness can be evaluated as a complement to information on effi cacy from clinical trials. This, in turn, can lead to real life strategies for stratifi cation for responsiveness to MS therapies. A second element will come from people with MS. They must be involved at all stages – as stakeholders and sources of patient centred data important for assessing the meaningfulness of therapeutic effects.

The time has come to work towards a common understanding between all stakeholders of how to make decisions for stratifi ed medicine in MS.

26


Making informed decisions about disease modifying treatments

Dr Hilary Bekker & Dr Ana ManzanoUniversity of Leeds

People with relapsing remitting multiple sclerosis (PwRRMS) have to make decisions about disease modifying treatments (DMTs). Clinical guidance is for practitioners to support patients in making informed decisions between treatments, after consideration of the risks and benefi ts of all options in the context of their lifestyle and experience of illness. Currently there is little evidence on how best to provide information tailored to support PwRRMS deliberating between the different components of these options. We will explore how using decision sciences pragmatically with clinical effectiveness evidence, patient experience surveys and service delivery pathways can inform interventions to help patients and practitioners share decision making between treatment options. We examine how people make decisions and how information impairs or enhances people’s choices. We will focus on techniques used in economics that help people trade-off their preferences for treatments that can be adapted for people with remitting multiple sclerosis and may be useful in interventions within the delivery of healthcare to support patient need and staff practices in enabling shared decision making.

New directions for MS genetics

Prof Stephen SawcerUniversity of Cambridge

Genome-wide Association Studies (GWAS) have successfully identifi ed common variants associated with many complex traits and have thereby transformed our understanding of such disorders. The technology behind these studies is now well refi ned, robust and highly cost effective. By applying these principles and methods the International Multiple Sclerosis Genetic Consortium (IMSGC) has already identifi ed more than 100 genetic variants associated with susceptibility to multiple sclerosis. However, to date these studies have largely ignored issues such as genetic infl uences on course and severity, which are central questions in the context of personalised treatment and care. Using the power of genetics to address these questions is an exciting new research direction which is likely to grow in the coming years. Insights gained from studying the genetic factors infl uencing phenotype and response to therapy are likely to be invaluable in the development of personalised therapy.

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C: Rehabilitation – New innovations and technology

Web-based physiotherapy for people affected by Multiple Sclerosis

Dr Lorna PaulUniversity of Glasgow

Due to reasons such as transport issues, work or caring commitments or living in a remote or rural locations some people with MS, and other long term conditions, have diffi culty in accessing traditional physiotherapy services. In an attempt to address this issue we have developed a web platform for the delivery of physiotherapy from which the physiotherapist can remotely review the persons programme and alter the programme depending on progress or otherwise.

Our initial pilot study, of 12 weeks of web-based physiotherapy, demonstrated that people with MS found the website easy to use and reported that it motivated them to do their exercise programmes. Thanks to funding from the MS Society, we are now conducting a multi-centre randomised feasibility study of a six month intervention of web-based physiotherapy with three months follow up.

This presentation will highlight the drivers for the development of web-based physiotherapy and the barriers which have been faced. The results of the pilot study in MS and an outline of the current study will be presented.

Digital platforms allow exploration of innovative developments so some of our early work around digitisation of exercises and integration of sensors will also be discussed.

Playful and Gameful Exercise

Dr Darryl Charles Ulster University

Physical rehabilitation can be an important contributing factor towards the wellbeing of people affected by MS. However, there can be barriers that can diminish continual engagement with exercise programmes. For example, it is often reported that proscribed exercises are tough, dull and uninteresting; this is mainly due to their inherent repetitive nature. Walking in particular is an important activity and is more interesting than prescribed rehab programmes. Unfortunately, there are also barriers that may prevent a person affected by MS from engaging in walking out doors. Such as the worry of falling or being self-conscious about walking in public. In this presentation we will consider these issues in relation to serious games, gamifi cation, and the use of modern game interfaces/controllers for support exercise and rehab. A core focus will be on the importance of playfulness and gamefulness and the use of mass produced game technologies to support exercise to help overcome some of the barriers to improved engagement with exercise.

Dr Charles will begin with an overview of research conducted at Ulster University over the past decade which looked at games and VR for engaging users with upper arm rehabilitation. He will continue to discuss more recent research which investigated the gamifi cation of non-game processes such as rehab and exercise and present the results of a new study on variation in the different ways that people may be motivated (gamifi cation types); considering factors such as playfulness and gamefulness. New natural user interfaces technologies such as the Leap Motion controller, the Myo arm band, Kinect 2 and the Omi 360 degree treadmill will be discussed with respect to arm and leg exercise and rehabilitation.

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Value for effort in balance exercise programmes – challenges and opportunities

Hilary GunnPlymouth University

Impaired mobility is a cardinal feature of MS and is consistently rated by people with MS as their highest priority and most important yet most challenging daily function. A signifi cant contributor to these diffi culties is impaired balance, which is also strongly associated with falls risk. Exercise modalities have the potential to be valuable interventions to improve balance and address falls; however, evidence suggests that achieving and sustaining the required intensity of highly challenging balance practice is critical to optimising effectiveness. This presentation will highlight some of the opportunities and challenges associated with supporting programme adherence in this context, incorporating evidence from our own work in falls in MS alongside research from other related areas of practice.

Enhancing adherence to behavioural interventions – the role of psychology

Dr Sarah ThomasBournemouth University

While there is evidence of the effectiveness of rehabilitation and exercise programmes for people with MS, adherence to traditional programmes is often poor with effects not maintained in the longer term. People with long-term disabling conditions such as MS face multiple barriers to participation in rehabilitation and exercise programmes including physical (e.g. pain, fatigue, mobility limitations and overheating), psychological (e.g. fear, embarrassment and lack of confi dence), social (no one to exercise with, no one to provide encouragement), and environmental (transport, cost, lack of suitable facilities/trained staff) factors.

Rehabilitation and exercise interventions are often brief, not always designed for implementation in ‘real world’ settings and follow-up beyond six months is uncommon. Adherence often drops off when supervised phases end and sometimes participants’ primary motivation for adhering during the study period is to please the research investigators.

In this presentation I will consider factors that might enhance engagement with rehabilitation and exercise interventions and how psychological theories and behaviour change techniques might offer a means to bridge the ‘intention-behaviour’ gap that we often observe.

I will illustrate the potential relevance of psychological theories and behaviour change techniques and some of the challenges faced using examples from a recent feasibility study of a physiotherapist supported home-based Nintendo Wii™ intervention (‘Mii-vitaliSe’).


29


The neurobiological basis of rehabilitation in MS

Prof Diego Centonze Tor Vergata University and Hospital, Rome, Italy

Clinical expression of brain damage varies over time and among individuals. This is particularly evident in multiple sclerosis (MS) where the expression clinico-radiological paradox has been coined to indicate the weak association between common neuroradiological markers of MS and clinical disability. Recent data suggest a possible role of adaptive synaptic long-term potentiation (LTP) in the clinical course of MS. We propose that the capacity of the brain to potentiate synaptic excitability in a long-lasting way is the brain’s core adaptive property to bridge neuronal damage and clinical expression in MS. LTP, in fact, consists in the strengthening of synaptic communication between two connected neurons, and is virtually able therefore to restore membrane excitability of neurons that have lost part of their synaptic inputs. Consistently, recent studies have shown that cortical LTP reserve, explored through transcranial magnetic stimulation (TMS), contrasts disability progression in MS. Promotion of cortical LTP through exercise therapy or TMS induces cortical remapping and ameliorates symptoms of MS. Along with its ability to enhance plasticity and recovery of function, exercise also interferes with infl ammation-driven neuronal damage, and might therefore have disease-modifying properties in patients with MS.

D: Modifi able risk factors for MS

Lung-specifi c immune activation in smokers and non-smokers diagnosed with multiple sclerosis

Dr Johan ÖckingerDepartment of Medicine, Karolinska Institutet, Stockholm, Sweden

To investigate the role of smoking and immune activation in the lung in MS, we have conducted bronchoscopies with bronchoalveolar lavage (BAL) on smokers and non-smokers diagnosed with MS (12 and 14, respectively), as well as healthy smokers (21) and non-smokers (33). The smokers included in the study had a mild to moderate smoking history (2-27 pack-years), and all had normal lung function. Samples collected from these individuals undergo a systematic investigation of immune activation, including lymphocyte subsets, phenotype and activation, innate immune activation, gene expression and antigen presentation, and data analysis is still in progress.

Our study confi rms that smoking is associated with an altered composition of immune cells in the lung characterized by 2-3 fold increase of the number of alveolar macrophages, a minor increase in the number of neutrophils and reduced CD4+/CD8+ T-cell ratio. The smokers among the MS-patients and healthy volunteers also displayed an overall increased activation of T-cells in the lung, however T-cells from non-smoking MS-patients display an increased expression of the activation marker CD40L. After in vitro stimulation, we found that the frequency of Foxp3+Helios+ regulatory T cells was reduced in BAL from all MS patients. We further investigated the role of smoke induced activation of infl ammasomes, an intracellular protein complex essential for the secretion of the proinfl ammatory cytokines IL-1beta and IL-18. Smokers showed increase infl ammasome activation in BAL cells, and displayed higher concentration of IL-1beta in both BAL-fl uid and serum, compared to nonsmokers. Alveolar macrophages and PBMCs from smokers stimulated in vitro with ATP showed increased NLRP3-infl ammasome activation compared to


30

MS Frontiers programmePresentation abstracts

non-smokers, whereas both smokers and non-smokers diagnosed with MS showed increased NLRP3-infl ammasome activation after stimulation with silica particles.

These results confi rm the role of cigarette smoking as an infl uential modulator of the immune system. Moreover, we have identifi ed altered numbers of defi ned populations of lung cells in MS patients and immune activation specifi c to both disease and smoke status. This further strengthens the hypothesis of the lung as an immunoregulatory organ in infl ammatory diseases and could represent biological mechanism underlying the association between smoking and increased risk for MS.

Sex hormones, obesity and multiple sclerosis risk

Julia Pakpoor University of Oxford

The demographic profi le of multiple sclerosis (MS) is one of its most intriguing features and one which causative hypotheses must account for. MS is universally more common in females compared to males, and MS in males is associated with greater disability progression and typically starts at a higher age compared to females. This has led to numerous studies exploring differences between males and females in immune system or nervous system function, which may be mediated by sex hormones. The evidence base implicating low testosterone levels as an important modifi er in both MS risk and disease course is growing, and low testosterone has been associated with a fi ve-fold elevation of MS rates in males when compared to a reference cohort, and also associated with greater disease severity and brain atrophy early in disease course. This session will focus on evidence supporting an important role for low testosterone as a risk factor of MS, particularly in males, and the more elusive role of oestrogen in MS risk will also be considered. Obesity in early life has relatively recently been consistently associated with an increase in MS risk. The interaction between sex hormones and obesity, as well as the interaction of these factors with other more established risk factors of MS such as vitamin D defi ciency will be discussed. Elucidating the role of sex hormones will be important in establishing causal pathways, identifying high risk groups, and ultimately preventing MS.

Cary JamesTerrence Higgins Trust

No abstract available.

31


Tuesday 30 JuneParallel sessions

A: Are we seeing better? New imaging methods and biomarkers

New spinal cord imaging techniques

Prof Olga Ciccarelli University College London Institute of Neurology

Recent advances in imaging techniques allow us to study in vivo the pathological processes occurring in the spinal cord of people with MS. Additionally, the relationship between pathological changes and clinical disability is better understood, and the mechanisms responsible for progression of disability are becoming clearer. New imaging methods are being used in clinical trials to assess the effi cacy of new medications. We are currently working towards translating these techniques to the clinical setting.

Update on CSF biomarkers of disease activity and progression

Prof Gavin Giovannoni Barts and The London School of Medicine and Dentistry

CSF biomarkers are a well-established aid in the diagnosis of MS and to exclude alternative diagnoses. More recently CSF biomarkers are being used to help monitor the underlying MS disease processes, aid in predicting the future course of MS, reduce the risk of disease modifying therapies and to diagnose complications of disease modifying therapies. Spinal fl uid biomarkers are being to be used to assess the response or lack of response to disease-modifying therapies. The current strategy of treat-2-target of no evident disease activity (NEDA) relies on frequent MRI assessments. The possible incorporation of spinal fl uid neurofi lament levels into the defi nition of NEDA promises to change the treatment paradigm and to improve the long-term clinical outcome of people with MS.

High fi eld MRI. What can we learn about MS?

Dr Nikos Evangelou University of Nottingham

Conventional neuroimaging has served MS very well for a number of years, facilitating early diagnosis and monitoring of the disease and treatments. Unfortunately, a great deal remains elusive in our efforts to understand the mechanisms of damage. Correlations of lesions with disability remain modest and still symptoms such as fatigue remain largely unexplained. Ultra high fi led imaging offers new possibilities by enhancing the sensitivity of MRI in detecting structural pathology and functional defi cits. Detecting central veins can help diagnose MS with confi dence, even when clinical uncertainty exists. The high special resolution helps identify and study gray matter lesions better. Moreover, a number of recent studies offer hope that molecular mechanisms will be better described with the use of spectroscopy and other functional studies.

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B. The many facets of fatigue

Performance related fatigue in multiple sclerosis

Dr Don Mahad University of Edinburgh

Fatigue, frequently encountered by individuals with multiple sclerosis, has perceptual and performance related components. The performance related aspects of fatigue (Fatigability), which may be measured objectively, have cognitive and motor elements. The underlying mechanisms of fatigability in MS are not completely understood. Demyelination and Uhthoff’s phenomenon as well as axon degeneration have been implicated in pathophysiology of fatigue in MS. Recent studies of post-mortem tissue from patients with progressive MS identifi ed consistent changes in mitochondria, the most effi cient producers of cellular energy. These mitochondrial respiratory chain enzyme defi ciency is most apparent within neurons, including motor and sensory neurons. We developed animals models that represent the neuronal mitochondrial changes and identifi ed motor fatigability as a clinical phenotype. This reversible phenotype appears prior to the onset of neurodegeneration and can be rescued by agents that target mitochondria. Understanding the pathophysiology of performance related fatigue or fatigability in MS may provide novel therapeutic targets for progressive MS at both symptomatic and disease modifying level.

Exercising infl uence on MS-related Fatigue: what do we really know?

Prof Tom Mercer Queen Margaret University Edinburgh


Understanding and managing chronic fatigue syndrome (CFS): similarities and differences with fatigue in other conditions

Prof Alison Wearden University of Manchester

Chronic fatigue syndrome (CFS) is characterised by severe, disabling fatigue which cannot be attributed to any other medical or psychiatric condition. Fatigue is usually accompanied by other symptoms, and results in signifi cant functional impairment and high social and economic costs. Over recent years, several explanatory models for CFS have been developed. A common feature of these models is the suggestion that the factors which trigger fatigue are not necessarily the same as those which maintain it. The maintenance of fatigue is explained in terms of a complex interaction of physiological dysregulation, behavioural, cognitive, emotional and social factors. This understanding has informed treatment approaches, including cognitive behaviour therapy, graded exercise therapy and pragmatic rehabilitation, all of which have been shown to be effective treatments for CFS. In this talk I will briefl y review the dominant model of fatigue in CFS and the evidence for treatments based on it. I will then examine the model in more detail and will consider to what it extent it can help us to understand and manage chronic disabling fatigue which occurs in the context of many other medical conditions, including MS.

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The practicalities of delivering fatigue

Vicky Slingsby Dorset Multiple Sclerosis Service, Poole Hospital NHS Foundation Trust

I will outline and discuss my experiences of delivering fatigue management intervention, including the FACETS programme and the benefi ts that this group can have on attitudes and helping to overcome barriers to change.

The EXIMS trial – impact on MS fatigue and lessons learned

Prof John Saxton Northumbria University

Fatigue is a highly prevalent debilitating symptom amongst people with multiple sclerosis (MS), with over half of the MS population describing it as one of their most severe symptoms. Fatigue symptoms are often present in the earliest stages of MS, when there is little evidence of disability. As the effectiveness of pharmacological and psychosocial treatments for MS fatigue is likely to be modest at best, alternative approaches to its management, particularly interventions that can be incorporated into long-term self-management strategies, are urgently needed. In contrast to traditional energy conservation approaches to fatigue management, ‘exercise therapy’ is now more frequently being recommended to people with MS because of the purported impact it can have on fatigue symptoms and other health outcomes, such as function and quality of life. Indeed, exercise has much potential to be a cost-effective self-management strategy for sustainable improvements in MS fatigue. This presentation will consider the role of exercise in MS fatigue management from the perspective of the EXIMS trial, a large-scale UK-based randomised controlled exercise intervention for people with MS. It will consider important lessons that were learned from the trial and qualitative feedback from study participants regarding the health benefi ts experienced and accessibility of exercise in the community.

C. Using big data to improve health and social care

The UK MS Register: A platform for enquiry and research

Prof David Ford College of Medicine, Swansea University

The MS Register has been funded by the MS Society to provide a means of understanding more about Multiple Sclerosis, particularly from the point of view of people living with the condition. Designed and operated by the Health Informatics Group at Swansea University, the Register contains data from over 10,000 people with MS from across the UK, who regularly provide updates on their condition, their treatments and outcomes into a purpose designed web portal. This data is combined within the Register with data collected from collaborating clinical sites and with data, where available, from routine sources such as hospitals and GPs, to gain a rounded picture of the participant’s health. The Register has built up a rich picture of how MS affects people and provides a platform to access many thousands of willing participants, willing to lend their data and their time to support research.

This talk outlines the basic elements of the MS Register, describes how it works, and details how researchers can gain access to it. It will then explore how the Register can be used in a wide range of research studies, from observational studies, surveys and cross-sectional studies, through to interventional research such as clinical trials. Some illustrative examples will be provided to aid understanding.

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FutureMS: Clinical, laboratory, and genomic predictors of disease activity in people with newly diagnosed relapsing onset multiple sclerosis: an observational cohort study

Dr Peter Connick University of Edinburgh

MS has been the pathfi nder disease for therapeutics in neurology over the past two decades. However, the increasing range of therapeutic (DMT) options and the wide variation in neuroinfl ammatory disease activity between patients, has brought into sharp focus the need to balance risk and benefi ts at the level of the individual. For heathcare funders, there is a linked need to ensure cost-effective use of these expensive therapeutics. In the language of stratifi ed/personalised medicine – to deliver the right drug at the right time to the right person.

Existing treatment pathways typically frame personalised MS-DMT decisions within a reactive strategy that responds to prior disease activity. Supported by Stratifi ed Medicine Scotland – Innovation Centre (SMS-IC), we are currently planning the FutureMS study: an observational study to develop tools that predict neuroinfl ammatory disease activity in people recently diagnosed with relapsing-onset multiple sclerosis.

David Davis NHS England


Ian McDonald Memorial LectureInsights from imaging multiple sclerosis

Prof David MillerUniversity College London

In the three or more decades that I have been seeing people with MS, there has been an enormous change in our understanding of the condition and in the way that it is diagnosed and treated. These advances have been brought forward through progress along numerous different lines of scientifi c research. There have been remarkable developments in clinical trial research that include innovative trial designs and novel pharmacological approaches. There are now multiple therapies available, with varying modes of action and effi cacy, to help control the relapsing remitting phase of MS. In this talk I will chart some of the progress over the last 30 years with a particular focus on the contributions from imaging. There are, nevertheless, still big challenges ahead. These include the pressing need to better understand the mechanisms of progressive MS and to develop effective neuroprotective and neuroreparative treatments to prevent or even reverse established disability. As in the past, the way forward will rely on cutting-edge scientifi c research, with a strong emphasis on multidisciplinary collaboration involving multiple investigators and research groups. I will discuss the potential role of current and emerging imaging methods in facilitating future progress.

35


Plenaries

Cognitive rehabilitation in multiple sclerosis: Looking back and moving forward

Dr Roshan das Nair Nottingham University Hospitals NHS Trust & University of Nottingham

Forty to sixty per cent of people with multiple sclerosis (MS) experience cognitive problems. These can be debilitating for the individual, and can affect their personal, family, social, and professional lives. Families and society at large are also adversely affected by this. It is therefore of no surprise that one of the top 10 research priorities of the MS Society is to answer the question ‘Which treatments are effective to improve cognition in people with MS’?

There is an emerging literature on how these cognitive problems can be addressed, and ‘cognitive rehabilitation’ has been identifi ed as a promising intervention. Cognitive rehabilitation is a structured set of therapeutic activities designed to retrain cognitive functions and help people cope with them. While there are some studies that demonstrate the effectiveness of cognitive rehabilitation, the overall evidence remains inconclusive or weak. However, past research has created opportunities for developing bigger and better studies that will help us determine what kinds of interventions work best for different cognitive problems. Indeed, the Cognitive Rehabilitation of Attention and Memory in Multiple Sclerosis (CRAMMS) trial seeks to investigate just this.

