Danish Multiple Sclerosis Center Annual Report 2011

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1 Department of Neurology THE Neuroscience Centre Copenhagen University Hospital Rigshospitalet Copenhagen, Denmark Danish Multiple Sclerosis Center Annual Report 2011

2 DMSC staff seminar DANISH Multiple sclerosis CENTER annual report 2011

3 Table of contents Annual Report A short review of 2011 in the Danish Multiple Sclerosis Center DMSC missions and aims Global Excellence in Health About the Danish Multiple Sclerosis Center Organization diagram Research activities 2011 Clinical research Neuroimaging Neurogenetics Neuroimmunology Routine analyses in Neuroimmunology Laboratory Scientific publications Peer reviewed original papers 2010 Peer reviewed original papers 2011 Prizes Honorary offices Scientific collaboration National International Collaboration with pharmaceutical companies Acknowledgements DANISH Multiple sclerosis CENTER annual report

4 Publisher: Danish Multiple Sclerosis Center Authors: Per Soelberg Sørensen Morten Blinkenberg Finn Sellebjerg Annette Oturai Helle Bach Søndergaard Poul Erik H. Jensen Photos: Morten Blinkenberg Per Witt Joachim Rode Dorthe Stauning Rasmussen Concept, design, graphic production and print: Datagraf St. Kongensgade København K Tlf DANISH Multiple sclerosis CENTER annual report 2011

5 Professor Per Soelberg Sørensen, MD, DMSc Director of the Danish Multiple Sclerosis Center (DMSC) A short review of 2011 in the Danish Multiple Sclerosis Center The Danish Multiple Sclerosis Center is a large multidisciplinary MS centre offering individualized MS therapy, including highly specialized therapies, to a large number of patients in the Capital Region of Denmark and other parts of Zealand. Many patients have been referred for treatment with either monthly infusion of Tysabri or initiation of treatment with the first oral therapy for multiple sclerosis, Gilenya tablets. In particularly the physical premises have not met the requirement of a modern efficient MS clinic and fortunately improvement of the premises of the MS Clinic has been initiated in Our patients, and in particular our patients receiving Tysabri infusions, have uncomplainingly put up with the cramped space in the infusion facilities. We look forward to have a more spacious room in We have further developed our core elements in our efforts to establish new therapies based on our research in biomarkers of therapeutic response, which have resulted in discovery of several molecules that might be implemented in the daily clinical practice. We have been involved in a worldwide genetic association study that has established more than 100 genetic markers for the susceptibility of multiple sclerosis, and the results were presented in the highly esteemed scientific journal Nature. This research was awarded the prize of the most important research accomplishment in 2011 in Denmark. The NeuroImmunology Laboratory has extended the services to all MS Clinics in Denmark and performs measurements of neutralizing antibodies against interferons and Tysabri and determination of the presence of CSF oligoclonal IgG-bands, which is of major importance in the diagnostic work of a patient. In August 2011 The Danish Multiple Sclerosis Center was awarded Global Excellence of Health This was a major accomplishment as only 5 out of 29 applicants among research centres and hospitals departments at hospitals and universities in the Capital Region of Denmark were awarded Global Excellence in Health. All together, Danish Multiple Sclerosis Center serves at a model of a strong synergy between research, development and treatment of MS and thereby holds an international prominent position and contributes to establish neuroscience as one of the strongest areas in Denmark. I hope you will enjoy reading the annual report of DMSC. Per Soelberg Sørensen DANISH Multiple sclerosis CENTER annual report

6 DMSC missions and aims The mission of Rigs hospitalet is to be the leading hospital in Denmark for patients in need of highly specialized treatment The missions of the Danish Multiple Sclerosis Center (DMSC) are: The aims of the DMSC are: to be the leading multiple sclerosis (MS) center in Denmark to be at the forefront of highly specialized management of MS to carry out research and development in MS at an advanced international level to collaborate scientifically and exchange knowledge in MS research to educate staff to a highly specialized level in their relevant fields to contribute with professional advice on MS to the healthcare community to meet people with MS at their terms with openness and respect to provide the optimal interdisciplinary patient care to all MS patients in the region and to patients from other regions in need of highly specialized therapy to carryout high quality research in MS with focus on clinical research, new therapies, MS genetics, neuroimmunology and MS pathology to teach undergraduate students and PhDstudents and stimulate their interest in MS research to educate post docs, MS physicians, nurses, secretaries and other professionals to a high level of knowledge of MS in their relevant expert fields to lead the national research in Denmark in partnership with other Danish researchers and to establish a broad international collaboration with MS research groups in Europe and from overseas. 6 DANISH Multiple sclerosis CENTER annual report 2011

