Danish Multiple Sclerosis Center Annual Report 2013

Department of Neurology · THE Neuroscience Centre ·
Copenhagen University Hospital · Rigshospitalet · Copenhagen, Denmark ·
www.ms-research.dk
Danish
Multiple Sclerosis Center
Annual Report
2013
DMSC missions and aims
The mission of Rigs­hospitalet 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:
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
The aims of
the DMSC are:
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 carry out 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.
DMSC staff seminar 2013
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Table of contents
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DMSC missions and aims
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A short review of 2013 in the Danish Multiple Sclerosis Center
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About the Danish Multiple Sclerosis Center
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Organization diagram
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Research activities 2013
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Clinical research
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Neuro Imaging
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Neurogenetics
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Neuroimmunology
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Routine analyses in Neuroimmunology Laboratory
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Scientific publications 2012-2013
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Honorary offices
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Scientific collaboration
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Collaboration with pharmaceutical companies
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Acknowledgements
Annual
Report
2013
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Professor Per Soelberg Sørensen,
MD, DMSc
Director of the Danish Multiple
Sclerosis Center (DMSC)
A short review of 2013
in the Danish Multiple Sclerosis Center
In 2013 Copenhagen hosted the 29th congress
of the European Committee on Treatment and
Research in Multiple Sclerosis (ECTRIMS) and the
18th Annual Conference of Rehabilitation in Multiple Sclerosis. Per Soelberg Sørensen was chairman
of the local organizing committee and several
colleagues at the Danish Multiple Sclerosis Center
(DMSC) were involved as members of the local organizing committee. The congress took place in the
Bella Congress Center and became the largest MS
meeting ever with more than 7600 active delegates
from 93 countries. Her Majesty Queen Margrethe
II attended the opening ceremony and enjoyed the
performance of the Safri Duo. The scientific programme included 93 oral presentation, 967 posters,
14 teaching courses, and 11 satellite symposia.
Overall, the congress was very successful and it
was appointed “Congress Host of the Year” at the
Copenhagen Congress and Event Award 2014 by
the Municipality of Copenhagen and the “Wonderful Copenhagen” committee.
DMSC got its second professor in May 2013
when Finn Sellebjerg was appointed professor
in neuroimmunology and multiple sclerosis at
University of Copenhagen, sponsored by the Danish Multiple Sclerosis Society. Moreover, Annette
Oturai was appointed associate research professor
from July 2013.
From January 2014 the Danish Multiple Sclerosis
Register that is supported by the Danish Multiple
Sclerosis Society will be associated with DMSC
and the leader of the register will be employed as
consultant at DMSC.
In 2013 we completed the refurbishment of the
MS Clinic with significant improvement in space
and comfort for our patients and better working
conditions for the personnel. Two new treatments
for relapsing-remitting multiple sclerosis were
Opening of the 29th ECTRIMS congress
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DANISH Multiple sclerosis CENTER annual report 2013
approved in Europe and taken in use at DMSC in
2013: Aubagio, the first 1.-line oral treatment, and
Lemtrada, a very effective therapeutic antibody
that only needs to be administered as a short series
of intravenous infusions every year.
The MS Research Unit has completed a placebocontrolled, double-blind clinical trial of EPO in
patients with progressive multiple sclerosis with
the aim to test if EPO could improve neurological
deficits, and the results will be reported at the next
ECTRIMS congress. Another trial in patients with
progressive multiple sclerosis has used monthly oral
methylprednisolone courses to decrease inflammation and disease progression. The study will be
completed early 2014.
Our study of mesenchymal stem cells for treatment of relapsing-remitting MS, which is as a part
of a large international collaborative investigator
driven study, has proceeded as planned in 2013
and approximate half of the patients have been
enrolled. In collaboration with the Novo Nordisk
Foundation Center for Basic Metabolic Research,
Section of Metabolic Genetics at University of
Copenhagen we have initiated an ambitious
project: “Studies of the role of altered gut bacteria
flora in the pathogenesis of multiple sclerosis”, in
which 200 multiple sclerosis patients from DMSC
will have their stools examined to study whether
patients with multiple sclerosis harbour a diseasespecific gut microbiota that promotes production of
immune-modulating metabolites and inflammatory
markers and plays an important role in the pathogenesis of multiple sclerosis.
Jeppe Romme Christensen defended his ph.d.
thesis “Systemic and intrathecal activation in multiple sclerosis – Emphasis on progressive multiple
sclerosis” in February 2013.
Other ph.d. studies comprise molecular biology
studies on immune activation in progressive MS
and studies of the interaction between genes and
environmental factors of importance for MS with
focus on vitamin D and vitamin D metabolism. Together with the Danish Multiple Sclerosis Register
we have completed a ph.d. study of gender aspect
of multiple sclerosis including the protective effect
of childbirth. This thesis will be defended in 2014.
Congress Host of the Year Award
A junior Consultant in DMSC, Mikkel Anthonisen, has succeeded in realising his project,
Sailing Sclerosis, in 2013. The project implies sailing
people with multiple sclerosis around the world
in a sailing boat. The boat will leave Copenhagen
in June 2014, cross the Atlantic and arrive at the
multiple sclerosis Congress (ACTRIMS-ECTRIMS)
in Boston in September 2014. Members of the staff
in DMSC will serve as neurologist to the people on
board at some of the legs of the journey.
I hope you will enjoy reading the annual report of
DMSC.
Per Soelberg Sørensen
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About
The Danish Multiple
Sclerosis Center
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The Danish Multiple Sclerosis Center
About the Danish Multiple
Sclerosis Center
The Danish Multiple Sclerosis Center (DMSC) is
the leading centre for treatment and research in
multiple sclerosis in Denmark and provides multidisciplinary care for more than 2000 MS patients,
offering both basic and highly specialized therapy.
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.
DMSC is composed of an MS Clinic and an MS
Research Unit. The MS Clinic is located at the 8th
floor of the main complex of Rigshospitalet where
the offices of professors and consultants are located. The MS Clinic contains the reception desk,
the secretary offices, the nurse offices, as well as
the outpatient consultation rooms, facilities for intravenous infusion-therapy with disease modifying drugs, and rooms for invasive procedures.
We have been designated highly specialized
function in providing therapy with strong immunosuppressants and experimental medications.
From 2011 we have been offering immunoablative
therapy followed by autologous stem cell transplantation to patients with very active MS and
accumulation of disability despite immunomodulatory or immunosuppressive therapy.
ACtive patientS iN DMSC
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DMSC is the Eastern Denmark centre for
treatment of children and adolescence with MS
and has a highly specialized function in treating
neuromyelitis optica. 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 highquality multi-disciplinary care for all our patients
with openness and respect. The staff comprises
two professors, one associate professor, 5 consultants, 1 staff neurologist and several external consultants working part time in the MS Clinic. There
is one leading nurse and 9 MS specialist nurses, 3
secretaries, a neuropsychologist, a physiotherapist
and a medical social counsellor.
The MS Research Unit is located partly in the
proximity of the MS Clinic, where most patientrelated 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
laboratory tests.