In this presentation, I will summarise the state of the science of cognitive rehabilitation in MS, provide an overview of the CRAMMS trial, and fi nish by sharing some ideas about how research could evolve further to help people with MS who experience cognitive diffi culties.

Microglia: A reintroduction

Dr Richard M. Ransohoff Biogen

Microglia arise during primitive hematopoiesis and initially enter the developing murine brain around E10.5, before other glia and prior to neuronal differentiation. During development, microglia interact extensively with neurons, helping to establish neuronal populations through infl uences on survival, apoptosis and corpse-clearance. As neuron-to-neuron contacts are forming during early postnatal life, microglia refi ne neuronal network properties by synaptic pruning.

Neuron-microglial and microglial-neuron dialogs are mediated by contact-dependent and soluble signals. As one example, fractalkine (CX3CL1) is a transmembrane chemokine expressed in the CNS solely by neurons, which also release soluble fractalkine to signal at a distance. The fractalkine receptor (CX3CR1) is restricted to microglia among CNS cells. Perturbation of fractalkine/fractalkine receptor signaling results in altered microglial function, with consequences observed from mid-gestation through aging and neurodegeneration. Using mice defi cient for fractalkine or its receptor provides a wealth of insights into microglial function in the intact CNS and may have direct clinical relevance, given a common hypomorphic CX3CR1 allele in humans. Examination of the mechanism underlying fractalkine regulation of microglial responses may yield information useful for translating model results to clinical application.

36

Poster Abstracts

1. Ethnicity and Multiple Sclerosis Prevalence in East London

Christo Albor, Timothy du Sautoy, Narmadha Kali Vanan, Kambiz Boomla, Klaus SchmiererBarts and The London School of Medicine and Dentistry, Queen Mary

Background: There is a perceived consensus that the incidence and prevalence rates of MS in countries with a White majority are lower in the minority ethnic population than in the White population. Often-cited UK-based studies relevant to this were conducted over twenty years ago. In our study we update the UK-based literature.

Methods: Electronic records from GPs in the four innermost east London boroughs were queried for the number of patients with an MS diagnosis, grouped by ethnicity, into 5-year age bands. Compared against total registered GP patients in the area (c.900K), we calculated the age-standardised MS prevalence separately, for White, Black and South Asian populations.

Results: Overall prevalence was 111 per 100K (152 for women, 70 for men). This was 180, 74, and 29 for the White, Black and South Asian populations respectively. The sex ratios (female:male) were 2.2:1, 2.1:1 and 2.8:1 respectively.

Conclusion: Inner east London is an ideal area to study ethnicity-specifi c prevalence, with a population that is 36% White, 16% Black, 30% South Asian and 18% Other. MS prevalence was considerably lower amongst Black and South Asian populations, compared to the White population, by 59% and 84% respectively. However, despite being lower that the White population, the prevalences rates we found for the Black and South Asian populations are much higher than that of Africa or the Indian subcontinent.

37

Poster Abstracts

2. Stem cells in Rapidly Evolving Active Multiple Sclerosis (STREAMS): a Phase 2 trial of autologous mesenchymal cell therapy

Rehiana Ali, Richard Nicholas, Steve Marley, Shahrukh Mallik, Renuka Palanicawandar, Belen Zamarreno, Francesco Dazzi, David Miller and Paolo MuraroImperial College London

Objective: To present the early results and progress of STREAMS (Stem Cells in Rapidly Evolving Active Multiple Sclerosis), a Phase 2 randomized, double-blind trial of autologous mesenchymal stem cells (MSCs) in highly active MS.

Background: A number of clinical trials have been attempting to exploit the potent immunomodulatory, neuroprotective and potentially reparative properties of MSCs however STREAMS is distinctive in design, recruiting only patients with highly active MS to this double-blind randomized controlled trial.

Design/Methods: 12 patients with highly active MS were recruited over 13 months to this randomized double-blind, crossover study in London, which is also part of the international consortium, MESEMS, which aims to recruit ~160 patients in total. Activity was characterised clinically by the presence of at least 1 relapse in RRMS/SPMS or disability progression of ≥1 EDSS point (if baseline EDSS ≤5.0) or ≥0.5 EDSS point (if baseline EDSS was ≥5.5) in PPMS/SPMS occurring in the preceding 18 months; and radiologically by the presence of at least one gadolinium enhancing lesion (GEL) on MRI brain within 6 months of the bone marrow harvest.

The patients received 1-2x106 MSCs/kg or placebo at Week 0 with treatment reversed at Week 24; the allocation was randomly generated. Clinical assessments and MRIs were performed in the intervening weeks (Weeks 0, 4, 12, 24, 28, 36 and 48). The co-primary outcomes were safety and the number of GELs on sequential MRIs between treatment groups. Secondary outcomes included combined MRI activity, number of relapses, disease progression and changes in the Multiple Sclerosis Functional Composite (MSFC) score. Exploratory work included an extensive fresh ex-vivo analysis of immune cell populations by 12-color fl ow-cytometry, mantoux tests, and novel in vitro mechanistic work to understand the immunomodulating action of MSCs.

Results: Culture duration has varied from 19-36 days. The mean yield of all 12 successful harvests was 3.10x106 cells/kg with only one harvest below target (0.44x106 cells/kg). All participants have received both infusions and as of April 2015, 10 patients have fully completed the trial. The remaining 2 patients complete their trial assessments on 21 May 2015.

No serious adverse events have been recorded.

Funding for a trial extension was granted by the MS Society to allow 5 more patients to be recruited: MSCs are in culture for 1 patient and a further 2 patients will be Screened in April 2015.

Conclusion: The results of the trial support both the safety and feasibility of mesenchymal stem cell therapy.

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Poster Abstracts

3. Hypoxia in neuroinfl ammatory demyelinating disease: a role for oxygen treatment?

Mario Amatruda, Alina Matis, Andrew Davies, Roshni Desai, Maren Lindner, Christopher Linington, Kenneth J. SmithInstitute of Neurology, University College London, London, United Kingdom

The mechanisms responsible for the neurological defi cits and demyelination in relapsing-remitting multiple sclerosis (MS) are complex. Neurological defi cits are typically attributed to demyelination and degeneration, but the evidence is that neuroinfl ammation per se can also play a direct role, by unknown mechanisms. Demyelination can have different appearances, with some indicating autoimmune mechanisms, while others indicate hypoxia. Indeed, we have recently demonstrated that the spinal cord can be severely hypoxic in rats with active experimental autoimmune encephalomyelitis (EAE), and that the hypoxia can be reversed by inspiring oxygen-enriched air. Here we examine the role of oxygen therapy with regard to neurological defi cits and demyelination in active EAE induced by recombinant myelin oligodendrocyte glycoprotein (rMOG) in DA rats, a model that reproduces many of the features of MS. We also explore whether hypoxia may contribute to the neurological defi cit in DA rats with passive transfer EAE, a model where paralysis can occur in the absence of demyelination.

In active EAE, exposure to 100% normobaric oxygen improved neurological function in 50% of the treated rats (n = 10) within only one hour of treatment, and the improvement reversed upon return to room air for another hour, underlining a specifi c, transient benefi cial effect of oxygen exposure on neurological function. To determine the best time to initiate treatment, oxygen (75%) was administered for 24 hours either at the fi rst, second or third day of disease expression. Oxygen always reduced the neurological defi cit (n = 18, p < 0.05), although the greatest improvement occurred with administration on the fi rst day of defi cit. We then tested the optimal duration for oxygen administration (24, 48 and 72 hours at 75% normobaric oxygen, n = 40) from the onset of disease, and found that the greatest benefi t was achieved with 48 hours exposure (p < 0.05). Interestingly, when administered at the onset of symptoms, oxygen reduced the severity of the disease progression for up to two additional days once returned to room air. Histologically, oxygen-treated animals were protected from demyelination in proportion to the duration of the exposure, and this protection was statistically signifi cant in rats treated with oxygen for 72 hours compared with room air controls.

In passive EAE an oxygen-sensitive probe inserted into the spinal cord revealed that the oxygen concentration of affected animals was lower than in controls, and histologically there was a signifi cantly higher expression of markers for tissue hypoxia. The fi ndings suggest that the neurological defi cits in passive transfer EAE may be caused, at least in part, by tissue hypoxia.

We conclude that tissue hypoxia is an important but currently overlooked cause of severe neurological defi cits and demyelination in neuroinfl ammatory disease, and that oxygen administration can promptly ameliorate the defi cits and protect against demyelination.

Selected for presentation during ‘Mechanisms of progression’

39

Poster Abstracts

4. Role of Vitamin D in T cell migration

Lisa Kelly, Joanne Hay, Nivedya Swarnalekha and Anne L. AstierUniversity of Edinburgh

CNS is crucial for MS pathogenesis, and the integrins VLA4 (± 4² 1 or CD49d/CD29) and LFA1 (± L² 2 or CD11a/CD18) are key to this process, and bind to their ligand VCAM and ICAM-1 upon activation. Herein, we have investigated the effect of vitamin D on expression and activation of VLA4 and LFA1 on activated human T cells. We have fi rst investigated the role of active vitamin D (calcitriol) on healthy CD4+ T cells by analyzing expression of CD46, CD11a, CD29 and CD49d on activated T cells, and assessing activation of VLA4 and LFA1 using a VCAM adhesion assay and staining cells with antibodies specifi c for activated beta2 integrins, respectively. Addition of calcitriol decreased expression of CD49d and CD29 as well as adhesion to VCAM. Calcitriol also slightly decreased CD11a expression and reduced activation of LFA1. Importantly, calcitriol had similar effects on the phenotype of memory CD4+ T cells isolated from healthy controls and patients with RRMS. These data provide novel insights into the mechanisms of action of calcitriol in T cell function, and suggest that vitamin D may be controlling T cell infi ltration into the CNS.

Selected for presentation during ‘Modifi able risk factors for MS’

5. VSN16 a safe, new drug to treat spasticity

David Baker, Gareth Pryce and David L SelwoodNeuroinfl ammation Group, Dept of Neuroscience, Blizard Institute, Bart’s and the London school of Medicine & dentistry, QMUL

Current symptomatic treatments for spasticity often exhibit intolerable side-effects that limit their early adoption and use following onset of spasticity in multiple sclerosis. We synthesized a novel compound, VSN16R, which exhibited anti-spastic activity in experimental autoimmune encephalomyelitis (EAE) in mice and was as active as baclofen and cannabinoids but lacked their sedative side-effect potential. The drug was found to be a novel, very potent ion channel modulator in vitro. VSN16R was orally active and remarkably well-tolerated (with over a thousand fold therapeutic window) despite administration of large doses and demonstrated no obvious, adverse neurobehavioural effects in mice. It was also well tolerated in other larger animal species and importantly humans, where it was found that VSN16R produced high bioavailability with over ten-hundred fold higher plasma levels than achieved with comparable doses of VSN16R that were therapeutic in rodents. The drug was without any adverse behavioural or other physiological events. This study identifi es a novel target for control of spasticity and suggests that VSN16R may be a useful novel anti-spastic agent, which offers tolerability advantages over existing treatments. This may facilitate adoption of earlier treatment following to development of spasticity in MS.


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Poster Abstracts

6. Investigation of social identity and mood in people with MS

Alex Barker, Nadina/B Lincoln, Roshan das Nair, Nigel HuntUniversity of Nottingham

Introduction: Changes to identity following a diagnosis of multiple sclerosis (MS) can have negative psychological effects on the individual. Mood disorders are common in people with MS with high rates of depression and anxiety.

The Social Identity Model of Identity Change (SIMIC) states that belonging to a number of groups before a life changing transition can protect people from the effects of this transition by providing support to rely on. Previously established social groups can form a secure base for identity reconstruction by providing a basis for social support, grounding and connectedness to others, allowing people to build new identities. The family is a social group that has been found to be a salient factor in adjustment to MS, a source of support for people with MS, and may enable the establishment of new identities.

Our aim was to investigate whether a person s family identity was associated with more positive mood, greater perceived social support and increased willingness to join new groups and establish new identities.

Methods: Participants with MS, recruited from an NHS Trust and the MS Society website, were sent questionnaires on family identity, mood, perceived social support, and willingness to engage in new groups. The measures used were the Social Identifi cation Scale, the Hospital Anxiety and Depression Scale, the Multi-dimensional Scale of Perceived Social Support, and the New Groups subscale of the Exeter Identity Transition Scale.

Results: 187 participants aged 24 to 85 years (mean 48.57, SD 11.03) were recruited, 133 (73.5%) were women. The majority had relapsing-remitting MS (55.9%) and years since diagnosis ranged from less than 1 year (4.4%) to over 15 years (22.1%).

Path analysis revealed that family identity was associated with social support (0.495, R2=0.245), willingness to engage in new groups (0.211, R2=0.045) and mood (-0.298, R2=0.089). Family identity infl uenced perceived social support more than willingness to engage in new groups, and perceived social support infl uenced mood (-0.420, R2=0.176) more than family identity (-0.298, R2=0.089) and willingness to engage in new groups (-0.216, R2=0.047).

Conclusion: Identifying with the family group was associated with better mood in people with MS. However this relationship can be better explained through the infl uence that family identity can have on perceived social support and their willingness to engage in new social groups. This supports the SIMIC in that family identity was associated with greater perceived social support and connectedness to others through an increased willingness to join new social groups.

41

Poster Abstracts

7. Optimization of a quantitative MRI myelin biomarker in the cervical spinal cord

Marco Battiston, Claudia A M Wheeler-Kingshott, Rebecca S SamsonUCL Institute of Neurology

Introduction: The spinal cord (SC) is involved in neurological disorders such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury (SCI), neuromyelitis optica (NMO) and dementia [1]. Magnetisation Transfer (MT) imaging is sensitive to SC pathology, and the MT ratio (MTR) has shown reductions in MS [2], and SCI [3]. Making quantitative measurements in the SC in vivo is challenging, although there is evidence such measurements can provide novel, sensitive markers for clinical outcomes. Developing fast SC imaging protocols for quantitative MR parameters sensitive to pathological processes is essential to increase understanding of how pathology contributes to disability, to predict outcomes and to evaluate repair mechanisms. We aimed to optimise the MTR sequence parameters to maximise its sensitivity to the Bound Pool Fraction (BPF), considered to be a biomarker of myelin in the brain and SC [4]. Simulations were used to determine combinations of acquisition parameters that maximised the sensitivity of the MTR to changes in the BPF. Optimal and non-optimal MTR protocols suggested from simulations were compared in terms of contrast both in phantoms and in the SC in vivo.

Methods: Simulated MTR values were generated using the two-pool model proposed in [5]. The MTR was simulated over all possible combinations of sequence parameters. MTR sensitivity to BPF (∂MTR/∂BPF) and also to T1 relaxation (∂MTR/∂R1f), were calculated. Scanning was performed using a 3T Philips Achieva MRI system. An optimal and a non-optimal sequence were compared in Bovine Serum Albumin (BSA) phantoms of concentration 20% and 25%, and in a healthy subject, imaging the C1-C2 levels of the cervical cord. MTR contrast-to-noise ratio (CNR) was examined among tissue types (i.e. different BSA concentration, or SC WM and GM).Results: Simulations show that ∂MTR/∂BPF can be increased and ∂MTR/∂R1f jointly decreased by reducing the interval between RF pulses (PRT), and reducing the number of RF pulses (N). In both phantom and in vivo experiments, CNR is increased using the optimal sequence, respectively 4.74 vs 1.42 in phantoms, 1.35 vs 0.87 in vivo.

Discussion: We showed that competing effects of MT and T1 relaxation in the MTR can be disentangled. MTR sequence optimisation provides improved sensitivity to the BPF, and enhances WM/GM MTR contrast. This is of particular interest for the SC, where tissue specifi c measurements cannot be performed due to the poor contrast. Improved sensitivity to BPF changes opens the possibility to use MTR as a biomarker for myelin content, with potential applications in SC pathologies, as MS, ALS, SCI and NMO. Additionally this optimisation method could be applied to other quantitative MRI techniques in the brain and SC to provide optimal protocols for imaging biomarker measurements, to be included in clinical trials of therapeutic strategies.

References: [1] Wheeler-Kingshott CAM, NeuroImage (2014); [2] Filippi M, Neurology (2000); [3] Cohen-Adad J, NeuroImage (2011); [4] Schmierer K, JMRI (2007); [5] Portnoy S, MRM (2007).

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Poster Abstracts

8. The role of lymphotoxin-a in grey matter pathology in multiple sclerosis

E Browne, R James, R Schalks, N Mazarakis and R ReynoldsImperial College London

Secondary progressive multiple sclerosis (SPMS) is characterised by an accumulation of neurological disability, which is suggested to be driven by cortical grey matter pathology and currently cannot be adequately treated. The presence of tertiary lymphoid organ-like (TLO) structures within the meninges has been reported in a large proportion of SPMS cases and is associated with more severe cortical pathology and faster clinical progression. Chronic meningeal infl ammation and TLO formation are therefore suggested to contribute to cortical pathology and progression. The cytokine lymphotoxin-alpha (LT± ) is suggested to be involved in TLO formation in other autoimmune conditions, and we showed a 2-fold upregulation of LT± gene expression using RT-PCR in post-mortem SPMS meninges (n=20) relative to controls. We investigated the hypothesis that LT± drives meningeal TLO formation in SPMS and exacerbates cortical pathology, using an animal model of cortical demyelination driven by meningeal infl ammation. Subclinical experimental autoimmune encephalomyelitis (EAE) was induced in dark agouti (DA) rats by immunisation with a low dose of recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG) in incomplete Freund s adjuvant (IFA). Stereotaxic injection of LT± and interferon-³ (IFN³ ) into the subarachnoid space (SAS) 21 days later produced substantial meningeal infl ammation in IFA- and rmMOG-immunised animals at 7 days compared to phosphate buffered saline injected controls. Focal CD79a+ B cell-rich areas were observed in the SAS of animals injected with LT± + IFN³ , accompanied by CD4+/CD8+ T-cells and microglial activation. In rmMOG-immunised animals, extensive subpial demyelination was observed underlying meningeal infi ltrates in a pattern reminiscent of SPMS. No demyelination was observed in IFA-immunised animals injected with LT± + IFN³ , suggesting that demyelination was not due to a directly cytotoxic effect of the cytokines on oligodendrocytes, but required the development of an anti-myelin autoimmune response. To study the effects of chronic cytokine expression we injected a VSV-G pseudotyped lentiviral vector (LV) with a full CMV promoter expressing green fl uorescent protein (GFP) or human LTað into the SA. Long-term expression of GFP was induced in meningeal epithelioid cells and subpial astrocyte end-feet up to 12 weeks after LV injection. Expression of human LT± in rat brains at 90 days post-LVLT± was confi rmed by RT-PCR, and human LT± was detected in rat CSF. SAS infi ltration by macrophages, B and T cells was observed together with cells expressing human LT± at 28 days post-LVLT± injection in naive and rmMOG-immunised animals. Extensive subpial demyelination and widespread, prominent microglial activation was observed in rmMOG-immunised animals at 28 and 90 days post-LVLT± , which was absent following LVGFP. Widespread microglial activation in the absence of demyelination was elicited in naive animals at 90 days post-LVLT± . Our results suggest that LT± is a potent inducer of meningeal infl ammation, and that chronic meningeal LT± expression is suffi cient to elicit widespread activation of cortical microglia in naive animals, but a pre-existing anti-MOG response is required for cortical demyelination in this model. Together with our fi nding of increased LT± in SPMS meninges this data suggests that LT± may contribute to subpial lesion formation and clinical progression in MS.

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Poster Abstracts

9. Early spinal cord MRI abnormalities are associated with MS-related disability fi ve years after a clinically isolated syndrome

Wallace J Brownlee, Patricia Alves Da Mota, Ferran Prados, Josephine K Swanton, Katherine A Miszkiel, Daniel R Altmann, Sebastien Ourselin, Claudia AM Wheeler-Kingshott, Olga Ciccarelli, David H MillerQueen Square MS Centre

Objective: To investigate the relationship of early MRI measures of spinal cord lesions and atrophy with disability 5 years after a clinically isolated syndrome (CIS).

Background: Spinal cord pathology is an important substrate for long-term disability in people with multiple sclerosis (MS). Focal spinal cord lesions and atrophy detected by MRI have been independently associated with disability in established MS. In the present study we investigate whether cord lesions and atrophy are related to disability in subjects who had developed MS 5 years after CIS.

Design/Methods: 121 patients (mean age 32.8 years, 60% female, 7 spinal CIS, 114 non-spinal CIS) were seen within 3 months of CIS and followed for a mean of 5.3 years. Brain and spinal cord MRI was performed on a 1.5T scanner. Spinal cord lesions were identifi ed by an experienced neuroradiologist from PD/T2-weighted sagittal images of the whole cord. Upper cervical cord cross-sectional area (UCCA) was measured using an active surface model from reformatted T1-volumetric cord images. MS was diagnosed using the 2010 McDonald criteria and disability measured using the Expanded Disability Status Scale (EDSS). Signifi cant disability after 5 years was defi ned as EDSS ≥3.