7 Global Excellence in Health The Capital Region of Denmark has established the development programme Global Excellence in Health with the objective to promote highly qualified professional environments of international standard within Health, both at universities and at hospitals in the Region. With globalisation, the Capital Region of Denmark is in a situation of continually increasing competition also as regards health care services. The appointment of Centres of Global Excellence aims at highlighting world class research environments at the regional hospitals and universities whose contributions towards improving health care services can be recognised as absolutely world class. Patients will benefit more effectively from results from fundamental research and development at the universities, when the collaboration between elite environments across universities, hospitals and the industry and business sector in the Region is intensified Thus, Global Excellence in Health is an international quality mark for the respective units. The award was presented to professor Per Soelberg Sørensen on behalf of the Danish Multiple Sclerosis Center on August 23, The international adjudicating committee gave as reason for the award, that the Danish Multiple Sclerosis Center represents a large multidisciplinary MS Clinic and research unit that offers a series of highly specialized functions. They are at the forefront using combinations of traditional and new treatments for multiple sclerosis and the results of their research has been established as therapeutic practice all over the world. The Danish Multiple Sclerosis Center is leading regarding tests for antibodies against biopharmaceuticals and their work has formed the basis for the development of international guidelines. The adjudicating committee has concluded that the Danish Multiple Sclerosis Center has a leading position, both at a national and international level. They perform relevant new clinical research and have an impressive international collaboration and influence and in particular the amount and quality of innovation and collaboration with the industry is striking. DANISH Multiple sclerosis CENTER annual report

8 About The Danish Multiple Sclerosis Center 8 DANISH Multiple sclerosis CENTER annual report 2011

9 DANISH Multiple sclerosis CENTER annual report

10 The Danish Multiple Sclerosis Center About The Danish Multiple Sclerosis Center The Danish Multiple Sclerosis Center (DMSC) is offering highly specialized therapy and is the leading centre for MS research in Denmark. Together with our Danish collaborators we are providing the vast majority of clinical and translational MS research in Denmark, and we collaborate with MS researchers from all over the world. DMSC is composed of a multidisciplinary MS clinic and a research unit. The MS Clinic is located at the 8th floor of the main complex of Rigshospitalet where the offices of the professor and consultants, the nurses offices, the reception desk and the secretary offices as well as the outpatient consultation rooms and facilities for intravenous therapy with disease modifying drugs and rooms for invasive procedures. In 2012 we will refurbish the area and get more spacious rooms for our patients and staff working in the MS clinic. DMSC provides a multidisciplinary care for approximately 2000 MS patients, and offers both basic and highly specialized therapy. The National Board of Health has appointed DMSC to perform highly specialized therapy with strong immunosuppressants and experimental therapies, and we have the regional function for treatment with the second generation of MS ACtive patients in DMSC therapies, Tysabri and Gilenya tablets. DMSC is a centre for children and adolescence with MS in Eastern Denmark and has a highly specialized function in treating neuromyelitis optica, once thought to be a variant of MS, but now considered to be a separate disease entity. DMSC also offers treatment of severe spasticity with an intrathecal baclofen pump, not only to patients with MS but also to other patients with diseases or traumatic injuries causing severe spasticity. It is the aim of the MS Clinic to provide high quality multi-disciplinary care for all our patients with openness and respect. The staff comprises a professor, 5 consultants, 2 staff neurologist and several external consultants working part time in the MS Clinic. There is one leading nurse and 9 MS specialist nurses, 4 secretaries, a neuropsychologist, a physiotherapist and a medical social counsellor. We serve patients from the Copenhagen capital region and many patients from neighbouring regions and from all over Zealand are referred for regional and highly specialized therapy. The MS Research Unit is partly located in the proximity of the MS Clinic, where most patients related to clinical research takes place and where the offices of 3 research nurses and 1 research secretary are embedded. The remaining part of the MS Research Unit is located on the first floor in the Michaelsen Building 63 and in the basement of building 93. These facilities contain the Neuroimmunology Laboratory and offices for the research staff. The laboratory is equipped with an 8-colour flow cytometer and facilities for doing real-time polymerase chain reaction (PCR). Further, the facilities contain the MS Biobank and the neurogenetics laboratory for DNA preparation and facilities for making routine tests. The focus of the research in DMSC is clinical research including neuroimaging, neuroimmunology, neurogenetics and, in particular, translational research aiming at implementing the findings in neurogenetics and immunology into new therapies of MS. 10 DANISH Multiple sclerosis CENTER annual report 2011

