MS frontiers 2013 brochure

Sofitel London, Heathrow 9-10 May 2013

MS Frontiers 2013

Bringing the research community together to beat MS

In association with

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Innovating healthcare, improving health.At Novartis, our goal is to provide high-quality healthcare solutions to address the evolving needs of patients and society in the UK. We believe that our dedication to innovation and our responsible approach will enable us to fulfill our mission to care for, and provide high quality treatments for, people with Multiple Sclerosis. Novartis is committed to playing a part in supporting those who are affected by the condition.

MUL13-C015 Date of Preparation April 2013


MS Frontiers programme

Contents 3. Contents

4. Welcome

5. Conference Programme

9. Biographies

16. Presentation abstracts

29. Poster abstracts

83. Notes

87. Sponsor information

3


4

Welcome

Welcome to MS Frontiers 2013.

I was delighted to accept the position of Acting CEO in February, not

least because it has allowed me to see at first hand the dedication and

commitment the research community shows to people affected by MS

and the MS Society.

At the MS Society we value research because we can see the difference

it makes to people with MS. But we want to make sure that the

research we fund will have the greatest impact on the lives of those

affected by MS. To that end, we’ve launched a new research strategy

(running from 2013 to the end of 2017).

The strategy was developed in consultation with the research community and people affected by

MS. It sets out our priorities for the next five years and outlines where we are with MS research as

well as highlights areas that need focussed attention, such as progressive MS. You can read the

strategy on our website www.mssociety.org.uk or we have a limited number of copies available at

our Information Stand.

In parallel to the strategy we are also running a priority setting partnership with the James Lind

Alliance, Association of British Neurologists, UK MS Nurses Association and the MS Therapy

Centres. This partnership will enable people affected by MS and health care professionals to set

research priorities to funders.

The aim will be to come up with a top 10 list of research questions that reflect the needs of people

with MS. Following a survey which closed in January, we have developed a ‘long-list’ of research

questions that people are now free to vote on. If you’d like to find out more about this important

project and vote on your research priorities please visit our poster for more information.

Finally, I hope this MS Frontiers gives you the opportunity to network, learn about the latest

findings in MS research and share your work. We look forward to working with you in years to

come to ultimately reach our aim: To Beat MS.

It is an exciting time for MS research with new treatments coming through and new breakthroughs

on the horizon and I feel privileged to be a part of that. Can I take this opportunity to thank you for

your help, support and interest which is greatly appreciated.

With best wishes,

Patricia

Patricia Gordon

Acting Chief Executive

MS Society


5

Conference programme

Thursday 9 May09:30-10:30 Registration & refreshments

10:30-10:50 Opening address Patricia Gordon, Acting Chief Executive, MS Society Prof. Sir Andy Haines, London School of Hygiene and Tropical Medicine and co-chair of the MS Society Research Strategy Committee

10:50-12:30 Inflammation and axonal damage: protective vs detrimental mechanisms

Prof. Frauke Zipp, Department of Neurology, Johannes Gutenberg University Medical Centre Mainz

Pragmatic Exercise Intervention for People with MS: the ExIMS trial

Prof. John Saxton, School of Allied Health Professions, University of East Anglia

Session chaired by Nick Rijke, Director of Policy and Research, MS Society

12:30-13:30 Lunch

13:30-15:30 Parallel sessions

A. Mechanisms of axonal damage Chair: Prof Hugh Perry, University of Southampton Invited Speakers: Dr Don Mahad, University of Edinburgh Dr Michael Coleman, The Babraham Institute Prof Sandra Amor, VU University Medical Center

B. Risk factors of MS Chair: Prof Gavin Giovannoni, Barts and the London NHS Trust Invited Speakers: Dr Ian Galea, University of Southampton Dr Ruth Dobson, Barts and the London School of Medicine Dr Robyn Lucas, The Australian National University

C. Exercise and Physical Activity for People with MS Chair: Dr Lorna Paul, University of Glasgow Invited Speakers: Prof Mathias Maurer, University Hospital Erlangen Dr Ulrik Dalgas, Aarhus University Prof Helen Dawes, Oxford Brookes University


6


15:30-17:30 Poster session with refreshments

17:30-18:30 Debate session There is compelling evidence that early aggressive

treatment of MS leads to long-term benefits for the patient and this should be considered the ‘norm’ in clinical practice

Chair: Dr Raj Kapoor, National Hospital of Neurology and Neurosurgery, Queen Square, London

For the motion: Prof. Gavin Giovannoni, Barts and the London NHS Trust Against the motion: Dr Nikos Evangelou, Queens Medical

Centre, Nottingham Hospitals NHS Trust

19:00-20:00 Drinks reception

20:00 Conference dinner


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Friday 10 May09:00-09:30 Registration & refreshments

09:30-11:30 Parallel sessions

A. Biomarkers and clinical outcome measures: challenges for progressive MS trials

Chair: Dr Raj Kapoor, National Hospital of Neurology and Neurosurgery, Queen Square, London

Invited speakers: Prof Richard Ruddick, Cleveland Clinic Prof David Miller, National Hospital for Neurology and

Neurosurgery Prof Gavin Giovannoni, Barts and the London School of Dentistry

B. Mind and body: The interface between psychological and biomedical in MS

Chair: Prof Roger Baker, Bournemouth University Invited speakers: Prof Trudie Chalder, King’s College London Prof Rona Moss-Morris, King’s College London Mr Stuart Nixon, Person with MS and MS Society Trustee

C. Innovations in symptom management, care and support

Chair: Dr Richard Warner, Gloucestershire Hospitals NHS Foundation Trust Invited speakers: Dr Rosie Jones, Frenchay Hospital Prof. Jon Marsden, University of Plymouth Prof. James Malone-Lee, University College London 11:30-11:45 Refreshments

11:45-13:30 Strategies for target discovery to promote remyelination

Prof Charles ffrench-Constant, University of Edinburgh

Achievements of the MS Register in the first three years and future plans

Prof. David Ford, University of Swansea

Session chaired by JOHN MILLER, MS Society Trustee 13:30-14:30 Lunch


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14:30-15:30 Ian McDonald Memorial Lecture

Mechanisms of tissue injury in Multiple Sclerosis: Lessons for understanding progressive MS

Prof Hans Lassmann Center for Brain Research, Medical University of Vienna, Austria

Session chaired by Prof. Richard Reynolds, Imperial College London

15:30-15:45 Close of conference


9

Biographies

Speaker biographiesFrauke Zipp - After studying Medicine in Germany, the USA, Canada and England, Frauke Zipp began her scientific career at the MPI Martinsried with Hartmut Wekerle in Neuroimmunology. During clinical training with Johannes Dichgans in Tübingen, she was a visiting scientist at the NIH. After a decade at the Charité, she moved to the Rhine Main Neuroscience Network (rmn2) as Director of the Department of Neurology at the University Medical Center Mainz within the Focus Program of Translational Neurosciences. She is currently spokesperson of a Collaborative Research Center on Multiple Sclerosis, one Co-Coordinator of the Competence Network of Multiple Sclerosis, a Council Member of ECTRIMS and a Board Member of ISNI. In 2014, she will be a chair of the ISNI conference taking place in Mainz (rmn2).

John Saxton is a Professor of Clinical Exercise Physiology in the Faculty of Medicine and Health Sciences at the University of East Anglia, Norwich. 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 age-related chronic conditions. He has worked with a number of clinical populations, including people with MS, cancer patients and survivors, patients with peripheral vascular disease and chronic heart failure. His research has been funded by the MS Society, the British Heart Foundation, Heart Research UK, Cancer Research UK and the American Institute for Cancer Research. In 2011 he was the editor of a book entitled “Exercise and chronic disease: an evidence-based approach”, published by Routledge, UK.

Hugh Perry was appointed Professor of Experimental Neuropathology at the University of Southampton in 1998. His research interests are in the field of interactions between the immune system and nervous system, and in particular how systemic infection and inflammation play a role in driving the progression of neurodegenerative disease. He has published more than 300 peer-reviewed papers. He is currently Chair of the MRC Neuroscience and Mental Health Board.

Don Mahad - I am interested in bioenergetics of progressive multiple sclerosis and my research focuses on the role of mitochondria in MS. My lab has made neuropathological observations indicating altered metabolism within neuronal cell bodies and demyelinated axons in progressive MS. We are exploring both the cause and consequences of these neuropathological observations with a view to identifying potential therapeutic agents for progressive MS

Michael Coleman did his PhD with Brian Anderton in London on neurofilament phosphorylation before moving to a postdoc with Kay Davies in Oxford in human genetics. He then did a second postdoc with Hugh Perry in Oxford where he, Laura Conforti and colleagues identified the slow Wallerian degeneration gene (WldS). His independent career took him to Cologne and then back to the UK at the Babraham Institute near Cambridge, where his work has focussed on the mechanism of action of the WldS protein, what it tells us about Wallerian degeneration itself, other proteins that regulate Wallerian degeneration and how to translate this into pharmacological methods to preserve axons. Other interests include the regulation of axonal transport, axon pathology in Alzheimer’s disease and age-related axon loss.


10

Biographies

Sandra Amor - My research experience extends across virology, pathology, immunology and neurosciences. I am head of the MS research group in Pathology at VU Medial Centre in Amsterdam. My commitment and dedication to research extends to understanding the needs of people with MS by organizing interactions between patients and scientists (Meet the Scientist) – for which we were awarded ‘Best Information award’ and by MS society in 2009. I am also involved in facilitating public awareness of disease including advertising and media. Together with Hans van Noort we have published a book ‘MS – the facts’ by Oxford University Press, centered on the major questions posed to us by people with MS at the Meet the Scientists forum.My research group of 7 people is focussed on understanding the first steps in lesion formation in MS. In addition to studying human tissues have developed models to mimic what we think happens in lesion formation. The studies of brain tissues from people with MS have revealed several new pathways in innate immune activation in the brain. Some of these are currently being tested in animals in an attempt to modulate the immune responses in the CNS.

Gavin Giovannoni was appointed to the Chair of Neurology, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London and the Department of Neurology, Barts and The London NHS Trust in November 2006. In September 2008 he took over as the Neuroscience and Trauma Centre Lead in the Blizard Institute of Cell and Molecular Science. Gavin did his undergraduate medical training at the University of the Witwatersrand, South Africa, where he graduated cum laude in 1987 winning the prizes for best graduate in medicine and surgery. He moved to the Institute of Neurology, University College London, Queen Square, London in 1993 after completing his specialist training in neurology in South Africa. After three years as a clinical research fellow, under Professor Ed Thompson, and then two years as the Scarfe Lecturer, working for Professor W. Ian McDonald, he was awarded a PhD in immunology from the University of London in 1998. He was appointed as a Clinical Senior Lecturer, Royal Free and University College Medical School, in 1998 and moved back to Institute of Neurology, Queen Square in 1999. He was promoted to Reader in Neuroimmunology in 2004. His clinical interests are multiple sclerosis and other inflammatory disorders of the central nervous system. He is particularly interested in clinical issues related to optimising MS disease modifying therapies. Gavin’s current research is focused on Epstein Barr virus as a possible cause of multiple sclerosis, defining the “multiple sclerosis endophenotype”, multiple sclerosis related neurodegeneration, multiple sclerosis biomarker discovery, multiple sclerosis clinical outcomes and immune tolerance strategies. Gavin’s team focus on translational research and therefore have an active clinical trial programme.

Ian Galea is Clinical Lecturer in Neurology at the University of Southampton. He has a research interest in neuroimmunology, including the role of systemic infections in disease progression in multiple sclerosis.

Ruth Dobson is currently a Clinical Research Fellow at the Blizard Institute, and an Honorary Specialist Registrar in Neurology at the Royal London Hospital. She currently holds an ABN/MS Society Clinical Research Training Fellowship, having previously been awarded a Brain Entry Scholarship by the Guarantors of Brain. Ruth has a national training number (NTN) in Neurology, and has completed 2 years of clinical higher specialist training in Neurology. Her research centres around the identification of predictive factors in early stage MS, and working towards the determination of a pre-symptomatic stage in MS, in order to enable the identification of an “at risk” population. Ruth is doing this through studying the siblings of people with MS, who themselves have not developed MS. Her hope is that this work will enable large scale preventative studies in the future.


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Biographies

Robyn Lucas is a medically trained epidemiologist and public health physician. After working in clinical medicine in New Zealand, Canada, the Solomon Islands and Australia, Robyn completed a PhD in 2005, examining the effect of environmental stressors and social conditions on immune function. She was the study coordinator for the Ausimmune Study, examining environmental risk factors for a first demyelization event, in Australian adults. She was published widely on vitamin D in relation to MS and first demyelinating events, and has additional interests in delineating the possible separate, independent beneficial effects of sun exposure and vitamin D status in multiple sclerosis. Robyn is an investigator on the AusLong study examining environmental risk factors for disease progression in MS, and also the Prev/ANZ Study, a clinical trial of vitamin D supplementation to prevent MS.

Lorna Paul is a physiotherapist and Reader in Rehabilitation at the University of Glasgow. Lorna has been involved in MS research for over 12 years and is particularly interested in the effect of exercise for people with MS. Lorna was a member of the MS Society Grant Review Panel 2 for a number of years.

Helen Dawes, Elizabeth Casson Trust Chair, leads the Movement Science Group based in the Faculty of Health and Life Sciences at Oxford Brookes University. Helen initially trained and practiced as a physiotherapist specializing in sport physiotherapy and working in the UK and New Zealand, prior to undertaking postgraduate training in exercise science and neuroscience. Helen then embarked on a PhD exploring exercise for people with neurological conditions. She has since then focused on optimizing performance of everyday activities through rehabilitation and on enabling physically active lifestyles in adults and children with disorders affecting movement such as: stroke, Parkinson’s, cerebral palsy and multiple sclerosis. Her research requires cross-disciplinary collaborations. In order to ensure that the research addresses important issues affecting people’s lives, all research activities are guided and monitored by User Steering Groups (adult and children). Her activities include research, teaching and the provision of a Clinical Exercise and Rehabilitation in the community. Her research spans from exploring underlying mechanisms affecting performance through to service delivery of subsequently developed interventions and tools.

Mathias Mäurer, MHBA, Professor of Neurology, Senior Neurologist1987 - 1994 Medical school, Würzburg, Baltimore1994 - 1999 Training in Neurology, Department of Neurology, University of Würzburg1999 - 2001 Post-doc-fellowship, Developmental Neurobiology, University of Würzburg2001 - 2006 Research group leader clinical immunology, Clinical research unit for multiple sclerosis

and neuroimmunology, University of Würzburg2004 - 2006 senior (staff) neurologist, Department of Neurology, University of Würzburg2006 - 2008 Head of the Clinical Research Group for Multiple Sclerosis and Neuroimmunology,

Department of Neurology, University of Erlangen-Nurembergsince 2008 Chairman Department of Neurology Caritas Krankenhaus Bad Mergentheim Academic Teaching Hospital University of Würzrburg

Ulrik Dalgas, PhD is an exercise physiologist specialized in MS rehabilitation. In particular most of his research focuses on the effects of exercise therapy in subjects with MS. His research covers the effects of different exercise modalities (e.g. resistance training and endurance training) and aspects of exercise therapy related to selected groups of MS patients (e.g. thermo-sensitive patients). The main focus is on muscle function. His newest studies have shown that the neural drive increases, following progressive resistance training in MS patients. Currently, he holds a position as board member in RIMS (Rehabilitation in Multiple Sclerosis) and is involved in studies conducted in the RIMS association. Here he is part of the


12

Biographies

steering committee of two large multicenter studies focusing on gait function in MS patients. Furthermore, he is the principal investigator of a Nordic exercise therapy study. Finally, he has contributed to the newly revised Recommendations on Rehabilitation Services for Persons with Multiple Sclerosis in Europe published by the European Multiple Sclerosis Platform (EMSP).

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 in 1981 and completed his postgraduate medical training in London. His initial research, at New York University Medical Center and in the University Laboratory of Physiology in Oxford, was on the basic electrophysiology of neurones in the cerebellum and substantia nigra. He completed his neurological training at University College London Hospitals and at the National Hospital, where he took up his present post in 1994. His main research interests are in the pathophysiology and treatment of demyelinating diseases. His work with Prof Kenneth Smith on axonal injury in MS suggested possible ways of achieving neuroprotection and preventing disability, which he translated into clinical trials of neuroprotection with lamotrigine in secondary progressive MS, and with phenytoin in optic neuritis. He is also involved in work with Prof David Miller on imaging techniques to investigate metabolic failure of the brain in MS, and in the International Progressive MS Consortium, which aims to expedite the development of therapies for progressive disease.

Nikos Evangelou is Clinical Associate Professor of Neurology at the University of Nottingham. His clinical training took place in Thessaloniki- Greece, Bristol, Oxford and Nottingham. He was awarded his DPhil in Oxford for his research in axonal loss in multiple sclerosis and he continues to be research active in the same field. Currently his research team focuses in neuropathology and imaging in MS. He is a member of the MS team in Nottingham with clinical responsibility for 2500 patients with MS in the East Midlands.

Richard A. Rudick, M.D.Professor of Medicine, Cleveland Clinic Lerner College of MedicineHazel Prior Hostetler Chair of Neurology, Cleveland ClinicDirector, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic. Vice Chairman, Research and Development in the Neurological Institute, Cleveland Clinic; oversees development efforts for the Neurological Institute and for strategic planning and oversight of research programs in the neurosciences. Dr. Rudick is co-investigator for the Case / Cleveland Clinic CTSC (Clinical and Translational Sciences Collaborative). The CTSC is an NIH supported grant to fund education and training of clinical investigators, and to fund infrastructure for clinical research across the city. Dr. Rudick directs the education and training component of the CTSC.

David Miller is Professor of Clinical Neurology at the Institute of Neurology, University College London and a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery, UCLH, London. His major clinical activities and research interests are based on multiple sclerosis. He leads a multidisciplinary research group using magnetic resonance methods to improve diagnosis, identify prognostic markers, understand disease mechanisms and monitor new treatments in MS. His research has been principally supported by the MS Society of Great Britain and Northern Ireland; a new high field MRI scanner was installed at UCL Institute of Neurology in autumn 2009 to continue this work. He has published extensively in peer reviewed medical literature. He previously served as Secretary of the Association of British Neurologists and International Society of Magnetic Resonance in Medicine and as Co-Chief Editor of the Journal of Neurology. He has been a recipient of the Sobek Prize (2005) and Dystel Prize (2009) for MS research, and is a Senior Investigator of the NHS National Institute for Health Research, Fellow of the Academy of Medical Sciences and Honorary Professor in the Department of Medicine, University of Otago, Christchurch, New Zealand.


13

Biographies

Roger Baker has worked in a dual role as researcher and clinical psychologist at Leeds, Aberdeen & Bournemouth Universities and in NHS Trusts specialising in Mental Health. He is Professor of Clinical Psychology at Bournemouth University and Consultant Clinical Psychologist with Dorset HealthCare NHS University Foundation Trust and is Chair of the MS Society’s Care and Services Grant Review Panel. He has specialised in the development of new emotion based therapies and assessments summarised in 3 books, ‘Understanding Panic Attacks and Overcoming Fear’, ‘Emotional Processing; healing through feeling’ and his latest book, ‘Understanding Trauma; how to overcome post traumatic stress’.

Rona Moss-Morris is Professor of Psychology as Applied to Medicine. She is head of the Health Psychology Section at the renowned Institute of Psychiatry, King’s College London. She is also a National Advisor to the Department of Health in England, for Increasing Access to Psychological Therapies for People with Long Term and Medically Unexplained conditions and represents the British Psychological Society on the Clinical Advisory Board of the British Society of Gastroenterology. She has been researching psychological factors that affect symptom experience and coping with chronic conditions for the past 18 years. This research has been used to design cognitive behavioural interventions, including web based interventions, for a range of patient groups. Randomised controlled trials to test the efficacy of these interventions form a key component of her research. Professor Moss-Morris’s work has been published in leading medical and psychology journals and texts including the Lancet, BMJ, Psychological Medicine, and Journal of Consulting and Clinical Psychology. She was Editor-in-Chief of Psychology and Health, the principal European health psychology journal from 2006-2010.

Trudie Chalder is Professor of Cognitive Behavioural Psychotherapy at King’s College London and is currently President of the British Association of Cognitive and Behavioural Psychotherapists. She has worked as a clinician and a researcher in the area of medically unexplained symptoms such as chronic fatigue syndrome and irritable bowel syndrome for about 25 years. She develops models for understanding and treating these conditions and evaluates the approaches within the context of randomised controlled trials in primary, secondary and tertiary care. Her more recent research interests involve developing cognitive and behavioural models and treatment of symptoms and disability associated with chronic diseases such as Cancer, Multiple Sclerosis and Inflammatory Diseases.

Richard Warner is a Nurse Consultant based at Gloucestershire Hospitals NHS Foundation Trust. Richard sits on the MS Society’s Care and Services research grant review panel and has been involved with the MS Society UK MS Register steering group

Rosie Jones completed PhD in Neuromuscular Physiology at the Dept. Physiology, Medical Sciences, University of Birmingham in 1971 and held research fellow and lectureship posts before moving to University College London and Charing Cross Hospital. Dept. of Clinical Neuroscience. Moved to University of Bristol in 1992 as Sen. Research fellow and Principal Clinical Scientist and also headed up the Bristol R&D Support Unit from 2000 to 2009. Currently Hon. Sen. Research Fellow, University of Bristol and based at Frenchay Hospital and University Hospitals Bristol.

Jon Marsden qualified as a physiotherapist in 1991; he undertook clinical rotations at the United Bristol Healthcare trust and the National Hospital for Neurology and Neurosurgery in London. From 1999 he worked as a postdoctoral scientist and MRC fellow in the Sobell Dept for Motor Neuroscience and Movement Disorders, UCL. Since 2007 he has been Professor of Rehabilitation at the School of Health Professions, University of Plymouth. His main research interests are in the pathophysiology and rehabilitation of walking and balance following peripheral and central nervous system damage


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Biographies

James Malone-Lee qualified from St. Thomas’ Hospital, London in 1975. He served with the Royal Army Medical Corps until 1981 when he moved to University College London as a lecturer in geriatric medicine. He was appointed senior lecturer in 1984 and promoted to a personal chair during 1994. In 1996 he was appointed to the Barlow Chair of Geriatric Medicine. In 1999 he was posted to the Whittington Campus of UCL Medical School as Professor of Medicine for that site. During thirty years he has worked as a clinical scientist focusing on common lower urinary tract symptoms, their pathophysiology, diagnosis and treatment. In that time he has maintained a keen interest in MS.

Charles ffrench-Constant graduated MA MB, BChir in Medicine from Cambridge in 1980, gaining MRCP in 1984 following posts at the Hammersmith at 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 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.

David Ford leads the MS Society funded UK MS Register project. He 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 University Director of the Health Informatics Research Laboratories, created through a collaboration between the College of Medicine, Swansea University and NHS Wales Informatics Service, the national programme for NHS IT for Wales. The Labs provide state-of-the-art facilities to design, prototype, test and evaluate innovative new information technologies for use in improving health and healthcare. David is also joint lead of the Health Information Research Unit for Wales (HIRU), which develops new ways of harnessing the potential of routinely collected information collected in health and other settings. HIRU’s main product is the SAIL Databank, an internationally recognised data linkage resource formed from a wide variety of routinely collected data from across Wales.David is Deputy Director of a new UK Centre of Excellence for E-Health Research (E-HIRC), funded by a consortium of top UK research funders led by the MRC.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. David is a member of numerous committees and national bodies relating to health informatics and health-related research. He has received research grants and consultancy contracts valuing over 35m over recent years.

Richard Reynolds studied Pharmacology at King’s College London from 1975 to 1981 before embarking on a career in MS research and has now been Professor of Cellular Neuroscience at Imperial College, London, for the last 13 years. He is the Scientific Director of the Multiple Sclerosis Society Tissue Bank and also heads an MS research unit in the Division of Brain Sciences on the Hammersmith Hospital campus. Professor Reynolds has been carrying out MS related research for the last 26 years and current research in the unit is designed to gain an understanding of the mechanisms involved in both neurodegeneration and repair processes in the brain in MS. This research is dependent on a supply of well characterised human brain tissue that has been collected by the MS Tissue Bank because of the desire of the MS community to contribute to the research in a practical way. This work has led him to be involved in teaching both science and medical students about MS and to travel around the British Isles helping people with the illness understand what is happening to them.


15

Biographies

Hans Lassmann graduated from Medical School at the University of Vienna in 1975. He then joined the Institute of Neurology of the University of Vienna for training in clinical and experimental neuropathology. In addition he spent one year as a post doc at the Institute for Basic Research in Developmental Disabilities in New York. In 1990 he became director of the Research Unit for Experimental Neuropathology of the Austrian Academy of Science and in 1993 Professor for Experimental Neuropathology in the University of Vienna. From 1999 to 2007 he was the founding director of the Center for Brain Research of the Medical University of Vienna. He is member of the Austrian Academy of Sciences and the Deutsche Akademie der Naturforscher Leopoldina. In 2005 he received the Charcot Award of the Multiple Sclerosis International Federation


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Presentation abstracts

Thursday 9 MayPlenary session

Inflammation and axonal damage: protective vs detrimental mechanisms

Zipp, Frauke, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2),

University Medical Center Mainz, Department of Neurology, [email protected]

Latest developments in Genetics indicate that Multiple Sclerosis (MS) is truly a primarily inflammatory disease.