Results: When the MS group with signifi cant disability (n=15) was compared with those without disability (n=69), there was a higher number of spinal cord lesions at baseline (median 2 vs 0, p<0.01), in addition to more new cord lesions (median 5 vs 1, p<0.01) and greater cervical cord atrophy (mean annualised change in UCCA -1.0695 vs -0.3266mm2, p<0.01) over 5 years. In a multivariable linear regression model, baseline cord lesion number (coeffi cient=0.48, p<0.01), number of new cord lesions (coeffi cient=0.19, p<0.01) and change in UCCA (coeffi cient=-0.17, p<0.01) were associated with EDSS (R2=0.55). Including brain T2 lesion load and atrophy measures only modestly increased the predictive power of the model (R2=0.61).

Conclusions: Spinal cord lesions and atrophy detected on MRI may be an important determinant of MS-related disability 5 years after CIS.

Selected for presentation during ‘Towards personalising treatment and care’

44

Poster Abstracts

10. A gym based group intervention for Early MS

Tania Burge, Angela Davies Smith, Rosie Jones, David CottrellBristol and Avon MS Centre (BrAMS) North Bristol NHS Trust

A gym based group intervention for people with Early MS and high level function

Background: Services for people with MS (pwMS) and high level problems (EDSS1-4) are limited within the NHS setting and physiotherapy is generally accessed at a later stage when disability is established. A new community service based in Bristol has been designed to improve gait and balance to promote better function and quality of life. This service aims to address whether an early intervention can offset development of disability due not only to disease progression but also to deconditioning and protective mobility behaviour. Taking advantage of community based resources encourages pwMS to participate in challenging activities they would normally avoid promoting increased activity levels. Additionally gym instructors gain knowledge about the needs and limitations of pwMS

Methods: A rolling 6 week programme of 1 hour a week group session held at Gloucestershire cricket club gym and home exercise plan is attended by maximum of 8 PwMS, recruited via the Bristol and Avon MS centre specialist physiotherapy clinics. Each session consists of a warm up, circuit training for core stability and balance, cardio vascular exercise and team games to encourage multitasking and improve balance reactions. This group is led by the Specialist MS Physiotherapist and a Gym instructor.

Inclusion criteria: High level balance problems, mobile without use of aids. Exclusion criteria: unable to attend at least 4 sessions.

Pre and post intervention outcomes measures: ABC Balance Confi dence Scale (ABC), Berg Balance Scale, 10m Timed Walk, Step Test, Goal Attainment Score.

Results: 29 PwMS, average age 43 (range 21-56), have been recruited. 26 pwMS have completed the course to date, of the 18 females 3 discontinued due to anxiety/bereavement. Results show improvement across the outcome measures: ABC scale mean improvement of 15%, Berg scale all improved or maintained maximum score and 76% demonstrated an improvement in the step test. Most reported positive subjective feedback on the impact of their improved balance and gait on quality of life. Benefi ts included return to work, going skiing or mountain biking and marathon running. None of these activities would have been possible for them at commencement of the course.

Conclusions: A high level community based exercise group has been shown to be benefi cial to independently mobile PwMS. The group environment with a rolling programme rather than a cohort was well received and enabled people to work to their maximum ability with support and example from others. This service is now established due to positive outcomes and patient feedback.

The importance of continuing to exercise to maintain the improvements is well documented; a spin off class of people who have completed the course continues circuits and balance activities. Run by the dedicated gym instructor at the cricket club enabling continued support from the specialist Physiotherapist.

Participants have also independently set up a support group to meet socially. They felt this was an excellent opportunity for mutual support between people with very similar level of function impacting on their lives.

The study will progress to a larger research project.

45

Poster Abstracts

11. The extent of neuronal loss across the MS neocortex: an unbiased quantitative histological study

Daniele Carassiti, Bente Pakkenberg, Francesco Scaravilli, Klaus SchmiererQueen Mary University London

Introduction: Neuro-axonal loss is the ultimate pathological substrate of chronic functional deterioration in people with multiple sclerosis (pwMS). Whilst acute immune-mediated axonal transection and Wallerian degeneration have been reported as mechanisms of axonal damage in and around active white matter (WM) lesions [1-3], the mechanisms of neuronal injury and death in the cortical grey matter (GM), potentially responsible for the slow accrual of disability observed during secondary progression, are less clear. As there is signifi cant variation of the reported degree of cortical neuronal loss [4-6] we estimated neuronal loss throughout the neocortex using unbiased sampling techniques.

Methods: Formalin fi xed brain hemispheres of nine pwMS (6 females, 3 males, age= 68 ± 5, disease duration= 27 ± 5 years) and fi ve reference cases (4 males & 1 female, age= 77 ± 6 years) with no known neurological disease were used. After measuring brain weight, lobar topography (frontal, parietal, temporal, occipital lobe) was marked on the cortical surface before hemispheres were dissected into 1.1 cm-thick coronal slabs, and processed for embedding in paraffi n. Of the resulting blocks, hemispheric sections were obtained and stained for Giemsa and H&E. Cortical neurons were identifi ed on 40 ¼ m-thick sections (Giemsa) using a x60 oil objective on a microscope equipped with a motorized stage controlled by StereoInvestigator software. Cortical area of interest (AOI) was manually outlined and counting disectors were cast randomly using an invariant grid for all samples. Stereology was then applied to calculate for each block: NV (total neurons counted/volume of all disectors) and VREF (AOI x 1.1 cm adjusted for tissue shrinkage). Results for all blocks were added and multiplied by 2 to provide total n neurons and volume for each neocortex. Student s ttest was used for analysis and p< 0.05 considered signifi cant.

Results: The total n neocortical neurons was reduced in MS compared to controls by 32% (14.9bn ± 1.9bn versus 21.9bn ± 2bn, p= 0.03). Neuronal density [neurons/mm3] was reduced by 28.6% (56195 ± 2991 and 78703 ± 4973, p = 0.001). Neuronal density was equally reduced across all cortical regions investigated (reduction of 28 to 32 % in frontal, motor, parietal, temporal and occipital lobes). Total cortical volume and brain weight were not signifi cantly different between MS and controls (265 ± 26 vs 278 ± 14 cm3, p = 0.7 and 1143 ± 56 vs 1167 ± 54 grams, p = 0.7).

Discussion: To our knowledge, this is the fi rst study estimating the extent of neuronal loss across the entire MS cortex using unbiased sampling techniques. The total n neurons we obtained in control cases was similar to previously reported fi gures [7] indicating robust methodology. Our results suggest MS leads to a moderate loss of neocortical neurons, particularly when comparing our fi gures with axonal loss in the spinal cord [8]. The lack of a signifi cant reduction in MS cortical volume and brain weight is unexpected and may be specifi c feature of our sample.

Acknowledgements: We thank Richard Reynolds, Djordje Gveric and their team (Imperial College London) of the MS Society’s UK MS Tissue Bank for providing tissue samples; and Barts and The London Charity for funding support.

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Poster Abstracts

References :1. Trapp, B.D., et al., Axonal transection in the lesions of multiple sclerosis. N Engl J Med, 1998.

338(5): p. 278-85. 2. Peterson, J.W., et al., Transected neurites, apoptotic neurons, and reduced infl ammation in

cortical multiple sclerosis lesions. Ann Neurol, 2001. 50(3): p. 389-400. 3. Dziedzic, T., et al., Wallerian degeneration: a major component of early axonal pathology in

multiple sclerosis. Brain Pathol, 2010. 20(5): p. 976-85. 4. Wegner, C., et al., Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology,

2006. 67(6): p. 960-7. 5. Magliozzi, R., et al., A Gradient of neuronal loss and meningeal infl ammation in multiple sclerosis.

Ann Neurol, 2010. 68(4): p. 477-93. 6. Klaver, R., et al., Neuronal and axonal loss in normal-appearing gray matter and subpial lesions

in multiple sclerosis. J Neuropathol Exp Neurol, 2015. 74(5): p. 453-8. 7. Pelvig, D.P., et al., Neocortical glial cell numbers in human brains. Neurobiol Aging, 2008. 29(11):

p. 1754-62. 8. Petrova N, et al., Demyelination, axonal loss, and atrophy of the multiple sclerosis spinal cord.

submitted to MS Frontiers 2015, 2015.

47

Poster Abstracts

12. Neuroprotection in Secondary Progressive Multiple Sclerosis: the MS-SMART trial

Jeremy Chataway on behalf of MS-SMART trialistsUCL Institute of Neurology

Background: Secondary progressive multiple sclerosis (SPMS) is intractable and new approaches are needed.

Aims: 1 To establish whether a putative neuroprotective drug (fl uoxetine, riluzole or amiloride) can slow

the rate of brain volume loss in SPMS over 96 weeks. 2 To establish that a multi-arm trial strategy is an effi cient way of screening drugs in SPMS and

can become the template for future work. 3 To examine the clinical effect of neuroprotection.

Methods and patients: MS-SMART is a multi-centre, multi-arm, double blind, placebo-controlled phase IIb randomised controlled trial. A total of 440 patients with SPMS will be recruited in England and Scotland and enrolment is currently open. Patients will be equally randomised to receive placebo or one of the three active and repurposed agents. The main inclusion criteria are: age 25-65, EDSS score 4.0-6.5, patients not on DMTs or selective serotonin re-uptake inhibitor (SSRI). Patients will be followed up for 96 weeks with outcome-data collected after 0, 24, 48 and 96 weeks. They will undergo an MRI scan at baseline, after 24 and 96 weeks. Additional sub-studies will evaluate further aspects of neuroprotection in subgroups of patients such as: advanced MR imaging eg MR tractography and spectroscopy; cerebrospinal fl uid (CSF) analysis for markers such neurofi lament light chains (NFL); and optical coherence tomography (OCT).

Results: Recruitment has commenced and will be presented at the meeting.

This independent research is awarded by the Effi cacy and Mechanism Evaluation Programme (EME) and funded by the Medical Research Council (MRC) and the Multiple Sclerosis Society (MS Society) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

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Poster Abstracts

13. Is Multiple Sclerosis an ‘Interferonopathy’?

Colin Crawford, PMD HardwickeRetired

Certain disorders such as Systemic Lupus Erythematosis (SLE) and Sjogren syndrome have been classifi ed as Type 1 interferonopathies because of aberrant type1 IFN signalling.

Large amounts of interferon alpha staining positively with CD123 are secreted from plasmacytoid dendritic cells (pDC)s in tuberculous and sarcoid lymph nodes. Although CD123 positive cells have not been confi rmed in mature tuberculous granulomas, they have now been found in epithelioid cells in human tuberculoid leprosy (Andrade et al Br J Dermatol 2015; 172: 268). A letter entitled “Epithelioid cells in tuberculosis are secretory and not macrophages” has been accepted for publication (Crawford. J Inf Dis 2015: in press). These granulomatous disorders could therefore be classifi ed as “interferonopathies”.

Although plasma cells have been described in multiple sclerosis (MS) lesions, these could be “p DCs” because they have subplasmalemmal linear densities (SPLDs) on their surface and are binucleate. Neither of these features have been found in plasma cells. Cells with SPDLs have also been found in sarcoidosis in lavage material, but not in controls. A specifi c marker CD138 indicates that plasma cells in MS are confi ned to the perivascular spaces. An autoimmune animal model of human tuberculoid leprosy has been produced by injecting rabbits with a homogenate of human sensory peripheral nerve plus adjuvant. Some of the rabbits have developed a state of granulomatous hypersensitivity. i.e. skin testing using a dilute suspension of sensory nerve in saline has produced an epithelioid cell granuloma The cytoplasm contains extensive rough endoplasmic reticulum fi lled with an electron dense product (Crawford et al Nature 1977; 265: 223-5). Cells with SPLD s have been produced in the dermis at skin test sites in this model. Plasma-like cells have invaded the endoneurium. and there is axonal degeneration and demyelination (Crawford and Hardwicke. Acta Neuropath 1979; 45: 1-7) There is no evidence that myelin is being stripped by macrophages. The most active fraction is a non-myelin antigen in doses of 1µg. A similar antigen may be present in the central nervous system. In experimental allergic encephalomyelitis (EAE), macrophages directly attack the myelin sheath and phagocytose the myelin. However, in MS, stripping of the myelin by macrophages has not been demonstrated by electron microscopy (Powell and Lampert Neurol Clin 1983; 1: 631). pDCs are increased in the cerebrospinal fl uid in MS patients who relapse. Interferon 1² is an antagonist of TLR9 and has been found to lower the level of interferon alpha. As hydroxychloroquine also inhibits interferon ± production in SLE, it could be used therapeutically in MS patients.Sifalimumab, a human anti- interferon monoclonal antibody could also be used

Conclusion: Multiple sclerosis can be classifi ed as a interferonopathy, with involvement of plasmacytoid dendritic cells and hence is primarily a disorder of the innate rather than the adaptive immune system. Anti-interferon therapy would be safe, rational, and is potentially effective. A non-myelin antigen is implicated in the pathogenesis of multiple sclerosis.

49

Poster Abstracts

14. Multiple sclerosis cerebrospinal fl uid is dominated by CCR6+ Th1 CD4+ T cells, and not Th17 cells

John Curnow, Siobhan Restorick, Ghaniah Hassan-Smith, Lindsay Durant, Seema Kalra, Michael R DouglasUniversity of Birmingham

Introduction: The pathogenesis of MS is thought to be driven by a combination of activated T cells and macrophages. There is accumulating evidence that suggests a dominant role for CD4+ Th17 (IL-17-secreting) T cells in disease pathogenesis. We wished to study the relative frequencies of different CD4+ Th subsets in patients with MS, asking whether the proposed dominance of Th17 cells is justifi ed.

Methodology: Matched peripheral blood and cerebrospinal fl uid (CSF) samples were collected from MS patients, and disease controls, at the time of routine diagnostic lumbar puncture. Isolated cells were stimulated in vitro to reveal their cytokine production capacity, and labelled with a combination of antibodies that included those specifi c for CD3, CD4, CD45RA, CCR7, CCR6, IL-17 and IFNgð.

Results: Consistent with published data, a relatively high percentage of memory CD4+ T cells, both in the blood and CSF, express CCR6. Although the entire IL-17-secreting Th17 T cell subset expressed CCR6 they were relatively rare cells, contributing less than 10% of the CCR6+ cells. Instead it was clear that IFNgð-secreting Th1 cells represented the dominant CCR6+ population in both compartments. These cells, described in the literature as non-classic Th1, expressed the Th17-related transcription factor RORC, but did not secrete any of the Th17-related cytokines (IL-17A, IL-17F, IL-21 and IL-22).

Conclusions: Our data clearly demonstrate that the dominant CCR6+ T cell population in MS CSF is a non-classic Th1 subset and not Th17 cells. These data have important implications for our understanding of the pathogenesis of MS and approaches to immunotherapy.

50

Poster Abstracts

15. Five year service evaluation of a Functional Electrical Stimulation (FES) clinic for people with MS and footdrop

Angela Davies Smith, Rosie Jones: Tania BurgeBristol and Avon MS Centre (BrAMS), North Bristol NHS Trust

In the Bristol area FES is not a NHS commissioned service. NICE have approved FES for drop foot of central neurological origin (IPG278) and people with MS have been shown to benefi t. In 2010 a pilot service was set up in the BrAMS Centre. The aims were to:• evaluate the effi cacy of tilt sensor triggered FES in people with MS.• evaluate the service to inform service development and commissioning.The WalkAide footdrop stimulator (Innovative Neutronics) is a wireless system using an integral tilt sensor programmed individually to determine stimulator on and off parameters to coincide with the swing phase of gait. Patient referral is via the BrAMS clinical team and wider neurological physiotherapy service. Referral criteria: MS and footdrop, purposely broad to evaluate tilt sensor triggering over a range of walking abilities. People were screened for normal FES exclusion criteria prior to attending.Initial appointment included assessment of walking ability and lower limb function. People suitable for FES could borrow an individually programmed stimulator for a home trial of 4-12 weeks, allowing everyday use during normal activities to determine effectiveness. On returning the test device they could decide whether to obtain a WalkAide, in which case reviews were 6-12 monthly or sooner if required. Data on long term use will be reported. Where appropriate non FES users were referred to a joint physiotherapy/orthotic clinic.From service commencement in January 2010 until December 2014 153 referrals were received (years diagnosed: mean 12, range 2-62). Walking ability ranged from predominantly indoors to independent community walkers. At initial assessment 99 people (65%) proceeded to home trial of FES and 54 (35%) did not.Of those completing a home trial 36 obtained devices for personal use (usage time to date: mean 37 months, range 4-58 months). Ten people obtained funding through NHS individual funding applications (this route was withdrawn after 3 years) and 26 users have purchased their own devices, four obtaining fi nancial support from other sources. Patient reported benefi ts are reduced fatigue, greater endurance, reduced trips and falls and improved balance and confi dence.The main reasons for not obtaining a WalkAide after a successful home-trial were cost (27%), not required yet (24%) insuffi cient mobility to benefi t (17%), walking problems requiring other management (17%) intolerance of stimulation sensation (5%).Of the 54 patients unsuitable at initial appointment main reasons were dislike of stimulation sensation (31%) more dominant problems requiring management (17%) and did not want a home trial (17%).Conclusions• Tilt sensor triggered FES can be used by people with MS and footdrop with a range of walking

capability and the referral criteria should now be further refi ned.• FES prevents falls and improves ambulation.• Although benefi t was experienced during a home trial some people are unable to access long

term FES.• FES users continue to use the device on a regular basis despite disease progression and a follow

up comparison study is indicated.Acknowledgements: The charity MS Research provided funding for the MS specialist physiotherapist and 10 WalkAide patient kits (Trulife Ltd).

51

Poster Abstracts

16. Regulatory T cells enhance oligodendrocyte differentiation in vitro

Marie Dittmer, Thomas O’Hagan, Peter Bankhead, Reinhold Medina, Yvonne Dombrowski, Denise FitzgeraldQueen’s University Belfast

One of the greatest unmet clinical needs in demyelinating diseases such as Multiple Sclerosis (MS) is to provide therapies that actively enhance the process of myelin regeneration (remyelination) in the central nervous system (CNS), which would lead to recovery of neurological function. Therefore uncovering the mechanisms that govern remyelination will prove highly benefi cial to patients. Oligodendrocytes and oligodendrocyte progenitor cells (OPCs) are the myelinating cells of the CNS and therefore play a central role in remyelination. It has been shown that cells of the adaptive immune system, particularly CD4+ T cells, promote remyelination in vivo however the contributions of distinct T cell subsets are not known. Based on our observations that regulatory T cell (Treg) depletion impairs remyelination in vivo, we hypothesized that Treg enhance remyelination through a direct effect on oligodendrocyte lineage cells.

To test this hypothesis, murine Tregs were fi rst differentiated in vitro, in parallel with non-polarized CD4+ T cell controls, and media from these cultures were harvested. The effects of these conditioned media on OPC proliferation, survival and differentiation were then investigated in an in vitro model of murine mixed glial cells. To elucidate the underlying signaling mechanisms, cells were stimulated with Treg-conditioned media in the presence or absence of specifi c neutralizing antibodies.

Soluble factors produced by Treg signifi cantly enhanced OPC differentiation without having an effect on OPC proliferation, survival or overall oligodendroglial numbers. We could further identify a soluble factor produced by Treg that mediates this differentiation-enhancing effect.

These studies suggest a novel benefi cial role of Treg in remyelination through the enhancement of OPC differentiation. Recently it was uncovered that Treg have an intrinsic repair function in muscle regeneration that is distinct from immune modulation. A similar intrinsic function in regeneration of myelin by driving OPC differentiation is likely. Molecular pathways through which the candidate Treg-secreted protein induces OPC differentiation are currently under investigation.


52

Poster Abstracts

17. Infl ammasome expression in demyelinated CNS lesions

Samara Fleville, Marie Dittmer, Denise/C Fitzgerald, Yvonne DombrowskiQueen’s University Belfast

Background: Infl ammasomes are multi-protein platforms in the cytosol that process pro-IL-1beta and pro-IL-18 into their active forms. Infl ammasomes can be activated by endogenous danger signals, such as those released upon tissue damage.

IL-1beta and IL-18 are pro-infl ammatory mediators that act on immune cells and on cells of the local tissue environment. In the CNS, astrocytes, microglia, neurons and oligodendrocytes express infl ammasomes, as well as receptors for IL-1beta and IL-18, indicating their ability to respond to infl ammasome activation.

Rationale and aim: Because infl ammasomes are implicated in both tissue destruction and in the response to tissue damage this study aims to specifi cally determine if infl ammasome activation is a component of the local tissue response to myelin damage in the CNS.

Methods: Focal demyelinated lesions were induced in the spinal cord white matter of C57BL/6 mice and infl ammasome components were analysed by immunohistochemistry at different timepoints after the demyelinating insult.