11 DANISH Multiple sclerosis CENTER annual report

12 Organization Danish Multiple Sclerosis Research Center Director: Professor Per Soelberg Sørensen MS clinic MS Research Unit Neurologists Professor Per Soelberg Sørensen Consultant Morten Blinkenberg Consultant Finn Sellebjerg Consultant Annette Oturai Consultant Karen Schreiber Consultant Ana Voldsgaard Staff neurologist Henrik Mathiesen Staff neurologist Melinda Magyari PhD student Stephan Bramow PhD student Lars Börnsen PhD student Jeppe Romme Christensen PhD student Rikke Ratzer PhD student Julie Maria Hejgaard Part time physician Kristin Sjølie Thygesen Part time physician Michael Lund Part time physician Mikkel Anthonisen Part time physician Morten Møller Part time physician Sarah Taudorf MS nurses Leading nurse Anne Hansen Dorthe Stauning Rasmussen Anette Husted Pedersen Lene Almind Julie Yoon S. Moberg Louise Nathalie Christiansen Maj Daae Christensen Sidsel Nielsen Mette Olesen Eva Radau Clinical research Professor Per Soelberg Sørensen Consultant Karen Schreiber Consultant Ana Voldsgaard Neuropsycologist Agnete Jønsson Staff neurologist Melinda Magyari Research nurses Vibeke Jespersen Joan Pietraszek Sidsel Nielsen Research secretary Annette Larsen Neuroimaging research Consultant Morten Blinkenberg Staff neurologist Henrik Mathiesen Genetic research Consultant Annette Oturai Senior research fellow Helle Bach Søndergaard Neuroimmunology research Ass. professor Finn Sellebjerg Senior research fellow Helle Bach Søndergaard PhD students Lars Börnsen Jeppe Romme Christensen Rikke Ratzer Julie Maria Hejgaard Junior research fellow Marianne Hansen Neuroimmunology Laboratory Laborarory leader Poul Erik Hyldgaard Jensen Laboratory technicians Leading Laboratory technician Joy Mendel-Hartvig Michael Jensen Vibeke Lindgaard Fuglholt Rikke Larsen Secretaries Annette Larsen Malene Møllesøe Kristina Egel Rasmussen Helle Vilhelmsen Neuropsychologist Agnete Jønsson Physiotherapist Lis Albrechtsen Medical social counselor Keld Nissen 12 DANISH Multiple sclerosis CENTER annual report 2011

13 Professor Per Soelberg Sørensen Ass. professor Finn Sellebjerg Consultant Morten Blinkenberg Consultant Annette Oturai Consultant Karen Schreiber Consultant Ana Voldsgaard Staff neurologist Henrik Mathiesen Staff neurologist Melinda Magyari Laboratory leader Poul Erik Hyldgaard Jensen Senior research fellow Helle Bach Søndergaard Leading laboratory technician Joy Mendel- Hartvig Leading nurse Anne Hansen DANISH Multiple sclerosis CENTER annual report

14 Research activities 2011 Clinical research Clinical research Neuroimaging Neurogenetics Neuroimmunology Neuropathology Routine analyses in Neuroimmunology Laboratory 14 DANISH Multiple sclerosis CENTER annual report 2011