Distinct conditions of immune responses in the target organ traditionally referred to as the brain’s ‘immune privilege’

make MS a peculiar and specific disease. Findings in patients are a complex amalgam of inflammation - typically

in subcortical, but also cortical disseminated lesions - and early injury of the neuronal compartment as well as

neurodegeneration.

Our data show a crucial and unique role of dendritic cells – which are suggested to be of importance in the

mechanism of action of several novel therapeutic strategies - for the initial step of invasion and then survival of IL-

17-producing Th17 cells within the target organ. Adhesion of T cells to neurons plays an important role as first step

in the damaging cascade within the central nervous system (CNS) on the one hand, but endogenous repair occurs

within the CNS despite an ongoing inflammatory attack on the other hand. Obviously, remissions of clinical relapses

point to repair capacities of the CNS and/or the immune system, resulting in strong inter-individual and course-

dependent differences.

Considering MS as both inflammatory and neurodegenerative has major implications for therapy, with CNS protection

and repair needed in addition to controlling inflammation.

Pragmatic Exercise Intervention for People with MS: the ExIMS trial

John Saxton

University of East Anglia

Exercise is an effective intervention for improving function, mobility and health-related quality of life in people

with multiple sclerosis (PwMS). Questions remain however, regarding the effectiveness of pragmatic exercise

interventions for evoking tangible and sustained increases in physical activity and long-term impact on important

health outcomes in PwMS. These issues, and improved knowledge of cost effectiveness, are likely to influence

key decisions of health policy makers regarding the implementation of exercise therapy as part of the patient care

pathway for PwMS. Hence, the primary aim of this study was to investigate whether a 12-week tapered programme

of supervised exercise, incorporating cognitive-behavioural techniques to facilitate sustained behaviour change,

was effective for evoking improvements in physical activity and key health outcomes in PwMS over 9 months of

follow-up. PwMS were randomised to the pragmatic exercise therapy intervention or usual care control group. The

intervention increased physical activity levels and resulted in significant improvements in fatigue and quality of life.

This presentation will report the main results of the trial and consider implications for future research.


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Parallel sessions

A: Mechanisms of axonal damage

Hugh Perry

University of Southampton

Injury to axons and the accompanying Wallerian degeneration is a major component of the pathology of multiple

sclerosis. Axon injury and the subsequent degeneration is and irreversible lesion and believed to underlie disease

progression. In this symposium speakers will present recent findings on the molecular events that underpin axon

degeneration and the response of the innate immune cells of the CNS.

Mitochondrial changes in neuronal soma and demyelinated axon in multiple sclerosis: implications for axon pathology.

Don Mahad

Centre for Neuroregeneration, Chancellor’s Building, University of Edinburgh

Mitochondrial abnormalities are now established in MS. Mitochondrial dysfunction resulting from respiratory chain

enzyme deficiency is a consistent feature of most cortical motor neurons and approximately one third of dorsal

root ganglia neurons in progressive MS. The demyelinated axons, however, showed an increase in mitochondrial

density, activity and motility. Subsequent studies indicate this axonal mitochondrial response to demyelination as

a homeostatic phenomenon. Neuropathological examination of a number of established models of MS has not

shown the type of mitochondrial abnormalities evident within neuronal soma in MS. Here, I discuss the mitochondrial

changes observed within neurons in progressive MS, their implications for axon pathology in progressive MS and

limitations of the existing models in recapitulating these mitochondrial changes evident within neuronal soma in MS.

Mechanisms of axon degeneration

Coleman, M. P., Gilley, J., Milde, S., Di Stefano, M., Nascimento-Ferreira, I., Orsomando, G. and Conforti, L.

The Babraham Institute

Structure-function studies of the slow Wallerian degeneration protein and related Nmnat isoforms indicate that

Nmnat activity within axons is critical for axon survival. Of the three mammalian isoforms, only Nmnat2 has been

confirmed to be an endogenous axonal protein. As it is a labile protein, axons are vulnerable to interruptions in

anterograde delivery of Nmnat2 such as that likely to occur in multiple sclerosis. Experimental nerve injury, or

knockdown or knockout of Nmnat2 can be used to model this interruption in supply. Thus, axons in primary culture

undergo Wallerian-like degeneration when Nmnat2 is knocked down, and peripheral nerve growth fails without

Nmnat2.

While Nmnat2 is delivered to axons on membrane-bound transport vesicles, we find that this is not its main site of

action. Its limited protective capacity for injured axons is greatly enhanced by dissociation from these vesicles to a

level similar to WldS, suggesting a cytosolic site of action. Intriguingly, Nampt, another protein that we find to be a

critical determinant of axon survival, is also cytosolic. This proximity may be important for Nmnat2 to sequester the

Nampt product, NMN, which accumulates in injured and explanted nerves and induces axon degeneration unless

an enzyme activity is present to remove it. Thus, Nampt inhibition phenocopies WldS. The pathway relationship

with other emerging regulators of axon survival such as Sarm1 will be the key to identifying the most promising

therapeutic targets for disorders of anterograde axonal transport.


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The Immune System in Neurodegenerative Diseases

Sandra Amor

VU University Medical Center

Neurodegeneration, the slow and progressive dysfunction and loss of neurons and axons in the central nervous

system, is the primary pathological feature of acute and chronic neurodegenerative conditions. Neurodegeneration

is also observed in many diseases including neurotropic viral infections, stroke, paraneoplastic disorders,

traumatic brain injury, and multiple sclerosis. Despite the many different triggering events, a common feature of

neurodegenerative diseases is chronic immune activation, in particular of microglia, the resident macrophages of the

central nervous system.

Apart from the pathogenic role of both innate and adaptive immune responses in neurodegenerative diseases,

emerging evidence indicates that those immune responses are also critical for neuroregeneration. I will review

the impact of immune responses on the CNS, and discuss their contribution to either damage or repair. A

better understanding of the interaction between the immune and nervous systems will be crucial to either target

pathogenic responses, or augment the beneficial effects of immune responses as a strategy to intervene in chronic

neurodegenerative diseases.

B: Risk factors of MS

Systemic infections and disease progression

Ian Galea

Clinical Neurosciences, Faculty of Medicine, University of Southampton

The relationship between systemic infections and progression of disability in multiple sclerosis is complex. Plenty

of evidence suggests that systemic infections precipitate relapses, and that lack of recovery from relapses may

contribute to progression, but the link between the two is tenuous. Systemic infections may also contribute

directly to the process of neurodegeneration, separate from relapses. The evidence for and against this concept,

from our group and others, will be presented. Dissecting the relationship between systemic infections and disease

progression is helping us understand the progressive phase, which is a priority.


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The MS endophenotype: vitamin D, EBV and genes

Dr Ruth Dobson

Barts and the London School of Medicine

Objective: An endophenotype is a concept that allows us to describe complex diseases with genetic and

environmental contributions. This enables the identification of an “at risk” population. We aim to describe an

endophenotypic gradient between healthy controls (HC), siblings of people with MS (PwMS) and PwMS.

Background: Siblings of PwMS have an increased risk of developing MS. This increased risk is thought to be a

result of genetic and environmental contributions. Epidemiological studies have identified factors contributing to

MS including smoking, vitamin-D, infection with and IgG titres against Epstein-Barr virus and HLA-DRB1*1501. A

genome wide association study (GWAS) in 2011 gave information regarding the contribution of HLA-type and non-

HLA SNPs to MS risk. We set out to integrate these into an endophenotypic risk score for MS.

Methods: PwMS (n=78), their unaffected siblings (n=121) and healthy controls (HC; n=103) were recruited. Serum

anti-EBNA-1 IgG, vitamin D and cotinine were measured. Subjects were genotyped for HLA-DRB1*1501 and all

HLA and non-HLA SNPs associated with MS using the Illumina immunochip. Previous infectious mononucleosis,

smoking and month of birth were recorded. The relative risks associated with these factors were established from

meta-analyses and integrated into an overall risk score for each individual. Full genetic data was available for 73

people with MS, 107 siblings and 99 HC.

Results: When the genetic contribution from HLA-DRB1*1501 alone was used, the mean risk score was

significantly higher for PwMS than for siblings or HC. Siblings had a risk score higher than HC. The differences

between the three groups became more apparent when all genetic information was integrated into the risk score.

Conclusions: This study demonstrates the validity of the risk score generated, which integrates genetic and

environmental risk factors. Siblings have a risk score intermediate to PwMS and HC, confirming their “at risk”

position in the endophenotype construct. Much of the MS risk in siblings can be attributed to genetics, with

environmental factors potentially providing the trigger for clinically apparent disease.


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Vitamin D, (sun exposure) and Multiple Sclerosis

Robyn M Lucas, National Centre for Epidemiology and Population Health, The Australian National University,

Canberra, Australia

Geographic variation in the occurrence of multiple sclerosis (MS), first reported in the academic literature in 19221,

and evidence from a number of epidemiological studies, suggest that MS is more common in populations living in

regions where levels of ultraviolet radiation (UVR, from the sun) are low (for example at high latitudes)2 3, in people

having low levels of sun exposure4 5, or with low vitamin D intake6 or vitamin D levels in blood7. Observations of a

correlation between MS and latitude or UVR levels suggest a link, but could also be explained by other factors that

vary by latitude – such as temperature, patterns of infection, diet and possibly genetic susceptibility (due to migration

patterns). Individual-level studies first examined sun exposure/vitamin D in people with MS, where it is difficult to

determine whether low sun exposure/vitamin D caused the MS, or MS caused the low sun exposure/vitamin D,

i.e. people with MS spend less time outside because of heat intolerance or disability. Stronger evidence came from

longitudinal studies where low vitamin D intake from supplements or low vitamin D levels in blood were associated

with increased risk of developing MS. But the intake data rely on participant’s recalling their diet and supplement

use, and an assumption about the vitamin D content of the supplements. Low vitamin D levels in blood provide

stronger evidence, but are unable to distinguish between the effects of sun exposure and those of vitamin D itself.

The Ausimmune Study was conducted in Australia from 2003-2008 to examine the effects of sun exposure, vitamin

D, other environmental factors and genetic factors on the risk of developing MS. Australia has a wide latitudinal

span and widely varying UVR levels – and it is warm in the north and cold in the south, so there is wide variation

in the amount of sun exposure people have, and their vitamin D levels. We recruited 282 people with a first clinical

diagnosis of CNS demyelination and 558 age and sex matched controls from the general population. There was a

latitude gradient in occurrence – a four-fold increase from the lowest latitude to the highest latitude regions8. People

with newly diagnosed disease reported lower sun exposure over their lifetimes and had lower vitamin D levels than

their matched population controls. Sun exposure was related to vitamin D levels, but lower levels of sun exposure

and lower vitamin D levels were both (independently) important for increased disease risk9.

What are the implications for prevention trials? The evidence suggests that maintaining higher vitamin D levels

could reduce the risk of developing MS. If low vitamin D and low sun exposure are independent risk factors for MS,

then vitamin D supplementation will provide a benefit, but not the full benefit of higher vitamin D levels (since these

reflect both sun exposure and vitamin D intake). Prevention trials with vitamin D supplementation are now required

to establish whether this intervention is able to decrease the risk of developing MS. Outstanding questions include:

1). When is the supplementation required? Is it in the period leading up to the diagnosis, over the whole of the

lifecourse, in utero, childhood? 2). Where is the best place to do such a study? In Australia, with high ambient UVR

levels, vitamin D levels in blood will reflect not only supplementation but sun exposure. To best understand the value

of vitamin D supplementation, would it be better to conduct a trial in a high latitude region, where vitamin D from sun

exposure is less likely to be important? 3). What will the comparison groups be, when many people who perceive

themselves at risk already take a vitamin D supplement? 4). What is the best study design, for this disease that is

relatively uncommon and may occur many years after the relevant risk exposure? In light of this, what are the funding

considerations? Many of these questions will be considered in discussion of the PrevANZ Study that is currently

underway in Australia, funded by MS Research Australia.

References

1. Davenport C. Multiple sclerosis from the standpoint of geographic distribution and race. Arch Neurol Psychiat

1922;8(1):51.

2. Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of Multiple

Sclerosis to latitude, solar radiation and other variables. 1960:132-47.

3. Simpson S, Jr., Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the

prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 2011;82(10):1132-41.

4. van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, et al. Past exposure to sun, skin

phenotype, and risk of multiple sclerosis: case-control study. Bmj 2003;327(7410):316-21.


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5. Kampman MT, Wilsgaard T, Mellgren SI. Outdoor activities and diet in childhood and adolescence relate to MS

risk above the Arctic Circle. J Neurol 2007;254(4):471-7.

6. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, et al. Vitamin D intake and incidence of

multiple sclerosis. Neurology 2004;62(1):60-5.

7. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple

sclerosis. Jama 2006;296(23):2832-8.

8. Taylor BV, Lucas RM, Dear K, Kilpatrick TJ, Pender MP, van der Mei IA, et al. Latitudinal variation in incidence and

type of first central nervous system demyelinating events. Mult Scler 2010;16(4):398-405.

9. Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, et al. Sun exposure and vitamin D are

independent risk factors for CNS demyelination. Neurology 2011;76(6):540-8.

C: Physical activity/exercise in MS

Exercise in multiple sclerosisMathias Mäurer, MD

Caritas Krankenhaus Bad Mergentheim, University of Würzburg, Germany

Due to the numerous symptoms of the disease, Multiple Sclerosis (MS) patients show an even more distinct physical

inactivity than the normal population. This inactivity leads to secondary complications like adiposity, cardiovascular

diseases, muscle weakness, pain or fatigue, which all can overlay the primary symptoms of MS and reduce health

and quality of life. Thus, physical activity and exercise should be considered a prerequisite for health promotion in

MS patients. There is no evidence to support the formerly assumed opinion that exercise can be harmful for MS

patients. In the contrary, the effectiveness of exercise in multiple sclerosis patients has been extensively proven,

especially in the past decade. Numerous studies have shown positive effects of aerobic or strength training on

symptoms and quality of life in MS patients. Although MS patients in general are considered to be quite inactive

there is a considerable amount of physically very active patients. In a recently performed survey we could identify a

large amount of MS patients that qualify themselves as very active. To address this very interesting subgroup of MS

patients we designed an internet base training program. As shown recently using internet technology might treat and

supervise patients more economically and more individually than conventional interventions, but systematic studies

are lacking. Data of an randomized controlled trial evaluating E-training will be presented.

Exercise and disease progression in MS

Ulrik Dalgas

Section for Sport Science, Dept. of Public Health, Aarhus University, Denmark

For many years patients with multiple sclerosis (MS) were recommended to avoid physical exercise. This advice

was given because it was noted that exercise could worsen symptoms and induce fatigue. Today we know that the

worsening of symptoms is a temporary phenomenon and that exercise poses the potential to reduce chronic fatigue.

An even larger change of paradigm is the fact that some researchers have started to suggest that exercise (or

physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow

down the disease process.

Recently, we conducted a systematic literature search on this topic, which showed that different methodological

approaches to the problem have been applied including (1) longitudinal exercise studies evaluating the effects on

clinical outcome measures, (2) cross-sectional studies evaluating the relationship between fitness status and MRI

findings, (3) cross-sectional and longitudinal studies evaluating the relationship between exercise/physical activity

and disability/relapse rate and, finally, (4) longitudinal exercise studies applying the experimental autoimmune

encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by

clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported

data (3) and data from the EAE model (4) indicate a possible disease-modifying effect of exercise, but the strength


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of the evidence limits definite conclusions. Taken together some evidence supports the possibility of a disease-

modifying potential of exercise (or physical activity) in MS patients, but future studies using better methodologies are

needed to confirm this.

Symptoms of fatigue following high intensity exercise in people with Multiple Sclerosis

Helen Dawes

Oxford Brookes University

The session will explore the exercise response and recovery during and following a single high intensity (maximum)

exercise session in people with Multiple Sclerosis (PwMS). PwMS benefit their mobility and function from

participation in high intensity exercise but some individuals tolerate this intensity less well than lower intensity

exercise. We explore recovery of symptoms of leg fatigue following high intensity exercise in relation to physiological

measures.

55 PwMS and 15 healthy, low active controls performed incremental exercise to voluntary exhaustion. Physiological

measures (expired air and heart rate), perceived breathlessness, and leg fatigue symptoms were measured during

and for ten minutes following exercise. Measures of baseline disability, activity, vitality and fatigue were recorded.

PwMS had a reduced exercise capacity but normal exercise response. PwMS reporting fatigue as an everyday

symptom exhibited reduced exercise capacity, but a normal exercise response compared to their non-fatigued

peers. Physiological markers and breathlessness recovered at the same rate in all groups. However when

considering symptoms experienced from exercise, symptoms of leg fatigue had recovered less at ten minutes

following exercise in PwMS compared to the control group and particularly in those reporting fatigue as an everyday

symptom.

We propose that PwMS have a normal physiological exercise response but that symptoms of leg fatigue after

intense exercise may require longer than expected to recover, particularly in individuals with higher baseline levels

of general fatigue. Leg fatigue symptoms monitored during recovery from physical activities may provide a sensitive

marker to guide appropriate physical activity in PwMS particularly in those managing high levels of general fatigue.

Debate

There is compelling evidence that early aggressive treatment of MS leads to long-term benefits for the patient and this should be considered the ‘norm’ in clinical practice

Chair: Raj Kapoor, National Institute of Neurology and Neursurgery, Queen Square, London

For the motion: Gavin Giovannoni, Barts and the London NHS Trust

Against the motion: Nikos Evangelou, Queens Medical Centre, Nottingham Hospitals NHS Trust

There is currently widespread debate about whether early aggressive treatment of MS is better for the patient in

the long-term. This debate will focus on the evidence behind early aggressive treatment of MS and review the

arguments for and against. Delegates will be asked to vote on the motion before and after the debate. Arguments

will address the following questions:

• Doesearlyaggressivetreatmenthaveanimpactondisabilityprogression?

• Howshouldbenefitsandrisksbeweighedupandwhatcan/needstobedoneinordertohelppeople

affected by MS make more informed decisions on treatment risks and benefits?

• Shouldtherebefirstandsecondlinetreatmentsorshouldeachpatientbeassessedindividually?

• Arecriteriaforassessingtreatmentfailureappropriate?


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Friday 10 MayParallel sessions

A: Biomarkers and clinical outcome measures: challenges for progressive MS trials

The Multiple Sclerosis Outcome Assessments Consortium: Accelerating Development of Treatments for Multiple Sclerosis

Rudick, R. (Cleveland, OH, USA); LaRocca, N. (NY, NY, USA), and Hudson, L.D. (Tucson, AZ, USA)

Successful development of disease-modifying drugs for relapsing forms of MS is a landmark achievement in

neurotherapeutics. Despite that progress, however, treatments that slow or halt disability progression by inhibiting

neural degeneration or promoting regeneration are lacking, representing a significant unmet medical need.

Trial designs that proved effective for new MRI lesions and relapses may not be optimal for detecting disability

progression. New designs that incorporate validated outcome measures focused on disability will be required.

The US FDA has established a pathway to qualify biomarkers, patient-reported outcomes, and clinician-reported

outcomes (ClinROs). With that in mind, the National Multiple Sclerosis Society (NMSS) has entered into a partnership

with the Critical Path Institute to create a new Multiple Sclerosis Outcome Assessments Consortium (MSOAC). The

MSOAC is a coalition of industry, academia, patient representatives, regulatory and other government agencies, and

the NMSS. To achieve its goal, the MSOAC will create a database of clinical trial and observational study datasets,

analyze these, and develop evidence leading to qualification of a new ClinRO measure of disability by FDA and EMA.

Participating companies, academic investigators, advocacy organizations, and regulatory agencies will be listed.

We will describe the project’s close collaboration with the FDA and EMA, and present details of the project plan.

The MSOAC represents a new paradigm in multidisciplinary, collaborative research in which all sectors of the drug

development enterprise cooperate in an effort to accelerate progress in developing treatments for progressive forms

of MS. The consortium will be well-positioned for additional collaborative projects aimed at accelerating development

of more effective treatments for MS.

Imaging outcome measures: challenge for MS trials

David Miller, National Institute of Neurology and Neurosurgery

Imaging techniques are a direct means of monitoring the pathology of multiple sclerosis (MS) in life. Because much

of the pathology is clinically silent, imaging offers a sensitive outcome measure in MS clinical trials. However, to be

a reliable surrogate measure, it should also reflect and predict a clinically meaningful outcome such as relapse rate

and development of disability. In relapsing remitting MS, new and gadolinium enhancing lesions are well established

as a surrogate outcome measure for relapses, as shown in multiple clinical trials. In progressive MS, the focus is

on imaging neurodegeneration and repair. Promising outcome measures are emerging, particularly brain atrophy,

which is the primary outcome measure in proof of concept trials of several experimental neuroprotective agents in

progressive MS. Lesion MTR is an outcome measure in several trials of experimental remyelinating therapies. These

and other emerging imaging markers of neuro-protection and repair will be discussed.


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B. The psychological impact of MS and the role of psychological interventions

Understanding adjustment to Multiple sclerosis: How can we help?

Rona Moss Morris, King’s College London

Multiple Sclerosis (MS) poses significant challenges for adjustment. It tends to be diagnosed at a time of life

when people are most productive. The disease imposes a lifetime of uncertainly and the possibility of increasing

symptoms and disability. In this paper I will present a model of adjustment to MS which we developed from a

systematic review of 72 published studies and qualitative interviews with 30 people with MS diagnosed within the

past 10 years and 15 of their spouses.

I will discuss factors which have been shown to be related to good adjustment such as seeking social support,

acceptance of the illness, positively reinterpreting situations, good health behaviours and a sense of control over the

illness. I will also consider factors which are related to worse adjustment in MS, such as high levels of perceived

stress, perceiving MS and symptoms as threatening, and avoidance coping strategies. I will show how we have

used this information to design a cognitive behavioural therapy (CBT) programme to assist adjustment to MS.

This CBT package was shown in a recent randomised controlled trial to be significantly more effective at reducing

distress in early stage MS than supportive listening. Finally – I will discuss new directions for this work based on

quantitative and qualitative analyses of the RCT findings.

C. Innovations in symptom management, care and support

Unraveling tremor: difficulties of quantifying a complex disabling symptom in MS and the development of a clinical tremor measurement workstation

Authors: Rosie Jones, Angela Davies Smith, North Bristol NHS Trust

David Western, Simon Neild, Rick Hyde, University of Bristol.

Tremor is often part of a complex upper limb movement disorder experienced by between 30-50% of people with

MS. It may vary from a mild intention tremor to large amplitude more random movements making everyday tasks

difficult or impossible resulting in a high level of dependence on others. Currently there is no fully effective treatment

for this problem.

Lengthy clinical scales used to fully assess upper limb movement, while useful in research, are time consuming

and challenging to the patient. They provide little information on the characterization of the movement disorder, are

prone to ceiling or floor effects and are rarely used in routine neurological practice. We aim to develop a clinical

workstation able to quantify tremor and provide detailed information about the nature of the movement disorder. The

system to be demonstrated records upper limb movements using five small 3D sensors attached over the sternum,

shoulder, upper arm, lower arm, and hand. The sensors record the orientation of each body segment at each

point in time. These data are combined with a simple model of the patient’s body geometry to reconstruct their

movements for review and analysis.

The workstation software allows the clinician to apply further processing to the recordings to distinguish tremor

from underlying purposeful movements or abnormal movements and to quickly extract objective information about

the occurrence of tremor and other movement characteristics such as amplitude and frequency. Measurements

may then be correlated with conventional clinical assessments of tremor, while also offering greater detail and

specificity. The calculations can be focused on the movement at the hand, but it is also possible to examine the

activity in individual joints and to define their separate contributions to hand movement. These capabilities will be

demonstrated during the workshop, and discussed in terms of their potential for the characterization, monitoring,

and treatment of movement disorders.


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The study is a work in progress and comments regarding the output and validation of the system are welcome. A

valid and reliable measure of upper limb movement dysfunction is needed if new strategies to treat this disabling

symptom in MS are to be developed and fully evaluated. The proposed clinical measurement system aims to deliver

rapid, user friendly, quantifiable information during full range movement representing normal everyday tasks.

This abstract summarizes independent research funded by the National Institute for Health Research (NIHR) under

the i4i (Invention for Innovation) programme (Grant Reference Number II-AR-0410-12030). The views expressed are

those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health

Assessing and Suppressing Tremor to enable Independence: Development of a Clinical Workstation.