To directly analyse the effect of infl ammasomes on oligodendrocytes, mixed glial cell cultures were treated with infl ammasome products IL-1beta and IL-18 and oligodendrocyte proliferation and maturation were analysed by immunohistochemistry.

Results: The infl ammasome component ASC was differentially expressed in local CNS cells and in infi ltrating immune cells over time after myelin destruction, indicating that infl ammasomes become activated following demyelination. Furthermore, IL-1beta and IL-18 were differentially expressed at different timepoints after demyelination, demonstrating the bioactivity and functional signifi cance of infl ammasome activation in response to myelin damage.

As glial cells express receptors for IL-1beta and IL-18, and therefore can respond to infl ammasome activity, we further analysed the direct effect of infl ammasome derived IL-1beta and IL-18 on glial cells in vitro. While IL-18 had no effect on oligodendrocytes, IL-1beta promoted myelin basic protein production without altering the number of differentiated APC+ oligodendrocytes. However, IL-1beta did not affect proliferation or survival of oligodendrocytes in vitro.

Conclusion: Our studies show that infl ammasomes are expressed after a demyelinating insult in the CNS in vivo, demonstrating that infl ammasomes are a key component of the CNS tissue response to myelin damage. In vitro, infl ammasome derived IL-1beta and IL-18 have differential effects on glial cells, and their individual roles after demyelination needs to be determined. Future studies will refi ne our understanding of infl ammasome expression after CNS demyelination and the effects of infl ammasome products on different glial cells.

53

Poster Abstracts

18. PR-Fampridine improves walking and quality of life in people with severe MS-related walking impairment

Renee Ewe, Hannah Steadman, Helen Bleasdale, Kate Bull, Rachel FarrellUniversity College London

Background: Walking impairment is a common and disabling symptom in people with Multiple Sclerosis (MS). Walking impairment is associated with unemployment, falls, reduced independence and quality of life. Prolonged release (PR) Fampridine has been shown to improve walking speed and quality of life in people with MS.

Objectives: To observe the long-term effi cacy of PR-Fampridine on walking, quality of life and functional ability when used in routine clinical practice.

Methodology: People with MS and walking impairment were reviewed in a specialist clinic comprised of neurologists and specialist physiotherapists. Eligible subjects (n=98) received PR-Fampridine 10mg twice daily. Walking speed was measured using the Timed 25 Foot Walk (T25FW) at baseline, after 2 weeks’ treatment (responder status), Week 14, Week 40 and on a 6-monthly basis thereafter. Other outcome measures assessed include patients’ perspectives on their walking disability using the Twelve Item Multiple Sclerosis Walking Scale (MSWS-12), health-related quality of life using the EuroQol 5-dimension instrument, 5-level version (EQ-5D-5L), VAS walking, falls log and functional goals of treatment. Responder status was based on a ≥20% T25FW velocity improvement compared to baseline with concomitant MSWS-12 improvement. Responders were categorised into quartiles based on their baseline walking speed, with the top quartile being the fastest 25% at baseline and bottom quartile being the slowest 25% at baseline; the difference in their response to PR-Fampridine was analysed.

Results: The mean age of all patients was 51.4 years old [34-73 years old]. 65 female subjects and 33 males were trialled. EDSS scores ranged from 6.0-7.0. 50 patients had secondary progressive MS, 14 had relapsing-remitting MS, 30 had primary progressive MS and 4 were uncategorised. The mean baseline T25FW velocity across all patients was 0.837ft/s [0.09 – 1.667 ft/s]. After 2 weeks, 74.8% of patients walked ≥20% faster than baseline. Mean change in T25FW velocity was 81.3% [21.2 – 453 %, p<0.0001] in responders versus -6.80% [-31.9-12.8%] in non-responders (p<0.0001). At 3 and 6 months, responders sustained improvement in walking speed versus baseline of 61.9% (p<0.0001) and 54.2% (p=0.431) respectively. The bottom quartile of patients at baseline walked 126.9% faster at 2 weeks, while the top quartile walked 59.7% faster (p=0.011). This difference was maintained at 3 months (106.2% vs 40.9%, p=0.072) and 6 months (130.0% vs 32.5%, p=0.172). At 2 weeks, MSWS-12 improved more in responders (-27.8, p<0.0001) compared to non-responders (-10.0) (p=0.186), while EQ-5D-5L index changed by +0.136 [-0.402 – +0.807, p<0.0001] in responders compared to - 0.053 [-0.464 – +0.206] in non-responders (p=0.02). Responders continued to have better EQ-5D-5L index scores at 3 months (0.115, p=0.0047) and 6 months (0.134, p=0.0046). At 6 months, functional goals of treatment were achieved in 87% of responders and 4 T25FW responders discontinued PR-Fampridine due to treatment failure (n=3) and impaired eGFR (n=1).

Conclusion: In a pragmatic study of people severely affected by MS, PR-Fampridine improves walking speed, subjects’ perception of walking ability and quality of life. This cohort has a higher responder rate than that of pivotal trials; this may be because their walking is more severely impaired.

54

Poster Abstracts

19. The Wii! – a tool for increasing activity levels and well-being in people with MS (Mii-vitaliSe)”

Louise Fazakarley, Thomas S, Thomas PW, Brenton B, Collyer S, Perring S, Scott R, Galvin K, Jones K, Hickson J, Hillier CBournemouth University

Background: People with MS (pwMS) typically have substantially lower levels of physical activity than the general population. There are many barriers to participation in physical activity for pwMS including psychological (e.g. fear, lack of confi dence), physical (e.g. pain, mobility impairment, fatigue), and environmental (e.g. lack of suitable facilities and support) factors. The Wii™ potentially overcomes some of these barriers and the balance board might be particularly helpful for balance and mobility - common issues for pwMS. Recent research suggests that the Wii™ can be used safely at home by pwMS who are mobile. Potential benefi ts include improved strength, standing balance, mobility and fi tness, and confi dence and well-being.

Mii-vitaliSe is a home-based, physiotherapist-supported Wii™ intervention for pwMS that we have recently developed and piloted in a randomised controlled study funded by the UK MS Society. What makes Mii-vitaliSe different from other published research in this area is the inclusion of behavioural change principles to support pwMS to overcome the kinds of barriers described above.

Relevance: Here we report fi ndings from a nested qualitative study with the aim of exploring experiences of Mii-vitaliSe from both participant and physiotherapist perspectives; in particular to gain greater insights into patterns of use and barriers to use.

Methodology: Interviews with participants in a pilot study testing the feasibility and acceptability of using the Nintendo Wii™ to increase activity levels in people with MS. 25 participants were purposively selected from the pilot study. 12 interviews took place after participants had been involved in the pilot study for 6 months and 13 after 12 months. Interviews were also conducted with the physiotherapists involved in the delivery of the intervention (n=2). Interviews were carried out using a pre-determined semi- structured interview guide enabling participants to describe their experiences of Mii-vitaliSe.

Findings: Participants described the Wii™ as ‘a fun way of physio’ and ‘exercise on tap’. Game preferences and usage patterns varied; average use in the fi rst 6 months was 20 mins x 2 days per week. Participants valued the physiotherapist support which helped to keep them engaged and found the resources helpful and relevant, particularly early on. Participants reported a wide range of benefi ts related to both physical and mental health (e.g. increased physical activity, improved mood, reduced stress, increased confi dence, better sleep, improved balance, strength and posture, better coordination, improvements in walking and relief in symptoms such as pain and fatigue). Some continued to use the Wii™ at 12 months and it also gave people confi dence to become more active in other ways. The main barriers to use were lack of time, work, other commitments, fatigue, holidays, and sunny weather. For a minority of people the Wii™ just wasn’t for them.

Conclusions: Findings suggest that Mii-vitaliSe offers an acceptable, fun and convenient way for pwMS to increase physical activity levels. The descriptive interview data provide fascinating insights into ways participants used the Wii™ and aspects considered benefi cial or not so benefi cial. We plan to refi ne Mii-vitaliSe in the light of feedback and undertake further development and evaluation.

55

Poster Abstracts

20. Identifi cation of Infl ammasome Expression and Activity in Experimental Autoimmune Encephalomyelitis (EAE)

Samara Fleville, Marie Dittmer, John Falconer, Pete Bankhead, Ingrid Allen, Denise Fitzgerald, Yvonne DombrowskiCentre for Infection and Immunity, Queen’s University Belfast

Background: EAE is an immune-mediated animal model of Multiple Sclerosis (MS). In this model, mice have multiple demyelinated lesions distributed throughout the central nervous system (CNS).

Infl ammasomes are intracellular, innate immune complexes known to have a pathogenic role in EAE development. In EAE, infl ammasomes are activated by danger-associated molecular patterns to mature and release pro-infl ammatory cytokines, IL-1² and IL-18.

Objectives: To identify infl ammasome activity in different CNS cells of the spinal cord; we aimed to establish immunofl uorescent staining of infl ammasome components.

To assess the effect of IL-1² on oligodendrocytes.

Methods: To establish immunohistochemistry protocols, spinal cord sections from EAE mice were stained for infl ammasome components AIM2, ASC and IL-1² .

To test the effect of IL-1² on oligodendrocytes, oligodendrocyte lineage cells were derived from frontal cortices of postnatal mice and treated with IL-1². Cultures were stained for oligodendrocyte lineage and myelin markers.

Results: We established immunofl uorescent staining for AIM2, ASC and IL-1² , and thus identifi ed infl ammasome activity in demyelinated spinal cord lesions.

In vitro, exogenous IL-1² signifi cantly enhanced myelin protein production from oligodendrocytes. IL-1² did not increase the number of mature oligodendrocytes.

Conclusions: AIM2, ASC and IL-1² immunohistochemistry demonstrated infl ammasome activity in demyelinated spinal cord lesions. Future studies will develop co-staining for CNS markers to determine which cells express infl ammasomes in EAE-induced lesions.

Our studies show that IL-1² drives oligodendrocyte maturation and myelin protein production in glial cultures. Future work will assess the effect of the infl ammasome product IL-18 on oligodendrocyte cells.

56

Poster Abstracts

21. The carry-over effects of aquatic physiotherapy for people with Multiple Sclerosis

Krishna Kishore Garikipati, Dr Leslie Gelling, Dr Hilary Engward, Dr Raija KuismaAnglia Ruskin University

Introduction: Since 2009, Burrswood Hospital has been offering a new service of aquatic physiotherapy for people with Multiple Sclerosis. Clinicians at the hospital and people with MS have indicated the need for understanding the carry-over effects of this service, however there is no available evidence in this area. The purpose of this research is to explore the carry-over effects and improve the knowledge in this area. The results of this research will help us to understand the carry-over effects and determine the need for continuation of the service. The conclusions could help therapists and patients in making evidence based decisions and will also help in developing the future research questions.

Relevance: This doctoral study is about the carry-over effects of aquatic physiotherapy for people with Multiple Sclerosis. This study is funded my Multiple Sclerosis Society, UK.

Methodology: Using the Grounded Theory methodology, 130 people with MS completed a course of six sessions of aquatic physiotherapy at Burrswood Hospital are being invited to participate. Two qualitative data collection methods are being used to collect data. The fi rst method of data collection is a letter to a friend. The second method of data collection is face-to-face semi-structured interview. The subsequent questions are being developed from the constant comparison data analysis. Full ethics approval has been gained from Anglia Ruskin University.

Results and Conclusion: This research is currently an ongoing professional doctorate research. To date, the researcher received the data from two participants and is in the process of analysing. Hence the results and conclusions are not available at the time of this abstract submission. The intention of this poster presentation is to share and discuss the ongoing doctoral research data collection and analysis procedures with researchers in the fi eld of Multiple Sclerosis and gain valuable feedback.

57

Poster Abstracts

22. Evaluation of NeuroText as a memory aid for people with multiple sclerosis

Rachel Goodwin, Nadina Lincoln, Roshan das Nair, Andrew BatemanUniversity of Nottingham

Background & aims: Memory problems are reported in 40-60% of people with multiple sclerosis (MS) (Rao et al., 1993), they can affect independence in activities of daily living and may limit their ability to benefi t from rehabilitation. There is some suggestion that external memory aids could be effective in reducing everyday memory problems for people with MS. However, previous research in the fi eld of memory rehabilitation for people with MS is inconclusive and of poor quality (das Nair et al., 2012). There is good evidence to support the use of NeuroPage, a memory aid service, in people with similar neurological conditions (Wilson et al., 2001). The aim of this study was to evaluate the effectiveness of the NeuroText service for people with MS who have memory problems.

Method: A multicenter, single-blind randomised controlled crossover design was employed, comparing NeuroText with a control. NeuroText is a service that sends reminder messages to people’s mobile phones at pre-arranged times. Participants identify memory problems such as “I forget to take my tablets” and agree on reminders they think would be useful, which they then receive by text at their chosen times. In the control condition participants receive non-memory texts, containing for example, news headlines. The control condition was developed to ensure that it was the specifi c content of the memory messages serving as a memory aid, rather than the act of simply receiving a message working as a prompt. Treatment effi cacy was determined by comparing treatment with control on a range of measures, including subjective memory reports, mood and quality of life.

Results: Fifty people with MS are currently taking part in the trial, across Cambridgeshire, Peterborough and Nottinghamshire. Group (treat fi rst versus control fi rst) by time (baseline, post-treatment) analyses of covariance will be conducted, with baseline performance as a covariate. Results will be available for presentation.

Selected for presentation during ‘Rehabilitation – New innovations and technology’’

58

Poster Abstracts

23. Gas6/TAM signalling induces myelination and dampens the damage in a toxin-induced demyelination model

Salman Goudarzi, Arthur Butt, Sassan Hafi ziSchool of Pharmacy and Biomedical Sciences, University of Portsmouth

During the progressive phase of multiple sclerosis (MS), a possible cause of remyelination failure is the blockade of differentiation of oligodendrocyte progenitor cells (OPCs). Therefore, one of the key aims of MS therapy is to stimulate OPC differentiation and thereby induce remyelination and repair to damaged axons in the central nervous system (CNS). The TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases, which have been shown to mediate cellular growth and differentiation, are all expressed throughout the CNS and thus could play a role in glial cell development. Furthermore, activation of the TAMs via their ligand, Gas6, leads to activation of intracellular signalling pathways which regulate a number of cellular processes including cell survival, proliferation, phagocytosis and immunomodulation, all of which are central in MS. Previous studies have shown both regenerative and immune suppressive functions for Gas6 by both stimulating remyelination as well as suppressing macrophage activation respectively. Here, we aim to investigate the effect of Gas6 on OPC maturation and differentiation, as well as the remyelination response to toxic injury in vitro.

We fi rst utilised optic nerves isolated from 2-month old C57/BL6 mice, treated or not with Gas6 for 72 h in culture, and evaluated the effect of Gas6 on the degree of myelination through expression of myelin basic protein (MBP) level by western blotting. Also, to investigate the effect of Gas6 on demyelination, cultured slices of mouse cerebellum (postnatal day 10) were treated with lysolecithin as a toxic non-immune model of demyelination in vitro. Our optic nerve culture studies revealed that Gas6 signifi cantly increased the expression of MBP by approximately two-fold after 3 days incubation in culture. In cultured cerebellar slices, co-incubation with Gas6 attenuated the level of demyelination induced by lysolecithin, by increasing the number of myelinated axons for about 50% as observed through microscopic MBP staining intensity and integrity of myelinated axon morphology.

In conclusion, we have shown in our various culture models that Gas6/TAM signalling stimulates production of MBP in CNS white matter, and consequently remyelination in the brain after toxic injury. The signalling mechanisms behind these cellular observations are currently under investigation. This work is generously supported by the MS Society through a PhD studentship grant.

59

Poster Abstracts

24. Histological metrics confi rm microstructural characteristics of NODDI indices in multiple sclerosis spinal cord

Francesco Grussu, Torben Schneider, Richard L Yates, Mohamed Tachrount, Jia Newcombe, Hui Zhang, Daniel C. Alexander, Gabriele C. DeLuca, Claudia A.M. Wheeler-KingshottNMR Research Unit, Queen Square MS Centre, Department of Neuroinfl ammation, UCL Institute of Neurology

Introduction: Multiple Sclerosis (MS) is a complex disease characterised by several pathological mechanisms. Neurite orientation dispersion and density imaging (NODDI) [1] is a novel diffusion-weighted (DW) MRI method that has shown promise in the MS brain, and could also be useful in the spinal cord, often involved in MS. Here, we investigated the relation between NODDI metrics and histology in the MS spinal cord, focusing on parameters quantifying neurite orientation dispersion and myelin density.

Methods: one specimen of fi xed MS lumbar spinal cord (sex: F; age: 67; MS subtype: chronic; last EDSS: 7) was scanned on a 9.4 T Agilent system. Multi-shell DW MRI data at a resolution of 0.160×0.200 mm×mm were acquired to derive NODDI metrics, quantifying the local density of neurites (neurite density index, NDI) and neurite directional coherence (orientation dispersion index, ODI, ranging from 0 for parallel neurites to 1 for dispersed neurites). Standard histological analysis was performed on the sample and digital images of sections stained with proteolipid protein (PLP) immunohistochemistry (quantifying myelin) and of Palmegren silver staining (demonstrating axons) were acquired at a resolution of 1×1 µm×µm with an Aperio Slide scanner. Subsequently, the images were processed in MATLAB to obtain maps of myelin staining intensity (MSI, from PLP) and circular variance (CV, from structure tensor analysis [2] of the silver staining) at a resolution matching the MRI voxel size. CV quantifi es the spread of the neurite orientations, minimum when CV = 0 and maximum when CV = 1. Region-of-interest (ROI) analysis was performed to compare NDI and ODI to MSI and CV. The ROI were manually drawn in the normal-appearing white and grey matter (NAWM/NAGM), in white matter and grey matter lesions (WML/GML). Correlation coeffi cients of the mean values within the ROIs were calculated among all pairs of metrics.

Results: visual inspection and box plots of the metrics within the ROIs proved that NDI was reduced in GML and WML compared to NAGM and NAWM respectively. ODI also appeared reduced in GML and WML if compared to NAGM and NAWM. Histology MSI was reduced in lesions if compared to normal tissue of the same type, and so was CV. MSI correlated selectively only with NDI (r = 0.84, p < 0.005) and CV only with ODI (r = 0.96, p < 0.001).

Discussion and conclusion: here we have investigated the histological correlates of NODDI indices in the MS spinal cord. NODDI NDI was sensitive to demyelination, whereas ODI detected changes in the coherence of dendrites and axons. In conclusion, NODDI provides biomarkers that can disentangle specifi c pathology features in MS and is confi rmed by histology. Hence, it has the potential for spinal cord imaging in MS.

References: [1] Zhang H et al, NeuroImage (2012); 61(4):1000-16. [2] Budde MD, Annese J, Front Int Neurosc (2013); 7: 3.

Acknowledgements: UK MS Society, EPSRC, NIHR BRC, UCL Grand Challenges, IoN NeuroResource, all technicians in Oxford. The fi rst and second listed authors are joint fi rst authors; the last two listed authors are joint senior authors.

Selected for presentation during ‘Are we seeing better? New imaging methods and biomarkers’

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Poster Abstracts

25. The role of chronic meningeal infl ammation in cortical pathology and disease progression

Rachel James, Eleanor Browne, Nicholas Mazarakis, Richard ReynoldsNMR Research Unit, Queen Square MS Centre, Department of Neuroinfl ammation, Imperial College London

The secondary progressive phase of multiple sclerosis (SPMS) is characterised by accumulating axonal loss and grey matter pathology. The presence of tertiary lymphoid-like structures in the meninges is associated with immune cell recruitment, greater cortical demyelination, substantial neuronal loss and shorter disease duration. Neuronal loss is greatest in the superfi cial layers closest to the meninges accompanied by a reduction in the density of astrocyte end feet at the pial surface. Analysis of RNA extracted from isolated meninges of MS cases with lymphoid-like infi ltrates has demonstrated increased gene expression for major pro-infl ammatory cytokines, TNF and interferon-g, which may diffuse through to underlying grey matter and be cytotoxic to cells of the cortex.

To test the hypothesis that cytokines produced in the meningeal compartment can drive GM pathology we have previously established a new experimental model. We stereotactically injected recombinant TNF and IFN-g into the subarachnoid space of the sagittal sulcus of DA rats. This resulted in meningeal infi ltrates of CD4+ and CD8+ T-cells and extensive subpial demyelination in animals immunised with a subclinical dose of MOG (Gardner et al, 2013). However, in this acute model, meningeal infl ammation was largely resolved by 14 days with no continuing signs of demyelination. In order to achieve chronic expression of cytokines we have created a HIV-1 based transfer vector to deliver continuous and sustained expression in meningeal cells for longer periods. A bicistronic construct was designed consisting of both human TNF and IFNg genes linked by a T2A sequence. This 2A peptide sequence contains a motif that allows cleavage through ribosomal skipping during translation resulting in the equimolar production of both proteins. The bicistronic construct is produced with a VSV-g envelope that produced effi cient transduction of meningeal cells resulting in cytokine expression for up to 3 months confi rmed by ELISA, PCR and western blot.