15 DANISH Multiple sclerosis CENTER annual report

16 Research activities 2011 Clinical research Clinical research group: Per Soelberg Sørensen, Morten Blinkenberg, Finn Sellebjerg, Annette Oturai, Ana Voldsgaard, Karen Schreiber, Henrik Mathiesen, Melinda Magyari, Lars Bornsen, Jeppe Romme Christensen, Rikke Ratzer, Julie Maria Hejgaard, Agnete Jonsson, Vibeke Jespersen, Joan Pietraszek, Sidsel Walther Nielsen, Anne Hansen, Annette Larsen. Therapeutic trials In 2011 we published the results of the SIMCOMBIN study, which is a Nordic multi-centre study directed from DMSC and conducted in 42 MS Centres in Denmark, Norway, Sweden and Finland. The study investigated simvastatin as add-on therapy to interferon-beta in de novo treated patients with relapsing-remitting MS. More than 300 patients participated in the trial. Unfortunately the results showed that there was no benefit of add-on of simvastatin to interferon-beta. We have in 2011 completed another combination treatment trial, which is a multi-centre European trial exploring the effect of Minocycline as addon therapy to interferon-beta in de novo treated patients. The results will be reported at the ECTRIMS congress in October We are currently performing several single-centre studies in patients with progressive MS in order to try to find treatment options for this phase of the disease that currently lags effective therapy. In this regard we study the effect of erythropoietin (EPO) on disability in patients with progressive MS and the aim is to include 56 patients and to finalize inclusion in spring We have performed a small safety study with eggs of the pig whipworm (Trichuris suis) taken orally every 2 weeks. This small trial has been completed, and the data was presented at the American Academy Meeting in April Unfortunately, we could not show any beneficial effects of treatment with Trichuris suis eggs neither as add- on to interferonbeta therapy or as mono-therapy. Hence, in the light of the negative results we have abandoned the start a larger phase II trial with inclusion of 80 patients. We have completed a small study investigating the in vivo biological response to interferon-alpha in MS patients, who have developed neutralizing antibodies against interferon-beta. We are able to demonstrate that a number of genes, which usually respond to injection of interferon-beta, could be elicited by injection of interferon-alpha, although the patients no longer had a response to interferon-beta. Hence, interferon-alpha could be a therapeutic option in these patients. Furthermore, we have conducted an exploratory trial of natalizumab (Tysabri) in patients with progressive MS and the results are currently being examined. Recently, we have initiated a similar trial investigating the effect of monthly cycles of methylprednisolone tablets. 16 DANISH Multiple sclerosis CENTER annual report 2011

17 In addition to these investigator-driven therapeutic trials, DMSC are taking part in clinical trials of new drugs sponsored and driven by the pharmaceutical industry. We are currently involved in trials of new indications for treatment with fingolimod and natalizumab, and we are involved in the development of three new monoclonal antibodies Alemtuzumab, Daclizumab, and Ofatumumab with strong effects on disease activity, and we take part in the assessment of a drug that improve gait function, Fampridine. Other clinical research trials In collaboration with the Danish MS Register we performed a study of changes in prevalence, incidence, and sex-ratio through the last decades and observed increased incidence rates, apparently confined to women, and demonstrated the dismissal of a true latitudinal gradient on the northern hemisphere. The collaboration has continued and currently we are investigating the increasing incidence in women. Whereas the incidence of MS has been almost unchanged in men, it has doubled in women since We are performing extensive analysis of possible factors that might have contributed to the increase of MS in women. We will explore demographic factors, such as changes in working conditions, marital status, childbirth, smoking habits and vitamin D intake. In 2010 we initiated a study exploring the role of vitamin D on clinical disease activity in MS. Vitamin D seems to yield some protection against encountering MS and may also influence the disease activity in established MS. DMSC is among the leading centres in the world regarding studies of antibodies against biological agents. We have extensively studied the effect of neutralizing antibodies against interferon-beta, most recently in an EU supported European study of neutralizing antibodies against interferon-beta (NABINMS study). We have introduced a new assay for detecting neutralizing antibodies based on a luciferase reporter gene under control of interferonbeta, and we have recently studied the relationship between antibodies binding to interferon-beta and antibodies neutralizing interferon-beta. Recently, we have published the results of an international study of the frequency of occurrence of antibodies against natalizumab together with MS centres in Sweden, Norway and Germany. We were able to show that fewer patients developed persistent antibodies against natalizumab compared with the observation in clinical studies. We have also shown that the propensity to develop antibodies against interferon-beta does not carry an excess risk of developing antibodies against natalizumab. We have concluded a study of titres of antibodies against natalizumab and have demonstrated that the titre already 3 months after start of natalizumab therapy predicts if a patient will develop permanent antibodies against natalizumab and, therefore, would have to stop natalizumab therapy. DANISH Multiple sclerosis CENTER annual report