Rosie Jones, Angela Davies Smith, Simon Neild, David Western, Richard Hyde

University Hospitals NHS Foundation Trust and North Bristol NHS Trust

Introduction: Between 30-50% of people with MS reportedly experience tremor. In MS this can be a particularly

complex movement disorder presenting as intention tremor and often accompanied by upper limb weakness, fatigue

and gross ataxic movements. Currently there is no effective treatment. The impact on daily activities often results in

a high degree of dependence. Routinely used clinical scales to assess upper limb tremor are useful but offer little

detailed information about the nature of the movement disorder.

One aim of this project is to develop a user-friendly, standalone clinical workstation with bespoke software enabling

recording and analysis of upper limb movements. The recording system comprises five 3D body worn sensors

(Xsens) recording standardised movements and functional tasks. Sections of recorded stored data can be selected

for more detailed analysis alongside clinical assessment. Data generated by the workstation are used to provide

quantitative analysis of type and severity of movement disorder, evaluation of treatment, and exploring the means of

defining suitability for neurosurgical intervention. The project is in progress and this abstract will concentrate on the

development of the clinical workstation.

Methodology: People with MS displaying various levels of abnormal upper limb movement and tremor are being

recruited from the BrAMS Clinical Centre at Frenchay Hospital, Bristol. Each subject undergoes clinical assessment

(Fahn Scale, Multidimensional Assessment of Tremor in MS, Brief Ataxia Rating Scale) and completes questionnaires

(MSIS-29, EQ-5D-5L) to evaluate tremor and its impact. The sensors are attached over sternum, shoulder, proximal to

elbow and wrist and dorsal surface of the hand. Recordings of a series of standardised movement tasks are made and

the data transmitted by wireless link to the workstation computer. Simultaneous video recordings are made.

Stored data and video can be played back for further analysis, subject feedback, quantitative tracking of symptoms

and further refinement of the workstation analysis programmes. Clinician and subject feedback is being used to

inform development of the workstation and its output.

Results: To date bilateral recordings have been completed with seven people with MS and three control subjects.

The standalone system provides real time data on tremor frequency, amplitude, origin and occurrence during

different phases of movement. Sample data derived from the recordings will illustrate:

1. Characterisation of movement disorder and severity

2. Development of workstation software and data presentation

3. Evaluation of treatment strategies

To date, recorded tremor amplitude has been shown to correlate with clinical tremor assessment and the occurrence

of tremor can be distinguished from larger amplitude intentional or non-intentional movements.

Summary: The development of the workstation enables the collection of real time quantitative data on upper limb

movement that can be carried out in a clinical setting, and stored for immediate and on-going comparative studies.

Simultaneous video recording provides visual record of movement for comparison with the clinical assessments. The

workstation will be demonstrated.


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This abstract summarises independent research funded by the National Institute for Health Research (NIHR) under

its i4i Programme (Grant Reference Number 11-AR-0410-12030). The views expressed are those of the author(s)

and not necessarily those of the NHS, the NIHR or the Department of Health.

Effect of Stretching on Stiffness and Range of Motion in People with Multiple Sclerosis

Jon Marsden

University of Plymouth

Hypertonia is seen in up to 85% of people with Multiple Sclerosis (pwMS) resulting in disability and functional

restrictions. Hypertonia can be caused by increases in passive stiffness and enhanced stretch reflexes (spasticity)

and is frequently managed clinically using passive stretches. However, recent systematic reviews suggest that

stretching may not be effective in improving passive stiffness and spasticity in people with an Upper Motor Neuron

syndrome. However, many of the studies to date vary considerably in the parameters of stretching used and this

may influence their findings. The impact of parameters of stretching such as the type of stretch, the applied force

and the duration of stretch on range of motion, passive stiffness and spasticity will be explored in this workshop.

Recent work has further highlighted that following an upper motor neuron syndrome muscle fibres can become

shorter and stiffer whilst the in series tendon may become more compliant and longer. As most stretch paradigms

apply force to both the tendon and muscle this raises the possibility that some stretches may not greatly affect the

stiffest component of the musculotendinous complex thus limiting their effectiveness.

Real progress in managing the bladder in MS

James Malone-Lee

University College London

Benefitting from a research grant for the MS Society we have applied recent discoveries about the diagnosis and

microbiology of urinary infection to people suffering from MS. Much to our surprise we found an extremely high

prevalence of undiagnosed urinary tract infection amongst MS sufferers with lower urinary tract symptoms. It would

seem that in many cases the infections had been present for years. We found that people were invariably affected by

mixed microbial infections which would be dismissed as contamination by most laboratories. During an observational

study we treated these infections with protracted antibiotic courses, sometimes using combined antimicrobials, and

observed remarkable changes in bladder symptoms, and more importantly, general system health and the impact of

MS symptoms (F=10, df=2, p<.0001). We were able to reduce the use of intermittent self-cauterisation substantially

to (12%) of patients. We obviated the use of urodynamics and other invasive investigations. These findings are now

subject to randomised controlled trial. A key finding was that there was a marked dose-response relationship in

the therapeutic effect, which dictates high antibiotic doses. A previous MS Society sponsored study conducted

here comes to our rescue on this point. We discovered the remarkable properties of topical bladder therapeutics by

administration of drugs directly into the bladder. Hence we are now working with non-engineers in order to develop

new formulations specifically for MS sufferers which will reduce invasive bladder access, for this purpose, to a

minimum


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Plenary Session

Strategies for target discovery to promote remyelination

Charles ffrench-Constant, University of Edinburgh

The Edinburgh Centre for Translational Research was established in 2007. The remit of the Centre is the discovery

and delivery of novel approaches to progressive MS. Our initial focus has been on enhancing remyelination based

on studies of the triad of -ologies in regeneration - tissue biology, stem cell biology and inflammation biology. I will

illustrate how our work, often performed in collaboration with Cambridge colleagues so as to realize the added

value of having two MS Society Centres, has led to the discovery of a number of novel targets for drug therapies.

The Centre has also been instrumental in catalyzing a number of significant translational and clinical developments

in Edinburgh based around regenerative medicine, and I will describe how the critical mass we have developed will

enable us to extend our work addressing the problems of progressive disease.

Achievements of the MS Register in the first three years and future plans

David Ford, University of Swansea

The MS Register Project, funded by the MS Society, is now in its second year of data collection. The project is

entering an exciting new phase, having developed and implemented a successful data collection methodology

during the pilot phase of the project. The project now aims to consolidate its work and build recruitment so that

useful research results can be delivered from the Register’s data.

The underlying tenet of the Register is to collect data from 3 sources, namely from clinical staff at specialist NHS

treatment sites; from other healthcare sources; and directly from people with MS via the Internet. This Internet

‘portal’ is available to all PwMS within the UK. The portal has been designed to capture a range of outcome

measures and accompanying data about all aspects of living with MS in the UK. Users are asked to answer up to

10 questionnaires and then return every 3 months to provide further information about their condition. This data is

then linked to their clinical record – initially if they live near one of the Registers 5 pilot sites and they have consented

to do so. The Register is also able to quickly deliver targeted questionnaires to any of the Portal’s registered users,

making it a powerful research platform to support a wide range of future research studies. The Register portal now

has over 10,000 users with a rapidly rising number of people consented at the clinical sites.

The Register team has already published 8 articles in peer reviewed journals and aims to raise the profile of the

Register as platform to the research community involved in MS research.


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Ian McDonald Memorial Lecture

Mechanisms of Tissue Injury in Multiple Sclerosis: Lessons for Understanding Progressive MS

Hans Lassmann (MD)Center for Brain Research, Medical University of Vienna, Austria Multiple sclerosis is defined as an inflammatory demyelinating disease, giving rise to focal plaques of primary demyelination in the white matter. This original definition has been expanded during the last decade by the observation of prominent lesions, which affect the grey matter, and by the presence of diffuse tissue injury in the entire brain. Active demyelination and neurodegeneration in the MS brain occurs on the background of inflammation, consisting of lymphocyte infiltrates and the activation of macrophages and microglia. Inflammation decreases with age of the patients and disease duration, and the inflammatory process becomes at least in part trapped behind a closed or repaired blood brain barrier. Demyelination and neurodegeneration is associated with microglia activation. A prominent role of oxidative injury is reflected by the appearance of oxidized proteins, lipids and DNA in degenerating oligodendrocytes, neurons and axons. In early disease stages, oxidative injury is mainly driven by inflammation and oxidative burst in microglia, which highly express components of the NADPH oxidase complex. With increasing age of the patients and disease duration additional mechanisms become apparent, which further amplify oxidative damage. These include age related accumulation of iron in the human central nervous system, as well as age, inflammation and chronic tissue injury related accumulation of mitochondrial injury and microglia activation. These data suggest that demyelination and neurodegeneration is driven by inflammation at all stages of the disease, but that in the progressive stage of the disease the brain and spinal cord tissue becomes more susceptible to further injury by additional factors, which are related to brain aging and the progressive accumulation per-existing damage within the central nervous system. While the inflammatory mechanisms, operating in early stages of MS, are well reflected in experimental models of autoimmune encephalomyelitis, these models have major limitations for the analysis of tissue injury in the progressive stage of the disease.


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Abstracts

1. Autologous stem cell transplantation depletes IL-17 producing, mucosal associated invariant T cells in multiple sclerosis

Abrahamsson S, D Angelini, A Dubinsky, E Morel, U Oh, J Jones, D Carassiti, R Reynolds, M Salvetti, P

Calabresi, A Coles, L Battistini, R Martin, R Burt, and P Muraro

Imperial College London

Autologous haematopoietic stem cell transplantation has been tried as an experimental strategy for the treatment of

patients with aggressive multiple sclerosis who do not respond to other immunotherapies. The procedure is aimed at

ablating and repopulating the immune repertoire by first mobilizing and harvesting stem cells from the patient’s own

bone marrow, administering an immunosuppressive treatment, and then re-infusing the stem cell.

“Non-myeloablative” conditioning regimens utilizing a reduced-intensity chemotherapy to achieve reduction of the

immune system without bone marrow suppression have been proposed to improve safety and tolerability. A clinical

trial with non-myeloablative autologous haematopoietic stem cell transplantation reported clinical improvement and

inflammatory stabilization in treated patients with highly active multiple sclerosis. Aim of the present study was to

understand the changes in the reconstituted immune repertoire bearing potential relevance to its mode of action.

Blood cells were obtained from 12 patients with multiple sclerosis participating in the aforementioned trial and

longitudinally followed for two years. We examined the phenotype and function of peripheral blood lymphocytes by

cell surface or intracellular staining and multi-colour fluorescence activated cell sorting.

During immune reconstitution post-transplantation CD4+ FoxP3+ T cells and CD56high NK cell subsets, associated

with immunoregulatory function, increased their proportions. In contrast, a CD161high proinflammatory CD8+ T cell

subset was virtually ablated at all time-points post-transplantation, but not significantly reduced in patients treated

with conventional interferon-β immunotherapy. The expression of T cell receptor Vβ7.2 and IL-18Rβ revealed that

the CD161highCD8+ T cells were mucosal-associated invariant T cells, a novel cell population originating in the gut

mucosa but expressing the central nervous system-homing receptor CCR6. Detection of central nervous system-

infiltrating mucosal-associated invariant T cells in post-mortem multiple sclerosis brain white matter active lesions

confirmed their involvement in the disease pathology. Characterization of this T cell subset by intracellular cytokine

staining demonstrated IFN-β and IL-17 production and lack of IL-10 production, demonstrating a pro-inflammatory

cytokine profile. Mucosal-associated invariant T cell frequency did not change after interferon-beta treatment and

was more profoundly depleted after autologous haematopoietic stem cell transplantation than in patients who had

received high-dose cyclophosphamide or alemtuzumab treatment alone, suggesting an additive or synergistic effect

of the conditioning regime components.

We propose that a favourably modified balance of regulatory and pro-inflammatory lymphocytes underlies the

suppression of central nervous system inflammation in patients with multiple sclerosis following non-myeloablative

autologous haematopoietic stem cell transplantation with a conditioning regimen consisting of cyclophosphamide

and alemtuzumab.


30

Abstracts

2. Remyelinating gene therapy by PDGFA delivered as a latent growth factor activated by inflammation

Annenkov A, Helene Gautier, Robin Franklin, David Baker, Charles ffrench-Constant, Yuti Chernajovsky

Bone and Joint Research Unit, Queen Mary University of London

We explore the possibility of promoting CNS remyelination using the oligodendrocyte progenitor (OPC) mitogen

PDGFA produced in a biologically inactive form that can be activated by matrix metalloproteinases (MMP). Such

a strategy confines biological activity of PDGFA to sites of neuroinflammation, characterised by increased MMP

expression. The latent state of PDGFA is achieved by fusion with TGFbeta1 latency associated peptide (LAP),

with MMP cleavage site between LAP and PDGFA. The recombinant gene for this fusion protein (LmP) has been

produced together with a number of control genes encoding 1) mouse PDGFA (mPDGFA), 2) the alternatively

spliced long isoform of mPDGFA (mPDGFA_L), 3) mPDGFA tagged with the au1 antigenic epitope at the C-terminus

(mPDGFAau1), 4) a fusion protein without MMP cleavable site (L_P). Both fusion proteins LmP and L_P are tagged

with au1 at the C-terminus. Each of the five genetic constructs has been subcloned in constitutive and inducible

lentiviral vectors for testing feasibility of this regenerative treatment in a number of experimental models, including in

vitro differentiation of OPC, ethidium bromide-induced demyelination, and experimental allergic encephalomyelitis.

Lentiviral particles containing genes for these genetic constructs have been produced and used for genetic

modification of primary OPC and the OPC line CG4. After optimisation of primary OPC transduction, genetically

engineered cells will be tested in vitro and in the demyelination models in vivo. The recombinant proteins have

been biochemically and functionally characterised using serum-free culture supernatants conditioned by 293T cells

that had been transduced with lentiviral vectors containing genes for these proteins. After treatment with MMP-1,

PDGFA was released from LmP, but not from L_P, as shown by immunoblotting with an anti-au1 antibody. PDGFA

expressed as a free protein and PDGFA released from LmP promoted growth of CG4 cells. Genetically modified

primary OPC and CG4 cells expressing the recombinant PDGFA constructs will be also used for modelling effects of

autocrine and paracrine secretion of PDGFA on OPC growth and differentiation.


31

Abstracts

3. Research Network: Involving people affected by MS in shaping research

Alison Astles1, Peter Bailey1, Sarah Bittlestone1, Neil Forbes1, Karen MacRae1, Sue Polson1, Sarv Kaur2

1 Research Network steering group members, MS Society2 Public Involvement Officer, MS Society

‘We are committed to involving people affected by MS in every aspect of our work.

We believe that only by fully involving people affected by MS in our research programme can we ensure that our

work reflects the needs, wishes and aspirations of people affected by MS.’ –

MS Society Research Strategy, 2013-2017.

The MS Society’s award winning Research Network has over 300 members, all affected by MS, who are committed

to working along side researchers to improve the quality and relevance of MS research projects.

Within the MS Society, Research Network members are involved in a range of activities: developing research

priorities, reviewing grant applications, influencing funding decisions, supporting projects by sitting on steering

groups and management boards, and communicating messages about research.

Members of the Research Network offer a wealth of experience and knowledge. When designing and implementing

research projects researchers are able to draw on their expertise to strengthen their research projects.

The MS Society has a dedicated Public Involvement Officer, Sarv Kaur, who supports public involvement in research.

The Public Involvement Officer works closely with both the Research Network and with researchers, assisting

researchers to improve the way people affected by MS are involved in shaping research. The MS Society also has

a Research Network steering group made up of Research Network members who advise the MS Society on the

development and direction of the Research Network.

Researchers are encouraged to involve people affected by MS at the very earliest planning stages. There are many

ways researchers can involve the Research Network in their research, some of which include:

•Reviewingresearchproposalsforrelevanceandcommentingonmethodsproposedtoensuretheyare

acceptable and sensitive to potential research participants

•Commentingon,anddevelopingaccessible,informationsheets,leaflets,posters,questionnairesetcpriorto

dissemination to the wider MS community

•Sittingonsteeringgroupsorprojectmanagementboards

•Participatinginmeetingsorfocusgroups

Researchers can find out more about working with the Research Network by contacting Sarv Kaur by email

[email protected] or calling 020 8438 0921.


32

Abstracts

4. A qualitative study of emotional experiences and help-seeking in women with MS*

Blundell Jones J, Sue Walsh, Claire Isaac

University of Sheffield

Background: High prevalence rates of depression and anxiety have been reported in Multiple Sclerosis (MS).

Treatments are effective but evidence suggests that individuals do not always seek help for emotional difficulties.

Help-seeking is influenced by factors such as perceptions of need and stigma.

Objectives: To develop understanding of the emotional experiences of people living with MS, and to explore how

such experiences are coped with and understood.

Design: Qualitative study with semi-structured interviews and follow-up

discussions. Interviews were analysed using Interpretative Phenomenological Analysis.

Participants: Ten women with a diagnosis of MS aged between 30 and 64.

Setting: A regional MS Clinic.

Results: Four overarching themes emerged from the data: Disclosure stress, Uncomfortable dependence, Facing

deterioration and One step at a time.

Decisions regarding sharing their diagnosis were difficult for the women as neither disclosure nor non-disclosure

was problem-free. Physical help from others was needed and valued but affected the women’s sense of self. MS

threatened further life changes due to symptom unpredictability, coping with this threat and facing losses could be

overwhelming. The emotional impact was a significant part of their lives but felt invisible to others especially services.

They worked hard to “keep going” physically (to manage

symptoms) as well as emotionally, and found strategies to avoid depression and anxiety. Women understood their

emotional experience in different ways but it appeared that reaching a point of feeling unable to cope with emotions

would stimulate help-seeking.

Conclusion: Women struggled emotionally with many aspects of living with MS

yet coping alone was a way of defying it and maintaining independence and control. Although women sometimes

needed emotional support, it seemed others did not either notice or understand; they wanted services to care more

holistically for them and needed more information. Not seeking help for distress was partially influenced by a desire

to keep things ‘normal’ and a lack of knowledge regarding service provision.

*Selected for presentation during ‘Mind and body: The interface between psychological and biomedical in MS’


33

Abstracts

5. Mindfulness based cognitive therapy for people affected by primary and secondary progressive Multiple Sclerosis

Bogosian, A, Prof. Rona Moss-Morris, Prof. Paul Chadwick

King’s College London

Mindfulness based interventions have been shown to reduce stress, depression and anxiety symptoms, improve

quality of life and decrease physical symptoms for people with a range of chronic conditions, including MS.

The aims of the project are:

1. To develop a distance delivered 8-week Mindfulness-Based Cognitive Therapy (MBCT) programme for

people with progressive MS.

2. To gain a better understanding of the potential benefits of MBCT for MS by repeatedly measuring process

of outcome measures across the programme.

3. To assess people’s experiences of the MBCT so that further modifications can be made to the protocol.

A detailed manual and protocol have been written for this study. The first stage of the evaluation included two people

affected by progressive MS. They took part in the programme on a one-to-one basis and gave detailed feedback.

The second stage involved one group of 4 people with progressive type of MS.

Participants took part in the mindfulness programme. The programme was delivered via Skype video-conferences.

The sessions lasted one hour and took place once a week, over an 8-week period. Participants completed

questionnaires 3 weeks before the programme started, at the beginning and end of the programme; process

measures were also completed weekly. In the end of the programme participants gave detailed feedback through a

telephone interview with an independent researcher.

Questionnaire data were plotted and visually inspected for each case to determine change over time. To get an

estimate of the changes on the primary outcomes, the data for each individual case were analysed using regression

analysis. Feedback interviews were analysed using thematic analysis.

Overall participant found the programme relevant and useful but also identified some problems, which are now

addressed. These problems included technical aspects of the interventions (Skype, online questionnaires), context

issues (some concepts needed more time to be explored or more relevant examples) and more information

regarding mindfulness and association with MS was needed. The results of these case studies were used to further

modify the mindfulness programme for people with progressive MS for the pilot randomised controlled trial that we

are currently conducting.


34

Abstracts

6. Dorsal root ganglia in MS: histological and mitochondrial changes

Campbell, G, Jessica A Santivanez, Elizabeth Bradbury, Doug M Turnbull, Bruce G Trapp,

Hans Lassmann, Don Mahad

University of Edinburgh

Introduction: In MS, sensory symptoms and findings are prevalent and they are understood to be the manifestation

of central nervous system (CNS) pathology. Despite the involvement of centrally projecting axons of dorsal root

ganglia (DRG) neurons and the proposal that DRG neurons are metabolically compromised (Waxman, 1993), DRG

have not been studied in MS patients.

Methods: We histologically characterized cervical and lumbar DRG, obtained at post-mortem, from progressive

MS (n=16), motor neuron disease (n=4), Parkinson’s disease (n=3) and controls (n=12) and explored DRG neuronal

mitochondria. Lumbar DRG were also derived from a thoracic spinal cord crush injury model. Histochemical and

immunohistochemical methods were used for both human and animal tissue. Molecular techniques included long-

range, real-time and single molecule PCR and sequencing of laser captured single DRG neurons from post-mortem

tissue.

Results: The cellularity of DRG was increased in MS compared with controls, with evidence of perineuronal glial

reaction (satellitosis) and greater HLA-positive elements. Total neuronal counts were decreased by 31% in lumbar

DRG from MS cases compared with controls. The size and density of DRG neurons, however, were not significantly

different in MS compared with controls. Retrograde neuronal changes (central chromatolysis) were evident in a

minority of DRG neurons (11.9%) in MS, although significantly more than in controls (2.7%), and apoptotic neurons

were not detected.

Strikingly, both lumbar and cervical DRG in MS contained a substantial number of neurons lacking in mitochondrial

respiratory chain complex IV (respiratory deficient) than controls (39% and 24%, respectively, of all DRG neurons in

MS versus 3% and 4.5% in controls). The difference in respiratory deficiency between lumbar and cervical DRG in

MS was statistically significant (p=0.01).

Respiratory deficiency in MND and PD DRG was comparable to controls. In MS, respiratory deficiency was

explained by high level of clonally expanded mitochondrial DNA (mtDNA) deletions and mtDNA depletion, when

investigated in single neurons. Furthermore, subunits of mitochondrial respiratory chain complex I and complex

IV were not detected in these neurons, indicative of the pathogenicity of mtDNA deletions. Only a small subset of

respiratory deficient neurons (9.3%) showed central chromatolysis in MS whilst the spinal cord crush injury model

DRG did not contain respiratory deficient neurons (despite 15.6% of chromatolytic neurons), indicating axon

transection as an unlikely cause of the DRG neuronal mitochondrial abnormalities in MS.

Conclusions: For the first time we show that the DRG in MS are abnormal. The abundance of respiratory deficient

DRG neurons, identified here, adds to the previous observations that most upper motor neurons in MS also contain

dysfunctional mitochondria. Together, these findings suggest that axon length may influence the generation of

mitochondrial abnormalities in the neuronal cell bodies in MS. The mitochondrial abnormalities in neuronal soma,

unrelated to axon transection, are likely to have important consequences for the integrity of axons, particularly in the

face of demyelination, and for the pathophysiology of progressive MS.


35

Abstracts

7. Accurate estimates of whole brain neuronal loss in multiple sclerosis: preliminary results using unbiased quantitative histology

Carassiti, D, Maria M Papachatzaki, Francesco Scaravilli, Klaus Schmierer

Queen Mary, University of London

Introduction: Evidence suggests neuro-axonal loss is the major substrate of chronic functional deterioration in

people with multiple sclerosis (pwMS). Whilst acute axonal transection and Wallerian degeneration have been

described as mechanisms of axonal damage in and around MS lesions (Trapp et al., 1998, Peterson et al., 2001,

Dziedzic et al., 2010), the mechanisms of neuronal injury in the cortex are less clear, though meningeal inflammation

may play a role (Howell et al., 2011). However, there is significant variation of the reported degree of cortical

neuronal loss (Wegner et al., 2006, Magliozzi et al., 2010) and the overall loss of neurons and the topographic

distribution of this loss in MS is unknown. Accurate quantification of cell populations including neurons is of

fundamental importance for a better understanding of MS pathophysiology. We applied unbiased sampling

techniques derived from stereology to quantify neuronal cell counts throughout the neocortex.

Methods: Formalin fixed brain hemispheres of two people with secondary progressive MS (one female, one male,

age= 47 and 92 years, disease duration= 31 and 60 years, brain weight = 1050g and 1310g respectively) and one

reference case (male, age= 78 years, brain weight = 1236g) with no known neurological disease were used. Lobar

topography (frontal, parietal, temporal, occipital lobe) was identified and marked with tissue dye on the cortical

surface. One hemisphere was then dissected into 1.1 cm thick coronal slabs, and images obtained of each slab

following a standard protocol. Each slab was then embedded in wax and 40μm-thick hemispheric sections were

obtained. To calculate tissue shrinkage images of entire sections at dissection and after embedding were obtained.