Injection of the bicistronic vector into the SA (2x109GC/ul) induced the formation of large aggregates by 7dpi containing CD4+ and CD8+ T-cells, CD79a+ B-cells and Iba1+ macrophages. These aggregates extended the length of the sagittal sulcus into the meninges across the surface of the cortex and spanned a distance many millimetres from the injection site. The aggregates were still present at 3 months after injection. Subpial demyelination accompanied by widespread microglial activation was observed underlying these cellular aggregates. Other work on human tissue suggests that high levels of TNF can act through TNFR1 receptors and initiate cell death in cortical neurons by activating pathways involved in necroptosis and apoptosis. RT-PCR on cortical RNA from bicistronic injected animals at 7 dpi shows an increase in expression of TNFR1 and downstream molecules RIP3 and MLKL compared to eGFP vector control animals. Immunofl uorescence staining on brains from 7 dpi animals shows the presence of Caspase-3+ and RIP3+ cells that appear to have the morphology of neurons. Our results suggest that TNF and IFNg are potent inducers of meningeal infl ammation and can activate TNF signalling pathways in cortical cells leading to neuronal death and subpial demyelination and thus may contribute to clinical progression in MS.

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Poster Abstracts

26. The Prevalence Of Chronic Lower Limb Oedema (CLLO) In Multiple Sclerosis (MS)

Vaughan Keeley, Lorraine Pinnington, Katie Riches, Margaret Phillips, Apostolos Fakis, Lal Vaithianathar, Michael Jones, Christine MoffattDerby Hospitals NHS Trust

Background: CLLO is a feature of advanced MS but may not always be recognised by health care professionals. It is generally thought to arise as a result of reduced mobility and impaired venous and lymphatic fl ow. Other factors that may contribute to this process include lower limb dependency, autonomic dysfunction, post thrombotic syndrome, disease modifying treatments, and, less frequently liver disease, cardiac and renal failure.

Previous studies using differing methodologies and populations have reported the prevalence to be 45% and 85% respectively (Solaro,2006; Arpaia 2010).

The aims of this study are to estimate the prevalence of CLLO amongst people with MS who are known to neurological and rehabilitation services in one hospital, to describe the severity, precipitating factors and secondary consequences of CLLO and to determine the extent to which CLLO is unrecognised. The possible relationships between the presence of CLLO and immobility and other factors will also be examined.

The project is in 2 phases: the fi rst is a questionnaire study and the second involves a detailed clinical assessment of a random sample of those taking part in phase 1. The preliminary results of the fi rst phase of the study are presented here.

Methods: A questionnaire was distributed to all patients (n= 607). It included socio-demographic details, the type of MS, self-reported presence of CLLO and any precipitating factors and secondary consequences. It contained the Multiple Sclerosis Walking Scale (MSWS-12) which assesses walking ability.

Results: 235 (38.7%) questionnaires were returned. The mean age of respondents was 55 years and the majority were female (73.5%). Two thirds of respondents had been diagnosed with MS for over 10 years. The most common type of MS was relapsing remitting. 101 (42.4%) respondents self-reported CLLO. Mean MSWS-12 scores were signifi cantly higher (indicating more diffi culty) in the group with CLLO:- 77.8 (95% confi dence interval (CI) 71.5 - 84.1) compared with 56.4 (95% CI 50.4 - 62.5) in those without CLLO. Furthermore the proportion of patients who could not walk at all was signifi cantly higher in the CLLO group (20.8%) than in those without CLLO (3.7%).

Conclusion: The prevalence of self-reported CLLO was higher in those with reduced mobility. This relationship is being examined further by clinical assessment in phase 2 of the study. If verifi ed, the results will confi rm that CLLO is common in people with MS. They will also inform future research into the treatment of this condition.

Funding: We are very grateful to the MS Society for funding this study.

Arpaia (2010) Thrombosis Research. 125 (4): 315-317.

Solaro (2006) Multiple Sclerosis. 12(5): 659-661.

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Poster Abstracts

27. Anger, Mood and Quality of Life in Multiple Sclerosis

Christianne Laing, Louise Phillips, Clare Cooper, Judith Hosie, Fiona SummersUniversity of Aberdeen

Background: Clinically it has been reported that some individuals with Multiple Sclerosis (MS) experience diffi culty controlling feelings of anger; this may negatively impact overall quality of life (QoL). In healthy people and other neurological populations anger expression, suppression and rumination have been shown to be detrimental to daily functioning, (e.g. personal relationships) and physical health. Therefore, the ability to control feelings of anger may improve mental and physical well-being, improving overall QoL. Little is known about the link between anger experiences and QoL in people with MS.

Aims and Objectives: Funded by the MS Society, the aim of this research was to determine which aspects of anger were the strongest predictors of QoL. It was hypothesised that people with MS who experienced feelings of anger or lack of control over their anger would also report lower QoL. Whether anger regulation diffi culties are linked to other factors, e.g. anxiety/depression, were also investigated, whilst controlling for disease severity. To our knowledge, no other study has investigated problems with anger and MS and its associations with QoL.

Method: 78 participants with MS completed questionnaires assessing emotion regulation (ERQ), anger (ARS, STAXI), mood (HADS) and QoL (WHO-QoL Bref) and disease severity (PDDS). The STAXI measures anger experience/control on 6 subscales: State Anger (intensity of feeling); Trait Anger (anger as a personality trait); Anger Expression-Out (tendency to express anger externally); Anger Expression-In (tendency to experience anger internally but not show it); Anger Control-Out (control of external anger expression); Anger Control-In (control of internalised anger). The WHOQoL measures self-reported on 4 subscales: Physical, Psychological, Social and Environmental.

Results: Regression analyses revealed that anger was signifi cantly associated with QoL in MS. Higher levels of experienced anger predicted both lower psychological (p = .01) and environmental (p = .04) QoL. Also, lack of control over the experience of anger predicted lower psychological (p =.01) and environmental (p < .01) QoL. Depression levels were also predicted by high levels of experienced anger (p < .01) and lack of control over anger (p =.01). In contrast, ruminating about anger was the strongest predictor of anxiety levels (p < .01). However when disease severity was controlled for, rumination ceased to be a signifi cant predictor of poor QoL.

Conclusion: The results demonstrate that feelings of anger are strongly associated with poor QoL in MS, even when disease severity is taken into account. Problems in controlling and ruminating about anger may also contribute to mood disorder in MS. Having a sense of control over angry feelings might improve QoL. This is a potential area for future intervention in management of the disease.

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Poster Abstracts

28. Predicting the disease progression: a combined CSF and MRI longitudinal study on grey matter damage in multiple sclerosis

R. Magliozzi, F. Facchiano, S. Rossi, M. Castellaro, A. Gajofatto, C. Cruciani, A. Bertoldo, O Howell, MD Benedetti, S.Monaco, R. Reynolds and M. CalabreseImperial College London, Division of Brain Sciences, London, UK; Dpt of Neurological and Movement Sciences, Verona University, Italy

Background: Multiple sclerosis (MS) is characterized by variable accumulation of motor, sensory and cognitive defi cits in particular during the progression (Weinshenker, 1996). Up to now, a reduction of the disease activity has been possible only in the relapsing remitting phase whereas no disease-modifying drug has proven effective in the progressive disease phase. Therefore, identifi cation of novel biomarkers for early diagnosis of rapidly progressive MS and appropriate timely therapeutic interventions (in the relapsing remitting phase) represent critical factors in ensuring more favorable long-term outcomes. In the last 15 years, it is becoming increasingly accepted that cerebral grey matter (GM) damage provides the best correlate of the rate of clinical progression (Reynolds et al, 2011; Calabrese et al, 2013), and that, meningeal infi ltrates represent the main source of infl ammatory/cytotoxic molecules that released in the CSF may mediate the tissue injury in the adjacent GM (Magliozzi et al, 2007; Howell et al., 2011).

Objectives: A new collaborative approach has been started in order to combine advanced MRI imaging of GM damage with an extensive analysis of proteins and infl ammatory molecules in patient s CSF with the ultimate aim to discover mechanisms of clinical progression and to predict disease evolution as early as possible.

Methods: The combination of a new type of proteomic approach (TRIDENT) and immune-assay technique (BioPlex) for the analysis of the baseline presence and levels of protein expression of more than 60 cytokines, chemokines and other cytotoxic/myelinotoxic molecules in the CSF samples collected at the onset of the disease from MS patients with high (n = 15) and low (n = 15) cortical lesion load, as revealed by 3-Tesla optimized advanced MRI sequences, and control cases (n = 10), all age matched and collected in the MS Centre of Verona, has been performed.

Results: Both proteomic and protein analysis have revealed the expression of different panels of molecules in the CSF of the two group of examined MS patients. In particular, pro-infl ammatory cytokines/chemokines and molecules related to monocyte/macrophage and innate immunity activity and to neurodegeneration have been found in the CSF from MS patients with higher cortical lesion load and more rapidly progressive course of the disease. In contrast, higher preponderance of immunoglobulin- and complement-related proteins and anti-infl ammatory cytokines/chemokines has been detected in the CSF from MS patients with lower cortical lesion load and less severe MS progression.

Conclusions: By defi ning more precisely the molecular and imaging substrates of MS-associated cortical damage, we shed light on potential pathological mechanisms of GM injury and new molecular biomarkers useful for patient stratifi cation and for the design of new therapeutic targets to prevent or block disease progression.

This study was supported by the Progressive MS Alliance (grant no PA 0124)


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Poster Abstracts

29. Meningeal infl ammation changes the balance of TNF signalling in cortical grey matter in progressive multiple sclerosis

R Magliozzi, C Cruciani, P Durrenberger, O Howell, F Roncaroli, E Aricò, MS Brignone, R ReynoldsImperial College London, Division of Brain Sciences, London, UK;Dpt of Neurological and Movement Sciences, University of Verona IT

Background: Neuroimaging and neuropathology studies indicate that accumulating grey matter (GM) pathology is the best correlate of clinical progression in multiple sclerosis (MS). Recent studies of cortical pathology in secondary progressive MS (SPMS) have shown that a more severe clinical course and the presence of extensive subpial GM lesions (GMLs) with signifi cant neuronal/glia loss and microglial activation are associated with increased diffuse infl ammation and the presence of lymphoid-like structures in the subarachnoid space.

Objectives: We investigated the hypothesis that infl ammatory/cytotoxic molecules diffusing from the meninges lead to pathological changes in signalling pathways within the underlying GM that could explain the extensive pathology.

Methods: By using Illumina HumanRef8 Beadchip arrays, we defi ned differentially expressed genes/pathways in subpial GMLs and normal appearing GM (NAGM) of the motor cortex from 20 post-mortem MS brains with and without meningeal infl ammation and 10 non-neurological controls, previously characterised for cellular pathology (Magliozzi et al, Ann. Neurol. 2010). Real time RT-PCR was used to verify changes in gene expression, while Western-blot analysis and immunohistochemical techniques (IHC/IFC) were performed to validate the expression and cell source of molecules of interest.

Results: Gene expression profi ling of GMLs and NAGM not only confi rmed the substantial GM pathological cell changes, but also demonstrated the upregulation of multiple genes/pathways associated with the infl ammatory response. In particular, genes involved in TNF mediated cell death/survival signalling were found to be signifi cantly deregulated in MS cases compared to controls. In particular, increased meningeal infl ammation was associated with a shift in the balance of TNF signalling away from the TNFR2 and NFkB anti-apoptotic pathway towards TNFR1 mediated RIP1/RIP3 dependent pro-necroptotic signalling. Western blot analysis confi rmed the differential protein expression of TNFR1/TNFR2 in the GM of SPMS linked to meningeal infl ammation. Furthermore, IHC/IFC showed the expression of TNFR1 predominantly by oligodendrocytes and neurons and of TNFR2 mainly by astrocytes in the same GM areas and MS cases.

Conclusions: These results support the hypothesis that the infl ammatory milieu, generated in the subarachnoid space by leptomeningeal immune cell infi ltration, has a fundamental role in the genesis of subpial GM pathology in progressive MS and that changes in the balance of TNF signalling may be a key to cortical tissue damage.

Study Support: Italian MS Foundation grant (FISM 2011/R/23) and grant of the Italian Ministry of Health (GR-2010-2313255). MS Society grants 978/12 and 007/14 to R Reynolds. Progressive MS Alliance grant no PA 0124.

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Poster Abstracts

30. The Scottish National Multiple Sclerosis Incidence Register: Lessons from the fi rst fi ve years

Paul Mattison, Weller B, O Riordan J, Overell J, Dodds H, Mowat-Brown GScottish National MS Register Steering Group

Scotland has some of the highest reported rates of multiple sclerosis, both incidence and prevalence in the world.

However accurate recording of defi nitive numbers has not been possible, most of the reported rates relying upon retrospective data which may contain inherent fl aws due to the uncertainty of accuracy of case ascertainment.

Understanding of putative aetiological factors in relation to the risk of developing multiple sclerosis has grown with considerable focus now on both genetic and environmental factors as possible causative factors responsible for the very high rates of multiple sclerosis in Scotland.

The Multiple Sclerosis Society, Scotland fi rst proposed the establishment of a national Scottish multiple sclerosis register, planning of which commenced in the 2006.

An expert steering group guided this development and made the decision that the register would be “purer” by only including incidence cases prospectively, recording each new case of multiple sclerosis made by a Consultant Neurologist in Scotland following established accepted diagnostic guidelines (McDonald criteria), thus ensuring that the Scottish register would uniquely contain only details of those patients who had a proven diagnosis of defi nite multiple sclerosis. Patients with clinically isolated syndromes were specifi cally excluded from inclusion in the register.

A core data set was agreed as to the initial information that would be collected following which a number of publicity events were held throughout Scotland to raise awareness of the register.

Data collection began in 2010, with each new diagnosis of multiple sclerosis made being reported to the register either by the diagnosing neurologist or MS nurse specialist attached to the neurology service where the diagnosis had been made.

Following the launch of data collection in 2010, responsibility for the register was taken over by the Scottish Government and incorporated within its Information Services Division which hosts several other national registers.

Annual reports have been published each year since the inception of the register. The cumulative data for the fi rst fi ve years of operation of the register is now being prepared for publication.

This accumulated data will be presented highlighting trends in incidence rates and geographical variations in different Scottish regions as well as demographic data relating to sex ratio, month of birth and family history of MS. Some of this yielding unexpected demographic trends.

An outline of future proposals for the use of the register in audit and research will be presented, such work being principally aimed at addressing the basic question of why Scotland has such an unenviable number of people affected by multiple sclerosis, and potentially of importance in countries that experienced signifi cant immigration from native Scots and who also have high rates of MS, for example Canada and New Zealand.

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Work is also in progress to examine the utilisation of relevant services by those included within the register, including access to specialist nursing, AHP and medical follow up. Preliminary data will be presented of disease modifying drug prescription rates for those patients diagnosed with MS in Scotland since the inception of data collection.

The Scottish multiple sclerosis incidence register is a unique tool for the gathering of epidemiological, aetiological and service planning purposes. The fi rst fi ve years data gives an important insight into the epidemiology of MS in a country with exceptionally high rates of the disease and points the way forward to targeting investigations to understand why this is the case.

Selected for presentation during ‘Using big data to improve health and social care’

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Poster Abstracts

31. Mechanisms mediating erythropoietin-induced myelination in oligodendrocytes

Manuela Mengozzi, Georgina Gyetvai, Florence Wedmore, Trisha Hughes, Alexander Annenkov and Pietro GhezziBrighton and Sussex Medical School

Available drugs approved for multiple sclerosis (MS) can slow down disease progression, but do not repair existing axonal damage, the main cause of permanent neurological disability.

We have shown that erythropoietin (EPO), a hematopoietic cytokine used to treat anaemia, is neuroprotective in models of injury and disease of the nervous system, including experimental autoimmune encephalomyelitis (EAE), a model of MS. EPO decreases demyelination and axonal damage and can act directly on oligodendrocytes to increase myelin oligodendrocyte glycoprotein (MOG) gene expression, suggesting that it might help repair damaged myelin in MS patients. However, EPO therapy in non-anaemic patients can increase the risk of thrombosis.

The aim of this study was to investigate the mechanisms by which EPO increases myelination in oligodendrocytes. EPO’s neuroprotective effects are mediated by a variety of intracellular pathways, including STAT5/STAT3, PI3K/Akt and MAPK/ERK; we used chemical inhibitors of these pathways to study their involvement in EPO-induced myelination. We also investigated EPO-induced changes in gene expression by microarray analysis.

Stattic, an inhibitor of STAT5 and STAT3 activation, signifi cantly inhibited EPO-induced MOG gene expression (4-fold; P < 0.001), measured in CG4 oligodendrocytes cells by qPCR at day 3 of differentiation; wortmannin, an inhibitor of PI3K/Akt, had no effect; surprisingly, two inhibitors of different components of the MAPK pathway had opposing effects: EPO-induced MOG was decreased in the presence of BIX02189, an inhibitor of ERK5 (2-fold; P < 0.01), but further increased by PD184352, that blocks ERK1/ERK2 (2.5-fold; P < 0.01).

These results suggest that EPO-induced myelination is mediated by STAT5/STAT3, but not by PI3K/Akt; the role of the MAPK pathway is more complex, with ERK5 and ERK1/ERK2 positively and negatively regulating EPO-induced MOG expression respectively. Gene expression microarray results confi rmed EPO-induced regulation of genes promoting a pro-myelinating phenotype, mainly downstream to the JAK/STAT and MAPK but also to the NF-kB signaling pathways.

Understanding the mechanisms by which EPO increases myelination might help identifying new therapeutic targets, leading to drugs active for remyelination but devoid of the adverse side effects associated with EPO treatment.

Supported by the European Development Fund Project PeReNE

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Poster Abstracts

32. Targeting of nanoparticles from nose to brain for MS

Parvathi Merugu, J.Raveedndra reddy, D.SubbaraoRaghavendra institute of pharmaceutical education and research

The aim of present research work was to formulate and optimize solid lipid nanoparticles (SLNs) of prednisolone acetate- loaded glyceryl monostearate (PA-GMS) using phase behaviours of hot microemulsions-ultra probe sonication technique. The pseudoternary phase diagrams were constructed from lipid/surfactant/co-surfactant at 60oc using prosim soft ware. The area of each ternary plot were measured using computer aided design(CAD) software. The mass ratio of GMS/surfactant-cosurfactant ratio/water were determined according to the region of hot microemulsion. The analogy/relationship between design factors and experimental data was assessed/ studied/ estimated using response surface methodology(RSM). A statistical technique of RSM with Box-Behnken design was framed to study and determine the infl uence of formulation independent variables including a solid lipid (x1), surfactant/co-surfactant ratio (x2), drug/lipid ratio (x3). The SLNs were prepared by a combination of hot microemulsion-ultraprobe sonication technique using GMS as the solid lipid, Tween 80,60,20,Cremophor RH40 and PEG400, ethanol as the surfactant and co-surfactant respectively. The dependent factors were particle size, entrapment effi ciency(%EE), drug release behavior. Characterization of the SLNs such as the particle size. Zeta potential, %EE, morphology, drug release property were measured, respectively.

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Poster Abstracts

33. Exploring the effectiveness of an untrained Natural Language Processing system to capture MS data

Rod Middleton, H Lockhart-Jones, KA Tuite-Dalton, Z Peng, R Gain, C Owen C, S Hughes, G McDonnell, JG Noble, Jones KHSwansea University

Background: The UK MS Register collects data from three primary sources, routine, directly from people with MS and from NHS Specialist Neurology sites. Data captured from the NHS is the most problematic for a number of well-established reasons: • IT Systems in place • Unit culture • Clinical staff time to carry out system entry • Priority of paper versus electronic records

The Register has an agnostic approach to data collection - it can be provided from any number of Clinical systems and securely transferred. This however assumes that all NHS sites make use of a specialised MS system and that staff have the time and inclination to keep it up to date. For those that do, the implication of backfi lling thousands of patient’s data is an almost insurmountable task with the reality being most UK sites only carry out prospective data collection.

It became apparent that there could be another method to capture large amounts of patient relevant data from well-established NHS sources; All clinical sites have dictated outpatient letters from a variety of multidisciplinary staff, which are rich in clinical information.

Aims: To discover to what extent an automated Natural Language Processing (NLP) software tool can capture the data accurately and appropriately.

Method: The UK MS Clinical Dataset (UKMSCD) comprises of 26 items, which are agreed upon by the Register Clinical Advisory Group. A total of 334 letters regarding 32 patients from 2 different hospital trusts were loaded into the system. The letters were in Microsoft Word and PDF formats and covered a variety of patient diagnoses and histories. The papers were loaded into the Clix CNLP software suite for processing. Clinical terminology was parsed by the engine and converted to SNOMED codes. These codes are converted to a JSON string, which can then be stored in a relational database.