18 Research activities 2011 Neuroimaging Neuroimaging research group: Morten Blinkenberg, Henrik Mathiesen, Per Soelberg Sørensen CCSVI Multiple sclerosis (MS) is considered to be an inflammatory, demyelinating disease of the central nervous system, characterized by autoreactive lymphocytes crossing the blood-brain barrier, initiating an autoimmune reaction that eventually leads to tissue damage and neuronal degeneration. Recently, an alternative hypothesis regarding the pathogenesis of MS has been proposed, suggesting an association between MS and extracranial venous stenoses: Chronic cerebrospinal venous insufficiency (CCSVI). It has been claimed that the use of extracranial high-resolution echo-colour doppler (US-CD) and transcranial colour doppler sonography (TCDS) offers 100% sensitivity and 100% specificity in discriminating patients with MS from controls. Yet other reports have questioned the presence of CCSVI as an MS specific pathological entity and have incorporated the use of sonography (US-CD and TCDS), phase contrast and contrast enhanced MRI venography, as well as conventional selective venography. These studies have either failed to find evidence for CCSVI in MS patients, or have not been able to use the presence of CCSVI to reliably distinguish MS patients from controls or MS from other neurological diseases. Prompted by these conflicting results, we have initiated an investigator-blinded study in which we compare US-CD and TCDS with magnetic resonance imaging (MRI) of the cervical veins and phase contrast MR blood flow measurements. In this way we aim to clarify, if an evaluation of Danish MS patients compared with matched healthy control subjects, shows characteristic CCSVI changes and fulfil the diagnostic criteria, and furthermore compare the possible changes, with changes in MRI measures of flow and morphology. Resting-state fmri Resting-state fmri is a new approach to assess functional brain connectivity by measuring the synchronous fluctuation in the blood-oxygen-level dependent signal between remote brain regions at rest. In collaboration with Danish research Centre for Magnetic Resonance, PhD-student Anne- Marie Dogonowski uses this method to study motor resting-state connectivity in MS. One study examines how MS affects the inter-regional motor resting-state connectivity and another study examines motor resting-state connectivity with increasing clinical disability in MS. Furthermore, two ongoing studies are examining the changes in local connectivity in MS and the longitudinal changes in resting-state motor connectivity during the recovery from an acute motor relapse. Preliminary results show, increased coupling between premotor cortex and the motor network, which might reflect an adaptive mechanism to maintain motor function with increasing clinical disability. These data highlight the potential of resting-state fmri to study disease-related functional reorganization of distinct brain networks in multiple sclerosis and encourage further research in this field. 18 DANISH Multiple sclerosis CENTER annual report 2011

19 Neurogenetics Neurogenetics research group: Annette Bang Oturai, Helle Bach Søndergaard, Julie Hejgaard, Finn Sellebjerg, Per Soelberg Sørensen Genetic and environmental factors confer susceptibility to develop MS. In DMSC we are involved in large, international studies of genetic factors in MS, and collect genetic samples from MS patients, which is stored in the Danish Multiple Sclerosis Biobank at our department. These samples form the basis for studies conducted either at our laboratory or in the laboratories of our collaborators. Prospectively collected clinical information is obtained from the Multiple Sclerosis Treatment Registry, storing data from all MS patients in Denmark who receive immune therapy. Gene chip technology of single nucleotide polymorphisms (SNPs) has made genome wide association studies (GWAS) possible. As members of the International Multiple Sclerosis Genetic Consortium (IMSGC) and as member of the steering committee (Annette Oturai), in collaboration with the Wellcome Trust in England, we conducted the world s largest MS genetic study, published in Nature in August 2011 (Sawcer, 2011). We identified 29 new disease susceptibility genetic variations and confirmed 23 others. Most genetic variations affected molecules related to the immune system, including two with relation to vitamin D metabolism. The results have significantly contributed to the understanding of MS disease biology. The discovery of many new MS genes gives us the opportunity to explore these and their interaction with selected environmental factors that may increase the risk of MS. For this work, we have received the Videnskab.dk price for This year s Danish research results. The award ceremony took place on 1 December 2011 at the Det Kongelige Danske Selskabernes Selskab at HC Andersens Boulevard in Copenhagen. We are highly interested in the interaction between genes and environmental factors of importance for MS, such as smoking, vitamin D and viral infections. Vitamin D is in focus these years as a possible, causative factor for many diseases. Vitamin D has a strong immunomodulatory potential, where the active metabolite 1,25-(OH)2D induces anti-inflammatory processes. Most of the biological effect of 1,25-(OH)2D is mediated by the vitamin D receptor, which affects gene expression, proliferation and differentiation of immune cells. Denmark is geographically located in an area with limited sunlight, resulting in a reduced vitamin D biosynthesis in large parts of the year. In a PhDproject performed by Julie Hejgaard we investigate the clinical and immunological effects of different vitamin D levels in MS patients and the effect of intervention with vitamin D3 substitution. An environmental and lifestyle questionnaire consisting of more than 100 questions (vitamin D intake, sunbathing habits, smoking, alcohol, mononucleosis, BMI and geographical upbringing) has been collected, adapted from a questionnaire developed by the Department of Clinical Neuroscience at Karolinska Institute in Sweden. We also analyze whether genetic polymorphisms in vitamin D metabolism are important for vitamin D levels, immune activation and clinical disease activity. DANISH Multiple sclerosis CENTER annual report