On the basis of Giemsa staining and morphological criteria neurons were identified and counted using a x60

objective on a microscope equipped with a motorized stage controlled by StereoInvestigator software. Stereological

principles were applied as follows: the cortex was outlined on a single section from each block (AOI) and counting

boxes (50μm x 50μm x 30 μm) were cast randomly using a constant grid (X: 3455 μm, Y:

4655μm) for all samples. The number of neurons in each slab was subsequently calculated according to NV x NREF

stereology method: NV = total neurons counted/volume of all counting boxes and NREF = AOI x cortical thickness.

Results: Cortical neurons stereological counts were 17 billion for the 1st and 9.6 billion for the 2nd MS case, and

19.8 billion for the control brain.

Discussion: To the best of our knowledge, this is the first study to estimate total neuronal loss in MS cortex using

the most accurate principles & technology (stereology). The total number of neurons we obtained in our control

case was similar to figures reported previously in a larger cohort (Pelvig et al., 2008). Future work will focus on (i)

expanding our sample size, (ii) including further cell populations (T & B cells, microglia/macrophages, astrocytes)

and morphological features (eg. neuronal size & synaptic arborisation), and (iii) investigating the association

between tissue damage in the cortex and the spinal cord to explore whether a tract specific pattern of neuro-axonal

degeneration contributes to chronic disease progression in MS (Kolasinski et al., 2012).


36

Abstracts

8. The functional significance of autoantibody-dependent pathomechanisms in multiple sclerosis

Chapple K, Eva-Marie Oesau, Maren Lindner, Christopher Linington

University of Glasgow

A significant proportion of children with multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM)

develop autoantibody responses directed against the extra-cellular domain of myelin oligodendrocyte glycoprotein

(MOG). Antibodies with similar properties mediate demyelination and exacerbate disease severity in animal models

of MS. However studies using myelinating cultures as an in vitro target suggest antibody titres are too low to mediate

widespread tissue damage in most of these young patients. To explore the possibility MOG-specific antibodies may

play some other more subtle non-lytic role in disease pathogenesis we investigated the effect of treated myelinating

cultures continuously with a monoclonal antibody specific for MOG (clone Z2), or an appropriate isotype control.

In this culture system the MOG-specific antibody inhibited ongoing myelination, but in the absence of an exogenous

source of complement was unable to induce demyelination. This inhibitory effect on myelination was associated

with microglial activation as determined by immunofluoresence microscopy for Iba-1 and ED-1. This observation led

us to explore whether this microglial response was associated with changes in expression of chemokines and/or

cytokines that may either enhance or suppress lesion formation in vivo. Transcriptional profiling using qPCR arrays

revealed that within 24 hours this MOG-specific mAb had increased expression of three chemokines (CCL5, CCL20

and CXCL11) implicated in the recruitment of effector T cells into the CNS. This increase in expression was transient

but results in increased secretion of biological active products as demonstrated by chemotaxis assays of culture

supernatants. Similar effects were observed in cultures treated with mAb recognizing surface exposed epitopes

of two other myelin associated antigens, proteolipid protein (clone O10) and sulphatide (clone O4). These results

suggest myelin-specific autoantibodies can contribute to the pathogenesis of inflammatory demyelinating diseases

such as MS by virtue of non-lytic effects that trigger secretion of chemokines predicted to trigger or exacerbate

inflammation within the CNS compartment.


37

Abstracts

9. The effect of TENS on chronic neuropathic pain in MS

Connolly G, Lorna Paul, Paul Mattison, Linda Miller, Christopher Weir


Background: Chronic neuropathic pain is a common and disabling symptom which adversely affects quality of life

in people with Multiple Sclerosis (MS).

Transcutaneous Electrical Nerve Stimulation (TENS) is effective in other chronic neuropathic pain conditions such as

spinal cord injury, but there is no evidence for its efficacy in MS-related central neuropathic pain.

Methods: A randomised, controlled, double-blind trial was undertaken comparing the hypoalgesic effect of active

TENS with placebo TENS in the treatment of chronic, central neuropathic pain in people with MS, over a two-week

treatment period. Participants were recruited from the MS Service, NHS Ayrshire and Arran, with a diagnoses of

lower limb neuropathic pain (score of ≥19 on the Pain Detect Screening tool for neuropathic pain), experienced for a

minimum of six months.

In the study, 46 participants were randomly allocated into one of two groups- active TENS or placebo TENS,

with both using the TENS machine for a minimum of four hours/day, for a two-week period. For the active TENS

group, standard ‘Conventional’ TENS settings were applied using a high frequency, low intensity electrical current

(frequency of 120Hz, strong but comfortable intensity, and pulse width of 200 ms), whilst a low frequency, low

intensity electrical current (frequency of 4 Hz, strong but comfortable intensity, and pulse width of 200 ms) was used

for the placebo application, which has no evidence of an analgesic effect, but still provides a sensory stimulus. In

both groups, two (5x13 cm) self-adhesive, hypo-allergenic electrodes were placed paravertebrally over the lumbar

spine to stimulate the spinal nerve roots.

The primary outcome measure was the 11-point Numerical Rating Scale of pain intensity (NRS-11). Participants

recorded their average daily leg pain on the NRS-11. Scores were recorded during the 7-day baseline and 14

day TENS intervention period. Secondary outcome measures included the Neuropathic Pain Scale (NPS), which

specifically measured the intensity of neuropathic pain and the Patients Global Impression of Change (PGIC), which

measures perceived change in overall pain state. Level of pain related interference on function was measured using

the Brief Pain Inventory (BPI).

Results: An analysis of covariance (ANCOVA) confirmed active TENS was significantly more effective at reducing

pain intensity (NRS-11) than placebo TENS, during the two week period with an adjusted difference of means of

1.26 (95% CI= 0.77-1.75; p<0.001)) between groups. An ANCOVA also showed active TENS as

significantly more effective at reducing neuropathic pain intensity (NPS),

than placebo TENS, during the two week period with an adjusted difference of means of 9.22 (95% CI=5.48-12.95;

p<0.001) between groups, with TENS being particularly effective for burning (p<0.001) and sharp pain (p=0.002).

The active TENS group were significantly more likely to describe an overall improvement in general pain state (PGIC),

than those who received placebo, with a statistically significant difference between the placebo and TENS groups

of 38.9 % (p= 0.004, X2= 8.39). TENS had no effect on pain-related interference with daily function (BPI) with an

adjusted difference of means 0.18 (95% CI=-0.13-0.5; p=0.2) between groups.

Conclusion: TENS was effective in the treatment of central, neuropathic pain in people with MS over a two-week

intervention period. Future studies may extend this intervention period to explore the longer-term effects of TENS for

pain in MS. TENS, an easy to use, inexpensive and non-pharmacological treatment has demonstrated success in

the long-term management of many chronic pain conditions, and could be useful in the MS population.


38

Abstracts

10. Autoimmune Model using a Human Non-Myelin Antigen

Crawford, C

Introduction: Experimental allergic encephalomyelitis (EAE) is the commonest animal model used in multiple

sclerosis (MS) research. Here macrophages attack the myelin sheath and ingest the myelin. In MS, however, ‘the

precise mechanism whereby removal of myelin from the axon is accomplished remains unknown. In many other

demyelinating diseases, stripping of myelin by macrophages has been demonstrated by electron microscopy;

however, this as yet has not been demonstrated in ultrastructure of MS’ ( Powell & Lampert. Neurol Clin 1983,1,

631). Ransohoff ( Nature Neurosci. 2012. 15, 1074) claims that the ‘histopathology of EAE resembled that of

MS’, citing

Waksman and Adams (Amer J Pathol. 1962, 41, 135). But this was only a light microscopy study, without

ultrastructural findings. Ransohoff also wrote ‘For the most part, EAE has proven poorly predictive of treatment

success in MS’ (Nature Neurosci 2012, 15, 1074). Improving the statistical analysis, as Baker et al. (Nature

2012,492, 41) recommends in publications based on EAE, will therefore not result in more effective treatment.

Methods: An alternative animal model has been developed, which reproduces the pathology of MS more closely.

Patients with non-lepromatous, paucibacillary leprosy can develop acute sensory loss suggesting that nerve

damage may be an autoimmune response to an antigen in sensory peripheral nerve and not a direct effect of

Mycobacterium leprae. Rabbits injected with human sensory peripheral nerve suspensions plus adjuvant produce

skin lesions similar to those in the human disease.

Results: Some of these rabbits have developed a state of granulomatous hypersensitivity. ie skin testing with non-

myelin antigens have produced an epithelioid cell granuloma ( Crawford et al Nature 1977, 265: 457; Crawford &

Hardwicke. Int J Dermatol. 2011, 50, 255 ).

At skin test sites, axonal damage was present in dermal nerves, which have been inflitrated with plasma-like cells

( Crawford & Hardwicke Acta Neuropathol. 1979, 45, 1). These could be plasmacytoid dendritic cells (pDCs), but

are not macrophages.

Skin lesions have been induced in Strain 13 but not Strain 2 guinea pigs.

Myelinated and unmyelinated axonal degenerative changes are present and non-phagocytic mononuclear cells have

infiltrated dermal nerves.

Discussion: pDCs have been identified in MS lesions (Balashov et al . Ann Neurol 2010, 68, 899) and increase in

the cerebrospinal fluid of patients who relapse (Longhini et al. J Inflamm 2011, 8, 2).. pDCs secrete large amounts

of interferon alpha.

Type1 interferons have been implicated in several autoimmune disorders such as systemic lupus erythematosis,

rheumatoid arthritis and Sjogren’s syndrome (Baccala et al. J Immunol. 189, 2012, 5976).

Attempts to induce tolerance using myelin antigens has failed in MS patients ( Faria & Weiner Immunol Rev

2005,206,232) The most active fraction in our experiments causing nerve damage is a non-myelin membrane

fraction in doses of 1μg (Hardwicke. & Crawford J Neurochem 1978, 30, 1609 1978). A similar antigen may be

present in the CNS , in which case tolerance could be induced ( Crawford http://www.jci.org/eletters/view/32132).

Conclusions: It may be possible to induce tolerance In MS patients using a non-myelin rather than a myelin

antigen.


39

Abstracts

11. Cerebro-spinal fluid biomarkers are promising. But what about the pain for patients?*

Angharad Davis, Ruth Dobson, Stefania Kaninia, Maria Espasandin, Amy Berg, Gavin Giovannoni,

Klaus Schmierer

Blizard Institute and The London School of Medicine and Dentistry

Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis of MS.

Serial measurement of CSF neurofilament levels is a promising tool to longitudinally assess axonal damage and

infer the effect of potentially neuroprotective drugs. Repeated lumbar punctures (LP), however, carry their own risks;

most commonly post-lumbar puncture headache (PLPHA), seen in approximately 30%. Studies serially measuring

CSF biomarkers are threatened by significant drop out rates due to PLPHA. Needle type used in LP is a modifiable

risk factor and studies have demonstrated a tenfold reduction in the incidence of PLPHA when using atraumatic

needles (ATN) instead of the standard cutting (traumatic) needle (TN). The American Academy of Neurology (AAN)

recommended ATN use in 2005. However, concern remains that ATN are rarely used in clinical practice. As part of

a service development audit at the Royal London Hospital we recorded frequency and severity of PLPHA in patients

undergoing LP within the day case unit.

104 LPs were performed using TN and ATN by trained operators with a minimum of two months experience in LP.

Patients were telephoned on days 2 and 7 by a blinded assessor. Presence, severity and duration of PLPHA were

documented using a standardised proforma. Analgesia use, GP and A&E visits as well as readmission to hospital for

inpatient treatment were also recorded. Frequency of PLPHA was compared using Fishers Exact test, and duration

using unpaired t-test. Two surveys were conducted; the first (i) collected data on ATN use amongst UK neurologists

attending the ABN conference, and the second (ii) to explore acceptability of serial LPs as part of research trials

using our blog for people with MS (pwMS).

The rate of PLPHA was significantly reduced with ATN use (17.1% vs 51.1% p<0.01). Five patients in the TN group

visited their GP due to PLPHA versus to nil patients in the ATN group (p=0.055). Three patients undergoing TNLP

had to be readmitted for inpatient treatment versus nil undergoing ATNLP (p=0.024). Five patients suffering PLPHA

following TNLP had time off work; a mean of 0.75 working days was lost per TNLP. No patients following ATNLP

required time off work (p=0.055).

Our survey among UK neurologists demonstrated (i) that despite awareness of ATN (78.4%), 53% never used ATN

for LP in clinical practice. Improved acceptability of LP in the clinical trials setting was seen amongst pwMS: 90% of

respondents in our survey of pwMS were willing to consider serial LP if ATN were used.

Our study confirms in a routine clinical setting results from previous research showing a significant reduction in the

rate of PLPHA with ATN LP.

Our patient survey suggests the use of ATN significantly improves acceptability of repeated LP in clinical trials.

Despite the now well documented advantages of ATNLP to reduce the number of people suffering from PLPHA,

however, ATN use among UK neurologists remains limited. A change in practice is required to reduce this evidently

modifiable risk factor (PLPHA) for patients and support the use of CSF biomarkers in MS research and standard

clinical care.

*Selected for presentation during ‘Biomarkers and clinical outcome measures: challenges for progressive MS trials’


40

Abstracts

12. Patients’, carers’ and providers’ experiences & requirements for support in self-management of MS: qualitative study*

Deibel F, Adrian Edwards, Michelle Edwards

Cardiff University

Background: Self-management is increasingly promoted for management of long term conditions, both for ethical

reasons of enhancing autonomy and for likely cost-effectiveness, but the nature and scope of self-management

strategies are currently highly variable. The Consortium of Multiple Sclerosis Centers identified the need for a

comprehensive, needs-based self-management program to address the constellation of multi-system symptoms

that occur in MS. There has, however, been little research into patients’ and providers’ perspectives on MS self-

management to inform the development of such a programme.

Objective: To identify patients’, carers’ and clinicians’ current experiences of self-management in multiple sclerosis

(MS) and their recommendations for the development of a future MS-specific self-management intervention

Methods: Qualitative study using focus groups and semi-structured one-to-one interviews with a purposive sample.

Subject participation was solicited via the MS Society Cymru and a purposive sample of patients and carers was

recruited via MS Society branch meetings. Three focus groups were held with twenty-five patients with moderate to

advanced multiple sclerosis and four carers. Ten clinicians were interviewed. Data underwent thematic analysis.

Results: Participants perceived multiple aspects of MS to be amenable to self-management but identified a current

lack of service provision to support their abilities to self-manage. Participants felt that to address both the physical

and psychosocial challenges posed by MS required better information provision, a strong relationship with healthcare

professionals, and a toolkit of self-management skills. Participants expressed concern at the lack of consideration

currently given to carers, which should be addressed in future provision. A comprehensive and interactive program

would combine the provision of tailored education with skill acquisition, developing competencies in information

seeking, symptom management, communication with healthcare professionals, lifestyle adjustments, and adapting

to the changing disease trajectory.

Conclusion: The diverse experiences of patients living with MS warrant a multidisciplinary, flexible and proactive

approach to improve their self-management capabilities, acknowledging both patients’ and carers’

unmet needs.

Practice Implications: The findings can be used to guide the development of future self-management interventions

specific to individuals with multiple sclerosis.

*Selected for presentation during ‘Innovations in symptom management, care and support’


41

Abstracts

13. Casting light on multiple sclerosis heterogeneity: the role of HLA-DRB1 on spinal cord pathology *

DeLuca G, Rose Alterman, Jenny L Martin, Arunesh Mittal, Samkeliso Blundell, Shannon Bird,

Harry Beale, Lai San Hong, Margaret M Esiri

University of Oxford

Clinical heterogeneity in multiple sclerosis is the rule. Evidence suggests that HLA-DRB1*15 may play a role in clinical

outcome. Spinal cord pathology is common and contributes significantly to disability in the disease. The influence

of HLA-DRB1*15 on multiple sclerosis spinal cord pathology is unknown. A post-mortem cohort of pathologically

confirmed multiple sclerosis cases (n=108, 34 males) with fresh frozen material available on which to do genetic

analyses and fixed material on which to do pathology was used.

HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched

HLA-DRB1*15 positive (n=21) and negative (n=26) cases for detailed pathologic analyses. For each case, transverse

sections from 3 spinal cord levels (cervical, thoracic and lumbar) were stained for myelin, axons, and inflammation.

The influence of HLA-DRB1*15 on pathologic outcome measures was evaluated. Carriage of HLA-DRB1*15

significantly increased the extent of demyelination (global measure: 15+: 23.7% versus 15-: 12.16%, P = 0.004),

parenchymal (cervical, P < 0.01; thoracic, P < 0.05); lumbar, P < 0.01) and lesional inflammation (border, P = 0.001;

periplaque white matter, P < 0.05) in the multiple sclerosis spinal cord. HLA-DRB1*15 influenced demyelination

through controlling the extent of parenchymal inflammation. Meningeal inflammation correlated significantly with

small fibre axonal loss in the lumbar spinal cord (r = 0.832, P = 0.003) only in HLA-DRB1*15 positive cases.

HLA-DRB1*15 significantly influences pathology in the multiple sclerosis spinal cord. This study casts light on the

role of HLA-DRB1*15 in disease outcome and highlights the powerful approach of using microscopic pathology to

clarify the way in which genes and clinical phenotypes of neurological diseases are linked.

*Selected for presentation during ‘Risk factors of MS’


42

Abstracts

14. Assessing fracture risk in people with multiple sclerosis: a comparison of three fracture risk scoring systems*

Dobson R, Sara Leddy, Sunay Gangadharan, Gavin Giovannoni

Blizard Institute

Objective: Suboptimal bone health is an important cause of morbidity. Multiple sclerosis (MS) has been associated

with a hazard ratio of hip fracture of 1.9–4.08. It was significantly associated with an increased risk of fracture in

the Global Longitudinal study of Osteoporosis in Women (GLOW) study (HR of fracture in MS 1.7; 95%CI 1.2-2.6).

Various fracture risk screening tools have been developed, including one specific to MS. We set out to compare the

results obtained by these in the MS clinic population.

Methods: 100 patients attending the MS clinic were studied, 88 provided sufficient details to have their 10-

year fracture risk assessed. The 10-year risk estimates of any fracture and hip fracture generated by each of the

algorithms were compared. Patients were questioned about their falls history, and the Activities-specific Balance

Confidence scale (ABC) and the Berg Balance Scale (BBS) calculated.

Results: No patients had a history of a prior fragility fracture. Mean 10-year fracture risk was 4.7% by FRAX

(standard deviation; SD 3.20, range 2.3-19.0), 2.3% by QFracture (SD 2.14, range 0.4-13.0) and 7.6% using the

MS-specific calculator (SD 5.05, range 2.0-25.0) (p<0.0001 for difference). The agreement between risk scoring

tools was poor. Bland-Altman plots revealed reasonable agreement between FRAX and QFracture at lower fracture

risk scores, but for patients with higher fracture risk a systematic error was apparent with QFracture consistently

giving lower risk estimates than FRAX (mean difference 2.68). There was a significant difference between all

three groups for the requirement for both DXA imaging (p<0.0001) and treatment (p<0.0001). Mean 10-year hip

fracture risk was 0.7% by FRAX (standard deviation; SD 0.95, range 0.1-5.6), 0.2% by QFracture (SD 0.55, range

0.0-4.8) and 3.4% using the MS-specific calculator (SD 7.78, range 0.0-55.0). Comparison of scores

generated similar Bland-Altman plots to those seen when examining the data for overall fracture risk. 49/100

patients reported falling in the preceding 6 months. 22 (52%) patients using a walking aid reported falls in the

preceding 6 months compared to 18% of those who did not require a walking aid (p=0.0004). Both the ABC and the

BBS were significantly different between fallers and non-fallers. Fallers were equally likely to be on bone protection

compared with non-fallers.

Conclusions: The agreement between these three fracture risk scoring tools is poor in the MS population. The MS-

specific fracture risk tool appears to over-estimate fracture risk. There remains much work to be done with regard

to assessing fracture risk in this population, who are at high risk of fracture and associated complications. There

must be consistency and accuracy in the way in which fracture risk is calculated prior to DXA imaging. The use

of a walking aid strongly predicts falls, which in turn affect fracture risk.

Further work is required to develop and validate an accurate fracture risk

scoring system for use in MS.

*Selected for presentation during ‘Innovations in symptom management, care and support’


43

Abstracts

15. Impact of anti-inflammatory FoxP3+ cells in toxin-induced demyelination in vivo*

Dombrowski Y, Paul Denver, Thomas O’Hagan, Denise Fitzgerald

Queen’s University Belfast, Centre for Infection and Immunity

Introduction And Objectives: In demyelinating diseases such as Multiple Sclerosis, CD4+ T cells have been

identified to drive remyelination - the repair of the insulating myelin sheath around neurons. However, the impact of

individual CD4+ subsets such as regulatory T cells (Treg) has not been determined. Here, the effect of FoxP3+Treg

on remyelination was studied in vivo using transgenic FoxP3+FoxP3-DTR mice in which FoxP3-expressing cells can

be selectively depleted by diphtheria toxin administration.

Methods: To induce demyelination in vivo 1.2 μl 1% (v/v) lysolecithin was injected ventrolaterally into spinal cord

white matter of 8 – 12 week old FoxP3-DTR mice. From day 2 pre-surgery, mice were injected daily with 1 μg

diphtheria toxin, to deplete FoxP3-expressing cells or with saline as a control. Spinal cords were harvested 10, 14

and 19 days post lesion (dpl), cryo-processed and analysed by immunohistochemistry.

Results: Unexpectedly, all FoxP3+ cell-depleted FoxP3-DTR mice developed clinical signs of paralysis between

3-5 dpl. On the experimental autoimmune encephalomyelitis (EAE) scale, mice were scored 4 - 4.5 reflecting full

hind leg paralysis. Additionally, mice lost up to 20% of their initial body weight. Preliminary results of phase contrast

microscopy and H&E staining did not reveal morphological differences between lesions of FoxP3+Treg depleted and

control FoxP3-DTR mice. However, preliminary staining of neurofilament showed differences in axonal pathology

between these groups.

Conclusions: FoxP3+Treg are major immune regulators and FoxP3+Treg-depleted mice are

unable to control inflammation. Thus, depletion of FoxP3+ cells may have resulted in uncontrolled CNS inflammation

in response to experimental demyelination, resulting in paralysis. However, the shape and size of the lesion did

not correlate with the clinical score suggesting that not the lesion morphology but its cellular composition or even

alterations beyond its boundaries such as axonal damage triggered paralysis. Further analysis of neuronal integrity

and remyelination will give insights into the cellular nature within and outside the lesion.

*Selected for presentation during ‘Mechanisms of axonal damage’


44

Abstracts

16. My MS, My Needs: Do feelings about income relate to getting what you need from health and social care services?

H Dorning1, G Luck1, E Holloway1.1Research team, MS Society.

Introduction: Evidence suggests that there is variation in access for services and support for people with MS in the

UK, and that access may be influenced by factors such as income, level of disability or location. This project aims

to find out if people across the UK are consistently accessing the services and support they need and to explore

possible associated factors which may be limiting access. In this stage of analysis we explored how feelings about

income relate to accessing the services and support people need.

Methods: A four page postal questionnaire was sent to all UK MS Society members who were over 18 and had

indicated a diagnosis of MS (N = 24,010). Questions were designed to find out if people were getting the key things

they needed from health and social care services; such as access to neurologists, social care support or treatments.

Participants were also asked standard questions about them and their MS, which included feelings about current

income level. Chi-squared cross tabulation analysis was used to explore how access to different services and

support relate to feelings about income level.

Results: 10,530 (44%) people responded to the questionnaire. Our analysis revealed that people who feel worse

about their income level are more likely to need care, support and services, but are less likely to get what they need.

This general trend was seen when exploring feelings about income with:

•Accesstosocialcaresupport

•Accesstosupportformoodandemotionalissues

•Beingofferedacarer’sassessment

•Accesstoapoweredwheelchair

•Accesstosupporttoremainphysicallyactive

•Accesstoinformationaboutdrugs

•AccesstoinformationaboutMS

These strong trends were not observed when exploring the relationship between feelings about income and access

to key health care specialists, including MS nurses and neurologists.

Conclusion: This analysis shows that people who feel worst about their income level have the highest need for

services but are least likely to be accessing them. More analysis is needed to explore the causality of this relationship

and how other factors are also relating to access to services and support.


45

Abstracts

17. MS and Decision Making - Emerging themes from an explorative study

Eccles A, Sara Ryan, Angela Coulter


Introduction: It has been argued that reactive and episodic healthcare systems are inappropriate for people

with long term conditions, and that a more proactive and planned approach which is person-centred should be

adopted for healthcare systems to be effective. Various models propose methods and re-organisation needed to

achieve this change. The Department of Health recommends that everyone with a long term condition should have

a personalised care plan and the General Medical Council guidelines advise that patients should be involved in

decision making in partnership with clinicians. Personalised care planning aims to ensure that patients’

values and concerns shape the way their condition is managed. Patients and clinicians identify and discuss

problems caused by or related to the patient’s health state, giving due consideration to both clinical information

and patients’ accounts of the practical, social and emotional effects of their condition(s) and treatment(s) on their

daily lives. Despite support for personalised care planning, in reality it has been reported that people with long term

conditions rarely experience or are familiar with this approach.