The focus of the research in DMSC is clinical
research, neuroimmunology, neurogenetics and,
in particular, translational research aiming at
implementing the findings in neurogenetics and
immunology into new therapies of MS.
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Organization
Danish Multiple Sclerosis Research Center
Director: Professor Per Soelberg Sørensen
MS clinic
MS Research Unit
Neurologists
Professor Per Soelberg Sørensen
Professor Finn Sellebjerg
Consultant Morten Blinkenberg
Ass. Professor Annette Oturai
Consultant Karen Schreiber
Consultant Ana Voldsgaard
Consultant Melinda Magyari
Staff neurologist Henrik Mathiesen
Staff neurologist Peter Roos
Clinical research
Professor
Per Soelberg Sørensen
Consultant Karen Schreiber
Consultant Ana Voldsgaard
Neuropsycologist Agnete Jønsson
PhD student Melinda Magyari
PhD student Eva Rosa Petersen
PhD student Rikke Ratzer
PhD student Julie Maria Hejgaard
PhD student Cecilie Ammitzbøll
Ext. Consultant Sarah Taudorf
Ext. consultant Mikael Lund
Ext. consultant Mikkel Anthonisen
Ext. consultant Janus Kaufmann
Ext. Consutant Lars-Henrik Krarup
Ext. Consultant Tina Dysgaard
Ext. consultant Stephan Bramow
Ext. consultant Cecilia Rajda
MS nurses
Leading nurse Anne Hansen
Dorthe Stauning Rasmussen
Anette Husted Pedersen
Lene Almind
Julie Yoon S. Moberg
Louise Nathalie Christiansen
Rie Forsberg Pedersen
Sidsel Nielsen
Mette Harborg
Karina Jørgensen
Research nurses
Vibeke Jespersen
Joan Pietraszek
Sidsel Nielsen
Research secretary
Annette Larsen
Neuroimaging research
Consultant
Morten Blinkenberg
Staff neurologist
Henrik Mathiesen
Genetic research
Ass. Professor Annette Oturai
Senior research fellow
Helle Bach Søndergaard
PhD students
Julie Maria Hejgaard
Secretaries
Annette Larsen
Malene Møllesøe
Pia Maria Sandstød Ibsen
Maiken Leth Svane
Neuropsychologist
Agnete Jønsson
Lisbet Marstrand
Physiotherapist
Lis Albrechtsen
Medical social counselor
Keld Stage
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Neuroimmunology
research
Professor Finn Sellebjerg
Senior research fellow Helle Bach
Søndergaard
Senior research fellow Lars
Börnsen
Senior research fellow Marina
Rode Von Essen
Part-time post doc Jeppe Romme
Christensen
PhD students
Rikke Ratzer
Cecilie Ammitzbøll
Julie Maria Hejgaard
Eva Rosa Petersen
Neuroimmunology
Laboratory
Head of Laboratory
Poul Erik Hyldgaard Jensen
Laboratory technicians
Leading Laboratory technician
Joy Mendel-Hartvig
Michael K. Jensen
Vibeke Lindgaard Fuglholt
Rikke Larsen
Freja Melissa Bekner
Betina Gall
Professor
Per Soelberg
Sørensen
Professor
Finn Sellebjerg
Consultant
Morten
­Blinkenberg
Ass. professor
Annette Oturai
Consultant
Karen Schreiber
Consultant
Ana Voldsgaard
Consultant
Melinda
Magyari
Staff neurologist
Henrik
Mathiesen
Laboratory
leader Poul Erik
Hyldgaard
Jensen
Senior research
fellow
Helle Bach
Søndergaard
Senior research
fellow
Lars Börnsen
Senior research
fellow
Marina Rode
Von Essen
Leading laboratory technician
Joy MendelHartvig
Leading nurse
Anne Hansen
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Research
activities 2013
Clinical research
Clinical research
Neuroimaging
Neurogenetics
Neuroimmunology
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Research activities 2013
Clinical and
epidemiological 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, Vibeke
Jespersen, Joan Pietraszek, Sidsel Walther Nielsen,
Anne Hansen, Annette Larsen.
Therapeutic trials of new medicine
Most of our efforts in therapeutic trials of new
medicine have been directed towards treatment
of patients with progressive forms of MS. 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 lacks effective therapy. These studies are
performed in collaboration with the Danish Research
Centre for Magnetic Resonance, Hvidovre Hospital.
We published the results of a proof-of-concept
phase II open-label study (Neurology 2014) of
the effects of treatment with natalizumab 300 mg
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every 4 weeks for 60 weeks in patients with
progressive MS. Compared with baseline findings natalizumab significantly reduced inflammatory molecules in the cerebrospinal fluid, and also
markers of axonal damage (neurofilament light)
decreased significantly. In addition, we showed a
reduction in disability (mean EDSS), reduction in
grey matter atrophy on MRI and increase in magnetisation transfer ratio. The findings suggest a role
of systemic inflammation in progressive MS, and
natalizumab treatment may have favourable clinical
effect in progressive MS patients.
In this regard we also studied the effect of
erythropoietin (EPO) on disability in patients with
progressive MS in a randomized double-blind trial.
56 patients with primary or secondary progressive
MS have been included and treated with either EPO
or placebo for 24 weeks. The primary outcome measure is the change from baseline to 24 weeks in a
composite measure of maximum gait distance, a test
of hand dexterity, and a neuropsychological test.
Secondary endpoints include clinical relapses, disability, and several MRI measures. The results will
be presented at the ECTRIMS/ACTRIMS congress
in September 2014.
We also completed a study of 30 progressive MS
patients in a pilot study of methylprednisolone
administered orally in monthly courses of 500 mg
for 3 days. The primary endpoint is the changes
in inflammatory molecules in the cerebrospinal
fluid (osteopontin, CXCL13 and matrix metalloproteinase-9), but also markers of axonal damage
(neurofilament light) and demyelination (myelin
basic protein) will be studied. In addition, we use
conventional and non-conventional MRI markers
(magnetization transfer ratio and diffusion tensor
imaging) as well as reduction in disability as secondary endpoints. The results of this study will also
be reported at the ECTRIMS/ACTRIMS congress i
September 2014.
In collaboration with the Stem Cell Unit at the
Department of Clinical Immunology, the Blood
Bank, Rigshospitalet and the MRI Department,
Hvidovre Hospital we have initiated a trial of
intravenous therapy with autologous mesenchymal
stem cells in MS patients. The primary objective of
the study is to assess the safety and the activity in
terms of reduction as compared to placebo in the
total number of contrast-enhancing lesions on MRI
over 24 weeks. The secondary objectives of the
study are to gather preliminary information on the
efficacy of the experimental treatment in terms of
combined MRI activity, clinical efficacy measures
and immunological markers. The study is a randomized double-blind study comparing treatment with
autologous mesenchymal stem cells vs suspension media at 24 weeks. After 24 weeks patients
initially assigned to suspension media treatment
will be shifted to the treatment with mesenchymal
stem cells, and a secondary analysis will compare
the number of adverse events and gadoliniumenhancing lesions in weeks 0-23 and 24-48 in these
patients. The study is a part of an international
collaboration between centres in Spain, England,
Sweden, Denmark, France, Germany and Canada
comprising in all 160 patients, of whom 25 patients
will be Danish. We have recruited half of the patients and enrolment will be completed in 2014.