Results: Of the 26 fi elds mandated 11 can be captured without further system training: • Gender • Appointment Date • MS Type • Past DMT • Date DMT Stopped • Present DMT • EDSS Score • Walking Distance in M • Time to Walk in S • Smoking • Symptoms

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Of the fi elds that remain, some can be captured with minimal system training primarily the demographics fi elds. Capture of these will bring the completeness to 19 out of 26 (73%). Others are more challenging such as onset localisation and date of conversion to Secondary Progressive MS.

Conclusions: While the initial fi ndings are promising, work up to this point has been largely manual. The next steps are to improve the accuracy of fi eld recognition and capture and then to automate the database analysis of those captured fi elds. In order to test the “improved” accuracy of the NLP engines’ output, a comparison will be made against the current standardised capture of data from a clinical site. Lastly we will test the observed output against selected paper case notes and clinician expertise.

Selected for presentation during ‘Using big data to improve health and social care’

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Poster Abstracts

34. EBV, Human Endogenous Retroviruses And Multiple Sclerosis: The Viral Hypothesis In The Aetiopathogenesis Of The Disease

Elena Morandi, Dimitru Constantin-Teodosiu, Bruno GranUniversity of Nottingham

Introduction: The aetiology of Multiple Sclerosis (MS) is still unknown, but there is strong evidence that environmental factors can trigger the disease on the background of genetic predisposition. Epstein-Barr virus (EBV) and Human Endogenous Retroviruses (HERVs) are strongly associated with MS: in normal conditions HERVs are silenced or expressed at low levels, but in some pathological cases, like MS, their expression is higher than in the healthy population. Our hypothesis is that EBV activates the MS-associated retrovirus (MSRV), which in turn activates innate immunity to drive MS pathogenesis. Our aims are to confi rm the association between the presence of these viruses and the causing and progression of the disease, to understand the mechanisms by which EBV induces the expression of MSRV and to fi nd out how MSRV can activate innate immunity.

Methods: We conducted a systematic review and meta-analysis of the association between HERVs and MS. Next, we used RT-PCR to study expression of MSRV in total blood of MS patients compared to Healthy Controls (HC) and Other Neurological Disease (OND) patients. We are also using Flow Cytometry to compare the expression of MSRVenv in different cell types and at different stages of the disease. Furthermore we have detected the expression of MSRVenv in EBV infected and uninfected B cells through both RT-PCR and Flow Cytometry.

Results: The systematic review suggests a strong association between HERVs and MS, in particular with the HERV-W family. The meta-analysis shows odds ratios of 44 and 32 for two different proteins of HERV-W: MSRVpol and MSRVenv respectively. Furthermore we have detected an increased expression of MSRVenv in MS patients compared with the control groups, and MSRVenv is also expressed more in EBV-infected cells than in uninfected B cells.

Conclusions: These results confi rm the link between EBV, HERVs and MS. We are planning further studies to better understand the role of the interaction between EBV and HERVs in the aetiopathogenesis of MS.

Selected for presentation during ‘Modifi able risk factors for MS’

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Poster Abstracts

35. The case for equitable provision: modelling sustainable caseloads for MS specialist nurses across the UK

Geralding Mynors, Bowen, AMultiple Sclerosis Trust

Background: There are 245 MS specialist nurses (MSSNs) across the UK, with very variable caseloads, suggesting inequitable and, where caseloads are particularly high, inadequate provision to meet the NICE requirement of a (minimally) annual specialist review for everyone with MS. The MS Trust has been at the forefront of supporting MSSNs through professional development and support to develop their services. The Trust’s GEMSS (Generating Evidence in MS Services) programme is currently working with 11 teams of MSSNs to evaluate and improve their services.

Aims: The MS Trust set out to establish a “sustainable”caseload for an MS specialist nurse providing a high quality, proactive service to patients with MS throughout the disease trajectory and to use this to inform a national map of MSSN provision across the UK against need, as measured by estimated MS prevalence.

Methods: An expert consensus group agreed standards for MS specialist nurse services and assumptions about their working patterns and practices; this process was informed by “real world” data from 40 MS specialist nurses taking part in GEMSS. A simple model was used to calculate the caseload which an MSSN could work with and a sensitivity analysis was used to identify how this varies with the underlying assumptions.

Results: A caseload of 358 people with MS per whole time MSSN is sustainable, assuming a mixed caseload of people with MS (from diagnosis through to progressive disease) and working in an area which is not excessively rural. A number of conditions must be met, including well-planned job plans, suffi cient administrative support, an effective policy to limit home visits to people who really need them and a high level of utilisation of clinic capacity. These results have subsequently been used to inform a report mapping specialist nurse provision across the UK (MS Specialist Nursing 2014: The Case for Equitable Provision) and to develop a workshop for MSSNs on optimising their use of service capacity.

Conclusions: It is possible to defi ne an optimal caseload for a specialist nurse service and to use this to inform local and national commissioning priorities for services. The resulting mapping process confi rmed that there are areas of the UK with signifi cant under-provision.

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36. Hippocampal mean diffusivity predicts cognitive impairment in Multiple Sclerosis

Emilia Padgett, Dr Afaf Elsarraj, Dr Robert Dineen, Prof Dorothee AuerUniversity of Nottingham

Background: Cognitive dysfunction, including impaired memory performance, is common in people with multiple sclerosis (MS) and signifi cantly impacts on quality of life. Previous studies have shown elevated hippocampal diffusivity to be predictive of cognitive impairment in Alzheimer disease, and we therefore propose that this may also be a quantitative biomarker of cognitive impairment in MS.

Methodology: Following REC approval, 26 participants with MS (20 RRMS and 6 SPMS) were recruited from the MS clinic of a tertiary neuroscience centre, with 24 age-matched healthy subjects recruited as controls. Participants with MS underwent clinical evaluation by the Expanded Disability Status Score (EDSS) and MS Functional Composite (MSFC) as well as cognitive assessment by the Montreal Cognitive Assessment (MoCA). All participants underwent 3-Tesla MRI (GE Discovery 750) with 1mm isotropic T1 volume and 2mm isotropic diffusion tensor imaging (DTI) with 32 diffusion-weighted directions, B=1000. Hippocampal volumes were manually segmented in accordance with the EADC-ADNI Harmonised Protocol for Manual Hippocampal Segmentation. Hippocampal volumes were normalised (nHV) to intracranial volume. Mean diffusivity (MD) images were thresholded with a value of 0.0018 s/mm2 to remove overtly CSF-containing voxels, and co-registered to the T1 volume. Hippocampal ROI s were used to extract hippocampal MD values for each subject. Group comparison was made between participants with MS and controls for imaging metrics. Regression models were constructed to test the relationship between imaging metrics and cognitive status in participants with MS.

Results: Signifi cant group differences were observed after adjustment for age between participants with MS and controls in left hippocampal volume (MS nHV=2.49, control nHV=2.73, p=0.035), left hippocampal MD (MS MD=0.00112 s/mm2, control MD=0.00099 s/mm2, p=<0.001) and right hippocampal MD (MS MD=0.00114 s/mm2, control MD=0.00112s/mm2, p=0.001). In a regression model left hippocampal MD, but not nHV or age, was found to predict MoCA performance (r=-.498, p=0.008).

Conclusion: Increased hippocampal diffusivity occurs is MS and is predictive of cognitive impairment in our cohort, even when allowing for hippocampal atrophy. Hippocampal MD should be evaluated further as a biomarker of cognitive dysfunction in MS.


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Poster Abstracts

37. Testicular Hypofunction and Multiple Sclerosis Risk: A Record-Linkage Study

Julia Pakpoor, Raph Goldacre, Olena O Seminog, Klaus Schmierer, Gavin Giovannoni, Michael J GoldacreUniversity of Oxford

Background: Gender is an important factor infl uencing multiple sclerosis (MS) risk and clinical course, but the role of gonadal hormones in MS is not well characterised. MS in males typically onsets at a later age compared to females, coinciding with an age-related decline in testosterone levels. This suggests that testosterone may be implicated in MS aetio-pathogenesis in males.

Objectives: To investigate a potential association between testicular hypofunction (TH), as a proxy for low testosterone levels, and MS risk. Given that hypopituitarism is a cause of low levels of gonadal hormones in both males and females, as a secondary aim we investigated a potential association between hypopituitarism and MS risk.

Methods: We analysed linked English national Hospital Episode Statistics and mortality data from 1999 to 2011. A TH cohort of 5049 males was constructed by identifying the fi rst recorded episode of day-case care or hospital admission in which TH was coded. A reference cohort (3.4 million males) and obesity cohort (given the possibility of obesity being a confounding factor) were constructed in similar ways. We searched for any subsequent day-case or inpatient admission for, or death from, MS in these cohorts. We calculated rates for MS, stratifi ed and then standardized by age, sex, calendar year of fi rst admission, region of residence, and socio-economic status. Using the same methodology, we also analysed the dataset for the risk of TH following MS in males (given the possibility of reverse causality), and the risk of MS following hypopituitarism in both males and females.

Results: The standardised rates of MS were 37.79 per 100,000 person-years in the TH cohort (based on 11 cases observed, and 2.4 expected) and 8.17 per 100,000 years in the reference cohort (based on 1734 cases observed, and 1742.6 expected). The adjusted rate ratio (RR) was 4.62 (95% confi dence interval 2.30-8.24, p<0.0001). In the TH cohort, all observed cases of MS occurred more than one year after fi rst episode of care for TH. The RR of MS following obesity in males was 1.47 (95% CI 1.20-1.80, p=0.0001). Given that the point estimate for MS following TH (4.6) lies outside the confi dence interval for MS following obesity, the difference is signifi cant and obesity is unlikely to be an important confounder. The RR of TH following MS was 1.07 (95% CI 0.43-2.2, p=0.98). Further, the risk of MS following hypopituitarism was signifi cantly elevated for males, RR=2.44 (95% CI 1.17-4.49), but not females, RR=1.58 (0.81-2.76).

Conclusions: We report a strong positive association (a fi ve-fold elevation of rates) between TH and subsequent MS in males. Secondly, our data suggest an increased risk of MS in men with hypopituitarism. We speculate that the differential effect observed in males vs. females supports the notion of hypopituitarism, in such a context, being a proxy for low levels of gonadal hormones (testosterone in males and oestrogen/progesterone in females). This is the fi rst human study to link low testosterone to increased MS risk. The strengths of this study are the huge size of the database and the person-based cohort design.

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Poster Abstracts

38. Cancer Risk is Not Increased in People with Relapsing Multiple Sclerosis Taking Cladribine

Julia Pakpoor, Giulio Disanto, Daniel Altmann, Sue Pavitt, Benjamin Turner, Monica Marta, Gunnar Juliusson, David Baker, Jeremy Chataway, Klaus SchmiererUniversity of Oxford

Background: A large phase III trial (CLARITY) of oral cladribine in people with relapsing multiple sclerosis (pwRMS) reported signifi cant effi cacy. However, concerns over the safety of cladribine have been raised by American and European regulatory bodies. Specifi cally, a suspected increased cancer risk was key for the rejection of cladribine for pwRMS by the European Medicines Agency (EMA) in 2011. The small number of observed cancers during the only phase III trial of cladribine in pwRMS may be insuffi cient to defi nitively assess cancer risk.

Objectives: To compare the cancer risk of cladribine in pwRMS taking part in the phase III trial CLARITY with other disease-modifying drugs (DMDs) in trials of pwRMS.

Methods: Meta-analysis of all phase III trials of licensed DMDs for pwRMS, and CLARITY. A PubMed search was done to identify relevant studies and references searched for further sources. Studies were eligible for inclusion if they reported the rate of cancers observed. Two-tailed Fisher’s exact test was used to compare cancer rates. Study heterogeneity was calculated using the proportion of pwRMS developing cancer in the treatment and placebo groups. Analysis was also done using the cancer rates reported in a recently completed phase III trial of oral cladribine in patients with clinically isolated syndrome (ORACLE MS).

Results: Eleven trials were selected for inclusion. Study heterogeneity was not signifi cant. Investigated treatments in these trials were cladribine, dimethyl fumarate, fi ngolimod, terifl unomide, natalizumab, alemtuzumab and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p= 0.4631) or all trials, ie. including those with an active comparator arm (0.67%, p=0.3669). No cancer was detected in the CLARITY placebo group whilst the combined cancer rate of all other placebo groups was 1.19% (p=0.0159).

The cancer rate of zero in the CLARITY placebo group is also lower than in the recent ORACLE trial (2.91%, p=0.0012). In contrast, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE (0.49%) (p=0.6546).

Conclusions: The main fi ndings of this study are fi rstly, that the rate of cancers was similar between the only phase III trial of cladribine in pwRMS and all other phase III trials of DMDs whilst secondly, signifi cant difference emerged when comparing the placebo groups of CLARITY (no cancers) with the placebo arms of all other phase III trials included in this study. Our study therefore suggests that cladribine in doses used in CLARITY and ORACLE does not increase the risk of cancer in pwRMS. The impression that it would appears driven by an unusually low cancer rate in the placebo group of CLARITY. Long term follow-up will help determine the cancer risk of all DMDs. Given its effi cacy, tolerability and convenience cladribine should be reconsidered for treatment of pwRMS.

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Poster Abstracts

39. The effects of demyelination on mitochondrial dynamics in vivo

Fabian Peters, Marija Sajic, Michael Duchen, Kenneth J. SmithUCL, Department of Neuroinfl ammation

Demyelination is a pathological condition believed to cause profound changes in the energy demand of axons. While a growing body of evidence suggests that mitochondria accumulate in demyelinated portions of axons (Campbell et al., 2012), much less is known about the effects of demyelination on mitochondrial dynamics.

We have investigated the effect of demyelination induced by topical application of lysolecithin on mitochondrial transport and function in the saphenous nerve in vivo. Mitochondrial movement was quantifi ed in the nerves of naïve animals and in sham-treated and lysolecithin-treated nerves on days 4, 8, 12, and 20 after lesioning (naïve n=5 animals, 104 axons; sham n=3 animals per time point, 314 axons; lysolecithin n=3 animals per time point, 292 axons). Mitochondrial membrane potential was assessed using TMRM and electrical stimulation was applied to increase mitochondrial traffi cking (Sajic et al., 2013). Mitochondrial transport was reduced by more than 75% in demyelinated axons on day 4 which coincides with the onset of electrical excitability of the demyelinated axolemma (Smith et al., 1982) and it remained signifi cantly reduced during the onset of remyelination until it returned to baseline around day 20.

We conclude that demyelination locally reduces mitochondrial transport. The local increase in mitochondrial mass may protect the axon acutely (Ohno et al., 2014), but deprive the distal axon of mitochondrial supply and so render it more vulnerable to degeneration, contributing to the late-onset degeneration found in demyelinating and dysmyelinating diseases (Joshi et al., 2015).

Cited publications: Campbell et al., 2012: “Mitochondrial changes within axons in multiple sclerosis: an update”, Current Opinion in Neurology

Sajic et al., 2013: “Impulse Conduction Increases Mitochondrial Transport in Adult Mammalian Peripheral Nerves In Vivo”, PLoS Biology

Smith et al., 1982: “Saltatory conduction precedes remyelination in axons demyelinated with lysophosphatidyl choline”, Journal of the Neurological Sciences

Ohno et al., 2014: “Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons”, Proceedings of the National Academy of Sciences of the United States of America

Joshi et al., 2015: “Deletion of Mitochondrial Anchoring Protects Dysmyelinating Shiverer: Implications for Progressive MS”, Journal of Neuroscience

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Poster Abstracts

40. Demyelination, axonal loss, and atrophy of the multiple sclerosis spinal cord

N Petrova, D Carassiti, DR Altmann, D Baker, F Scaravilli, K SchmiererBlizard Institute

Background: Demyelination is the most obvious pathological feature of MS pathology, however axonal loss likely the main contributor to chronic disease deterioration (CDT). Association of demyelination with axonal loss in chronic MS remains unclear, possibly due to lack of access to tissue samples and/or technical reasons. Volumetric indices from magnetic resonance imaging (MRI) including spinal cord (SC) atrophy (SCA) are used to infer axonal loss and predict disability. Results, however, have been inconsistent.

Objectives: To accurately quantify the extent of axonal loss and atrophy in the MSSC and explore their relationship with demyelination.

Methods: Formalin fi xed post mortem SC (PMSC) were supplied by the MS Tissue Bank and patient records reviewed. PMSC were dissected in 5mm thick axial tissue blocks and processed for embedding in paraffi n. Of each block, 10µm sections were stained for myelin basic protein (MBP) and SMI-31. Total axial area as well as the region containing the lateral cortico-spinal tract (CST) were outlined and four counting frames (size: 120x120µm2) cast over each CST. Axons >3µm and ≤3µm were counted separately. Lesions were identifi ed on MBP sections. Differences between patients and controls were examined using linear mixed models with the measure being compared as the response variable, and a fi xed effect group indicator; fi xed effect cord region indicators were included in all models, as were other potential confounders as fi xed effect covariates.

Results: PMSC of 13 people with MS (pwMS; 6 men and 7 women, age= 62 ± 3 years, disease duration= 24 ± 3 years), and fi ve controls (2 men and 3 women, age= 84 ± 8 years) were included. At least 9/13 pwMS were wheelchair-dependent. A total of 398 tissue blocks were produced. Total axonal loss in MS was 59% throughout (p<0.0001). Small and large diameter axons were not differently affected (p= 0.973). In blocks with lesions (n=88), demyelination was greater in GM than WM at thoracic level only (50.2% vs 13%; p= 0.002). The proportion of demyelinated GM in 77 blocks with GM lesions was 42.3%. The proportion of demyelinated WM in 88 blocks with WM lesions was 13.7% (no difference between cord levels). Total spinal cord area was decreased in MS by 20% at cervical level (p= 0.003); similar trend differences at thoracic and lumbar levels. CST area was signifi cantly lower only at thoracic level (p=0.037). Negative association was detected between axonal density and disease duration (p=0.032); however no association between axonal loss and (i) demyelination (p= 0.497) and (ii) atrophy (p= 0.546).

Conclusion: The degree of axonal loss in the MS CST is massive, which may explain the signifi cant limb dysfunction in the vast majority of pwMS. Axonal loss was indiscriminate of axonal thickness questioning previous reports suggesting size selective vulnerability. Axonal loss across the PMSC was associated with disease duration. However, no correlation emerged between axonal loss and (i) demyelination and (ii) atrophy. SCA appears to be only partially refl ective of axonal loss, perhaps explaining why MRI indices of SCA have been inconsistent predictors of disability.

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Poster Abstracts

41. Novel pharmacological blockade of mitochondrial cyclophilin D/MPTP is neuroprotective in experimental multiple sclerosis

Gareth Pryce, Justin Warne, Julia Hill, Xiao Shi, Felicia Lennerås, Fabiola Puentes, Maarten Kip, Laura Hilditch, Paul Walker, Michela Simone, Edith Chan, Greg Towers, Alun Coker, Michael Duchen, Gyorgy Szabadkai, David Selwood and David BakerNeuroinfl ammation Group, Dept of Neurosciecne, Barts and the London school of Medicine & Dentistry, QMUL

The permeability transition pore (PTP) of mitochondria forms as a result of low ATP levels, oxidative stress and high Ca2+ concentrations. The mitochondrial PTP is a recognised drug target for some neurodegenerative conditions such as multiple sclerosis (MS) and for ischaemia – reperfusion injury. Mitochondrial peptidylprolyl isomerase, cyclophilin D (CypD, ppif) is a positive regulator of the pore and genetic downregulation or gene knockout improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases such as cyclosporine (CsA) and sanglifehrin show no selectivity between the tightly conserved cyclophilin isoforms. We designed and synthesised a new mitochondrially targeted CsA analogue, JW47, this utilized a quinolinium tethered to CsA at the [Bmt]1 position. Biological evaluation revealed a potent and selective cellular inhibition of CypD and the mitochondrial PTP, with reduced cellular toxicity and immunosuppression compared to CsA. An X-ray structure of JW47 bound to CypD validated the design strategy and revealed some additional unexpected interactions of the ligand with the enzyme. JW47 also showed less interaction with drug transporter molecules and satisfactory pharmacokinetics with signifi cant entry of the compound to the CNS Administration of JW47 in a disease model of neurodegeneration in MS demonstrated signifi cant protection as evidenced by; improved clinical score, improved neurological performance measured by rotarod assessment and enhanced neuronal content quantifi ed by neurofi lament quantifi cation in the spinal cords of treated mice after the relapse phase of disease.

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Poster Abstracts

42. Measurement of cerebrospinal fl uid free light chains is more sensitive and specifi c than oligoclonal bands

Emma Rathbone, Ghaniah Hassan-Smith, Lindsay Durant, Atalanti Tsentemeidou, Lakhvir Assi, Jeffery Faint, Seema Kalra, Michael R Douglas, S. John Curnow

Introduction: The use of oligoclonal bands (OCB) in the cerebrospinal fl uid (CSF) as a confi rmatory diagnostic marker for multiple sclerosis (MS) is widespread. However, in the past few years there have been a number of studies that suggest the use of an alternative test; the measurement of CSF free kappa light chains (FLC). These studies suggest that CSF FLC may provide a more sensitive and/or specifi c test.