Relevance: Multiple sclerosis (MS) is a long term condition which is characterised by uncertainty because the

condition is highly complex and personalised with largely inconclusive research evidence into prognosis, pathogenic

mechanisms and effective treatments. Due to its unpredictable nature, people are faced with many uncertainties

about how they might expect MS to affect them. There are countless choices about therapies, information use, self-

management, support, and the timing of when to make such choices.

These decisions are all likely to be shaped by various factors, including a person’s values and priorities, social

circumstances, the research evidence, availability of choices, side effects and symptoms. Such factors may also be

further affected as people live with and learn about what is particular about their own MS experience. This positions

the experience of living with MS as particularly relevant to the process of decision making and in turn personalised

care planning.

Methodology: A series of in-depth qualitative interviews with people with MS are being carried out to explore

their experiences of healthcare decision making, interactions with healthcare professionals and the relevance and

experience of personalised care planning in reality. Drawing from a grounded theory approach, on-going analysis will

be conducted, interviews will be coded and emerging themes identified.

Finding: Early emergent themes identified from descriptions of decision making, interactions with healthcare

professionals, information use, and decision support needs will be discussed in this paper.


46

Abstracts

18. Expression of Calreticulin and Other Endoplasmic Reticulum Stress Molecules in a rat model of inflammatory demyelination

Mary Ní Fhlathartaigh, J. McMahon, R. Reynolds and U. FitzGerald

NCBES, National University of Ireland, Galway, Ireland

Endoplasmic reticulum (ER) stress is a homeostatic signalling pathway, linked to many neurological diseases

including multiple sclerosis (MS).

Studies of human tissue in our lab have shown ER stress-associated molecules at increased levels, particularly at

the edge of chronic active white matter lesions (1), in early biopsy MS samples (2) and in cortical lesions (3).

Increasing evidence suggests that calreticulin (CRT), a multifunctional ER-resident protein and ER stress responder,

plays a role in cell clearance and it has been implicated in autoimmunity. To complement our human tissue research,

we have set up an experimental autoimmune encephalomyelitis (EAE) animal model of inflammatory demyelination in

Dark Agouti (DA) rats and report here the profile of expression of calreticulin and other ER stress signalling molecules

in demyelinated spinal cord lesions and control samples.

All work carried out was approved by the local animal ethics committee. To induce spinal cord demyelination, the

DA rats (n=5) were injected intradermally at the base of the tale with 25 – 50 micrograms of recombinant murine

myelin oligodendrocyte (rmMOG) protein mixed with incomplete Freund’s adjuvant (IFA). Control rats were injected

with a PBS/IFA adjuvant (n= 5) or with 100 microliters of PBS only (n=5). Animals were then monitored over a 43-day

period and clinical scores assigned based on motor deficits. Molecular analyses of dissected tissue spanning the full

length of the spinal cord was carried out by real-time PCR to determine transcriptional expression profiles of Grp78 /

BiP, CHOP, ATF4, CRT and XBP-1. BiP and CHOP showed a trend towards up-regulation whereas ATF4 and spliced

XBP1 displayed a downward trend in EAE, compared to controls, but this was not statistically significant. In contrast,

immunohistochemical staining of tissue sections allowed semi-quantitative comparison of protein expression in

different anatomical sub-regions, including the lesion (L), lesion edge (LE), normal-appearing white matter (NAWM),

central canal (CC) and grey matter (GM). Statistical analyses revealed that CHOP (p<0.001),

p-EIF2 alpha (p<0.01) and CRT (p<0.05) were significantly increased in EAE spinal cord white matter lesions and in

the normal-appearing white matter compared to healthy control tissue. Interestingly, there was also an up-regulation

of CHOP (p<0.05), and p-eIF2 alpha (p<0.01) in the grey matter and central canal of diseased spinal cord tissue

when compared to saline and IFA controls. Morphological criteria and dual immunofluorescent labelling confirmed

expression of many of these ER stress proteins in neurons, astrocytes, microglia or oligodendrocytes. An intriguing

finding which hints at a possible role for CRT in the stimulation of innate immunity and/or myelin clearance, was

the localisation of CRT to the rim of ORO-positive myelin fragments and the punctate or ‘patchy’ nature of CRT

staining seen when tissue was dual-labelled with CRT and GFAP or IBA1. These results are the first demonstration

of significantly higher levels of CRT in rodent EAE.

CHOP and p-eIF2 alpha data has also not been reported in rat EAE, although similar findings have been published in

murine models. This study highlights the potential importance of ER stress in inflammatory demyelination.


47

Abstracts

19. Understanding and assessing dual-tasking deficits in people with Multiple Sclerosis

Frei LS, Lorna Paul, Breda Cullen, Colin O’Leary, John Norrie, Jonathan Evans


Introduction and Aims: Many situations in everyday life require us to do two or more tasks at the same time

(referred to as ‘dual-tasking’). The ability to dual-task has previously been shown to be impaired in various

neurological conditions and our research group has recently shown that this is a symptom that also affects some

people with MS, including in the early stages of the disease. Whilst some consequences of impaired dual-tasking

might be considered relatively mild (e.g. having to stop walking in order to converse), there are also more serious

potential implications for safety as it has been suggested that difficulty with dual-tasking may increase the likelihood

of falls.

The aim of this study is two-fold: (1) to understand the underlying mechanisms of dual-tasking deficits in people with

MS, and (2) to test the suitability of a paper-and-pencil tracking task for assessment of dual-tasking deficits.

Methodology: To date, we have compared a group of people with MS (N=23) with a healthy control group (N=17)

under four conditions that examine single and dual task performance on motor and cognitive tasks. In two of these

conditions, participants are walking (motor task) while repeating lists of numbers (digit span - cognitive task). This

number task can be either easy or difficult. In the other two conditions, participants are tracking circles on a piece of

paper (motor task) while doing the easy or hard number task.

Preliminary Results: We hypothesised that people with MS would be more impaired in the dual tasks compared to

single tasks than control participants. Our preliminary results support this hypothesis as we have found that walking

speed decreases more in patients than in healthy controls under dual task conditions. However, the difficulty of

the number task does not seem to make a difference to this deficit. Preliminary analysis of the tracking task data

indicates that there was no significant difference between patients and controls in terms of the impact of dual task

conditions compared to single task conditions.

Conclusion: The present study provides further evidence that cognitive motor dual tasking is compromised in

MS. The lack of differential impact of difficulty level of the digit span task suggests that the deficit underlying the

dual tasking problem is a deficit in divided attention. However if this was the case we would also expect a deficit to

be apparent on the tracking task. Data collection will continue in order to further compare conditions with greater

statistical power.


48

Abstracts

20. Developing a health outcome (QALY) measure for use in the economic evaluation of treatments for multiple sclerosis

Goodwin E, Colin Green

University of Exeter Medical School

Introduction: Many economic evaluations employ generic preference-based measures of health-related quality of

life, such as the EQ-5D, to quantify the outcomes of treatments. Research has shown that these generic measures

may fail to capture the full impact of the disease and its treatment when applied to multiple sclerosis (MS). A

condition-specific preference based measure (CSPBM) for MS may provide a more appropriate, sensitive and

responsive alternative, and may improve the quality of decision-making about the cost-effectiveness of treatments

for MS.

This poster describes the first stage in deriving a CSPBM from an existing MS-specific health-related quality of

life (HRQoL) measure: converting the HRQoL measure into a standardised format for describing health states that

may be experienced by people with MS (a ‘classification system’). The aim of this stage is to reduce the size of

the HRQoL measure to render it suitable for a preference elicitation (valuation) survey, while minimising the loss of

descriptive information.

Methods: The MS Impact Scale (MSIS-29) was used to provide the basis for this classification system. A

conceptual framework of HRQoL in MS was developed, based on previous research undertaken with people with

MS, and items from the MSIS-29 were mapped to this framework. Rasch and psychometric analysis were then

undertaken to identify the most appropriate single item to represent each dimension of the framework. Further

Rasch analysis determined whether the number of item response levels could be reduced without losing descriptive

information. This analysis was undertaken using responses to the MSIS-29 (n=529) from the South West Impact of

MS (SWIMS) study, a prospective, longitudinal cohort study of people with MS in Devon and Cornwall. All stages of

the analysis were repeated on a validation sample (n=528).

Results: One item was identified to represent each of the following dimensions of HRQoL in MS: general physical

function, mobility, employment, social function, fatigue, cognition, depression and general emotional wellbeing.

Overall goodness of fit to the Rasch model was achieved for both subscales of the MSIS-29, and the selected items

performed well against both Rasch and psychometric criteria. There was no evidence to suggest that the number of

item response levels could be reduced, therefore the four-level structure of the MSIS-29 was retained.

Conclusion: The application of Rasch and psychometric criteria proved successful in converting the MSIS-29 into

a classification system (the MSIS-8D), which is suitable a valuation survey, and for development of a CSPBM. The

next stage of this research will involve a valuation survey to obtain numerical preference values for a sample of

health states described by the MSIS-8D, and statistical modelling will be used to estimate preference values for the

remaining MSIS-8D health states. These preference values can then be used to calculate quality-adjusted life years

(QALYs), and to inform decisions about the cost-effectiveness of treatments for MS.

Acknowledgements: this research is funded by the Multiple Sclerosis Society.


49

Abstracts

21. Expression of Gas6-Axl signalling mediators in the mouse central nervous system

Goudarzi S, Arthur Butt, Sassan Hafizi

University of Portsmouth

Background: The TAMs are a family of homologous receptor tyrosine kinases composed of Tyro3, Axl and Mer.

These receptors, and their natural ligands, Gas6 and Protein S, are expressed in the central nervous system (CNS)

and are believed to play key roles in a number of major cellular processes including cell proliferation and survival,

phagocytosis and immunomodulation, all of which are central to multiple sclerosis (MS). Initial studies have shown

that Gas6/TAM receptor signalling is potentially important in oligodendrocyte regulation and remyelination. The aim

of this project is to determine in greater detail expression of TAMs and ligands in the rodent CNS, and also through

which mechanisms Gas6/TAM signalling may potentially regulate oligodendrocyte regeneration.

Methodology: Samples of brain regions and optic nerve were harvested from different ages of C57/BL10 mice.

Brain tissue was processed for both protein expression (western blot and immunofluorescent staining) and mRNA

expression

(qRT-PCR) analyses.

Results: Western blot of protein extracts from adult, P14 and P7 mice showed there to be a high expression of

Tyro3 in all adult brain regions and optic nerve, as well as moderate expression of Axl and Mer throughout. Analysis

by qRT-PCR revealed mRNA expression of all three TAMs throughout all brain regions and ages tested. Interestingly,

the expression of TAMs was markedly lower in optic nerve in relation to brain, whereas in direct contrast, there

was a very high expression of Gas6 in adult optic nerve, compared to lower expression in brain. Furthermore,

immunofluorescent staining and confocal microscopy revealed abundant Tyro3 expression throughout the adult

cortex, which was predominantly cell membrane localised.

Conclusions: In this study, we have demonstrated that all members of the TAM receptor family, as well as their

common ligand Gas6, are expressed throughout the mouse CNS during post-natal development. Furthermore,

there is a distinct, prominent expression of Gas6 in white matter tissue relative to the brain, suggesting a special role

in oligodendrocyte regulation. The results from this study pave the way for a thorough analysis of the role of TAMs

in the mechanisms behind oligodendrocyte regeneration after demyelinating injury in MS. This work is generously

supported by a PhD studentship from the MS Society to S. Goudarzi, and a Research Grant from the Royal Society.


50

Abstracts

22. What are the potentially modifiable psychological factors associated with pain severity and interference in Multiple Sclerosis?

Anthony M. Harrison, Rona Moss-Morris, Lance M. McCracken, Angeliki Bogosian

Division of Health Psychology, Institute of Psychiatry, King’s College London

Background: Pain is a common and disabling symptom affecting 40-80% of people with Multiple Sclerosis (MS).

MS pain is often chronic, arising from injury to nerve tissue (neuropathic pain) or related to degenerative muscle

or joint dysfunction (non-neuropathic pain). Drug treatments focusing on pain reduction in MS have demonstrated

limited efficacy and a large proportion of people experience pain that is uncontrollable.

In primary chronic pain conditions psychosocial factors have been studied extensively, guided by clear theoretical

models. These studies have shown that severity of pain is not strongly associated with pain interference i.e. the

extent to which pain interferes with activities of daily life and functioning, including general activity, work, mood,

relations with others and sleep. Pain interference is more strongly associated with psychosocial factors, and

interventions designed to address these factors, demonstrate significant improvements in pain related disability

and quality of life. Comparatively, there is a lack of psychological research focusing on pain secondary to long-term

neurological conditions. MS pain is linked to disease processes and is experienced within the context of other

potentially debilitating symptoms. The purpose of this review was to understand psychosocial aspects of pain

severity and interference in the context of MS.

Specific objectives

1) Quality assess studies looking at modifiable cognitive, emotional, behavioural and social factors associated

with MS pain severity and interference.

2) Identify and synthesise evidence for associations between these psychosocial factors and pain severity

and interference in MS.

3) Determine if associations differ for neuropathic and non-neuropathic pain and type of MS.

4) Construct a preliminary theoretical model of MS pain.

Relevance: The review highlights psychosocial factors that might be targeted in future treatments. This research

improves our understanding of MS pain and will assist the development of treatments empowering people to

manage their pain.

Methodology: Inclusion criteria were MS pain quantitative research studies utilizing standardized pain severity and

pain interference measured in relation to cognitive, emotional, behavioural and social factors. A search strategy

was applied to three online databases (PsychInfo, Medline and Web of Science) and references of relevant online

articles were searched and authors contacted to identify unpublished studies in October 2012. Information about

study design, sample size, MS type, time since diagnosis, psychosocial and pain measures and key findings were

extracted. Twenty-seven studies were ranked good, medium or poor according to a quality assessment checklist

and a narrative synthesis was conducted.

Results: Most included studies identified moderate to large relationships between increased pain severity and

pain interference with depression, the belief that the consequences of pain are worse than they actually are (pain

catastrophizing) and that pain is unrelenting (pain constancy). The tendency to accept pain as a natural phenomena,

without attempting to avoid, ignore or reduce it through physical or mental effort (pain willingness) was the strongest

predictor of pain interference. No studies looked at differences in psychosocial factors in relation to type of MS or

type of pain.

Conclusion: Evidence identified relationships between MS pain severity and interference and several psychosocial

factors, endorsing a biopsychosocial approach to understanding MS pain. While a preliminary model of MS pain is

proposed, increasingly rigorous and coherent research guided by a comprehensive theory is required.


51

Abstracts

23. Improving the quality of information used in cost-effectiveness analyses of treatments for MS: health state (QALY) values

Hawton A, Colin Green, John Zajicek, Dave Wright

University of Exeter Medical School

Introduction: Decisions about the cost-effectiveness of health care treatments are often founded on the cost-

per-quality-adjusted life-year (QALY) of these interventions. For example, the UK’s National Institute for Health and

Clinical Excellence (NICE) requires cost-per-QALY information when making decisions about which treatments to

fund.

QALYs combine length and quality of life in a single outcome measure, with the ‘quality’ weight commonly being

derived from general population preferences for particular health states. These ‘quality’ weights are often called

health state values (HSVs).

HSVs of the health states that people with MS experience have mostly been estimated from cross-sectional postal

surveys sent via patient associations, which have the potential for both selection and response bias. As such, the

validity of using the resulting HSVs in cost-effectiveness analyses (CEAs) of treatments for MS has been questioned

and, in part, has hampered decision-making regarding the funding of MS treatments.

Aim: To describe HSVs of the health states of people with MS using data from a prospective, longitudinal, cohort

study, in a manner suitable for use in CEAs of treatments for MS.

Methods: Data from the South West Impact of MS (SWIMS) project were used for analysis.

SWIMS is an ongoing prospective, longitudinal, cohort study which aims for a whole population sample of people

with MS in Devon and Cornwall. Participants complete six-monthly measures, including the EQ-5D and the SF-36

(SF-6D), which assess individual’s health status, and HSVs can be calculated from them.

Most CEAs stage MS disease progression by the Expanded Disability Status Scale (EDSS), and previous methods

for providing HSVs when individuals have experienced relapses have been fairly crude. Therefore, HSVs were

analysed according to EDSS scores, and by the characteristics of relapses that individuals experienced.

Results: As of October 2012, SWIMS had data from 1,441 respondents, over an average of eight time points. The

mean (sd) age of the sample was 53.9 (11.4) years, and 73.6% were female. All forms of MS were represented and

the mean (sd) time since diagnosis was 13.0 (10.0) years.

Data included 2,152 EDSS scores, which were matched to HSVs derived from the EQ-5D and SF-6D. HSVs

worsened by disease progression from 0.85 (EQ-5D) and 0.70 (SF-6D) at EDSS stage 0, to 0.04 (EQ-5D) and 0.53

(SF-6D) at stage 8.

The mean difference in HSVs due to a relapse was 0.08 (EQ-5D) and 0.05 (SF-6D). Data were also available on the

impact on HSVs of relapse frequency, severity and endurance.

Conclusion: SWIMS provides a unique opportunity to provide high quality data regarding the HSVs of health states

experienced by people with MS. This is the first study to present HSV data from a prospective, longitudinal, cohort

study, and the first study to present HSV estimates for MS using the SF-6D. In addition, HSVs for detailed features of

relapses, as described in SWIMS, have not been previously reported.

This HSV data can be used to aid methodologically-sound CEAs of treatments for MS and to help improve the

validity of decisions that are made regarding the funding of MS interventions.


52

Abstracts

24. Omega 3 supplementation/fish consumption and quality of life, depression, fatigue, disability and disease activity in MS

Jelinek GA, Emily J Hadgkiss, Tracey J Weiland, Naresh Pereira, Claudia H Marck, Dania M van der Meer,

Catriona Tate

Emergency Practice Innovation Centre, St Vincent’s Hospital, Melbourne, Australia

Background: The role of omega 3 supplementation and fish consumption in secondary and tertiary prevention of

multiple sclerosis is controversial, although there is some evidence to support a beneficial effect.

Methods: We surveyed a large cohort of people with MS recruited via Web 2.0 platforms, requesting information

on type of MS, relapse rates, disability, health-related quality of life, depression, fatigue, omega 3 supplementation,

including type and dose, and frequency of fish consumption, using validated tools where possible.

Results: Of 2265 respondents, those taking supplements and those consuming fish more frequently had

significantly better quality of life, in all domains, less disability, and reduced likelihood of depression and fatigue.

For fish consumption, there was a clear dose-response relationship for these associations. There were also trends

towards lower relapse rates and reduced disease activity, significant only for flaxseed oil supplementation, which was

associated with over 50% lower relapse rate over the previous 12 months.

Conclusion: Risk modification represents an important aspect of secondary and tertiary prevention of multiple

sclerosis; we have added to the evidence base showing that fish and omega 3 consumption may be important

factors. Further studies of fish consumption and randomised controlled trials of omega 3 supplementation (preferably

using flaxseed oil) for people with MS are required.

25. Does IL-33 have a beneficial or detrimental role in MS disease?*

Hui-Rong Jiang, Debbie Allan, Damo Xu, Susan C Barnett, Christopher Linington, Foo Yew Liew

University of Strathclyde

Interleukin (IL)-33, a member of the IL-1 cytokine family, is an important modulator of the immune system associated

with several immune-mediated disorders. High levels of IL-33 are expressed by the central nervous system

(CNS) suggesting a potential role of IL-33 in autoimmune CNS diseases. The aim of this study is to investigate

the expression and function of IL-33 in the development of MS disease by using an animal model of the disease:

experimental autoimmune encephalomyelitis (EAE). We first studied the expression of IL-33 and its receptor ST2

in the CNS tissues using immunohistochemical staining. To understand the effect of IL-33 in MS development, we

examined EAE severity in mice treated with recombinant protein IL-33 or PBS, and the immune responses were

analysed. Finally the effect of IL-33 in CNS myelination was investigated. Our data show that IL-33 and its receptor

ST2 are highly expressed in the spinal cord, and ST2 expression is markedly increased in the spinal cord tissue of

EAE mice.

Furthermore, IL-33 treatment at the priming stage of EAE development (from day 2-8 after immunisation) significantly

exacerbates EAE, while treatment of

IL-33 after EAE onset (from day 12-20) attenuates EAE severity when compared with the PBS-treated controls. In

vitro, the presence of IL-33 in the culture reduces the number of myelinated axons. Our study demonstrates that

IL-33/ST2 signalling pathway has an important but complex role in the development of MS disease. Further studies

investigating the mechanisms of IL-33 effects in modulating MS disease will significantly advance our general

understanding of the molecular mechanisms of MS disease.



53

Abstracts

26. The physical and psychological impact of Multiple Sclerosis using the MSIS-29 via the web portal of the UK MS Register*

Kerina H Jones, David V Ford, Philip A Jones, Ann John, Rodden M Middleton, Hazel Lockhart Jones,

Jeffrey Peng, Lisa A Osborne and J Gareth Noble

Swansea University

Introduction: The MSIS-29 was developed to assess the physical and psychological impact of MS. The aims of this

study were to use the responses to the MSIS-29 via the web portal of the UK MS Register to: examine the internal

properties of the scale delivered via the internet, profile the cohort, and assess how well the scale measures impact

of disability on the potential workforce.

Methods: Between May 2011 and April 2012, 4558 people with MS completed the MSIS-29(v.1). The responses

were collated with basic demographic and descriptive MS data and the resulting dataset was analysed in

SPSS(v.20).

Results: Internal consistency was high (Cronbach’s alpha 0.97 MSIS-29-PHYS,

0.92 MSIS-29-PSYCH). The mean MSIS-29-PHYS score was 60.5 (50.6%) with a median of 62 and the mean

MSIS-29-PSYCH score was 24.8 (43.8%) with a median of 24. Physical scores increased with age and disease

duration (p<0.001, p<0.001), but there was a weak negative relationship between psychological scores and age

(p<0.001). The odds of people having an employment status of sick/disabled were 7.2 (CI 5.5, 9.4, p<0.001) for

people with a moderate physical score, and 22.3 (CI 17.0, 29.3, p<0.001) for people with a high physical score

(relative to having a low physical score).

Conclusions: This largest known study of its kind has demonstrated how the

MSIS-29 can be administered via the internet to characterise a cohort, and to predict the likely impact of disability on

taking an active part in the workforce, as a reasonable proxy for the effects of MS on general activities.

The findings examining MSIS-29-PHYS and MSIS-29-PSYCH scores against age support the use of two sub-

scales, not a combined score. These results underline the importance of using a scale such as this to monitor

disability levels regularly in guiding MS care to enable people to be as active as possible.

*Selected for presentation during ‘Biomarkers and clinical outcome measures: challenges for progressive MS trials’


54

Abstracts

27. Assessing and Suppressing Tremor to enable Independence: Development of a Clinical Workstation.

Rosie Jones, Angela Davies Smith, Simon Neild, David Western, Richard Hyde

University Hospitals NHS Foundation Trust and North Bristol NHS Trust

Introduction: Between 30-50% of people with MS reportedly experience tremor. In MS this can be a particularly

complex movement disorder presenting as intention tremor and often accompanied by upper limb weakness, fatigue

and gross ataxic movements. Currently there is no effective treatment. The impact on daily activities often results in

a high degree of dependence. Routinely used clinical scales to assess upper limb tremor are useful but offer little

detailed information about the nature of the movement disorder.

One aim of this project is to develop a user-friendly, standalone clinical workstation with bespoke software enabling

recording and analysis of upper limb movements. The recording system comprises five 3D body worn sensors

(Xsens) recording standardised movements and functional tasks. Sections of recorded stored data can be selected

for more detailed analysis alongside clinical assessment. Data generated by the workstation are used to provide

quantitative analysis of type and severity of movement disorder, evaluation of treatment, and exploring the means of

defining suitability for neurosurgical intervention. The project is in progress and this abstract will concentrate on the

development of the clinical workstation.

Methodology: People with MS displaying various levels of abnormal upper limb movement and tremor are being

recruited from the BrAMS Clinical Centre at Frenchay Hospital, Bristol. Each subject undergoes clinical assessment

(Fahn Scale, Multidimensional Assessment of Tremor in MS, Brief Ataxia Rating Scale) and completes questionnaires

(MSIS-29, EQ-5D-5L) to evaluate tremor and its impact. The sensors are attached over sternum, shoulder, proximal

to elbow and wrist and dorsal surface of the hand. Recordings of a series of standardised movement tasks are made

and the data transmitted by wireless link to the workstation computer. Simultaneous video recordings are made.