Currently, we take part in an EU supported study
ABIRISK (Immunogenicity: assessing the clinical
relevance and risk minimization of antibodies to
pharmaceuticals). The project aims to provide an
integrated approach to anti-drug immunization,
bringing together, in an extensive and coordinated
manner, a large network of clinicians from various
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Research activities 2013
specialties with broad experience in the care of
patients, biologists and scientists specialized in the
mechanisms of immunogenicity, and, in addition,
collaboration with a large network of private pharmaceutical companies.
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 natalizumab,
and in the development of three new monoclonal
antibodies, alemtuzumab, daclizumab and ofatumumab, with strong effects on disease activity.
Epidemiological research
In collaboration with the Danish MS Register we
have performed extensive analysis of possible factors that might have contributed to the increase of
MS in women. At the American Academy of Neurology Meeting in April 2013, using data from the
Danish Multiple Sclerosis Registry, we presented
the results of a nationwide study comprising 1403
MS patients aged 15-55 at clinical onset between
2000 and 2004. We showed that childbirths within
five years before clinical onset reduced the risk
of MS in women, but not in men. Considering the
possibility of reversed causation, which was not
supported by the data, pregnancy could exert a
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certain protection against MS on a biological basis,
lasting up to five years. We did not identify any
physical or social environmental factors which
could explain the gender discrepancy in the incidence increase. Further studies are needed to reveal
possible etiological occupational exposures in MS.
Recently we performed a pilot study of the impact
of co-morbidity in MS patients and the importance
of co-morbidity has evolved into a ph.d. study.
The studies in women with MS continue with
exploration of environmental factors, such as smoking habits and vitamin D intake. Vitamin D that
seems to yield some protection against encountering MS may also influence the disease activity in
established MS, and in 2010 we initiated a study
exploring the role of vitamin D on clinical disease
activity in MS.
Paediatric MS
Paediatric MS carries a relatively higher mortality
and morbidity than adult MS but little is known
about symptoms and paraclinical findings at the
first demyelinating event in a Danish setting and
the nationwide incidence of paediatric MS have
never been described in Denmark. In 2013 we initiated two studies aiming at answering these questions and results are expected in 2014.
Neuro Imaging 2013
Neuroimaging research group:
Morten Blinkenberg, Henrik Mathiesen,
Per Soelberg Sørensen
Magnetic resonance spectroscopic imaging (MRSI)
provides in vivo information about neuronal damage, loss, or dysfunction by measuring decreases
of N-acetyl aspartate (NAA). In the human brain
NAA is almost exclusively found within neurons
and neuronal processes and therefore serves as a
marker of neurodegeneration and disease progression in MS. In 2013 we completed data evaluation
of a cohort of newly diagnosed relapsing remitting
MS patients studied by serial MRI and MRSI for
two years and clinical examinations performed up
to 7 years after the primary MRI.
The study shows a relationship between baseline
MSRI and clinical disability after 2 and 7 years and
in this way MRSI may be used as a predictor of
long-term disease outcome in MS.
Studies on resting-state fMRI, assessing functional brain connectivity, were continued in 2013 in
collaboration with Danish Research Centre for Magnetic Resonance, PhD Anne-Marie Dogonowski.
Our studies show, that worsening of disability in
MS results in increased coupling between regions
of importance to motor function, which might
reflect an adaptive mechanism to maintain motor
function, as a consequence of disease progression.
Furthermore, people with MS have better integrity
of cortical motor connectivity compared with deep
brain regions, again speaking for a relative higher
preservation of motor function compared with oth-
er neural networks. Finally, studies of local neural
connectivity in people with MS show disintegration
in the cerebellum, underlining the integrative role
of the cerebellum in motor function, processing input from spinal as well as cerebral motor regions. In
conclusion, our data provide a better understanding
of the functional reorganization of distinct brain
networks in MS patients as a consequence of the
neurodegenerative disease, which may find use in
current and future rehabilitation programs.
All results have been published in 2013 and data
processing from resting-state motor connectivity studies during recovery from an acute motor
relapse is still ongoing.
In 2013 we also initiated an imaging study with
a quite different focus than the brain. Corticosteroids are widely used in the treatment of MS,
both for acute relapses and as add on treatment to
interferon-beta. A rare side effect of corticosteroids
is avascular osteonecrosis characterized by focal
necrosis of bone tissue and followed by collapse of
architectural bony structure. A former study has
reported a high prevalence of osteonecrosis in MS
patients (15.2%) receiving a high cumulated dose
of methylprednisolone, although this has never
been confirmed. In the current study our aim is to
determine the prevalence of avascular osteonecrosis in a well characterized cohort of MS patients,
treated with monthly courses of high dose methylprednisolone or placebo, as add on treatment to
interferon beta-1a i.m (the MECOMBIN study).
Bilateral femoral MRI is performed in order to
determine the presence of avascular osteonecrosis.
Results of the study are expected in 2014.
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Research activities 2013
Neurogenetics
Neurogenetics research group:
Annette Bang Oturai, Helle Bach Søndergaard,
Julie Hejgaard, Eva Petersen, Finn Sellebjerg,
Per Soelberg Sørensen
MS-genetics
One major step towards revealing the genetic component in MS was taken in 2013 identifying 48 new
MS genetic variations. We participated in the study
as part of the International Multiple Sclerosis Genetics Consortium (IMSGC) investigating thousands
of MS patients and controls in the “Immuno-chip
project” (study of common autoimmune disease
genes). We are now looking forward to the next
step investigating the first so called “MS-chip”
(replication and fine-mapping of all known MS
genes). The study includes more than 1000 Danish
MS patients/1000 controls, all together a total of
more than 18.000 MS patients and 18.000 controls
and more than 288.000 single nucleotide polymorphisms (SNPs).
Gene-environment interaction
Several of our studies focus on investigating geneenvironmental interactions, based on information
from a newly collected questionnaire from 2000
Danish MS patients and 5000 Danish blood donors
including more than 100 questions on lifestyle
and environmental factors (e.g. smoking, alcohol,
mononucleosis, BMI, sun habits, geographical
upbringing).
Vitamin D
Vitamin D is known to have a strong immunomodulatory potential and accumulating evidence
supports a beneficial effect of vitamin D in the
pathogenesis and disease course of MS. Genomewide association studies (GWAS) have shown
significant associations between serum levels of
25(OH)D and SNPs in several key genes in the vitamin D metabolism. In 1500 MS patients we have
examined the association between 25(OH)D and
six GWAS SNPs, season, age, sex, eye colour, body
mass index, vitamin D supplements, smoking, fish
intake, sun habits and severity of MS. We found
effects of environmental factors on 25(OH)D levels
and to our knowledge for the first time, effects of
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SNPs in genes important for 25-hydroxylases in
the liver (CYP2R1, gene) and vitamin D metabolism
(GC, gene).