Methodology: We used Freelite (Binding Site) assays to determine the levels of free light chain, both kappa and lambda, in paired CSF and serum samples from a large collection of patients where a diagnostic lumbar puncture procedure was performed.

Results: CSF kðFLC was detected in >95% of all clinically isolated syndrome and relapsing remitting MS patients. Only rarely was there a detectable elevation in CSF free light chains for the other neurological disease or other infl ammatory neurological disease groups. Receiver operating characteristic analysis revealed that CSF kðFLC analysis alone provided a 95% sensitivity and 98% specifi city for all MS groups. Importantly, 4/6 OCB negative samples were classifi ed as positive using the FLC test.

Conclusions: These data support the use of sensitive assays for detection of CSF free light chain, as a preferred test to OCB analysis, in the diagnostic work-up of patients suspected of having MS.

This work has been published doi: 10.1016/j.jneuroim.2014.08.003.

80

Poster Abstracts

43. Design and Enrolment Procedures for the Terifl unomide (Aubagio[R]) Pregnancy Registry

David Rogg, Kerstin Hellwig, Christine Lebrun-Frenay, Diane Daniel, Nicola Seferta, Myriam Benamor, Stephanie Tcherny-Lessenot, Philippe Truffi net, Angelo GhezziGreater Manchester Neurosciences Centre

Introduction: Terifl unomide, approved for treatment of relapsing-remitting multiple sclerosis (MS), is contraindicated for use in pregnancy, based on signs of developmental toxicity in rats and rabbits. During terifl unomide clinical trials, despite a requirement for contraceptive use, a small number of pregnancies occurred. There were no signs of structural or functional defi cits in newborns. It is important to continue to collect data regarding terifl unomide exposure in pregnancy. The International Terifl unomide Pregnancy Exposure Registry will enable comparison of birth defects (congenital malformations, foetal deaths, termination due to foetal anomaly) in terifl unomide-exposed pregnant women with those reported in the European Surveillance of Congenital Anomalies (EUROCAT).

Methods: The registry is a voluntary, multinational, prospective, observational, exposure-registration study. Pregnant women with MS with terifl unomide exposure (any dose any time after Day 1 of last menstrual period until pregnancy end) can enrol. In the UK, healthcare professionals (HCPs) as well as patients (via their HCP) can submit information relating to terifl unomide-exposed pregnancies to the National Coordinating Centre, Manchester, UK. National Coordinators will liaise with HCPs to collect information on terifl unomide-exposed pregnancies and coordinate patient enrolment. Once a new terifl unomide-exposed pregnancy is reported, they will contact the patient in order to obtain their signed informed consent and confi rm that they meet the inclusion criteria, before enrolling the patient in the registry. National Coordinators continue to liaise with patients during pregnancy and, should pregnancy result in a live birth, up until the infant reaches 1 year of age. Identifi able patient details are retained by the National Coordinator and de-identifi ed prior to sending to the National Coordinating Centre for review and processing. Pregnancy outcome data, including birth defects and infant characteristics during the fi rst year of life, will be collected. The registry will recruit 196 women to achieve 104 live births providing 80% power to detect a 3.95-fold increase in risk ratio of birth defects associated with terifl unomide exposure vs EUROCAT.

Results: Enrolment commenced early in 2015 and will continue until December 2019. Interim results will be reported when available.

Conclusions: This registry aims to provide data on pregnancy outcomes and infant development during the fi rst year of life from terifl unomide-exposed pregnancies, and will help physicians provide better counselling for women exposed to terifl unomide during pregnancy.

Study supported by Genzyme, a Sanofi company.

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Poster Abstracts

44. The complexities of integrating large datasets: SWIMS and the UK MS Register

Jeanette Sanders, Jeremy Hobart, Rod Middleton, Katie Tuite-Dalton, John Zajicek, Wendy IngramPlymouth University Schools of Medicine and Dentistry

Introduction: Both the UK MS Register and the South West Impact of MS (SWIMS) Project aim to improve understanding of MS by collecting longitudinal data from people with the condition. Since 2004, SWIMS has focussed on the comprehensive characterisation of a geographically defi ned cohort in South West England, whilst the MS Register has amassed UK-wide information since 2011 which is less detailed but comprises a far greater number of people.

Background: Given the projects’ similarities, we intend to pursue ways to integrate and align the collection, management and sharing of data. Each project has already created a unique dataset. When combined, these data will yield a valuable resource available to the wider research community. The studies do, however, have differences in the content, scheduling and methods of collecting information.

Aims:• To merge two datasets and provide the research community with one anonymous dataset

containing linked clinical, patient-reported and health service data, whilst preserving data provenance.

• To explore ways to optimise future data collection whilst reducing participant burden and increasing the quality of data available to the research community.

• To develop guidance for other researchers and organisations wishing to link projects and share data.

Methods: We are developing a general process of transferring routine clinical data into a standardised electronic database which will be trialled in the SWIMS cohort. The subsequent integration of the SWIMS data into the MS Register will require:• views of participants and people with MS to be sought;• permission for changes from: Participants, Ethics Committee and local Governance;• development of new study documentation;• risk assessment for transfer of data storage and management:• development of mechanisms to transfer and store data;• development of new data management system;• alignment of data scheduling; and• agreement on data to be collected/ the questionnaire content.

Complexities: Successful integration of the projects is not trivial and many issues need to be resolved including:• 75% of SWIMS participants complete booklet by post; Register participation is solely online.

Central management of the SWIMS cohort by the MS Register requires accommodation of the postal cohort.

• SWIMS participants complete booklets every six months; Register participants every quarter.• Although there are 5 common questionnaires, each project collects additional, differing

information.

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Poster Abstracts

• Consent cannot be obtained from those participants who are lost to contact. Special provisions are needed for this subset and those who refuse to re-consent.

• The numbers of joint participants is currently unknown but this cohort would benefi t most by alignment projects.

Conclusions: Integrating SWIMS and the UK MS Register is a valuable step for both projects. We recognise the value of collaborating with other groups holding large datasets and intend to consider how our decisions will impact upon potential for further data-sharing for example with EUReMS. Both SWIMS and the MS Register are committed to sharing information with other researchers to advance understanding of MS and through this to improve the treatment options for people with MS.

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Poster Abstracts

45. Patient-orientated longitudinal study of Multiple Sclerosis in south west England (The South West Impact of Multiple Sclerosis)

Jeanette Sanders, John Zajicek, Wendy Ingram, Jeremy HobartPlymouth University Peninsula Schools of Medicine and Dentistry

Background: SWIMS is a prospective, longitudinal, patient-orientated study of MS and Clinically Isolated Syndrome (CIS) in Devon and Cornwall. Launched in 2004, SWIMS is designed to complement clinical data by collecting comprehensive information about MS from the patients’ perspectives, something lacking in most earlier longitudinal studies. Low migration rates make Devon and Cornwall ideal locations for a long-term study of MS. Also, since Devon and Cornwall are comprised of both rural and urban communities, we expect the fi ndings to be applicable to other geographical areas.

Aims: SWIMS aims to:• obtain a better understanding of how MS impacts on individuals over time;• improve our understanding of how various symptoms impact on people with MS;• improve how MS is measured in clinical trials; and• develop ways of predicting the course of MS for individuals based on information provided very

early on in the disease course

Methods: SWIMS participants have a neurologist-confi rmed diagnosis of MS or CIS. Routine clinical data recorded at local clinic attendances is provided to SWIMS. Repeated responses over several years to ten of the most commonly employed Patient Reported Outcome Measures (PROMS) are collected, as are data on: details of onset and diagnosis, symptoms, medication, contact with health care services and perceived deterioration. Data is collected every six months for those with MS and annually for those with CIS.

Results: Since 2004 over 1,700 people from Devon and Cornwall (approximately 75% of all those invited) have been recruited. Recruitment and follow-up continue to date. In the last decade 84% of the 20,000 questionnaire booklets sent to participants have been returned. By the end of 2015 we expect to have 10 years follow-up data on nearly 200 people, of whom approximately 18% would have Primary Progressive MS (PPMS). By the end of 2017 however, we expect to have 10 years data on approximately 600 people, of whom about 100 would have PPMS. This dataset is unique and expanding.

Conclusion: Until now, very little long-term data has been available about MS in the UK however, the SWIMS dataset now contains suffi cient information for analyses to start to investigate:• the changing needs of both people with MS and the Health Service.• the suitability of each PROM for different research/clinical settings. Many of the PROMS are now

included in clinical trials as primary outcome measures. Uniquely, SWIMS allows direct comparisons between these measures.

• models to predict the future clinical course of the disease for an individual patient, to guide disease management and treatment targeting.

SWIMS provides a valuable and growing resource for MS researchers. SWIMS has a history of successful collaboration with colleagues researching mobility, physical falls due to MS, exercise regimes for MS and health economics in MS. We would welcome further collaborations that would advance understanding of MS and through this improve the treatment options for people with the condition.

84

Poster Abstracts

46. A comparison of Functional Electrical Stimulation and Ankle Foot Orthoses for the treatment of foot drop in Multiple Sclerosis

Linda L Miller, Elaine E Coulter, Anna A Smith, Lorna L Paul, Danny D Rafferty, Roy R Bowers, Paul P Mattison NHS – Ayrshire & Arran

Background: Foot drop is a common problem affecting walking resulting in tripping and an increased risk of falls in people with MS (pwMS). Ankle Foot Orthoses (AFOs) and Functional Electrical Stimulation (FES) are treatment options for foot drop. There is some evidence of the orthotic effects of FES and AFO on walking speed and effort of walking. The cost utility, therapeutic effects and effects on fatigue, physical activity, community ambulation and disability of either treatment are unknown.

Purpose: The purpose of the study is to investigate the orthotic and therapeutic effect of FES and AFO on walking speed, oxygen cost of walking, fatigue, physical activity, quality of life, falls and disability. The study will also investigate the cost effectiveness, frequency of use and patient experience of both treatments.

Methods: Eighty-four pwMS, who have persistent, treatment naive foot drop, will be recruited into this 3 year study from NHS Ayrshire & Arran and NHS Greater Glasgow & Clyde, Scotland, UK. Participants are randomised to receive AFO or FES treatments. Outcome measures include self-selected walking speed, oxygen cost of walking, Timed 25-Foot Walk, EQ-5D and cost utility analysis, physical activity, Multiple Sclerosis Impact Scale 29, Modifi ed Fatigue Impact Scale, MS walking scale-12, Activities-specifi c Balance Confi dence scale, falls frequency, Extended Disability Status Scale, Psychological Impact of Assistive Devices scale and frequency of use. Outcomes are undertaken at baseline, 3, 6 and 12 months. Focus groups will be conducted at the end of the study to explore the patient experience of treatment options.

Results: To date 13 pwMS have been recruited and baseline and week 12 assessments have been completed. Recruitment and data collection are ongoing. Preliminary results will be analysed and presented.

Conclusion: Currently the decision to prescribe AFO and FES is based on user and clinician preference rather than evidence and cost utility.

Implications: This project will inform clinical practice and policy at local, national and international levels in the management of foot drop in MS. Results of this project may inform FES and AFO prescription for foot drop in other neurological conditions.

Key words (3): Multiple Sclerosis; Gait; Foot Drop

Funding acknowledgements: This research study is funded by the MS Society. The authors would like to thank Buchanan Orthotics Ltd, Glasgow, Odstock Medical Ltd, Salisbury, and PAL Technologies Ltd, Glasgow for their assistance with this project.

Ethics approval: Ethical approval was given by the West of Scotland Research Ethics Committee (ref: 14/WS/0014).

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Poster Abstracts

47. “Things that help us with our life, to manage our condition”: Assistive Technologies in Multiple Sclerosis

L Squires, N Williams, V Morrison School of Psychology, Bangor University

Background: People with Multiple Sclerosis (PwMS) are provided assistive technologies (AT), such as mobility equipment, to self-manage their condition, maintain their health and improve their independence and quality of life. Upto £200 million is spent annually on providing equipment and while there is no offi cial record of AT use, it is estimated that 50% of PwMS will use mobility AT following diagnosis. Despite the potential gains from using AT, devices are often abandoned or misused within the fi rst year of receipt wasting millions of taxpayers money on devices that are clearly not meeting the needs of PwMS. We aimed to explore what role biopsychosocial factors play in the uptake and continued use of AT and the health or psychosocial outcomes of using such devices, and how AT use is involved in the self-regulation process (i.e. is AT use a form of coping with disability?; Leventhal, 1992). We address those questions amongst those affected by MS (including those living with and providing care for a PwMS).

Methods: Two PwMS, one carer and one health and social care professional focus groups (N =14, 5, 4 respectively) were conducted using a semi-structured framework. Discussion topics included personal experiences and perceptions of AT, and the impact of using AT on MS. Data was audio-recorded, transcribed verbatim and analysed thematically in this exploratory study (Braun & Clarke, 2006; 2013).

Findings: Identifi ed themes included: Advancing AT (technological advances, AT awareness, illness progression); Getting AT it (barriers to AT access, acceptance, balancing need and want); Use it or lose it? (factors in continuing AT use, optimism, social support, training); Pros & Cons (independence, lease of life, stigma, frustration).

Discussion: Illness acceptance emerged as a key theme in explaining participants AT use. Use may be associated with acceptance, social support of carers, perceived positive outcomes. Good healthcare professional to PwMS communication is required to ensure AT matches user needs. These infl uences on PwMS continued use of AT may help maximize health gains for PwMS. Such fi ndings inform an ongoing longitudinal questionnaire study.

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Poster Abstracts

48. Associations of Assistive Technology use among People with MS

L Squires, N Williams, V Morrison School of Psychology, Bangor University

Background: It is estimated that 30% of assistive technologies (AT), such as mobility devices, are abandoned within the fi rst year of receipt despite the potential physical and psychological gains from use. These devices are not meeting the needs of People with MS (PwMS) or given the chance to help those PwMS improve their independence and quality of life. Our qualitative fi ndings found that AT use was infl uenced by personal factors (e.g. illness acceptance and mood), device factors (e.g. appearance of device, ease of use) and external factors (e.g. AT service, social support). We further investigated such factors in regards to continued AT use.

Methods: 125 PwMS completed the following battery of measures at recruitment and 3 months subsequently: nature and frequency of AT use, perceptions of AT, illness perceptions (BIPQ), impact of MS (MSIS-29), illness acceptance (ACHC), anxiety and depression (HADS), optimism (LOT-R), social support (DSSI), self-effi cacy (GSES) and impact of AT (PIADS-10). This paper addresses data from those who were current AT users at T1 (n=100).

Findings: Mobility devices were the most common ATs used in the sample (52%) with other devices including memory aids, transfer and support aids, toileting and adaptations to their car and home.

At T1, there were signifi cant concurrent associations between AT use or non-use and whether or not PwMS were confi dent in using their device Ç ² (1) = 8.01, p = .04, with odds of AT use being 11.07 times higher if PwMS were confi dent in using their device. AT use was also signifi cantly correlated with age (rpb = .21), appearance of device (rpb = .20), ease of learning to use (rpb = .22), ease of use, (rpb = .25), psychological impact of device (rpb = .20), physical impact of MS (rpb = .20) and depression (rpb = .21; all ps < .05) at T1.

At T2, 71% of PwMS were still using their AT device and this was associated with T1 levels of depression (rpb = .28), mood (rpb = .03), and acceptance of MS (rpb = -.23; all ps < .05), and concurrent T2 mood (rpb = .23), enjoyment from use (rpb = .03; p < .05) and time saved by using device (rpb = .30), access to device, (rpb = .32; p < .001).

In terms of predicting T2 AT use: no single predictor emerged as signifi cant, with trends seen for age (e.g. older, T1), marital status (e.g. with signifi cant other, T2) and illness acceptance (e.g. lower scores, T1 and T2).

Discussion: Personal (e.g. confi dence and illness acceptance) and device (e.g. appearance, ease of use) factors are associated with PwMS use of AT. Further research is needed to explore the predictors of AT use in order for healthcare and AT services to better meet the needs of PwMS and maximize potential gain.

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Poster Abstracts

49. Evaluation of an information and resilience-focused day for children who have a parent with MS

Rachel Tams, Audrey Daisley, Nuala Reeves Oxford University Hospitals NHS Trust

Background: When a parent has MS, children are faced with many challenges. These include understanding symptoms of MS, dealing with changes in roles within the family and worries about the future tasks that may be more diffi cult given their developmental level and amount of information available to them. Although limited, research suggests that this group of children are vulnerable to a range of psychosocial diffi culties (e.g. Packenham and Cox, 2012) – but problems may be prevented or reduced with interventions providing children with information, the opportunity to explore coping strategies, and enhance their social support networks (e.g. Coles et al 2007). Recent reviews highlight a scarcity of interventions with children (e.g. Razaz et al 2014) and conclude further studies are required.

Aims: This study evaluates an information and resilience-focused day for children who have parent with MS. The 1-day programme, originally adapted from an “MS in the Family Day” workshop (Mutch and Ridley 2004), provides children with age-appropriate information about MS, an opportunity to discuss their experiences and feelings, and to develop resilience through exploration of positive coping strategies. The day has run on 2 occasions to date (data from these days form the pilot study) and a third day is planned for May 2015. Our poster will present data from all three days. We are interested in whether attending the programme: 1) is a positive experience for children, 2) increases their understanding of MS, and 3) is perceived as a positive intervention by parents.

Method: Children identifi ed via professionals working with the parent were invited to attend the fi rst two days. In the pilot study a children’s evaluation form was completed at the end of the day. Understanding of MS was explored by informally assessing children’s ability to answer their own questions by the end of the day. In addition, parents were contacted 1 month post-group to gain their views. Changes for our forthcoming third children’s day (May 2015) include modifi cation of group material (with increased focus on strengths-based/resilience-focused exercises) and more rigorous evaluation (e.g. additional pre/post measures of children’s understanding/level of distress, parental satisfaction measure, longer-term follow up).

Results: In total 16 children attended the fi rst 2 information days (age range 9-15). 14 (88%) completed the evaluation form. Of these 100% rated the day as positive – and all were able to correctly answer the questions they raised initially. All parents gave positive feedback and none reported increased distress in children post-group. Data for day 3 will be included in our fi nal poster.

Conclusions: Children and parents rated the fi rst two children’s days positively, with no indication of adverse effects. As sample size was small and evaluation measures limited, further development/evaluation of the programme is planned and will be presented in our poster presentation.

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Poster Abstracts

50. Quantifying upper limb tremor in people with multiple sclerosis (MS) using a wrist worn motion sensor

Stefan Teufl , Dr. Jenny Preston, Prof. Frederike van Wijck, Dr. Ben Stansfi eld Glasgow Caledonian University

Introduction: Over 25% of people with MS have tremor, which considerably affects daily function and quality of life. Interventions to reduce tremor are assessed using clinical scales and questionnaires, but there is currently no method that measures tremor characteristics objectively and during free-living conditions. Such a method would provide clinically important information on how effective interventions are in reducing tremor and how tremor manifests itself throughout the day. This proof-of-concept project used a wrist worn motion sensor to establish an objective measurement of arm tremor in people with MS.

Methods: Four participants with tremor due to MS and 10 healthy controls performed standardised tasks (ARAT/FAHN) wearing a wrist-worn motion sensor (AX3, triaxial accelerometer). Frequency content of the signal was examined in Matlab, using Fast-Fourier analysis based on a 3s window in all three axes and for the resultant signal. Content above 3Hz was identifi ed, as it was hypothesised that this would only be apparent in those with MS during periods of observed tremor and not in control participants. An experienced Occupational Therapist rated tremor according to clinical scales as the gold standard for tremor detection. Video observation was used to control the consistency of tremor rating. Furthermore, participants were asked to wear the motion sensor for three consecutive days at home and fi ll in a diary to help understand the context of the measured motion patterns.

Results: Where tremor was observed to occur in those with MS it was possible to detect it using a simple frequency cut-off at 3Hz. A 100% detection rate with no false positives was achieved in this initial sample. None of the control participant data produced false positive results for tremor occurrence. Only in an activity specifi cally designed to simulate tremor, the detection algorithm showed the presence of tremor. Examination of all three axes for evidence of tremor ensured all occurrences of tremor were detected. The use of the resultant acceleration signal did not allow the detection of all instances of tremor.

Discussion and conclusions: The results provide encouragement that a simple tremor detection algorithm may be possible in those with MS. This algorithm should rather be based on data of each individual axis of acceleration data than on the analysis of the resultant signal. The algorithm must be tested in a wider group of people with MS associated tremor to ensure wide applicability. A triaxial sensor seems to be required to capture all dimensions of tremor. This solution will allow multi-day, free-living tremor monitoring to assess the effectiveness of interventions.