Stored data and video can be played back for further analysis, subject feedback, quantitative tracking of symptoms

and further refinement of the workstation analysis programmes. Clinician and subject feedback is being used to

inform development of the workstation and its output.

Results: To date bilateral recordings have been completed with seven people with MS and three control subjects.

The standalone system provides real time data on tremor frequency, amplitude, origin and occurrence during

different phases of movement. Sample data derived from the recordings will illustrate:

1. Characterisation of movement disorder and severity

2. Development of workstation software and data presentation

3. Evaluation of treatment strategies

To date, recorded tremor amplitude has been shown to correlate with clinical tremor assessment and the occurrence

of tremor can be distinguished from larger amplitude intentional or non-intentional movements.

Summary: The development of the workstation enables the collection of real time quantitative data on upper limb

movement that can be carried out in a clinical setting, and stored for immediate and on-going comparative studies.

Simultaneous video recording provides visual record of movement for comparison with the clinical assessments. The

workstation will be demonstrated.

This abstract summarises independent research funded by the National Institute for Health Research (NIHR) under

its i4i Programme (Grant Reference Number 11-AR-0410-12030). The views expressed are those of the author(s)

and not necessarily those of the NHS, the NIHR or the Department of Health.


55

Abstracts

28. Validation of two neuropsychological batteries for assessing fitness to drive in people with multiple sclerosis

Kontou E, Dr Claire Isaac, Professor Nadina Lincoln

University of Nottingham

Rationale: Abilities that underlie driving behaviour could be significantly impaired in individuals with multiple

sclerosis, but research evidence on cognitive assessments for predicting fitness to drive in people in this neurological

population is sparse.

Objectives: The study aimed at investigating the concurrent validity of the Multiple Sclerosis Driver’s Screening

Assessment (MSDSA) and the Rookwood Driving Battery (RDB) for assessing fitness to drive in multiple sclerosis.

Methods: Twenty-nine participants with MS were recruited from a wide range of settings and completed the two

neuropsychological batteries in the community (mean age=49 years, SD=8.37). The MSDSA and RDB classifications

were compared.

Results: MSDSA and RDB classified twenty-four participants (83%) as safe to drive. There was moderate inter-

rater agreement between MSDSA and RDB pass/fail classifications (β=0.53, p<.001). The MSDSA showed 100%

sensitivity for fail classifications and 89% specificity when compared against the RDB. The MSDSA total score

significantly correlated with the Road Sign Recognition (p<.001) and Information Processing (p<.01) MSDSA

subtests, but only Road Sign Recognition was predictive of MSDSA outcome. Visual Es-Fs (attention and visual

perception) and Comprehension (verbal and executive

skills) RDB subtests were predictive of cognitive impairment and accounted for almost 60% of the variance in RDB

total scores. Clinical characteristics of MS were not significantly correlated with MSDSA and RDB outcomes.

Conclusions: There is good agreement between MSDSA and RDB pass classifications. The MSDSA was better at

identifying unsafe participants compared to the RDB. The Road Sign Recognition was more accurate in predicting

MSDSA pass rather than fail classifications (92% sensitivity for pass, 40% specificity). MSDSA and RDB subtests

assessing attention, visuospatial perception and executive function skills appear to be related to driving ability in

individuals with MS. It is suggested that a combination of cognitive tests can be used as screening measures to

assess fitness to drive in this clinical population. A larger study is recommended to compare discrepancies between

the two batteries against an on-road test. Future studies should also consider methodological, practical and ethical

limitations on conducting research on fitness to drive in people with multiple sclerosis.


56

Abstracts

29. Anger Regulation and Quality of Life in Multiple Sclerosis*

Laing C, L. Phillips, C. Cooper, J. Hosie, F. Summers

University of Aberdeen

Funded by the MS Society, this research aims to examine problems with the regulation of anger in individuals

with multiple sclerosis (MS) and the impact that has on their daily lives, including personal relationships, social

participation, and their overall quality of life (QoL). It intends to do this by gathering questionnaire data assessing

measures of emotion regulation, anger, mood, QoL and disease progression. A structured interview study will then

be conducted in order to explore these issues further. The end goal is to develop a questionnaire investigating anger

which could be used, not just with MS, but also across different clinical groups.

MS is a chronic, degenerative disease of the central nervous system. Many people with MS report difficulties with

emotion regulation (ER) including depression and mood disorders (Finger, 1998). Causes of these difficulties are

not well understood, but evidence from other clinical populations indicates that ER problems may have implications

for well-being and overall QoL (Middelkamp et al., 2007). Research has infact shown that use of an effective ER

strategy in individuals with MS predicted better environmental and psychological QoL (Phillips et al., 2009).

Of particular interest in this study is the control of anger. Clinical observation has revealed that some individuals

with MS have more difficulty controlling their feelings of anger than those without and that this may have a negative

impact on their overall QoL. Indeed, unrestrained expressions of anger have been linked to social maladjustment

(Deffenbacher, 1992), and negative effects on personal relationships (Mauss et al., 2007). On the other hand, it has

been demonstrated that chronic suppression of anger is harmful to physical health (Mittleman et al., 1995). It is

likely, therefore, that the ability to manage the subjective experience of anger will have a positive impact on mental

and physical well-being – and hence overall QoL

This research therefore aims to establish whether some people with MS experience more problems controlling

their feelings of anger than those without. Moreover, we aim to find out whether this difficulty predicts problems in

close personal relationships, everyday functioning and consequently overall QoL. The possible links between the

dysregulation of anger and disease severity, mood and depression will also be explored.

Participants (n=70) will be recruited from NHS Grampian and assessed on questionnaire measures of emotion

regulation, anger, mood, QoL and disease progression. Questionnaire results will inform Phase 2 of the study -

structured interviews with MS patients and ideally, their spouses/carers.

Most QoL measures in MS focus solely on physical symptoms of the condition; however other aspects of MS may

also have a significant impact. It is important, therefore, that these emotional issues are more widely assessed as

they might influence well-being as much as the more widely recognised motor symptoms.

*Selected for presentation during ‘Mind and body: The interface between psychological and biomedical in MS’


57

Abstracts

30. FGF9 inhibits remyelination via an off target effect on astrocytes*

Lindner M, Ariel Arthur, Christina Elliott, Anna Williams, Edgar Meinl, Hans Lassman, Christopher Linington


Demyelination plays a central role in the pathophysiology of multiple sclerosis (MS) not only because it disrupts

nerve conduction, but also because of effects that compromise axonal survival. There is a growing consensus that

any effective treatment for MS must include a component that restores or enhances remyelination by endogenous

oligodendrocyte progenitor cells (OPC). However achieving this goal requires a far better understanding of why

remyelination fails in the first place. We now report that FGF9 is selectively up regulated in demyelinating MS lesions

and acts to inhibit (re)myelination in vitro. To explore the mechanism involved we compared the activity of FGF9

to that of FGF2, another member of the FGF family with well characterised effects on OPC differentiation and

myelination. FGF2 acts directly on OPC to stimulate proliferation, while at the same restricting their differentiation into

mature oligodendrocytes. In contrast, FGF9 is neither an OPC mitogen, nor is it able to inhibit OPC differentiation

directly. However, OPC differentiation and myelination in myelinating cultures were inhibited by supernatants

harvested from FGF9 treated astrocytes, even in the presence of an excess of FGF9 neutralising antibody.

Microarray studies were performed to identify astrocyte derived factors responsible for this inhibitory effect. This

approach identified several potential candidates that were significantly up regulated by FGF9 in astrocytes. These

included LIF, a member of the GP130/IL6 cytokine family that is generally described as having pro-myelinating

effects, although our own studies indicate when present in excess relative to other GP130/IL6 family members it

will inhibit myelination in vitro. Our experiments demonstrate that FGF9-mediated signal transduction in astrocytes

disrupts their ability to maintain a growth factor milieu that can support myelination. However using FGF9 neutralizing

antibodies in vitro could restore myelination to control values without causing any obvious deleterious effects

indicating FGF9-mediated signal transduction may provide a novel and safe strategy to enhance lesion repair in MS.



58

Abstracts

31. Analysis and screening of an antibody phage display library from B cells infiltrating brain tissue of people with progressive ms

Magiore C, Gavin Giovannoni, Joanne Martin, Ahuva Nissim

Queen Mary University of London

Introduction: The detection of immunoglobulins, called oligoclonal bands (OCBs), in the cerebrospinal fluid (CSF) of

people with multiple sclerosis

(PwMS) has a very high sensitivity and supports the diagnosis of MS. The immunoglobulins are also found in the

brain tissue of PwMS showing a diffuse involvement of the brain in the immune response. The life-long presence of

the immunoglobulins may indicate that the triggering agent is persistent and cannot be cleared. Nevertheless, the

specific target of the immune response is still controversial.

Objectives: To analyse the immunoglobulin repertoire in brain of PwMS and to build a phage display antibody library

from infiltrating B cells as a source of antibody fragments against auto-antigen candidates.

Methods: Snap-frozen brain blocks, supplied by the UK MS tissue bank, from 14 progressive MS cases with a ratio

M:F of 2:5 and an average age at death of 51.8±12.2y have been used in our study. A cDNA pool obtained from

the cases has been used to amplify heavy and light chains by variable region family specific primers and cloned in

a phagemid vector to build a single chain fragment variable (scFv) library. The built phage display library has been

biopanned on a recombinant fusion protein, MP4, carrying epitopes of two myelin proteins, i.e. myelin basic protein

(MBP) and proteolipid protein (PLP).

Results: A scFv library with a diversity of ~ 5.8*10^7 was obtained. VH genes repertoire before selection showed

that VH1 and VH2 families were significantly overrepresented compared with adult healthy controls. A typical long

VH-CDR3 with average length of 48±14 bp was also observed. In addition, MP4 specific binders were raised.

Conclusion: Our data confirm a characteristic antigen-driven immune response.

Biased phage display antibody library from MS may be a valuable tool to identify antibody fragments to target MS

auto-antigens for possible diagnostic/therapeutic application.


59

Abstracts

32. Validity of the Addenbrooke’s Cognitive Examination – Revised (ACE-R) in Multiple Sclerosis

Margeviciute R, Mara Sittampalam1, Peter Connick1, Siddharthan Chandran1, Thomas Hieronymus Bak1,2

1 Centre for Clinical Brain Sciences, The University of Edinburgh

2 Department of Psychology, The University of Edinburgh

Background: Cognitive impairment occurs in 43-70% of patients with multiple sclerosis.

The benchmark Brief Repeatable Battery of Neuropsychological tests (BRB-N) is well established and widely used,

but it requires specialised equipment and training. Moreover, being focused on memory, speed of processing

and frontal-executive functions, it offers limited coverage of language and visuospatial functions. However, recent

evidence suggests (Connick et al, Behavioural Neurology, in press) that these two domains can be affected in MS

independently of other cognitive functions.

The Addenbrooke’s Cognitive Examination – Revised (ACE-R) represents an attractive candidate for screening tool.

It is brief, easy to administrate in the clinical setting. Its multidimensionality allows separate assessment of five

distinct cognitive domains. Its utility has been well-established across a range of neurodegenerative and subcortical

disorders.

Objective: To validate ACE-R for use in the MS population and compare its clinical utility with the BRB-N.

Methods: A total of 106 MS patients (21 PP, 34 SP and 51 RR) and 30 healthy controls were assessed with the

ACE-R and BRB-N. MS patients were classified as having cognitive impairment if their performance score on at least

one of ACE-R or BRB-N subtests differed from control by more than 2 standard deviations.

Results: The patients and controls were matched for age (PP 50.8 (±6.7), SP 52.2 (±9.7), RR 43.3 (±8.2), controls

50.7 (±12)), gender and education. The progressive patients had higher EDSS scores (PP 5.6 (±4), SP 6.2 (±1.4), RR

3.3 (±2)) and longer disease duration (PP 8 (±4) years, SP 16.8 (±9) years, 8.3 (±6)). Test protocols were scored by

two independent raters.

Inter-observer reliability for the ACE-R was high (Cronbach’s Alpha 82%).

Intra-observer reliability for the ACE-R was excellent (Cronbach’s Alpha 99%). The ACE-R had high construct validity,

and was able to discriminate very well patients from controls (Kolmogorov-Smirnov D = .56, p<.0001). We have

performed convergent validation and the agreement between the ACE-R and BRB-N was moderate (Krippendorff’s

alpha 0.453). The overall ACE-R score was significantly correlated with all BRB-N subtests (with Selective Reminding

test r=.523 p<.001; with 10/36 Spatial Recall test r=.285 p=.003; with SDMT r=.568 p<.001; with PASAT r=.578

p<.001). A total of 61 MS patients failed on at least one ACE-R subtest, while 67 patients failed on at least one of

BRB-N tests. 12 patients, who did not fail on any of the BRB-N tests, were picked up with ACE-R: 5 RR, 2 PP and

5 SP. Out of these cases, the progressive MS patients failed mostly on fluency and visuo-spatial domains; the RR

cases mostly on memory and fluency. This suggests possible differences in cognitive profiles between different MS

subgroups.

Conclusions: These data support the concurrent and discriminative validity of the ACE-R in MS. As the battery is

brief, multidimensional and has been adapted in many countries and in over 30 languages, it is well suited to screen

for cognitive dysfunction in MS population.


60

Abstracts

33. Factors influencing the applied torque during manually applied plantarflexor stretches in people with Multiple Sclerosis

Marsden J, J Ofori, J Hobart, J Zajieck, J Freeman

Plymouth University

Background: People with Multiple Sclerosis (pwMS) often experience muscle stiffness, caused by changes in

passive stiffness and/or spasticity. Increases in stiffness are commonly managed with stretching; however there is

minimal evidence about the stretch-related parameters that effectively reduce stiffness.

Aims: To determine the magnitude of plantarflexor torque pwMS can produce at the ankle during commonly

prescribed manual stretches for the plantarflexors and establish the relationship between the applied torque and

symptom severity, disability and ankle passive stiffness and spasticity.

Methods: Four stretches were investigated; stretching in step standing (WALL); using a step (STEP); pulling the

ankle into dorsiflexion (PULL) and standing in a frame (FRAME). Joint position and the forces applied through the

foot were measured using 3D motion analysis and torque transducers.

Slow (5o/s) and fast (170o/s) stretches were applied via a motor and used to quantify the degree of passive stiffness

and stiffness related to stretch reflex activity. The functional level of participants and their symptom severity was

measured using the Expanded Disability Status Scale (EDSS), Barthel Index, Multiple Sclerosis Spasticity Scale

(MSSS-88) and Multiple Sclerosis Walking Scale (MSWS-12).

Results: PwMS (n=27, EDSS 4.5-7.0) were compared to age and gender matched controls (n=15).

PwMS achieved less lengthening of the gastrocnemius compared to matched controls (P<0.05) but similar ankle

torques reflecting increased activation of the plantarflexor muscles during the stretch. Stretch-reflex related ankle

stiffness was higher in pw MS and ankle muscle strength and functional ability was reduced. The plantarflexor torque

produced during manual stretches was not correlated with functional ability or degree of ankle stiffness although

people with lower functional ability tended to prefer the more supported PULL and FRAME stretches

Conclusion: PwMS achieve a shorter gastrocnemius length when stretching. Higher plantarflexion torques are

produced when stretching in standing, however this is associated with higher plantarflexor muscle activity in pwMS

suggesting that the stretch is not entirely passive in nature. Functional ability does not affect the mean torques /

gastrocnemius length that can be achieved but it does influence the preferred type of stretch and the duration a

stretch can be maintained.


61

Abstracts

34. The effects of applied torque and stretch duration on range of movement, passive stiffness and spasticity in people with Multipl

Marsden J, J Ofori, J Hobart, J Zajieck, G Bugmann, P Gibbons, J Freeman

Plymouth University

Background: 80% of pwMS have an increase in muscle stiffness caused by changes in passive stiffness and/

or spasticity. Increases in stiffness are commonly managed with stretching. However, the current evidence base

for stretching is variable and there is a paucity of literature regarding the stretch-related parameters that effectively

reduce stiffness.

Aims: To determine the effects of stretch duration and applied torque on peri- and post stretch changes in

plantarflexor passive stiffness, stretch reflex excitability and ankle range of motion in people with Multiple Sclerosis

(pwMS).

Participants: Participants with clinically defined Multiple Sclerosis (n=14; age 57 ± 10 yrs), with a median EDSS 6

(range 4.5-7.0) who self-reported leg stiffness were recruited.

Methods: The application of a constant torque stretch using three different torque values [high (0.42Nm/Kg),

medium (0.30 Nm/Kg) and low (0.18 Nm/Kg)] over either 30 minutes or 10 minutes was investigated. For both

stretch durations participants were seen on three occasions separated by a minimum of three days. The order of the

applied torque was randomised. Ankle stiffness (∆torque / ∆position) was measured peri- and post stretch and at 10

minute intervals over a 30 minute period by passively moving the ankle into plantarflexion using a motor. Slow (5o/s)

and fast stretches (170o/s) were used to quantify the degree of passive stiffness and stretch reflex activity.

ROM was monitored throughout the course of the experiment.

Analysis: The effect of applied torque on passive stiffness, stretch reflex activity and ROM, were compared using a

repeated measures analysis of variance (ANOVA).For all statistical tests, the level of significance was set at P<0.05.

Results: Higher applied torques were associated with greater increases in ankle ROM (P<0.001). Passive stiffness

decreased with stretching but there was no effect of the applied torque. Passive stiffness significantly decreased by

27% (±19%) following a 30 minute stretch (P<0.05) and only subsequently increased by 4% in the 30 minutes post

stretch period. Ten minutes of stretching resulted in a 13% decrease in passive stiffness(P<0.05) . However, this

returned to baseline levels within10 minutes post stretch.

There was no significant change in stretch reflex excitability following a 30 minute stretch, regardless of the torque

applied (P>0.05). There was a significant change in stretch-evoked stiffness following a 10 minute stretch

(P<0.05). Post hoc tests revealed a significant 25% (±46%) decrease in stretch-evoked stiffness immediately post

stretch; this then significantly increased 10 minutes post stretch, such that it was 31% (±60%) higher than baseline

levels.

Conclusions: Constant torque stretches applied for 10- 30 minutes significantly improved ankle range of movement

in pwMS; this was more pronounced when higher forces were applied. Longer duration stretches resulted in greater

improvements in passive muscle stiffness. Rebound increases in spasticity after the end of a stretch were seen,

these were temporary and the cause of this change and their effects on function requires further investigation


62

Abstracts

35. Effects of ankle stretches on muscle fascicle strain and musculo-tendinous length

Marsden J, J Ofori, J Hobart, J Zajicek, P Gibbons, G Bugmann, A Hough, J Freeman

Plymouth University

Background: People with Multiple Sclerosis (pwMS) often present with ankle plantarflexor hypertonia. Studies with

people with cerebral palsy and stroke suggest that the Achilles tendon can be longer and less stiff and the muscle

fascicles are shorter and stiffer than normal.

Aims: This study aimed to (a) compare tendon and muscle length and muscle fascicle strain in people with MS and

matched controls and to (b) assess the effects of a constant torque stretch on these properties.

Methods: Ten pwMS and 12 age and sex matched healthy controls were assessed. The effects of a 10 min

constant torque stretch on (a) Passive stiffness of the musculo-tendinous complex (b) muscle and tendon length and

(c) muscle fascicle strain was determined.

Passive stiffness of the musculo-tendinous complex was measured using motor-driven ankle perturbations (5 o/s,

15o amplitude, x6 repetitions).

Measurement of muscle and tendon length: The position of the proximal and distal attachments of the plantarflexors

were identified using infra-red markers. The musculo-tendinous junction (MTJ) was identified with ultrasound.

Infrared markers on the ultrasound head determined the position of the musculotendinous junction relative to the

distal and proximal attachments using 3D motion analysis and from this muscle and tendon length.

Measurement of fascicle muscle strain: During ankle perturbations, plantarflexor muscle fascicle motion was

measured using ultrasound.

Subsequently, the motion of 3 regions of interest (ROI) within the muscle closest to the MTJ were determined using

a frame-by-frame cross-correlation image analysis. The percentage strain was defined as: (ROI displacement/

gastrocnemius muscle length) x100.

Analysis: The total, muscle and tendon lengths and the percentage strain of the medial gastrocnemius muscle in

pwMS and controls before and after stretching were compared using between groups repeated measures ANOVA

(SPSS 17.0, IBM) Results Muscle and tendon length: The total length of the gastrocnemius muscle-tendon complex

tended to be shorter in the pwMS (P=0.08). PwMS with higher passive stiffness of the musculo-tendinous complex

had longer tendon lengths (R=0.62 P<0.05).

Percentage strain of muscle fascicles: There was no significant difference in muscle fascicle strain between pwMS

and the control group. PwMS who had higher passive stiffness of the musculo-tendinous complex showed a greater

muscle fascicle strain (R=0.62 P<0.05).

Effects of stretching: Muscle length did not change following a 10 minute stretch. In contrast muscle fascicle strain

significantly increased (F(1,9)=5.07 P=0.05).

Discussion: PwMS who had a stiffer overall muscle-tendinous complex had longer tendon lengths and showed

greater muscle fascicle strain. This suggests that the area of increased stiffness must be located outside of the

measured ROI. As the free tendon is longer (and possibly more compliant) in people with greater passive stiffness

the increased stiffness may lie within the muscle belly.

The increase in muscle strain following a stretch was not accompanied by a change in muscle length suggesting

that the increase in displacement was not uniform across the whole muscle / tendon. Constant torque stretches may

therefore not affect the stiffest part of the muscle-tendon complex.


63

Abstracts

36. Detection of differentially expressed calreticulin in the serum of EAE rats and in serum isolated from individuals with multiple sclerosis

Mary Ní Fhlathartaigh†, Jill McMahon†, Eibhlín Higgins†,*, Timothy Counihan* and U. FitzGerald†

†National University of Ireland, Galway, Ireland; *University Hospital, Galway, Ireland.

Calreticulin (CRT) has classically been associated with protein quality control within the endoplasmic reticulum,

where it normally functions in concert with its membrane-bound homologue calnexin, to ensure correct folding of

glycosylated secretory or membrane-bound proteins. However, under certain pathological conditions, or following

induction of cellular stress, secretion of CRT has been reported. While the function of circulating CRT has yet to

be fully elucidated, there is speculation that it could affect the innate and adaptive immune response and CRT has

been linked to the pathogenesis of the autoimmune disorder, rheumatoid arthritis. To determine if secretion of CRT

was occurring during experimental autoimmune-induced demyelination, blood samples drawn from Dart Agouti (DA)

rats in which spinal cord demyelination had been induced following injection of myelin oligodendrocyte glycoprotein

mixed with incomplete Freund’s adjuvant (n=5), were tested by ELISA for the presence of secreted CRT and levels

were compared to those found in control animals (n=5 saline, n=5 injected with incomplete Freund’s adjuvant). Data

showed that the 244 + 21 ng/ml of CRT detected in EAE sera was significantly lower than the 308 +18 found in IFA

(p<0.05) or the 347 + 20 ng/ml found in saline controls (p<0.01).

The opposite was found when blood samples taken from 14 individuals suffering from relapsing-remitting multiple

sclerosis and from 11 healthy controls were tested by ELISA for CRT. The multiple sclerosis sample cohort was

derived from 10 females and 4 males who had an average age of 37.5 years (+ 9.8) and a disease duration of 7.9

years (+ 7.1). Healthy controls sampled consisted of 8 females and 3 males, who had an average age of 38.6 +

16.8 years. ELISA analysis of serum samples detected a mean level of 428 (+ 40) ng / ml in persons with MS, which

was 28 % higher than the average 335 (+ 17) ng /ml seen in controls (p<0.05). When data generated by individuals

with MS was sub-divided into two groups, depending on whether or not patients were on Natalizumab, mean CRT

levels were lower in Natalizumab-treated patients (382

+ 48 ng/ml, n=9) than in those who were not on Natalizumab (67 ng/ml, n=5).

Moreover, the mean value for Natalizumab-treated patients was still higher, but no longer differed significantly from

healthy control CRT levels, while significant differences (p<0.05) were retained between non-Natalizumab samples

and controls. Taken together, the data from EAE animals and from individuals with multiple sclerosis hints that the

possible roles of circulating CRT in rat and human demyelinating disease warrents further study.


64

Abstracts

37. The impact of self-selected walking speed on the effect of FES on the physiological cost of walking in MS

Miller L, Danny Rafferty, Lorna Paul, Paul Mattison

NHS Ayrshire & Arran/ Glasgow caledonain University

Introduction & Background: Around 75% of people with MS (pwMS) present with walking limitations which

impacts on independence in activities of daily living, productivity and quality of life. Foot drop is a common problem

affecting walking in MS with weakness and spasticity at the ankle resulting in foot drop causing a reduction in

walking speed and an increase in the energy cost of walking. There is evidence that Functional Electrical Stimulation

(FES) has an orthotic effect on gait by increasing speed and reducing physiological cost of walking in pwMS,

however previous studies have recruited participants with self-selected walking speeds considered to be lower than

that required for community ambulation i.e <0.8m/s. This study aimed to investigate the effects of FES in people with

MS who walked at a range of walking speeds.