Smoking
It is known that both HLA genes and smoking
increases the risk of MS. However, the effect and
interaction of smoking and HLA type on treatment
response have not yet been investigated. We have
investigated if smoking status and HLA type are
associated with disease activity and disease severity in interferon-beta (IFN-beta) treated relapsingremitting MS patients and demonstrate for the first
time a higher disease activity and severity in MS
patients who smoked before and during treatment
with IFN-beta. Furthermore, the effect seems to be
modulated by HLA-DRB1*15:01. The previously
reported interaction between HLA genes, smoking
and MS susceptibility may therefore also affect
disease course
BMI, mononucleosis and alcohol
In order to determine the most important genetic
and environmental-lifestyle factors for age at MS
disease onset in Danish MS patients we investigated
about 1500 patients and tested the predictive value
for age of MS onset for: body mass index, smoking
habits smoking, alcohol consumption sex, previous
mononucleosis, education, HLA-DRB1*15:01 and
HLA-A*02:01. We found that high BMI at age 20,
previous mononucleosis and high alcohol consumption between age 15-19 are the most important
known factors for lowering age at onset in Danish
MS patients
Genetic influence on oligoclonal band status
The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in MS. In a
Scandinavian collaboration, genetic differences in
MS relating to OCB status were studied. Data from
earlier GWAS were compared in 1367 OCB positive
and 161 OCB negative MS patients, and nine of the
most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. Results
showed that SNPs from the HLA complex and six
other loci were associated to OCB status. The study
confirmed both shared and distinct genetic risk for
MS subtypes in the Scandinavian population de-
fined by OCB status and indicates different clinical
characteristics between the groups. This suggests
differences in disease mechanisms between OCB
negative and OCB positive MS patients with possible implications for patient management.
Genetic influence on treatment
and clinical outcome
Investigations of the genetic influence on how
patients respond to various disease modifying
treatments are important to guide the most effective treatment for each patient.
Previously, six single nucleotide polymorphisms
were suggested to be associated with the response
to treatment with IFN-β. We investigated these
variants in 575 patients with relapsing-remitting
MS followed prospectively after the initiation of
their first treatment with IFN-β. These gene vari-
ants in IRF5, IRF8 and GPC5 did not show association with risk of relapse or disease progression in
this patient cohort. However, the analyses showed
that the pre-treatment relapses and clinical disease
activity during the first two years of treatment
may be associated with disease progression in MS
patients treated with IFN-β.
The chemokine receptor CCR5 may be important
for the recruitment of pathogenic T cells to the CNS
in multiple sclerosis (MS). A deletion in the CCR5
gene, which results in lower gene expression of
this receptor, could possibly lower disease activity in MS patients. We investigated the impact
of CCR5Δ32 in patients treated with Natalizumab
(tysabri) and found a less severe disease in patients
carrying the deletion, but no effect on disease
activity in the investigated cohort.
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Research activities 2013
Neuroimmunology
Neuroimmunology research group:
Finn Sellebjerg, Cecilie Ammitzbøll, Sophie
Buhelt, Lars Börnsen, Marina Rode von Essen, Poul
Erik Hyldgaard Jensen, Ditte Jonesco, Annette
Bang Oturai, Eva Rosa Petersen, Rikke Ratzer,
Birgitte Romme Nielsen, Jeppe Romme Christensen,
Helle Bach Søndergaard, Per Soelberg Sørensen
Neuroimmunology of MS
The extent to which inflammation is involved in the
pathogenesis of MS remains controversial. There
is compelling evidence that treatment strategies
targeting systemic immune activation or migration
of immune cells to the brain and spinal cord prevent
relapses in MS. Some researchers do, however,
argue that primary neurodegenerative processes are
more important, and that inflammation and relapses
have no major impact on the long-term evolution of
the disease.
In our research we focus on the role of immune
activation and inflammation in the pathogenesis
of MS. This is achieved by studying the activation
of blood cells, cerebrospinal fluid (CSF) cells and
soluble inflammatory mediators in blood and CSF.
We compare these in patients with relapsing-remitting, primary and secondary progressive MS, study
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how treatment alters these factors, and whether
they are influenced by genetic, environmental and
lifestyle factors associated with the risk of developing MS. Furthermore, we study whether immune
activation correlates with clinical and magnetic
resonance imaging measures of disease activity.
In order to investigate these processes in detail,
we combine molecular biology studies with flow
cytometry studies of leukocyte phenotypes and
functional studies of antigen reactivity, migration
and cytokine secretion.
The overall aim of the neuroimmunology research
at DMSC is to identify immune activation processes
that drive the disease evolution in MS and to understand differences between the different subtypes of
MS, in this way describing the effects of MS treatment on the immune system, and how genetic and
environmental factors increase the risk of MS and
influence immune activation and inflammation.
Molecular biology studies
In the molecular biology studies we investigate
mRNA and protein expression and measure the
expression and function of microRNAs, which are
small, non-coding RNA molecules that regulate the
degradation and translation of mRNA. In 2013 we
published a study on the expression of microRNA
in blood cells, serum and plasma in relapsing-remitting MS. This study showed that several microRNAs are differentially expressed in blood cells and
plasma, and that one specific molecule (miR-145)
may be a useful biomarker for diagnosing MS. In
another study we compared gene expression by Affymetrix DNA arrays, and found that gene expression is quite comparable in patients with relapsingremitting, primary and secondary progressive MS.
Differentially expressed genes were associated with
immunoinflammatory processes, arguing for a role
of these processes in all subtypes of MS.
Ongoing studies further investigate the role of microRNAs in MS and investigate how MS-associated
genetic variants influence gene expression and immune cell functions in MS. These studies include:
•Studies of microRNA and immune activation in
pregnant patients with MS
•Studies of microRNA biomarkers in serum and
CSF
•Studies of microRNA effect of treatment with
interferon-beta and glatiramer acetate
•Studies of the effects of an MS-associated
genetic variant in the gene encoding the interleukin-2 receptor alfa-chain in patients with MS
and healthy control subjects
•Studies of the effects of MS-associated genetic
variants on the expression of pro-inflammatory
and immunoregulatory cytokines
Immune activation in MS
We have conducted a series of studies addressing
the immune activation in blood cells and CSF in
patients with relapsing-remitting, primary and secondary progressive MS. These studies complement
our microarray studies, and implicate several subtypes of T lymphocytes in the pathogenesis of MS.