20 Research activities 2011 Neuroimmunology Neuroimmunology research group: Finn Sellebjerg, Helle Bach Søndergaard, Poul Erik Hyldgaard Jensen, Jeppe Romme Christensen, Lars Börnsen, Rikke Ratzer, Annette Bang Oturai, Per Soelberg Sørensen Neuroimmunology of MS It is clearly established that disease activity in relapsing-remitting MS is caused by repeated inflammatory attacks with demyelination and axonal damage in the CNS. Disease activity is initiated by activation of immune cells outside the CNS. These activated immune cells, especially T cells, circulate in blood and gain access to the CNS by crossing the blood-brain barrier. The role of immune cells in progressive MS is more controversial. Some studies suggest that progressive MS results mainly from a gradual loss of function due to prior damage to oligodendrocytes and neurons. Other studies suggest that there may still be inflammation in the CNS in progressive MS, and that there is a correlation between inflammation and ongoing tissue damage even at this stage. We study immune activation within the peripheral blood compartment and in the CNS, by studying cerebrospinal fluid (CSF) samples, to gain more insight into the relationship between immune activation and disease activity across the clinical spectrum of MS. For these studies we use a combination of flow cytometry and gene expression studies. Molecular biology studies The activation of immune cells requires coordinated expression of a multitude of genes. Gene expression is directly controlled by the activity of transcription factors that are either constitutively expressed in active forms, expressed in forms that require activation by other signals, or are inducible upon cellular activation, and furthermore are directly involved in the transcription of DNA into messenger RNA (mrna). The regulation of gene expression does, however, depend on the integration of a vast number of extrinsic and intrinsic factors that interact to regulate accessibility of specific genes (epigenetics), transcription factor activation, and a number of post-transcriptional processes that are all important for the function of the immune system. Endogenous, small RNA molecules termed microrna (mirna) have a key role in regulating the translation of protein from mrna in the cytosol. mirna can either induce the degradation of mrna, or can inhibit the translation of mrna into protein by binding to the 3 untranslated region of mrna molecules. Since future treatment of MS may well include strategies to alter the expression of specific genes by interfering directly with either mrna or mirna within cells, an improved understanding of these processes is of interest. In recent studies mirna molecules have been identified that are differentially expressed in MS patients and healthy controls, and it has been suggested that pathogenic immune activation in MS may, indeed, reflect changes in mirna expression. In studies of mirna expression in MS, we have found that even patients with MS in clinical remission have an mirna expression profile that differs considerably from the expression profile observed in healthy controls. The differentially expressed mirnas are not only expressed in the T cells thought to be pivotal in the pathogenesis of MS. Instead, studies of mirna expression in subsets of blood immune cells demonstrate that some of the differentially expressed mirnas are expressed mainly in cell types such as B cells, dendritic cells and monocytes or in natural killer cells. We are continuing studies of mirna expression in pregnancy and in MS patients treated with disease-modifying drugs to extend our understanding of the role of mirna in MS. Other studies address the gene expression profile in blood immune cells from healthy control subjects and patients with relapsing-remitting, primary or secondary progressive MS as part of a ph.d. study of Rikke Ratzer. The aim of these studies, which will be completed in 2012, is to identify the extent to which systemic immune activation differs across the different subtypes of MS. The studies are complemented by studies of gene expression in subtypes of immune cells isolated by immunomagnetic cell sorting and studies of gene expression in patients treated with methylprednisolone. Immune activation in progressive MS We are currently completing an analysis of activa- 20 DANISH Multiple sclerosis CENTER annual report 2011

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