Methods: Twenty participants with MS who had been using FES for a minimum of

6 months were recruited from the NHS Ayrshire & Arran FES service. A Pre-test Post-test design was used. The

participants walked around an elliptical course with and without FES at their self-selected walking speed for 5

minutes. A COSMED K4b2 (Cosmed, Rome, Italy) gas analysis system was used to measure the percentage of

expired oxygen (O2) during walking and this was used to calculate the O2 cost of walking. Data was used from

between minutes 3 and 4 of the walking test when a steady state was achieved. Walking speed was calculated by

measuring the distance travelled during 5 minutes. Paired t-tests were used to investigate the difference between

walking with and without FES with respect to walking speed, O2 uptake and O2 cost of walking.

The participants were split into two groups based on their self-selected gait speed (without FES) using a cut off of

0.8m/s which defines the walking speed required for community walking. Walking speed, O2 uptake and O2 cost of

walking with and without FES was compared within each group with the level of significance being set at p<0.05.

Results: Walking speed significantly improved with FES (0.69 ms-1 (±0.31)) compared to without (0.73ms-1 (±

0.28), p=0.043) and there was no non-significant difference in O2 cost of walking with FES (0.33 mL min-1

kg-1 m-1 (± 0.16)) in comparison to without (0.36 mL min-1 kg-1 m-1 (± 0.2))( n=20). For participants walking at

speeds of <0.8m/s significant improvements in walking speed (p=0.005) and oxygen cost of walking (p=0.02) were

noted using FES (n=11), however participants walking at speeds of >0.8m/s demonstrated no difference in walking

speed with FES and a significant increase in O2 cost of walking with FES in comparison to without (p=0.004)( n=9).

Conclusion: It appears that pwMS who have slower walking speeds demonstrate greater improvement in gait speed

and O2 cost of walking compared to those with faster gait speeds. The increase in O2 cost of walking following FES

noted in faster walkers requires further investigation. The results from this pilot study will help to inform future clinical

decisions around the prescription of FES in MS.


65

Abstracts

38. The effect of reflexology on quality of life and symptoms in people with moderate to severe disabilitly in MS: A pilot RCT

Miller L, Elaine McIntee, Paul Mattison

NHS Ayrshire & Arran/ Glasgow caledonain University

Introduction and Background: Much of the recent research effort in MS has concentrated on disease modifying

drugs and regenerative medicine; however there are a large number of patients who are do not have access to

these treatments. Many people with MS are turning to complementary therapies which may offer an option for

symptomatic management. Reflexology has the potential to offer symptomatic relief and enhance quality of life.

Previous studies have evaluated the impact of reflexology in MS and found mixed results in people with mild to

moderate disability. This pilot randomised single blind placebo controlled trial aimed to examine the feasibility and

effectiveness of delivering reflexology to people more severely affected by MS.

Methods: Twenty people with MS presenting with an EDSS score of between 6.5 and 8 were recruited from the

NHS Ayrshire & Arran MS service and randomised into either a reflexology treatment group or a sham reflexology

group (consisting of a lower leg and foot massage). All participants attended as an out patient once weekly for 8

weeks. The primary outcome measure was the Multiple Sclerosis Impact Scale (MSIS 29) and secondary measures

included Visual Analogue Scales assessing symptoms of bladder, bowel, muscle stiffness and spasm, pain and

quality of sleep. Measures were taken at baseline, immediately following the intervention (8 weeks) and 8 weeks after

treatment finished (16 weeks). Statistical analysis used the Mann-Whitney U test for between group differences given

that the outcome measures did not follow a normal distribution. Within group differences were analysed by Wilcoxon

Signed Rank test and significance was set at p<0.05.

Results: There were no statistically significant differences between the two groups at either 8(p= 0.538) or

16(p=0.112) weeks for the primary outcome measure. Non significant improvements were seen in the reflexology

group with the total MSIS29 reducing from 92.3(±20.9) to 75.6(±3.3) and in the sham reflexology group from 91.3(±

29.9) to 81.5(± 18.5) after 8 weeks of treatment. Small improvements were also noted in most of the secondary

outcome measures at 8 weeks and most scores returned to baseline at follow up. There were no differences

between the groups at 8 weeks except for bladder function (p= 0.003) which demonstrated improvements for the

sham reflexology group.

Conclusions: The results of this study suggest that reflexology can be feasibly delivered and was well tolerated by

people who were moderately to severely affected by MS. Overall the results do not support the use of reflexology for

symptom relief in a more disabled multiple sclerosis population and are strongly suggestive of a placebo response.


66

Abstracts

39. Efficient delivery of IFN- to the spinal cords of EAE mice

Lisa Mullen, Gill Adams, David Gould, David Baker, Yuti Chernajovsky

Bone & Joint Research Unit, Queen Mary, University of London

Interferon (IFN)-ß is now the treatment of choice for the relapsing/remitting form of multiple sclerosis (MS). However,

given the fact that IFN-ß is effective in only 50% of patients, and with an efficacy of c. 30%, there is obviously a need

to continue the search for other, better treatments.

To overcome the limitations of short half-lives and pleiotropic effects of most cytokines, we created fusion proteins

of the latency-associated peptide (LAP) of TGF-ß with a therapeutic cytokine. The furin cleavage site in LAP was

replaced with a collagenous matrix metalloproteinase (MMP) cleavage site or an aggrecanase cleavage site and

TGF-ß was replaced with IFN-ß. We previously showed that LAP-MMP-IFN-ß was latent (inactive), but became

active when released by cleavage with recombinant MMP. Release of IFN-ß biological activity could be detected by

incubating LAP-IFN-ß with cerebrospinal fluid (CSF) from meningitis and MS patients but not with serum, plasma or

CSF from non–inflammatory brain diseases. Latent IFN-ß had an extended half-life compared to the free IFN-ß (37

times longer).

We demonstrate here that the original specificity of the cleavage site can be changed to that of an aggrecanase

cleavage site. Aggrecanases are regulated by pro-inflammatory cytokines and are overexpressed in the spinal cord

of MS patients and in mice with experimental autoimmune encephalomyelitis (EAE) and may play a role in CNS

extracellular matrix changes in MS.

Using a mouse LAP-agg-IFN-ß fusion protein we demonstrate that this molecule is efficiently cleaved in vitro by

recombinant aggrecanase, producing a highly stable therapeutic cytokine. We also show, using a transgenic mouse

expressing firefly luciferase from an IFN-regulated promoter, that the half-life of this fusion protein was increased 40-

fold compared to the free cytokine in mice with EAE. Furthermore, we also definitively show efficient delivery of IFN-ß

to the spinal cords of mice with EAE using the LAP fusion protein, with limited effects in other tissues.

The results shown here indicate that production of IFN-ß in latent form could be used to reduce the risk of side-

effects and increase the serum half-life of the cytokine, while achieving high local concentrations at the spinal cord.

We have now established that latent IFN-ß can penetrate the blood-brain-barrier in EAE mice and this could pave

the way for a more effective treatment of the symptoms of MS by enabling higher doses to be safely administered.


67

Abstracts

40. Glycosylation on CD46 modulates its regulatory function

Ni Choileain S, Anne L. Astier

University of Edinburgh

The lack of regulatory T cell function is a critical factor in the pathogenesis of autoimmune diseases. Notably, in

patients with multiple sclerosis, ligation of the complement regulator CD46 does not induce secretion of the critical

anti-inflammatory cytokine IL-10, while it induces differentiation towards an IL-10-secreting Type 1 regulatory

phenotype (Tr1) in healthy T cells. The molecular mechanisms responsible for this defective pathway are still mostly

unknown.

Proteolytic cleavage of CD46 occurs upon T cell activation and has been shown to be important to regulate T cell

activation and cytokine production. CD46 ectodomain contains 3 N-glycosylation and multiple O-glycosylation sites.

T cell development, differentiation and activation modulate the glycosylation profile of glycoproteins on T cells, and

levels of glycosylation of several glycoproteins have been shown to control T cell responses.

Herein, we report that CD3-mediated T cell activation induces deglycosylation of CD46, thereby promoting

shedding of CD46 and IL-10 production. Using glycosylation inhibitors or specific CD46 glycosylation mutants, we

demonstrate contrasting roles of N- and O- glycosylation in CD46 downregulation and function, with antagonistic

roles on proliferation and production of IL-10 and IFNβ. These glycosylation changes appear to be defective in

RRMS T cells, leading to increased levels of CD46 expression on activated T cells. These changes are modulated

by addition of active Vitamin D that restores CD46 expression in activated MS T cells. These data provide a unique

mechanism for regulating CD46 regulatory functions on T cells.

Moreover, they explain, at least in part, why this pathway is defective in MS, giving novel insights into MS

pathogenesis and providing new avenues to design future immuno-therapies.

41. Neuronal overexpression of human tau influences the myelin regeneration

Bernardino Ossola, Chiara Cossetti, Matteo Dogana’, Elena Giusto, Chao Zhao, Michel Goedert, Alastair

Compston, Stefano Pluchino, Robin Franklin, Maria Grazia Spillantini

University of Cambridge

It is widely accepted that axonal degeneration plays an important role in the neurological disabilities people affected

by multiple sclerosis (MS). The accumulation of axonal and neuronal loss drives the clinical aspects of MS during

the progressive stage. We recently demonstrated the presence of pathological forms of tau in both experimental

autoimmune encephalomyelitis mice and MS lesions, observing a positive correlation between the disease stage

and the degree of tau hyperphosphorilation and aggregation. We thus hypothesized that the progression of tau

pathology is a determinant of progressive axonal degeneration in MS and maybe also influence remyelination.

To this end we studied a well characterized remyelination that follows a focal demyelination of the spinal cord (SC)

in mice overexpressing human mutated P301S tau. Human P301S tau transgenic mice develop well characterized

progressive tau pathology in the central and peripheral nervous systems.

Interestingly, we observed a significant shrinkage of axons in the SC of the P301S tau transgenic mice at 2

months of age when there is a clear expression of the transgenic protein, but with very limited tau pathology

(hyperphosphorylation and aggregation).

Fourteen days after the focal demyelination caused by the injection of lysolecithin in the SC of 2 months old mice,

we found an increased number of myelination oligodendrocytes in the lesions of P301S tau transgenic mice

compared to wild type (WT). On the other hand the number of oligodendrocytes precursor cells seems to be similar

in either mouse line.

Together, these data suggest that P301S tau transgenic mice compared to wild type mice have improved myelin

regeneration. Our data suggest that an injured axon signals to the microenvironment to facilitate the regenerative

process.


68

Abstracts

42. Selective ERbeta agonist -neuroprotective treatment in MS

Österlund M, Pernilla Fagergren, Maria Sjöberg

Karo Bio AB

Current therapies for MS are primarily targeting the immune system exerting anti-inflammatory actions, they are

effective in the relapse remitting phase when the degree of inflammation is high but has limited effects in the

progressive phase when the degree of neurodegeneration is high. There is a big unmet medical need for neuron

sparing therapies with other modes of action than attenuating the inflammation. Recently published studies have

revealed positive effects of estrogen in experimental autoimmune encephalomyelitis (EAE) that are mediated by both

estrogen receptor (ER) subtypes, alpha and beta. However the mechanisms of action are not identical for the two

ER subtypes, both subtypes mediates symptomatic relief and neuroprotection but only ERalpha show significant

antiinflammatory actions.

By using an ERbeta agonist for neuroprotective treatment in MS, the ERalpha-mediated side effects, such as

increased cancer risks and thrombosis, would be avoided.

The present study was conducted to evaluate the effect of a Karo Bio proprietary ERbeta agonist (KB-C) on the

neurological disease symptoms observed in the model of relapsing-remitting EAE (RR-EAE) in Dark-Agouti rats.

RR-EAE was induced in female rats by subcutaneous injection of emulsion consisting of homologous spinal cord

homogenate. KB-C was tested at 0.41 and 2.0mg/kg s.c. twice daily from D14 (onset of remission from the first

attack) to D25 post-immunization. KB-C significantly reduced the disease symptom over the total treatment period

by about 28% after 2 mg/kg treatment but no effect was observed at 0.4mg/kg. Immunohistochemical analyses

showed reduced spinal axonal degeneration in KB-C treated animals.

Moreover, we confirm ERbeta-induced neuroprotection after in vitro glutamate excitotoxicity. Rat fetal cortical

neurons were cultured for two weeks. The cultures were incubated with KB-C 24h prior to a 20 min glutamate

exposure (40 μM), followed by further KB-C incubation for 48h.

Microtubuli-associated-protein-2 and neurofilament were immunostained for neuron and neurite evaluation

respectively. KB-C both increased the number of neurons and the amount of neurite network surviving the glutamate

insult already at low nM concentrations.

Taken together, the selective ERbeta agonist reduce neurological scorings in a relapsing–remitting EAE rat model

and show neuroprotective effects after glutamate excitotoxicity in vitro, suggesting ERbeta agonists as a possible

novel neuroprotective therapy of MS.


69

Abstracts

43. Breast-feeding and multiple sclerosis relapse risk*

Julia Pakpoor, Giulio Disanto, Melanie V. Lacey, Kerstin Hellwig, Gavin Giovannoni, Sreeram V.

Ramagopalan


Background: An increased relapse rate immediately post-partum in multiple sclerosis (MS) patients is well

established; however, no consensus has been reached regarding the impact of breastfeeding on post-partum

relapse risk.

Women with MS currently make a difficult choice between not restarting disease-modifying drugs and breastfeeding,

or restarting therapy and not breastfeeding, or curtailing the duration of breastfeeding. In this study we aimed to

meta-analyse all available data to give a more accurate estimate of the impact of breastfeeding on the risk of post-

partum relapse.

Methods: A search of the PubMed database was undertaken using the search terms ‘‘breastfeeding’’ and ‘‘multiple

sclerosis’’. There was no time period restriction. Abstracts of the identified studies were hand-searched to select

studies comparing post-partum relapse occurrence in a breastfeeding (BF) versus not breastfeeding group (not

BF). Studies were excluded if they were not available in English, an interventional drug trial where drug effect was

the primary aim, or if they did not compare relapse occurrence in breastfeeding versus not breastfeeding mothers.

Authors were contacted if raw data was not available in a suitable study. The inverse variance with the random

effects model in Review Manager 5.1 was used to calculate the overall odds ratio (OR) and 95% confidence interval

(95% CI) of having at least one post-partum relapse in MS patients who breastfeed versus those who do not.

Results: In total twelve studies were selected for inclusion, yielding a total of 869 MS patients who breast-fed versus

689 MS patients who did not.

Women who did not breastfeed were almost twice as likely to have at least one post-partum relapse [OR 0.53 (95%

CI 0.34–0.82)]; however, significant heterogeneity was present. Sensitivity analysis showed that inclusion of only the

eight prospective studies had an OR = 0.46 (0.30–0.70) with no significant heterogeneity. Further, we found that

the pre-pregnancy relapse rate and the relapse rate during pregnancy were not significantly lower in women who

breastfed compared to women who did not. Three studies included data on the use of disease-modifying therapies

(DMTs) before pregnancy; women who breastfed were significantly less likely to use DMTs than women who did not

breastfeed.

Conclusions: We found that women with MS who breastfeed are almost half as likely to experience a post-partum

relapse compared to women who do not.

However, there is a strong possibility for confounding as shown by the finding that women who breastfed were

significantly less likely to use DMTs before pregnancy, suggesting that the choice to breastfeed may be associated

with more benign pre-pregnancy disease activity, and thus women with more severe MS may be less likely to

breastfeed because of disability and/or in order to restart medication. Importantly, this study highlights the need for

a large prospective study to assess the influence of breastfeeding on post-partum relapses in MS patients, with

detailed measures of pre-, during and post-pregnancy disease characteristics and treatment recorded, in order to

reach a robust conclusion as to whether breastfeeding truly influences disease outcome for MS patients, families

and their caregivers.



70

Abstracts

44. Prioritising important research questions for multiple sclerosis – a partnership between people affected by MS and healthcare professionals.

Mital Patel1, Ed Holloway1, Susan Kohlhaas1, Nick Rijke1, Sally Crowe2, Karen Chong3, Roger Bastow3, Gwen

Covey-Crump3, Paul Bull3, Grace Hazlett4 Neil Kemsley5, Waqar Rashid6, Richard Warner7.

1 Multiple Sclerosis Society 2 James Lind Alliance3 Multiple Sclerosis Society’s Research Network 4 UK MS Specialist Nurses Association5 MS National Therapy Centres6 Association of British Neurologists7 Specialist MS nurse, Gloucestershire Neurology Service

The field of MS research is vast, as is the number of potential projects which could be funded. As funders of MS

research it is essential that the MS Society identifies clear research priorities to allow for the strategic allocation of

resources and for research outcomes to have the most impact on people affected by MS.

In 2012 the MS Society embarked on a MS priority setting partnership (MS PSP) to facilitate the identification

of research priorities that are shared by people affected by MS (PaMS) and healthcare professionals. This work

is facilitated by the James Lind Alliance (JLA), an internationally recognised and independent organisation, who

have an established process to identify and prioritise research uncertainties, taking into account existing research

evidence. The MS PSP will result in a ‘Top 10’ list of research priorities.

The MS PSP ran a large scale survey in 2012 to gather research uncertainties from anyone with an interest in MS.

The survey was completed by 507 individuals who submitted 1084 questions. Using the JLA protocol and criteria

set by the steering group an information specialist analysed all survey submissions - similar questions within scope

were grouped and indicative questions created. Questions were checked against systematic reviews to identify

which questions are ‘true research uncertainties’. This process resulted in 67 research uncertainties taken forward

for prioritisation.

The steering group are now carrying out a two-stage prioritisation exercise to reach the top 10 MS research

uncertainties. Interim prioritisation began in April 2013 with the launch of a survey which invites PaMS and healthcare

professionals to vote for their top questions. Results from the survey will be collated and a shorter list created. This

shorter list will be considered at a workshop in July 2013 in which people PaMS and healthcare professionals will

express their views, hear different perspectives and think more widely about MS to ultimately identify the 10 most

important questions in MS. During Frontiers researchers are invited to give their views on the importance of some of

the questions listed in the interim prioritisation survey.

The interim prioritisation survey is online here: www.mssociety.org.uk/jla and closes on 24 May 2013.


71

Abstracts

45. Physiotherapy Led Web-Based Rehabilitation For People With Multiple Sclerosis

Paul L, Elaine Coulter, Linda Millar, Paul Mattison, Angus McFadyen.


Introduction: Web-based telerehabilitation has many advantages over conventional, face to face rehabilitation.

In terms of accessing physiotherapy, telerehabilitation may be useful for people who are unable to access

‘conventional’ rehabilitation such as those who work, who live in rural locations, who are housebound, who have

transport problems or for whom the effort/stress of getting to the therapy location outweighs the benefits gained [1,

2]. On-demand, web-based interventions are also available 24 hours a day and thus the patient can chose the time

of their ‘therapy’ to suit their own personal circumstances.

Purpose: To explore the effectiveness of physiotherapy led, web-based rehabilitation for people moderately affected

with Multiple Sclerosis (MS) and to assess the technical feasibility and participant satisfaction with the programme.

Methods: The website was developed in association with a patient advisory group with guidance from the MS

Society web accessibility policy and the Scottish Accessibility Information forum. The website consists of a library of

exercise videos, exercise diary, and advice and exercise guidance pages.

Thirty people with MS (EDSS 5.0-6.5; 6 Male, 24 Female; average age 52±11

years) were recruited from the MS Service NHS Ayrshire and Arran.

Participants were randomly allocated to receive usual care or receive 12 weeks of an individualised web-based

exercise programme consisting of aerobic, strengthening and/or balance exercises. Participants were telephoned

weekly to monitor their progress and their programme was remotely altered by the physiotherapist. Participants

were assessed at baseline and after 12 weeks of intervention or usual care (conventional physiotherapy if required).

Outcome measures consisted of the 25ft walk, Timed Up and Go, Berg Balance Scale, MS Symptom Checklist,

MS Impact Scale-29, Hospital Anxiety and Depression Scale and Leeds MS Quality of Life Scale. For those in the

intervention group semi-structured interviews were conducted following completion of participant’s programme.

Results: The study is ongoing and all participants have been recruited. Data collection will be completed by the end

of April 2013.

Discussion: Web-based physiotherapy may be an option for people for whom accessing face to face physiotherapy

is difficult. Depending on the results of this pilot study larger scale studies will be undertaken to assess the

effectiveness of web-based physiotherapy over a range of levels of disability.

This study was funded by Chief Scientist Office, Scotland.

References:

1 Brennan DM, Barker LM (2008) Human factors in the development and implementation of telerehabilitation

systems. Journal of Telemedicine and Telecare. 14, 55-58.

2 Learmonth Y, Miller L, Paul L, Mattison P, McFadyen A (2011) The effects of a twelve week leisure centre based,

group exercise intervention for people moderately affected with Multiple Sclerosis: a randomised controlled pilot

study. Clinical Rehabilitation. 26(7), 579-93.


72

Abstracts

46. Outcome Measures for studies of Exercise in Multiple Sclerosis: Recommendations from an international, multi-disciplinary consensus meeting.

Paul L, Coote S, Crosbie J, Dixon D, Hale L, Holloway E, McCrone P, Renfrew L, Saxton J, Sincock C, White L.

Introduction: There is growing evidence that exercise is beneficial for people with MS however many studies are

small and underpowered and the heterogeneity of outcome measures used hinders meta-analysis of the data.

The Cochrane Review (2005) identified the need for a core set of outcome measures for exercise studies so that

future meta-analyses would provide sufficient, robust evidence to guide clinicians on exercise prescription for

people with MS. However, to date, a core set of outcome measures has not been agreed. This paper presents the

recommendations of an international consensus meeting convened to identify a core set of outcome measures for

use within exercise studies in MS.

Methodology: The consensus group consisted of 12 people from a range of professional backgrounds;

physiotherapy, exercise science, exercise psychology and health economics as well as a representative from the MS

Society and two expert patients with MS. Participants attended from the UK, New Zealand, Ireland and the USA.

The International Classification of Functioning, Disability and Health (ICF) was used as the framework for discussion,

in particular the recently published ICF Core Sets for MS (Coenen et al 2011). The 40 body functions, 7 structures

and 53 activities and participation categories were classified as a) not affected b) potentially affected or c) unlikely to

be affected by exercise. 57 categories were thought to be affected or potentially affected by exercise. These 57 were

discussed and collapsed into clusters. A framework was used to recommend outcome measures for categories

within each cluster.

Results: The recommendations of the group were that studies of exercise interventions in MS include the following

simple outcome measures: the MSIS-29 or MSQoL54 for the assessment of quality of life, the Fatigue Severity

Scale (FSS) (uni-dimensional) or the Modified Fatigue Impact Scale (MSIF) (multi-dimensional) for the assessment of

fatigue, the timed up and go (TUG) or the 6 minute walk test (6MWT) for the assessment of muscle function/mobility

and hip:waist ratio or body mass index for the assessment of body composition. A measure of activity level for

people who are non-ambulatory could not be identified.

The group also recommended that these outcomes were augmented by qualitative evaluation and that an evaluation

of the cost/benefit of the exercise intervention should be included based on nationally accepted methods.

Conclusion: There is an urgent need to develop a robust outcome measure to evaluate activity levels in people who

are non ambulatory. In addition, there is a need for the research agenda in MS to extend beyond the disability focus,

to consider the effects of exercise on the prevention of secondary health problems such as cardiovascular disease

and diabetes.

The meeting was funded by the Multiple Sclerosis International Federation and supported by the MS Society.


73

Abstracts

47. Epicatechin promotes the generation of oligodendrocytes ex vivo in the mouse optic nerve

Pieropan F, Andrea D. Rivera, Asmita V. Patel, Roz Gibbs, Paul Cox and Arthur Butt


Phosphatidylinositol-3 kinase (PI3K) and its downstream target Akt are involved in a number of cell processes

including cell survival and proliferation. The flavanol epicatechin is known to be a strong antioxidant and

neuroprotective agent. Notably, a known PI3K inhibitor, LY294002, is a synthetic derivative of quercetin, a flavonol

structurally related to epicatechin.

the PI3K inhibitor LY294002 is a derivative of quercetin, a flavonol structurally related to epicatechin. We

hypothesised therefore, that epicatechin may act as pro-survival factor for oligodendrocytes. We examined this in

ex vivo optic nerve organotypic cultures. All procedures were in accordance with the Animal Scientific Procedures

Act (1986). Transgenic mice aged postnatal day (P) 35 were used in which oligodendrocyte specific genes drive

the expression of fluorescent reporters: the sox10-EGFP strain was used to identify oligodendrocytes and their

precursors (OPCs), and PLP-DsRed to identify differentiated oligodendrocytes (OLs). Mice were killed humanely

and optic nerves (ONs) with the retina intact (ON-retina) were maintained in culture for 3 days in vitro (DIV), either in

normal medium or medium containing LY294002 or epicatechin at different concentrations. At 3 DIV, optic nerves

were examined by confocal microscopy and cell counts performed in a constant field of view (FOV) and significance

determined by ANOVA followed by Bonferroni post hoc test. Compared to controls (OPCs 107 +/- 1.9 per FOV, n=

4; OLs 26.8 +/- 2.5 per FOV, n=7), respectively, epicatechin

(20μM) significantly increased OPCs (118.3 +/- 1.8 per FOV, n=4; P<0.0001) and OLs (49.5 +/- 2.2 per FOV, n=4;

P<0.0001), whereas LY294002 (50 μM) significantly decreased OPCs (87.2 +/- 1 per FOV, n=4; P<0.0001), but

statistically didn’t affect mature oligodendrocytes (47.6 +/-10.6 per FOV=4, P>0.05) .