Interestingly, a recently discovered T lymphocyte
subset (follicular helper cells), which are important
drivers of antibody responses, seems to be particularly important in patients with relapsing-remitting
onset of the disease. We are now exploring these
findings further in a series of ongoing studies:
•Activation of naïve, central memory and effector
T cells in MS
•The effect of smoking and other exogenous risk
factors on immune activation in MS
•The effect of genetic risk factors on immune
activation in MS
•Immune activation and autoreactive T cells in
relapsing-remitting MS
•Immune activation and autoreactive T cells in
progressive MS Cytokine effects on T cells in MS
Effects of MS therapy and biomarkers
The development of biomarkers that can be used
as surrogate outcomes in clinical trials and identify
patients with different responses to specific treatments is an important research area in MS. We have
sought to identify biomarkers for the response to
treatment with glatiramer acetate and interferonbeta for several years, and published studies in
2012 and 2013 suggesting that flow cytometry
may be useful to identify effects associated with
an insufficient response to treatment. We have also
tried to identify genetic variants associated with
the response to treatment with natalizumab and
interferon-beta, but until now these attempts have
not been successful. In parallel, we have studied
CSF biomarkers for use in early trials in progressive
MS, and have identified factors that are associated
with tissue damage and which are inhibited by
treatment with natalizumab in progressive MS.
We recently completed a study investigating the
effect of monthly pulse methylprednisolone treatment in progressive MS, and are currently analyzing these results in detail. Other ongoing studies
investigate the effects of treatment with mesenchymal stem cells as part of an ongoing, multicentre
phase 2 study, and we continue our attempts to
identify biomarkers for treatment response for
other MS therapies. These studies investigate:
•Effects of mesenchymal stem cell treatment on
immune activation and autoreactive T cells in MS
•Immune activation and autoreactive T cells in MS
patients treated with natalizumab
•Immune activation and autoreactive T cells in MS
patients treated with fingolimod
•Immune activation and autoreactive T cells in MS
patients treated with dimethyl fumarate
•Chemokines and gene expression in patients
treated with interferon-beta
•Gene expression and disease activity in patients
treated with glatiramer acetate
DANISH Multiple sclerosis CENTER annual report 2013
21
Research activities 2013
Routine analyses in the
Neuroimmunology Laboratory
Neuroimmunology Laboratory
research group:
Poul Erik H. Jensen, laboratory technicians:
Joy Mendel-Hartvig, Michael Kolbjørn Jensen,
Vibeke Fuglholt, Rikke Larsen, Freja Melissa
Bekner, Betina Gall.
Diagnostic evaluation
The presence of oligoclonal IgG-bands in CSF is of
interest in the diagnosis of MS. In 2013 we have
analyzed 1304 patient samples, using isoelectric
focusing of CSF and corresponding plasma samples
for the characterization of immunoglobulin G bands.
In the autoimmune disease myasthenia gravis,
autoantibodies against the acetylcholine receptor
(AChR) may cause a diminished binding of ACh on
muscular surfaces and thereby a reduced impulse
transmission to the postsynaptic membrane of the
neuromuscular endplate occurs. For diagnostic and
therapeutic purposes, we measure the concentrations of these autoantibodies from patient serum
samples, using a radio-immunoassay kit, and in
year 2013 we analyzed 1011 patient samples.
The measurements of antibody concentration
22
DANISH Multiple sclerosis CE NTER annual report 2013
against aquaporin-4 are used for the diagnosis of
neuromyelitis optica (NMO) and patient samples
analyzed in 2013 increased in number to 81.
Measurement of neutralizing antibodies
Subgroups of MS patients, treated with interferonbeta (IFN-β) or Tysabri, generate neutralizing
antibodies, which diminish the therapeutic effects.
IFN-β molecules bind to leucocytes and a specific
up-regulation of MxA mRNA in the cells occur.
Neutralizing antibodies may abolish this effect,
and therefore we measure the neutralization of
IFN-β by antibodies in acell culture-based based on
luciferase-induced expression, and further by the
MxA mRNA-expression as a biological response to
treatment with IFN-ß. In 2013 we have analyzed
1263 patient samples for neutralizing antibodies,
and 85 patient samples for MxA mRNA expression.
The action of Tysabri differs from IFN-β, since it
blocks mononuclear cell binding to endothelial cells.
In this way Tysabri inhibits mononuclear cells from
entering the central nervous system. The generation
of neutralizing antibodies to Tysabri in MS patients
blocks the biological effects of Tysabri. In 2013 we
analyzed 496 blood samples for the presence of
antibodies to Tysabri by ELISA.
DANISH Multiple sclerosis CENTER annual report 2013
23
Scientific
publications,
prizes,
collaboration,
acknowledgements
Scientific publications 2012-2013
Prizes
Honorary offices
Scientific collaboration
Acknowledgements
Scientific publications
Publications 2012-2013
Peer reviewed original papers
Ali S, Paracha N, Cook S, Giovannoni G, Comi G,
Rammohan K et al. Reduction in Healthcare and
Societal Resource Utilization Associated with Cladribine
Tablets in Patients with Relapsing-Remitting Multiple
Sclerosis: Analysis of Economic Data from the CLARITY
Study. Clinical Drug Investigation. 2012;32(1):15-27.
Jensen PEH, Sellebjerg F, Søndergaard HB, Sørensen PS.
Correlation between anti-interferon-β binding and
neutralizing antibodies in interferon-β-treated multiple
sclerosis patients. European Journal of Neurology.
2012;19(10):1311-7.
Blinkenberg M, Mathiesen HK, Tscherning T, Jønsson A,
Svarer C, Holm S et al. Cerebral metabolism, magnetic
resonance spectroscopy and cognitive dysfunction
in early multiple sclerosis: an exploratory study.
Neurological Research. 2012 jan;34(1):52-8.
Kondziella D, Hansen K, Gonzalez T, Gideon P, Christiansen I, Sellebjerg F. Antithyroideaantistof hos to
patienter med subakut dementiel udvikling, ataksi og
myoklonus. Ugeskrift for Laeger. 2012;174(9):577-9.
Blinkenberg M, Akeson P, Sillesen H, Lövgaard S,
Sellebjerg F, Paulson OB et al. Chronic cerebrospinal
venous insufficiency and venous stenoses in multiple
sclerosis. Acta Neurologica Scandinavica. Supplementum. 2012 dec;126(6):421-7.
Lund H, Jønsson A, Andresen JG, Rostrup E, Paulson OB,
Sørensen PS. Cognitive deficits in multiple sclerosis:
correlations with T2 changes in normal appearing brain
tissue. Acta Neurologica Scandinavica. Supplementum.
2012;125(5):338-44.
Braendstrup P, Langkilde A, Schreiber K, Ravnborg M,
Sellebjerg F, Vindeløv L. Progression and CSF Inflammation after Eradication of Oligoclonal Bands in an
MS Patient Treated with Allogeneic Hematopoietic Cell
Transplantation for Follicular Lymphoma. Case Reports
in Neurology. 2012;4(2):101-6.
Lyksborg M, Larsen R, Sørensen PS, Blinkenberg MB,
Garde E, Siebner HR et al. Segmenting Multiple
Sclerosis Lesions Using a Spatially Constrained KNearest Neighbour Approach. Campilho A, Kamel M,
red. I: ICIAR’12 Proceedings of the 9th international
conference on Image Analysis and Recognition –
Volume Part II. Springer. 2012. s. 156-163.
Brambilla P, Esposito F, Lindstrom E, Sorosina M,
Giacalone G, Clarelli F et al. Association between
DPP6 polymorphism and the risk of progressive
multiple sclerosis in Northern and Southern Europeans.