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Poster Abstracts

51. Mii-vitaliSe: A pilot randomised controlled trial of a home gaming system (Nintendo Wii!)

Sarah Thomas, Louise Fazakarley, Peter W Thomas, Sarah Collyer, Sarah Brenton, Steve Perring, Rebecca Scott, Kate Galvin, Fern Thomas, Kelly Jones, Jo Hickson, Charles Hillier Bournemouth University Clinical Research Unit

Introduction: Over the past decade the benefi ts of physical activity for people with MS (pwMS) have been recognised. With all exercise programmes, however, there can be challenges in starting and maintaining motivation and it can be particularly challenging for pwMS to keep active due to factors such as fatigue and lack of confi dence, transport and suitable facilities. By making physical activity fun, engaging and accessible, active home gaming systems offer an innovative way of overcoming some of these barriers. We have developed a home-based physiotherapist-supported Wii intervention (“Mii-vitaliSe”) for pwMS that uses commercial software. Here we report the fi ndings of a study to explore the feasibility of conducting a full scale evaluation of its effectiveness and cost-effectiveness.

Methods and analysis: 30 ambulatory, relatively inactive pwMS were randomised to receive Mii-vitaliSe immediately, or after 6 months. Outcomes (measured at baseline and 6 and 12 months later) included balance, gait, mobility, hand dexterity, accelerometry and self-reported physical activity levels, fatigue, self-effi cacy, mood, quality of life. We also gathered data on health utilisation and the costs of delivering Mii-vitaliSe. A qualitative nested study is reported elsewhere. As this is a pilot study analyses were descriptive and focused on estimating key feasibility parameters (recruitment, retention, questionnaire completion and Wii use rates, SDs of potential primary outcomes) and testing data analysis processes.

Results: 30 people were randomised to either the immediate or delayed group. Mean (SD) participant age was 49.3 (8.7) years, 90% were female, around half had been diagnosed with MS <6 years ago and 60% had not used a home gaming system before. The recruitment rate was 31%. Two people withdrew from the study due to medical issues. Follow-up data were available for 29 people (6 months) and 28 people (12 months). Questionnaire return rates were 97%. There were no serious adverse events reported. Assessment of effectiveness was not an aim for this pilot study, although we note that for the self-reported outcomes 16/26 of the standardised effect sizes are in the direction of benefi t (though CIs are wide and span zero). Accelerometer data were available for 90% of planned measurement occasions. The estimated mean physiotherapy time spent delivering Mii-vitaliSe per participant was 12 (2.6) hours (£384). Mean number of days on which the Wii was used during the fi rst 6 months was 2 per week, with a mean use of 24 minutes per day.

Discussion: This study provides essential preparatory work prior to a larger trial. Results are encouraging, and suggest a full scale trial of effectiveness and cost-effectiveness would be feasible and is warranted. Remaining uncertainties for a future trial are: (a). choice of primary outcome (participants reported a wide range of benefi ts) (b). choice of control group (the current delayed Wii control group design would preclude longer term follow-up) (c). release of the next generation console (Wii U) since the start of the study, and (d). model of delivery of Mii-vitaliSe (taking into account current care pathways for people with MS). Further work is underway to address these uncertainties.

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52. Is Yawning A Warning for Multiple Sclerosis?

Simon B N Thompson, IMSPIRE International Collaboration Bournemouth University

Yawning is a new and signifi cant area of neurological research, important because of the emerging knowledge that excessive yawning might potentially identify underlying neurological disorders, particularly multiple sclerosis (MS).

The link between cortisol levels and yawning is not fully understood; however, strong evidence of a link between yawning and fatigue, and multiple sclerosis, is emerging and it has been shown that people with MS who excessively yawn also have raised brain temperature levels.

Investigation has revealed that brain temperature levels following fatigue in people with MS may be lowered by yawning. Published work has shown that in healthy people yawning is also associated with raised cortisol levels, the hormone responsible for regulating stress and immune response. Therefore, cortisol is thought to be important in people with MS perhaps as a protective system against the effects of brain over-heating.

Mechanisms involved in excessive yawning are common between several neurological disorders, for example, as parakinesia brachialis oscitans following brain-stem ischaemic stroke. Cortisol levels may provide the answer to a potential new diagnostic tool for identifying underlying neurological disorders, such as MS.

A common symptom of MS is fatigue and excessive yawning. Since yawning and cortisol have been shown to be intimately linked during fatigue, it is possible that rises in cortisol levels are different and greater in people with MS as compared with healthy controls.

The mechanism involving yawning and cortisol continues to challenge scientists and the Thompson Cortisol Hypothesis (2011) and Expanded Hypothesis (2014) has proposed that cortisol may be the common link among neurological disorders. Cortisol, in saliva, is a reliable indicator of the level of cortisol in the blood and has been used as a non-invasive immediate collection technique for measuring cortisol levels.

Clinical researchers at Bournemouth University (BU) led by Associate Professor Dr Simon Thompson have begun research into this area and are now collaborating as part of the International Scientifi c Council into MS called IMPSIRE that involves Université Paris X Ouest Nanterre La Défense; Université Paris 5 René Descartes; Université Paris 8 St Denis; Clinical Research & Imaging Centre (CRIC), University of Bristol; Southmead Hospital, UK; and Ligue Française contre la Sclérose en Plaques.

Preparatory study has started with BU and the Hôpital Universitaire Amiens, Université Paris X Ouest Nanterre La Défense, and Jules Verne Université de Picardie, France using functional Magnetic Resonance Imaging (fMRI) following induced fatigue together with measuring saliva cortisol levels. It is intended to elaborate on this study at CRIC with further fMRI studies involving people with MS.

International IMPSIRE collaboration aims to benefi t people with MS and involves users of services as well as clinical researchers. It is hoped that this will lead to the development of an early diagnostic biomarker of MS using cortisol levels.

Poster Abstracts

91

MS Frontiers programmePoster Abstracts

53. Designing an information resource to explain diagnostic lumbar puncture and promote best practice

Alison Thomson, Angharad Davis, Adam Paterson, Gavin Giovannoni, Klaus Schmierer Queen Mary, University of London

Introduction: The lumbar puncture (LP) procedure is an important test in neurological practice. Appropriate information is key to both preparing patients for this invasive procedure and facilitating use of atraumatic LP needles to minimize adverse effects such as local pain and post-LP headache.

Methods: A cross-disciplinary team (designers, clinicians and people with multiple sclerosis (pwMS)) developed a website to explain the LP procedure at The Royal London Hospital (Barts Health NHS Trust, UK). User testing was carried out to review both the visual design and functionality of the resource for people with visual and cognitive limitations.

Results: After successful testing “www.clinicspeak.com/LumbarPuncture” is being used in the informed consent process for clinical trials involving pwMS at our institution and is being piloted in our day unit and A&E departments. The website includes what to expect, how to deal with adverse effects, why cerebrospinal fl uid is examined and information on the atraumatic needle.

Conclusion: The resource provides an appropriate way of communicating sensitive, yet important information to patients. It also demonstrates an innovative way of spreading best practice and encourages the widespread adoption of atraumatic needles for LP in both clinical and research settings. The resource will be demonstrated at the meeting.

Selected for presentation during ‘Towards personalising treatment and care’

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54. Inhibition of relapsing experimental autoimmune encephalomyelitis using a mouse CD52-specifi c monoclonal antibody

Stephanie von Kutzleben, Gareth Pryce, William Siders, David Baker Barts and the London School of Medicine and Dentistry

Multiple Sclerosis (MS) is a major neurodegenerative disease, which is believed to arise following autoimmune attack on the central nervous system. There are immune therapies that can inhibit the development of relapsing multiple sclerosis. One of the most-effective, approved-therapies is Alemtuzumab, a humanised CD52-depleting monoclonal antibody (mAb), whose major side-effect is the development of secondary B-cell mediated autoimmunities following immune reconstitution. We have shown that it is possible to re-establish immune tolerance by T cell depletion, using CD4-depleting mAb followed by intravenous antigen. The aim of this project was to assess tolerogenic activity following CD52 depletion in experimental autoimmune encephalomyelitis (EAE) using a mouse-specifi c CD52 (mCD52) IgG2a depleting mAb. The kinetics of CD52-mediated depletion was examined using fl ow cytometry and showed a signifi cant reduction in the percentage of CD4+ and CD8+ T cells from treatment onset. Depletion was extensive and persistent. B cell depletion was much less marked in lymphoid tissue, in contrast to T cell depletion. Relapsing-remitting EAE was induced in adult Biozzi ABH mice following immunization with mouse spinal cord homogenate in Freunds adjuvant. In some instances this immunization was repeated to trigger further disease episodes to assess immunological tolerance induction. As anticipated, a short course of mCD52 mAb inhibited both acute and relapsing EAE. However as T cell levels returned, disease inhibition was transient and relapses returned within a number of weeks. Furthermore disease could be re-induced by further antigen-rechallenge within approximately one week, despite marked T cell depletion. Whilst, the effi cacy of mCD52-depleting mAb recapitulates the inhibition of relapsing MS using human CD52-specifi c depleting mAb, the therapeutic effect, although marked, did not show the longevity of treatment compared to humans. Importantly in contrast to CD4-specifi c depletion, CD52-mediated depletion in mice did not induce robust myelin-specifi c immunological tolerance, possibly due to the deletion of cells regulating autoimmunity. This supports a view that autoimmunity may be an inherent consequence of the mechanism of action of Alemtuzumab.

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55. Brain network organisation corresponds to changes in white matter integrity in MS

Thomas Welton, Afaf Elsarraj, Robert A Dineen University of Nottingham

Background: The brain can be thought of as an interconnected network of regions. Using MRI images, a network model of the brain can be constructed, from which various metrics can be calculated. This appraoch is becoming more common in neuroscience and there is potential for network metrics to be used as markers of cognition in diseases like MS. It is therefore important to test whether the network metrics are suitable for this purpose. One element of this testing is to see whether the network metrics are responsive to brain injury as it ocurrs in MS.

Objective: We aimed to test whether brain network properties were responsive to changes in (1) MS lesion load and (2) mean diffusivity (a measure of white matter integrity).

Method: Nineteen volunteers with MS each had two MRI scans of their brain, approximately 6 months apart. The MRI scans included high-resultion scans (for counting the volume of lesions), a “functional MRI” scan (for looking at brain activity during rest), and a ”diffusion tensor” scan for looking at the structure of the brain s white matter.

A researcher manually inspected the high resolution structural images to count the lesion volumes for each scan.

To construct the brain networks, the functional images were fi rst split into 168 areas corresponding to the folds of the brain s surface. Then, the amount of signal from each area over time (representing the amount of brain activity) was extracted. For each pair of brain regions, we calculated the amount of similarity between their signals, which is known as their “functional connectivity” (or strength of connection). We then removed all the connections which did not reach a certain threshold, so that only the strongest connections remained. Finally, we calculated the properties of the networks, such as how clustered it is, or how many connections need to be traversed to travel from one brain region to another.

Mean diffusivity was measured by taking the average value across the whole brain mean diffusivity image, which was derived from the diffusion tensor scan.

We used a correlation test to see whether the volunteers who had the greatest changes in lesion volume and mean diffusivity between their fi rst and second scans also had the greatest changes in network properties.

Results: On average, the volunteers had a greater volume of lesions after the 6-month period than before (mean increase of 2,670 mm3). The volunteers who had the greatest changes in mean diffusivity had strong decreases in the “clustering” and “small-worldness” network metrics. This fi nding indicates that the brain networks of volunteers whose white matter was degradedthe most demonstrated organisational changes (a decreased local integration and effi ciency).

Conclusion: Some brain network properties are responsive to changes in white matter structure caused by MS. This result is a step toward validating brain network metrics as suitable for use as biomarkers in trials of new treatments for MS. Future research will determine the relevance of this result to cognitive performance (e.g. memory and attention).

Selected for presentation during ‘Rehabilitation – New innovations and technology’’

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56. Psychological attributes and work instability in those working with MS

Charlotte Wicks, Ward K, Stroud A, Tennant A, Ford H Leeds Teaching Hospitals NHS Trust

People with MS (PWMS) often stop working earlier than they would wish because of the progression of their MS. However, there are other reasons why people may give up work: how well they manage their symptoms, the amount of social support they have, the fl exibility of their employers, and how they cope psychologically with the demands of MS and work. We know very little about the link between psychological factors and staying in work, but if more could be understood this may lead to psychological and practical interventions to help people stay in work.

This study aims to investigate relationships between psychological factors, work instability and MS across a 2½ year time period.

221 employed PWMS completed a baseline questionnaire pack which was made up of validated scales of key themes in July-September 2013. Scales were chosen that covered a total of 12 areas and were made into a single questionnaire pack. 211 participants completed the questionnaire again after 8 months. The study will ask participants to complete this questionnaire pack at two further time points.

221 employed PWMS were recruited. Mean age was 40.6; 75.1% were female. 91% had relapsing-remitting MS (RRMS) with just 3% transitioning to the progressive form after 8 months. 213 (96.4%) completed the baseline questionnaire, 199 completed month 8. There was no signifi cant difference between responders and non-responders for age, gender or type of MS. Disease progression was mostly stable with just 3% transitioning from RRMS. There was a signifi cant fall in the numbers with relapsing-remitting MS reporting that a relapse was confi rmed by a health professional during the previous 6 months, from 32.4% at baseline to 20.6% at 8 months. 57.2% were at medium/high risk of job loss, with only marginal changes in work instability at 8 months. 14% reported high physical and psychological impact of MS at baseline which remained unchanged. There was a strong association between risk of job loss and both physical and psychological variables. While physical attributes remained mostly stable, some psychological variables fl uctuated signifi cantly, e.g. depression fell from 24.6% to 14.5%. Although some psychological attributes remain stable at group level, this masked internal movements in either direction.

For example, the percentage reporting moderate of high levels of self -effi cacy (93%) remained stable, but of those reporting high levels of self-effi cacy at baseline only 69.1% retained this level at 8 months. No changes were reported in levels of fatigue or pain over this period.

Similar variation was seen the optimistic-pessimistic characterisation (LOT-R). While percentage optimistic remained the same (28.6%), this masked internal movements in-and-out of these states (33.6%).

While the physical aspects of the condition remained mostly stable, some psychological attributes changed signifi cantly, while others, displaying stability at the group level, showed subtle shifts within, suggesting that psychological attributes may continuously fl uctuate.

Longitudinal studies of this kind should be able to determine intra-and inter-individual changes in such attributes, and seek to identify where such changes impact on Work Instability.

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57. Targeting cannabinoids to the mesenteric lymph nodes for enhanced immunomodulatory effects in the treatment of multiple sclerosis: In vitro and ex vivo studies

Atheer Zgair1, 2, Jonathan C. M. Wong1, Peter M. Fischer1, David A. Barrett1, Cris S. Constantinescu3, and Pavel Gershkovich1*1 School of Pharmacy, University of Nottingham, Nottingham, UK2 College of Pharmacy, University of Anbar, Anbar, Iraq3 Division of Clinical Neuroscience, University of Nottingham and Queen’s Medical Centre, Nottingham, UK

Introduction: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are natural lipophilic cannabinoids currently used to alleviate multiple sclerosis (MS)-associated spasticity (commercially available as oromucosal spray, Sativex®). In addition, experimental autoimmune encephalomyelitis (EAE) studies suggest that CBD and THC could have therapeutic immunomodulatory effects in the treatment of MS [1, 2]. The intestinal lymphatic system is a major host of immune cells. Therefore, targeting CBD and THC to the intestinal lymphatic system could add therapeutic immunomodulatory benefi ts to the symptomatic effects in the treatment of MS.

Oral co-administration with long-chain triglycerides (LCT) can facilitate the intestinal lymphatic transport of lipophilic drugs that can associate with chylomicrons (CM).

Therefore, the aim of this study was to evaluate intestinal lymphatic transport potential and associated immunomodulatory effects of CBD and THC.

Materials and methods:1) In vitro lipolysis model is aimed to predict the fate of lipophilic drugs administered orally in

lipid-based formulation. CBD and THC were separately dissolved in LCT and dispersed in the biorelevant intestinal medium. Lipolysis was initiated by the addition of pancreatic lipase/

co-lipase. Following lipolysis the medium was separated to lipid, micellar and sediment fractions by ultracentrifugation, and levels of CBD and THC in each fraction were determined by HPLC.

2) The degree of association with plasma-derived CM was previously described to have linear correlation with intestinal lymphatic availability [3]. CBD and THC were incubated with rat CM. One hour later, CM were separated by density gradient ultracentrifugation. The concentrations of CBD and THC in CM were determined using HPLC.

3) Peripheral blood mononuclear cells (PBMC) proliferation assay measures the ability of lymphocytes to proliferate in response to a stimulus. CBD and THC (0.01 – 20 g/mL) were incubated with mitogen-stimulated human PBMC (phorbol myristate acetate and ionomycin (PMA + I, 50 + 5 g/mL)) for 48 hr. ELISA kit based on bromo-2’-deoxyuridine (BrdU) incorporation was used to assess PBMC proliferation.

Results1) In vitro lipolysis demonstrated that 32.8% ± 2 and 46.4% ± 6.2 (mean ± SEM, n = 6) of the

administered dose of CBD and THC are recovered in micellar fraction, respectively, and therefore will be readily available for absorption following co-administration with LCT.

2) Ex vivo CM association showed that 73.7% ± 3.6 (n = 7) and 72.5% ± 3.6 (n = 5) of CBD and THC, respectively, can associate with rat CM (mean ± SEM).

3) At concentrations ≥ 5 g/mL both CBD and THC were able to inhibit the proliferations of stimulated PBMC (n = 4).

96


Conclusions1) At least one-third of CBD and THC dose will be available for absorption following oral

co-administration with LCT.2) More than 70% of the absorbed dose of CBD and THC is expected to be delivered to the

systemic circulation solely by the lymphatic system.3) CBD and THC can achieve concentrations in intestinal lymph hundreds-fold higher than

those recovered in plasma. At these concentrations (≥ 5 g/mL), CBD and THC will lead to immunomodulation that could be of substantial therapeutic value in the treatment of MS.

1 Lyman, W.D., et al., J Neuroimmunol, 1989. 23(1): p. 73-81.2 Kozela, E., et al.,. Br J Pharmacol, 2011. 163(7): p. 1507-19.3 Gershkovich, P. and A. Hoffman, Eur J Pharm Sci, 2005. 26(5): p. 394-404.

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This meeting is sponsored by the Pharmaceutical Industry with the presence of exhibition stands. Please note that the MS Society has been solely responsible for organising the MS Frontiers programme. Sponsors have had no infl uence over the selection of speakers or the organisation of the conference.

Exhibitors:Biogen Idec Limited

Genzyme, a Sanofi company

Novartis Pharmaceuticals UK Limited

Ottobock

Teva UK Limited

Sponsors

Sponsors

98


Caring Deeply. Changing Lives.TM

Through cutting-edge science and medicine, Biogen discovers, develops and delivers to patients worldwide innovative therapies for the treatment of neurodegenerative diseases, haematologic conditions and autoimmune disorders.

Founded in 1978, Biogen is the world’s oldest independentbiotechnology company. Caring Deeply. Changing Lives.

www.biogen.uk.com

BI-PAN-0389a. Date of preparation: May 2015

Genzyme, a Sanofi company, has pioneered the development and delivery of transformative therapies for patients aff ected by rare and debilitating diseases for over 30 years. With a focus on rare diseases and multiple sclerosis, we are dedicated to making a positive impact on the lives of the patients and families we serve.

Date of preparation: May 2015. GZUK.MS.15.05.0219

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Our commitment to research and neurologyNovartis has been developing patient therapies in neurology for more than 60 years.

Our pipeline and launched products target multiple neuroscience disease areas such as Schizophrenia, Multiple Sclerosis, Attention Deficit Hyperactivity Disorder (ADHD), Epilepsy, Parkinson’s Disease and Alzheimer’s Disease.

Novartis was the highest Pharmaceutical investor in R&D, in 2014 spending 23% of total net sales.

We were rewarded with the Most Innovative Pipeline award from Med Ad News for 2011, 2012 and 2013.

www.novartis.co.ukMUL15-E005a

March 2015

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Notes

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MS Frontiers programmeNotes

MS SocietyMS National Centre372 Edgware RoadLondon NW2 6NDT: +44 (0)20 8438 0700

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MS Society CymruCwrt y Deml / Temple CourtHeol y Gadeirlan / Cathedral RoadCaerdydd / Cardiff CF11 9HAT: 029 2078 6676

MS Society Northern IrelandThe Resource Centre34 Annadale AvenueBelfast BT7 3JJT: +44 (0)2890 802 802

[email protected] 0808 800 8000

The MS Society is a registered charity in England and Wales (1139257)

and Scotland (SC041990), and a company limited by guarantee (07451571).

Health & Medicine

Ms frontiers handbook 2015