The results denoted epicatechin had a positive effect on oligodendrocyte lineage cells which is in accordance with

the hypothesis of activating the pro-survival PI3K/Akt signalling pathway.

LY294002, as expected, decreased OPCs ex vivo supporting its role as inhibitor of the PI3K/Akt pathway. We are

currently validating this mechanism of action by Western blot analysis and molecular modelling.

Supported by HEIF.


74

Abstracts

48. Fatigue experience and salivary cortisol in everyday life in relapsing-remitting multiple sclerosis*

D. Powell, W. Schlotz, R. Moss-Morris, C. Liossi

University of Southampton

Background: Fatigue is commonly experienced in multiple sclerosis, and can have a significant impact on patient’s

daily living. Despite this, the prospective observation of fatigue in everyday life has received limited attention in past

research, and its aetiology is not well-understood. Given the regulatory role of cortisol (a hormone secreted by

the adrenal gland) in energy metabolism, any dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis would

be relevant to fatigue. The study seeks to explore the nature of everyday fatigue experience in relapsing-remitting

multiple sclerosis (RRMS) with a case-control design. We will test whether (1) mean fatigue experience is higher in

RRMS than controls; (2) day trajectories of fatigue (increase or decrease over time) is different between groups; and

(3) cortisol secretory activity is implicated in fatigue as experienced in everyday life.

Methods: Forty-four individuals with RRMS and 40 healthy controls were given a handheld device to prompt salivary

cortisol assessments via auditory alarm over four consecutive weekdays. This took place as participants went

about their usual activities. On each day, saliva samples were prompted upon awakening, and 30 and 45 minutes

afterwards, to determine the cortisol awakening response: a term describing the typical increase in HPA axis activity

upon awakening. Six further prompts were then made each day between 10.30am and 8.00pm to represent the

diurnal cortisol slope. Alongside these prompts, the device presented questions to be answered by the participant

regarding their current fatigue, stress, mood, and activity.

Analysis: Participant recruitment is now complete, but data is still being collated. Analyses will utilise multilevel

modelling (mixed effects models) to account for the hierarchical nature of the data (assessments nested within days

within individuals), and to permit tests of within-person associations.

Implications: The study contributes to our understanding of the aetiology of fatigue in RRMS, and of its experience in

everyday life.

*Selected for presentation during ‘Exercise and Physical Activity for People with MS’


75

Abstracts

49. Emotional Skills and Social Functioning in Multiple Sclerosis

Radlak B, Prof. Louise Phillips, Dr Clare Cooper, Dr Fiona Summers

University of Aberdeen

The following research is work in progress.

Multiple Sclerosis (MS) is the most common cause of brain-related illness in young adults in the UK and the

impact of MS on physical abilities, mood and cognitive functioning is well acknowledged (Calabrese et al., 2004).

However, very few studies have investigated how MS might link to problems with emotional skills. Given the pattern

of neurological problems associated with MS, it is plausible that emotional skills are particularly affected in some

people with MS. This is an important area to investigate, as problems with emotional skills have been shown to have

adverse effects on mental health, quality of life, and social relationships.

Important emotional skills include the ability to: (i) identify people’s feelings (emotion perception), (ii) understand

others’ thoughts, intentions and knowledge about the world (perspective-taking) (iii) understand and accurately

react to the emotional states of others (empathy), and (iv) regulate one’s own emotional states (emotion regulation).

These skills are essential for social engagement, mood and quality of life. Previous research has demonstrated

that difficulties in these emotional skills in clinical populations (traumatic brain injury, stroke or dementia) are linked

to lower interpersonal functioning, lower social participation, higher levels of depression and poorer quality of

life (Bornhofen & McDonald, 2008; Spell & Frank, 2000; Phillips et al., 2010). However, there has been very little

research conducted into this topic in MS. MS was found to impact on many aspects of well-being, including social

engagement (Chopra, Herrman, & Kennedy, 2008). It is therefore important to understand which factors might cause

poorer social functioning in MS, with one potential candidate being emotional skills.

The first aim to be addressed is therefore the effect of MS on a range of emotional skills outlined above (emotion

perception, perspective-taking, empathy, and emotion regulation).

The second aim concerns the links between these emotional skills and more general aspects of disease severity,

cognitive performance and mood. Of particular importance are the attentional control skills which have been shown

to be important in a range of emotional skills, such as emotion perception (Phillips et al., 2008), and perspective-

taking (Bull et al., 2008).

A final aim of the current project is to look at connections between the emotional skills and measures of social

functioning and quality of life in MS. This will include an assessment of social participation, activity limitations,

information about participation and satisfaction in social relationships, and subjective assessment of satisfaction with

social functioning.

Approximately 70 participants with MS will be recruited from NHS Grampian and assessed on behavioural measures

of emotion perception, perspective-taking, empathy and cognitive functioning. Participants will also be assessed

on questionnaire measures of emotion regulation, mood, social participation and quality of life. This research is

approved by the NHS Research Ethics Committee and data collection is underway.

Considering the importance of emotional skills on social participation and well-being, the results from this study will

be used to guide interventions to improve emotional skills for people with MS.


76

Abstracts

50. The role of pro-inflammatory cytokines in grey matter pathology in MS

Reynolds R, Renee Schalks, Eleanor Browne, Christopher Gardner, Djordje Gveric, Federico Roncaroli

Division of Brain Sciences, Imperial College London

Introduction: Secondary progressive multiple sclerosis (SPMS) is characterised by an accumulation of chronic

neurological disability, suggested to be driven in part by cortical grey matter pathology. Subpial demyelinated

lesions in the grey matter are associated with the presence of tertiary lymphoid organ-like (TLO) structures within

the meninges and the subsequent diffusion of pro-inflammatory cytokines may be responsible for the underlying

pathology. Because increasing meningeal pathology is linked to a more severe disease course, it is important to

identify the cytokines involved.

Methods: In order to test this hypothesis we are developing an animal model of cortical demyelination driven by

meningeal inflammation involving chronic delivery of cytokines into the subarachnoid space (SAS) of the rat brain.

Dark Agouti rats were immunised with a subclinical dose of the myelin protein, myelin oligodendrocyte glycoprotein

(rmMOG) followed 21-23 days later by stereotaxic injection of the proinflammatory cytokines tumour necrosis factor

(TNF), lymphotoxin alpha (LTa), with or without interferon –gamma (IFNg), into the meningeal space overlying the

cerebral cortex. This was designed to mimic the situation found in the MS brain. The effect of the cytokines on the

various cellular components of the meninges (T-cells, B-cells and macrophages) and the underlying tissue (myelin,

oligodendrocytes, astrocytes, microglia and neurons) was then analysed using immunohistochemistry.

Results: Meningeal inflammation was substantially increased in MOG-immunised animals injected with LTa ±

IFNg, to a greater extent than those injected with TNF + IFNg. Large T cell-rich aggregates were observed in

the subarachnoid space of animals receiving LTa. Acute subpial demyelinating lesions were formed following the

injection of both LTa ± IFNg and TNF + IFNg, similar to those seen in MS. In order to mimic the chronic inflammatory

conditions seen in the MS meninges we have carried out pilot experiments to try to deliver the cytokines over

a prolonged period using lentiviral delivery. When a VSV-G pseudotyped lentiviral (LV) vector carrying the green

fluorescent protein (GFP) gene was injected into the subarachnoid space of naïve rats, the LV vector induced

extensive and long term GFP expression up to 3 months after injection in the area surrounding the injection site.

Expression was localised to epithelioid cells of the meninges, subpial astrocyte end feet and a small number of

pyramidal neurons. The distribution and length of expression achieved using the LV vector appeared optimal for

achieving the chronic bathing of the surface of the cerebral cortex in pro-inflammatory cytokines required to develop

this novel model.

Conclusions: Our results suggest that LTa and TNF produced as a result of meningeal inflammation may both

perpetuate the inflammation and also cause sub-pial pathology similar to that seen in MS. Therefore, the therapeutic

modulation of inflammation in the meninges by down-regulating these pro-inflammatory cytokines represents a new

possible avenue for treatment in progressive MS.


77

Abstracts

51. Using routine point-of-care data for research: The East London Multiple Sclerosis Cohort

Richards O, Christo Albor, Sreeram Ramagopalan, Klaus Schmierer

Barts and The London School of Medicine and Dentistry

Background: Few geographically-linked datasets of people with multiple sclerosis (MS) exist in the UK. The

development of these datasets enriched with clinical information would aid in testing etiological hypotheses,

comparing disease progression between treatment regimes, and recruiting clinical trial participants. The population

in East London (defined here as The City, Hackney, Tower Hamlets, and Newham) is of particular interest because of

its ethnic mix, which is reflected by its population with MS.

Methods: Identifying cases: Based on existing outpatient clinic lists at The Royal London Hospital, a list of MS

patients was created on ‘Cerner Millennium Software’ (CRS). MS patients that were matched to the PCTs of Tower

Hamlets, Newham, and City & Hackney formed our East London MS Cohort.

Phase 1 of coding clinical data (ongoing): Scanned clinical letters are manually searched to code key variables on

each patient’s CRS hospital

record: MS course, year of onset, first symptoms, and whether on disease-modifying treatment.

Phase 2 of coding clinical data (ongoing): When patients attend outpatient clinics, they are given questionnaires

asking for further MS-related information. Completed questionnaires combined with updates from consulting

clinicians are used to code further variables on patients’ CRS hospital records.

Preparing data for analysis: Coded clinical data of MS patients are extracted from CRS hospital records using the

CRS ‘Explorer Menu’. This data is then anonymised in the secure network, before analysis with Stata statistical

software.

Results: 1,230 MS patients attending the Royal London outpatients department have been identified. 451 of these

patients make up our East London MS Cohort. They account for 60% of the count of MS patients identified by GP

records.

The mean age of the cohort is 48 and there is a 2.4:1 female:male ratio. 62% are White, 16% Black, 9% Asian,

13% Other. This shows an over-representation of White MS patients relative to the area’s population. Based on GP

counts crude prevalence of MS per 100,000 was 145 for White, 78 for Black, 28 for South Asian, 18 for Other and

92 overall).

Currently, data coding of all MS patients using the outpatient service is in progress. Whilst disease course has been

coded in 50% of our cohort by now, the remaining items of interest have been coded for approximately 20% of

patients.

Conclusion: The demographic characteristics of White MS patients in our cohort are very similar to those recently

described in another UK-based geographically-linked MS cohort of 620 patients in Wales which was 97% White.

The authors described a mean age of 51, a female:male ratio of 2.4:1, and a prevalence of 146 per 100,000 (Hirst,

et al. 2009). What is thus unique to our cohort is its ethnic diversity, allowing us to explore the prevalence of MS in

ethnic minorities. Once coding is complete the dataset will enable further studies into the epidemiology of MS such

as the effect of migration and other factors with impact on the risk of developing MS, and treatment outcomes.

Reference: Hirst C, et al. J Neurol Neurosurg Psychiatry 80: 386–91.


78

Abstracts

52. Lithium generates oligodendrocytes ex vivo in the mouse optic nerve.

Rivera A, A.Butt


The loss of oligodendrocytes (OLs) followed by their regeneration is a hallmark of relapse-remitting multiple sclerosis

(MS). Regeneration of OLs is the function of a significant population of oligodendrocyte precursor cells (OPC) that

persist in the adult brain. Understanding the mechanisms that regulate OL regeneration is therefore of potential

benefit for identifying therapeutic interventions. On a previous MS Society grant, we provided evidence that glycogen

synthase kinase 3-ß (GSK3ß) is a potent negative regulator of multiple pathways that regulate OL proliferation,

survival and differentiation in the developing brain (Azim & Butt, 2011). A key finding was that lithium, a potent but

non-specific inhibitor of GSK-3 ß, was far more effective than the specific GSK-3 ß inhibitor ARA-014418. Presently,

we are examining the mechanisms of action of lithium in adult optic nerves, in organotypic cultures. Adult transgenic

mice were used in which OL-lineage specific genes drive the expression of fluorescent reporters: Sox10-GFP

for OLs and OPCs, and PLP-DsRed for differentiated OLs. All procedures were in accordance with the Animals

Scientific Procedures Act (1986). Mice were killed humanely and optic nerves (ONs) with the retina intact (ON-retina)

were isolated and maintained in organotypic culture conditions for 3 days in vitro (DIV) in normal medium or medium

containing Lithium (20mM). Lithium dramatically increased Sox10+ and PLP+ OLs compared with control (p<0.05,

unrelated t-test), indicating a positive effect on pathways regulating OL proliferation, survival and differentiation;

the effects of lithium were significantly different than treatment with ARA-014418m or Wnt3a, which inhibits GSK3β

via the canonical Wnt-β-catenin pathway. The results suggest that, in addition to inhibiting GSK3β, lithium acts

via pathways that regulate OL generation in the adult. To examine this, we performed a genome-wide microarray

analysis of optic nerves following the different treatments. The results indicate that lithium specifically and significantly

down-regulated the Wnt signalling pathway and ID (inhibitor of differentiation) proteins, which are negative regulators

of OL differentiation. Western blot analysis demonstrated that lithium dramatically down-regulated Pdgfra, a

marker for OPCs, and significantly increased the transcription factors Olig2 and Sox10, which are essential positive

regulators of OL differentiation and targets of ID2/4. The results identify potential pathways by which lithium

promotes the generation of OL in situ in the adult CNS.

Andrea Rivera is supported by an Anatomical Society PhD Studentship


79

Abstracts

53. Human ES-derived OPCs fire action potentials and respond to RXR signalling at physiological oxygen tensions.

Stacpoole S, S Spitzer, B Bilican, A Compston, R Karadottir, S Chandran, R Franklin

Cambridge University

An understanding of the biology of the oligodendrocyte lineage, and in particular the signals which promote

oligodendrocyte precursor cell (OPC) differentiation and myelination, could lead to new therapeutic approaches

to repair in Multiple Sclerosis (MS). Human embryonic stem cells (hES), by virtue of their pluripotentiality and

ability to self-renew, represent a potentially unlimited source of oligodendrocyte lineage cells. The first step is to

generate neural precursor cells (NPCs), which can be achieved through the default model of neural conversion.

Developmentally, OPCs arise from the well characterised pMN domain of the spinal cord, with around a 20%

contribution from the dorsal cord, and from three distinct areas of the forebrain marked by expression of Nkx2.1,

Gsh2 and Emx1. These insights allow rational application of morphogens such as sonic hedgehog, retinoic acid and

fibroblast growth factor-2 to direct hES-NPCs, which have a default dorsal and rostral identity, towards a regional

identity from which OPCs can arise.

We have established a novel system to achieve the specification of NG2/PDGF-Rβ/OLIG2+ OPCs at low,

physiological (3%) oxygen, from both forebrain and spinal cord origins, with up to 98% of cells expressing NG2.

These OPCs can mature to express O4 (38%) and subsequently into GALC, O1 and MBP+ oligodendrocytes, in

coculture with hES-derived neurons.

MBP+ Investigation of the electrophysiological properties of human OPCs shows similarities to rat OPCs, with

large voltage-gated sodium currents and the ability to fire action potentials. Application of a selective RXR agonist

to human OPCs increases the proportion of O4+ oligodendrocytes that express MBP+ from 5% to 30%. Thus,

we have established a developmentally engineered system in which the effects of putative agents to enhance

remyelination can be tested on human cells prior to clinical application.


80

Abstracts

54. Improving the outpatient experience for people with multiple sclerosis by engaging focus group to envisage the future.

Thomson A, Carol C Rivas, Tosh T Denholm, Gavin G Giovannoni

Queen Mary, University of London

Introduction: The NHS has put great effort into service redesign, improving information and the patient experience

for people with long-term conditions, although the MS Trust reported in 2011 that little has changed within MS

services. This study aims to improve the outpatient experience for people with multiple sclerosis (PwMS) who

attend the outpatient department at The Royal London Hospital (RLH). Objectives are to: first engage PwMS and

outpatient staff to participate in focus groups; second, analyse the data derived to produce clinic information for

future users of the service; third, determine points in the patient journey to improve information dissemination.

Relevance: In 2011 the MS Society reported the general direction of care for PwMS has overall been moving

towards supporting people to remain independent and to enable them to manage their condition themselves.

The RLH outpatient department aims to follow this by empowering and supporting PwMS when attending clinic.

Creating a multi-disciplinary group of participants with diverse perspectives and knowledge of the outpatient service

will increase the chance of generating innovative ideas.

Methodology: Qualitative study using focus groups consisting of PwMS separately from and alongside staff nurses,

nursing assistants, junior sisters and reception staff. Session One: discussions around the current experience of

being treated and working in the RLH, recording feelings as contours on an OS Map of the patient journey. Session

Two: discuss an ideal journey (like going on holiday) to illustrate the stages of a pleasurable experience, broken

down into: (1) preparation, (2) check-in, (3) wait, (4) destination, (5) departure, (6) returning home. Props are used

to prompt discussions about the interactions within this ideal journey. Session Three: redesign the ideal service

interactions to the outpatient clinic.

Results: 5 PwMS and 12 outpatient staff members contributed to 3 focus group sessions. Regardless of staff time

constraints, all staff invited contributed to the project sharing their feelings, stories and suggestions. The physical

props enhanced the interaction between PwMS and staff, stimulating discussion, gaining insights and generating

ideas to pursue topics in greater depth. The initial metaphor was successfully adopted by the participants and

catalyzed another 7 metaphors of service experiences. The entrepreneurial engagement of the service users

increased the validity of the design proposals and potentially adoption of the improvements. Staff highlighted

potential practical problems whereas patients ensured ideas were holistic.

Suggestions included a patient ‘chat room’ in clinic, service crib sheets and outpatient staff training on MS.

Conclusion: This proof-of-concept study employed creative methods of visual mapping, metaphors and physical

‘props’ to engage participants to speculate about future health experiences and interactions. Feedback from

participants and collected data showed the success in uptake of the props was due to the design and attention

to detail in crafting the metaphor of an ideal journey. This contributed to the participants valuing the activity and

investing their own ideas and feelings in the service improvement activity.

Metaphors enabled participants to remove themselves from current financial, organisational and physical constraints,

enabling them to suggest sustainable improvements for the outpatient clinic.


81

Abstracts

55. Characterising the transcriptomic and proteomic profile of astrocytes in normal appearing white matter in multiple sclerosis

Waller R, P.R. Heath, M.N. Woodroofe, S. Francese, S.B. Wharton, P.G. Ince, N.P.

Rounding, B. Sharrack*, J.E. Simpson* (*Joint senior author)

University of Sheffield

Introduction: Multiple sclerosis (MS) is a chronic, neuroinflammatory demyelinating disease of the central nervous

system (CNS). Typical white matter lesions in MS are surrounded by areas of non-demyelinated normal appearing

white matter (NAWM) with complex pathology, including blood brain barrier dysfunction, axonal damage and glial

cell activation. Astrocytes, the most abundant cell type within the CNS, may respond and/or contribute to MS. We

aimed to investigate the transcriptomic and proteomic profile of astrocytes in NAWM to determine whether specific

astroglial changes exist in the NAWM compared with control WM, which contribute or prevent lesion development.

Materials and methods: An enriched population of GFAP+ astrocytes from snap frozen, post-mortem control

WM (5 cases) and NAWM (5 cases), were isolated using laser capture microdissection. RNA extracted from

approximately 1,000 GFAP+ cells was amplified, labelled and hybridised to Affymetrix Human Genome U133 Plus

2.0 gene microarrays. The chips were scanned using a GC30007G scanner and the data processed using the

GCOS and GeneSpring 11x software (Agilent). The Database for Annotation Visualisation and Integrated Discovery

(DAVID) was used to group genes according to their function and identify functional pathways. Ongoing validation is

being carried out on candidate genes using qRT-PCR, immunohistochemistry and matrix-assisted laser desorption

ionization mass spectrometry on 5 additional control and 5 MS cases.

Results: GFAP+ astrocytes isolated from MS NAWM showed a significant GFAP+ up-regulation of genes involved

in protection against oxidative stress and iron metabolism, including metallothionein I-II, ferritin and transferrin,

compared to astrocytes from control cases.

Conclusions: Altered regulation of iron homeostasis and response to oxidative stress in NAWM may reflect adaptive

changes associated with the pathogenesis of MS white matter lesions. An understanding of the role of astrocytes

within the NAWM could lead to identification of novel therapeutic targets for treatments in MS.


82

Abstracts

56. MicroRNA-146a suppresses leukocyte adhesion through inhibitting NFkB activation

D Wu, C Cerutti, M Lopez-Ramirez, G Pryce, J King-Robson, D Baker, G Michael, M Hirst, D Male, I Romero

The Open University

Blood-brain barrier (BBB) dysfunction is a hallmark of inflammatory neurodegenerative diseases such as multiple

sclerosis. BBB mainly formed by cerebral endothelial cells, BBB dysfunction is characterised by increased

permeability, increased leukocyte adhesion to cerebral microvasculature and migration into cerebral parenchyma.

BBB dysfunction is manifested by decreased expression of tight junction molecules (e.g. ZO-1, claudin-5) and

increased expression of adhesion molecules (e.g. ICAM-1, VCAM-1) and chemokines (e.g. CCL2, CXCL10) in brain

endothelial cells, however the underlying molecular mechanisms remain elusive. Proinflammatory cytokines such

as TNFa and IFN? and one of their downstream signalling molecules NFkB have been shown to play an important

role in BBB breakdown. MicroRNAs (miRNAs) have recently emerged as key regulators of cellular function and

pathogenic responses through inducing target gene silencing. MiRNA-146a (miR-146a) has been demonstrated

as a NFkB-dependent gene and a negative regulator of NFkB in human monocytes. Here, we have identified the

protective role of miR-146a in leukocyte adhesion through inhibiting NFkB signalling in human cerebral endothelial

cells via suprressing the expression of IRAK1 and TRAF6.

57. The Influence of HLA-DRB1 on Cortical Demyelination in Multiple Sclerosis*

Yates R, Margaret M Esiri, Jacqueline Palace, Gabriele C DeLuca


Background: Multiple Sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous

system, and displays marked clinical variability. Evidence suggests that the HLA-DRB1 locus may influence clinical

outcome. Cortical pathology is common in MS, often occurs early in disease, and correlates with measures of

clinical disability, including cognitive impairment. Currently available MRI techniques are unable to visualise the full

extent of disease affecting the cortex, and thus the utilization of post-mortem tissue is necessary to study disease

here. The influence of HLA-DRB1*15 on cortical pathology is unknown, and is the subject of the current study.

Methods: A post mortem cohort of pathologically confirmed MS cases (n= 44, 11

males) was used. HLA-DRB1 alleles were genotyped to select a subset of age- and sex-matched HLA-DRB1*15+ (n=19)

and HLA_DRB1*15- (n=25) cases for detailed pathologic analyses. For each case, adjacent sections from the motor cortex

were stained for myelin and microglial inflammation, to evaluate the extent and type of cortical pathology.

Results: In our cohort, evidence of cortical myelin loss was common (occurring in 43/44 cases (98%)). Absolute

demyelination was more pronounced in those patients that died younger (r = -0.333, p = 0.027), and this occurred

independently of disease duration. Interestingly, the effect of age on the extent of cortical demyelination was

restricted to HLA-DRB1*15+ patients (r = -0.612, p=0.005), with no such relationship observed in HLA-DRB1*15-

patients. On evaluation of cases with an age of death less than the median age of death (<61 years), the extent

of cortical demyelination was significantly greater in HLA-DRB1*15+ compared to HLA-DRB1*15- cases when

controlling for age, gender, and duration of disease (p=0.01).

Conclusions: In summary, our preliminary data suggests that HLA-DRB1*15 status has a significant impact on

the extent of cortical demyelination in younger patients. This study highlights the utility of microscopic pathology in

elucidating the way in which genes and clinical phenotypes of neurologic diseases are linked. Future work aimed at

discovering the mechanisms by which HLA-DRB1*15 influences cortical demyelination will be necessary to identify

therapeutic targets that may impact long-term outcome.



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