Neuroscience Letters. Supplement. 2012;530(2):155-60.
Martinelli-Boneschi F, Esposito F, Brambilla P, Lindström
E, Lavorgna G, Stankovich J et al. A genome-wide
association study in progressive multiple sclerosis.
Multiple Sclerosis. 2012;18(10):1384-94.
Börnsen L, Christensen JR, Ratzer R, Oturai AB, Sørensen
PS, Søndergaard HB et al. Effect of Natalizumab on
Circulating CD4(+) T-Cells in Multiple Sclerosis. P L o S
One. 2012;7(11):e47578.
Romme Christensen J, Börnsen L, Khademi M, Olsson T,
Jensen PE, Sørensen PS et al. CSF inflammation and
axonal damage are increased and correlate in progressive multiple sclerosis. Multiple Sclerosis. 2012.
Cohen JA, Reingold SC, Polman CH, Wolinsky JS,
International Advisory Committee on Clinical Trials
in Multiple Sclerosis, Sørensen PS. Disability outcome
measures in multiple sclerosis clinical trials: current
status and future prospects. Lancet Neurology Network. 2012;11(5):467-76.
Romme Christensen J, Börnsen L, Hesse D, Krakauer M,
Sørensen PS, Søndergaard HB et al. Cellular sources of
dysregulated cytokines in relapsing-remitting multiple
sclerosis. Journal of Neuroinflammation. 2012;9:215.
Coles AJ, Twyman CL, Arnold DL, Cohen JA,
Con­favreux C, Fox EJ et al. Alemtuzumab for
patients with relapsing multiple sclerosis after diseasemodifying therapy: a randomised controlled phase 3
trial. Lancet. 2012;380(9856):1829-39.
Comi G, Cook SD, Giovannoni G, Rammohan K,
Rieckmann P, Sørensen PS et al. MRI outcomes with
cladribine tablets for multiple sclerosis in the CLARITY
study. Journal of Neurology. Supplement. 2012.
26
Jensen PEH, Koch-Henriksen N, Sellebjerg F, Sørensen PS.
Prediction of antibody persistency from antibody titres
to natalizumab. Multiple Sclerosis. 2012;18(10):1493-9.
DANISH Multiple sclerosis CE NTER annual report 2013
Sellebjerg F, Krakauer M, Limborg S, Hesse D, Lund H,
Langkilde A et al. Endogenous and recombinant type I
interferons and disease activity in multiple sclerosis.
P L o S One. 2012;7(6):e35927.
Sellebjerg F, Hesse D, Limborg S, Lund H, Søndergaard
HB, Krakauer M et al. Dendritic cell, monocyte
and T cell activation and response to glatiramer
acetate in multiple sclerosis. Multiple Sclerosis.
2012 feb;19(2):179-87.
2013
2012
Sellebjerg F, Krakauer M, Khademi M, Olsson T, Sørensen
PS. FOXP3, CBLB and ITCH gene expression and
cytotoxic T lymphocyte antigen 4 expression on CD4(+)
CD25(high) T cells in multiple sclerosis. Clinical and
Experimental Immunology. Supplement.
2012;170(2):149-55.
Sørensen PS, Bertolotto A, Edan G, Giovannoni G, Gold
R, Havrdova E et al. Risk stratification for progressive
multifocal leukoencephalopathy in patients treated
with natalizumab. Multiple Sclerosis. 2012;18(2):
143-52.
Sørensen PS. Effects of neutralizing antibodies to
interferon beta in multiple sclerosis: a logical paradox.
Multiple Sclerosis. 2012;18(2):131-2.
Sørensen PS. Deaths and disability from natalizumab
are no longer tolerable: No - (they can be avoided).
Multiple Sclerosis. 2012;18(8):1070-2.
Sørensen PS. Dødsfald i forbindelse med tvangsfast­
holdelse af svært agiterede personer bør kunne undgås.
Ugeskrift for laeger. 2012;174(40):2367.
Thirup P, Koch-Henriksen N, Sørensen PS. Sclerose­
behandlingsregistret. Ugeskrift for laeger.
2012;174(42):2537.
Bo Baslund, Ulla Feldt-Rasmussen, Jens Kastrup, Per
Soelberg Sørensen (editors). Textbook of Medicine
(Lærebog i Medicin). FADLS Forlag, Copenhagen 2012.
Author of several chapters.
International Multiple Sclerosis Genetics Consortium,
Sørensen PS. Network-based multiple sclerosis pathway
analysis with GWAS data from 15,000 cases and 30,000
controls. American Journal of Human Genetics. 2013
jun 6;92(6):854-65.
International Multiple Sclerosis Genetics Consortium
(IMSGC). Analysis of immune-related loci identifies
48 new susceptibility variants for multiple sclerosis.
Nat Genet 2013; 45:1353-1360.
Beecham AH, Patsopoulos NA, Xifara DK, Davis MF,
Kemppinen A, Cotsapas C et al. Analysis of immunerelated loci identifies 48 new susceptibility variants for multiple sclerosis. Nature Genetics. 2013
ov;45(11):1353-60.
Blinkenberg M, Sellebjerg F, Leffers AM, Madsen CG,
Sørensen PS. Clinically silent PML and prolonged
immune reconstitution inflammatory syndrome in
a patient with multiple sclerosis treated with natalizumab. Multiple sclerosis (Houndmills, Basingstoke,
England). 2013 aug;19(9):1226-9.
Comi G, Cook SD, Giovannoni G, Rammohan K,
Rieckmann P, Sørensen PS et al. MRI outcomes with
cladribine tablets for multiple sclerosis in the CLARITY
study. Journal of Neurology. 2013;260(4):1136-46.
Dogonowski A-M, Siebner HR, Sørensen PS, Wu X,
Biswal B, Paulson OB et al. Expanded functional
coupling of subcortical nuclei with the motor restingstate network in multiple sclerosis. Multiple Sclerosis.
2013 apr;19(5):559-566.
Dogonowski A-M, Andersen KW, Madsen KH, Sørensen
PS, Paulson OB, Blinkenberg M et al. Multiple sclerosis
impairs regional functional connectivity in the cerebellum. NeuroImage. Clinical. 2013 nov 27;4:130-8.
Dogonowski A-M, Siebner HR, Sørensen PS, Paulson OB,
Dyrby TB, Blinkenberg M et al. Resting-state connectivity of pre-motor cortex reflects disability in multiple
sclerosis. Acta Neurologica Scandinavica. 2013 mar
6;128(5):328–335.
Hegen H, Millonig A, Albrecht N, Bertolotto A, Comabella
M, Giovannoni G, Guger M, Hoelzl M, Khalil M, Lindberg R, Polman CH, Rudzki D, Schautzer F, Sellebjerg
F, Skrobal A, Sørensen PS, Deisenhammer F. Early
detection of neutralizing antibodies to interferon-beta
in multiple sclerosis patients. Mult Scler [E-pub ahead
of print].
Leone MA, Barizzone N, Esposito F, Lucenti A, Harbo
HF, Goris A, Kockum I, Oturai AB, Celius EG, Mero IL,
Dubois B, Olsson T, Søndergaard HB, Cusi D, Lupoli S,
Andreassen BK; International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2, Myhr KM, Guerini FR; PROGEMUS Group;
PROGRESSO Group, Comi G, Martinelli-Boneschi F,
D’Alfonso S. Association of Genetic Markers with CSF
Oligoclonal Bands in Multiple Sclerosis Patients. PLoS
One. 2013 Jun 13;8(6):e64408. doi: 10.1371/journal.
pone.0064408. Print 2013.
PMID: 23785401 [PubMed – in process]
Lund H, Krakauer M, Skimminge A, Sellebjerg F, Garde E,
Siebner HR et al. Blood-brain barrier permeability of
normal appearing white matter in relapsing-remitting
multiple sclerosis. P L o S One. 2013;8(2):e56375.
Magyari M, Koch-Henriksen NI, Pfleger CC, Sørensen PS.
Reproduction and the risk of multiple sclerosis.
Multiple sclerosis (Houndmills, Basingstoke, England).
2013 okt;19(12):1604-9.
DANISH Multiple sclerosis CENTER annual report 2013
27
Scientific publications
Magyari M, Søndergaard HB, Sellebjerg F, Sørensen PS.
Preserved in vivo response to interferon-α in multiple
sclerosis patients with neutralising antibodies against
interferon-β (REPAIR study). MSARD 2013; 2: 141146.
Mathiesen HK, Sorensen PS. Prolonged-release fampridine improves walking in a proportion of patients with
multiple sclerosis. Expert review of neurotherapeutics.
2013 dec;13(12):1309-17.
Mechelli R, Umeton R, Policano C, Annibali V, Coarelli
G, Ricigliano VAG et al. A “candidate-interactome”
aggregate analysis of genome-wide association data in
multiple sclerosis. P L o S One. 2013;8(5):e63300.
Mero I-L, Gustavsen MW, Sæther HS, Flåm ST, BergHansen P, Søndergaard HB et al. Oligoclonal band
status in Scandinavian multiple sclerosis patients is
associated with specific genetic risk alleles. P L o S One.
2013;8(3):e58352.
Modvig S, Degn M, Horwitz H, Cramer SP, Larsson HBW,
Wanscher B et al. Relationship between cerebrospinal
fluid biomarkers for inflammation, demyelination and
neurodegeneration in acute optic neuritis. P L o S One.
2013;8(10):e77163.
Møller M, Søndergaard HB, Koch-Henriksen N, Sorensen
PS, Sellebjerg F, Oturai AB. The chemokine receptor
CCR5 Δ32 allele in natalizumab-treated multiple
sclerosis. Acta Neurol Scand [E-pub ahead of print].
Olsson T, Achiron A, Alfredsson L, Berger T, Brassat D,
Chan A et al. Anti-JC virus antibody prevalence in
a multinational multiple sclerosis cohort. Multiple
sclerosis (Houndmills, Basingstoke, England). 2013
okt;19(11):1533-8.
Paulson OB, Sørensen PS. Neuroonkologi. I Paulson
OB, Thage O, Waldemar G, red., Neurologi i 100 år:
beretninger fra Rigshospitalets neurologiske afdeling.
[Nationalt Videnscenter for Demens]. 2013. s. 112-115.
Pedersen EG, Hallas J, Hansen K, Jensen PEH, Gaist D.
Late-onset myasthenia not on the increase: a nationwide register study in Denmark, 1996-2009. European
Journal of Neurology. 2013;20(2):309-14.
Pedersen EG, Pottegård A, Hallas J, Friis S, Hansen K,
Jensen PEH et al. Use of azathioprine for non-thymoma
myasthenia and risk of cancer: a nationwide casecontrol study in Denmark. European journal of neurology: the official journal of the European Federation of
Neurological Societies. 2013 jun;20(6):942-8.
28
DANISH Multiple sclerosis CE NTER annual report 2013
Ratzer R, Søndergaard HB, Christensen JR, Börnsen L,
Borup R, Sørensen PS et al. Gene expression analysis of relapsing-remitting, primary progressive and
secondary progressive multiple sclerosis. Multiple
sclerosis (Houndmills, Basingstoke, England). 2013
dec;19(14):1841-8.
Romme Christensen J, Börnsen L, Khademi M,
Olsson T, Jensen PE, Sørensen PS et al. CSF
inflammation and axonal damage are increased
and correlate in progressive multiple sclerosis.
Multiple Sclerosis. 2013;19(7):877-84.
Romme Christensen J, Börnsen L, Ratzer R, Piehl F,
Khademi M, Olsson T et al. Systemic inflammation
in progressive multiple sclerosis involves follicular
T-helper, Th17- and activated B-cells and correlates
with progression. P L o S One. 2013;8(3):e57820.
Schreiber K, Voldsgaard A, Sørensen PS. Der er begrænset
effekt af interferonbeta til behandling af sekundær
progressive multipel sklerose--en gennemgang af
et Cochranereview. Ugeskrift for laeger. 2013 maj
6;175(19):1342-4.
Sellebjerg F, Hesse D, Limborg S, Lund H, Søndergaard
HB, Krakauer M et al. Dendritic cell, monocyte and
T cell activation and response to glatiramer acetate
in multiple sclerosis. Multiple sclerosis (Houndmills,
Basingstoke, England). 2013 feb;19(2):179-87.
Svenningsson A, Falk E, Celius EG, Fuchs S, Schreiber K,
Berkö S et al. Natalizumab treatment reduces fatigue
in multiple sclerosis. Results from the TYNERGY
trial; a study in the real life setting. P L o S One.
2013;8(3):e58643.
Søndergaard HB, Hesse D, Krakauer M, Sørensen PS,
Sellebjerg F. Differential microRNA expression in blood
in multiple sclerosis. Multiple sclerosis (Houndmills,
Basingstoke, England). 2013 dec;19(14):1849-57.
Søndergaard HB, Hesse D, Krakauer M, Sørensen PS,
Sellebjerg F. Differential expression of microRNA in
multiple sclerosis. Mult Scler 2013; 19: 1849-1857.
Sørensen PS. Multipel sklerose. I Paulson OB, Thage O,
Waldemar G, red., Neurologi i 100 år: beretninger fra
Rigshospitalets neurologiske afdeling. [Nationalt
Videnscenter for Demens]. 2013. s. 72-80.
Theibich A, Dreyer L, Magyari M, Locht H.
Demyelinizing neurological disease after treatment
with tumor necrosis factor alpha-inhibiting agents
in a rheumatological outpatient clinic: description
of six cases. Clinical rheumatology. 2013 nov 8.
Honorary offices
Honorary offices
A: National
Annette Bang Oturai:
Board member of the Danish Society for Multiple Sclerosis (DAREMUS)
Board member of the Torben Fogh and Erik Trier foundation. 2006
Finn Sellebjerg:
Chairman of the Danish Society for Research in Multiple Sclerosis (DAREMUS)
Chairman and board member of the Research Committee of the Danish Multiple Sclerosis Society
Morten Blinkenberg:
Board member of the Research Committee of the Danish Multiple Sclerosis Society
Per Soelberg Sørensen:
Chairman of the Danish Multiple Sclerosis Group
Chairman of the Foundation for Neurological Research
Board member of the Gangsted Foundation
Board member of the Johnsen Legacy for Research in Multiple Sclerosis
Chairman of the Scientific Committee of the Board of Application of Expenses Therapies in Denmark
B: International
Annette Bang Oturai:
Danish member of the Strategy Group within the Multiple Sclerosis Genetics Consortium (IMSGC).
Danish leader of the Nordic Multiple Sclerosis Genetic Group.
Finn Sellebjerg:
Member of the Multiple Sclerosis International Federation (MSIF), International Medical and
Scientific Board
Chairman of the European Federation of Neurological Societies, “Task Force on Treatment of Multiple
Sclerosis Relapses”
Member of the European Federation of Neurological Societies “Scientist Panel on Multiple Sclerosis
and Demyelinating Diseases”
Member of the European Council for Treatment and Research in Multiple Sclerosis
Per Soelberg Sørensen:
Member of the Editorial Board, European Journal of Neurology, 2003 –
Member of the Editorial Board, Multiple Sclerosis Journal, 2010 –
Member of the Editorial Board, Therapeutic Advances in Neurological Diseases, 2005 Executive board member and treasurer of the European Committee for Treatment and Research in
Multiple Sclerosis (ECTRIMS), 2010 –
Member of the medical advisory board of the International Federation of Multiple Sclerosis Society, 2010 –
Member of the International Advisory Committee on Clinical Trials on MS under the sponsorship of the
US National MS Society and ECTRIMS, 2010 –
Chairman of the Teaching Course Committee, European Committee for Treatment and Research in Multiple
Sclerosis (ECTRIMS), 2010 –
Member of the Congress Organizing Committee for the European Committee for Treatment and Research
in Multiple Sclerosis (ECTRIMS), 2010 –
DANISH Multiple sclerosis CENTER annual report 2013
29
Scientific collaboration
Scientific collaboration
National
The Danish Multiple Sclerosis Register, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (Nils Koch-Henriksen, MD)
Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Denmark
(Peter Garred, Jacob Larsen MD, Lars Ryder ,
Klaus Rieneck, MD, Hans O. Madsen, MD)
Department of Neurology, Ullevål University
Hospital, Oslo, Norway (Elisabeth G Celius, MD)
Department of Neurology, Haukeland Hospital,
Bergen, Norway (Professor Kjell-Morten Myhr)
Institute for Inflammatory Research, Copenhagen University Hospital, Rigshospitalet, Denmark
(Christian Enevold-Johansen MD, Professor Klaus
Bendtzen)
Department of Neurology, Huddinge University
Hospital, Karolinska Institute, Huddinge, Sweden
(Professor Jan Hillert, Eva Åkesson, MD, Helena
Modin, MD)
Department of Epidemiology Research, Statens
Serum Institut, Copenhagen, Denmark (Trine Rasmussen Nielsen, MD, Henrik Hjalgrim, MD, professor Mads Melbye, Peter Michael Bager, ph.d.)
Department of Clinical Neuroscience and
Centrum for Molecular Medicine Karolinska
Insitutet at Karolinska University Hospial, Solna
171 76 Stockholm, Sweden (Professor Tomas
Olsson, associate Professor Ingrid Kockum)
Department of Human Genetics, Aarhus University, Denmark (Bjørn Andersen Nexø)
Institute of Biological Psychiatry, Mental Health
Center, Sct. Hans, Denmark (Thomas Werge)
Blodbanken, Copenhagen University Hospital,
Rigshospitalet, Denmark (Henrik Ullum)
Laboratory of Neuropathology, Copenhagen
University Hospital Rigshospitalet, Copenhagen,
(Henning Laursen, MD)
Danish Research Center for Magnetic
Resonance, Hvidovre Hospital, (Professor Olaf
Paulsen, Professor Hartwig Siebner, Ellen Garde,
MD, Henrik Lund, MS)
Faculty of Life Sciences, University of
Copenhagen, Denmark (Professor Christian M.O.
Kapel, Professor Allan Roepstorff, Professor Stig
Milan Thamsborg)
Cell Therapy Unit, The Blood bank, Department
of Clinical Immunology, Rigshospitalet (Anne
Fischer-Nielsen, MD, Roberto Oliveri, MD)
International
Nordic MS Genetic Network: Collaboration
between the Nordic countries: Sweden
(Huddinge, Lund, Gothenburg, Stockholm),
Norway (Oslo, Bergen), Finland (Helsinki) and
Denmark (Copenhagen)
30
Institute of Immunology, Rikshospitalet,
University Hospital, Oslo, Norway (Anne
Spurkland, MD, Hanne F. Harbo, MD, professor
Frode Vartdal)
DANISH Multiple sclerosis CE NTER annual report 2013
Department of Neurology, Lund University
Hospital, Lund, Sweden (Professor Magnhild
Sandberg-Wollheim)
Department of Neurology, Gothenburg
University Hospital, Gothenburg, Sweden
(Professor Oluf Andersen)
Institute for Molecular Medicine Finland,
University of Helsinki, Finland (Janna Saarela)
University of Cambridge, Neurology Unit,
Addenbrooke’s Hospital, Cambridge, United
Kingdom (Stephen Sawcer, MD, Professor
Alastair Compston)
“International Multiple Sclerosis Genetic
Consortium” (IMSG): MS genetic collaboration
between 15 countries from Europe, USA, Canada
and Australia
Immunochip Consortium: autoimmune diseases
genetic collaboration between 20 countries from
Europe, USA, Canada and Australia
Sankt Joseph Hospital and Ruhr University,
Bochum, Germany (Professor Ralf Gold)
Department of Neurology, Turku and University
of Turku (Associate Professor Juha-Pekka
Eralinna)
Department of Neurology, Hopital Henri Mondor,
Creteil, France
University of Helsinki, Finland (Professor
Markus Farkkila)
Heinrich-Heine-University, Dusseldorf,
Germany (Professor Hans-Peter Hartung)
Department of Immunopathology, Brain
Research Center, Medical University of Vienna,
Vienna, Austria. (Professor Hans Lassmann and
Josa Frischer, MD)
Ospedale Universitario San Luigi, Torino, Italy
(Professor Auturio Bertolotto)
Queen Square, London, The United Kingdom
(Professor Gavin Giovannoni)
Department of Neurology, Mayo Clinic,
Rochester, Minnesota, USA (Professor
Claudia F. Lucchinetti)
Innsbruck Medical University, Innsbruck,
Austria (Professor Florian Deisenhammer)
VU Medical Centre, Amsterdam, The
Netherlands (Professor Chris Polman)
General Charles University, Prague, Czech
Republic (Professor Eva Havrdova)
Utrecht University, Utrecht, The Netherlands
(Professor Hub Schellekens)
Hospital Universitari Vall d’Hebron, Barcelona,
Spain (Professor Xavier Montalban)
Collaboration with pharmaceutical
companies on clinical trials
Novartis, Denmark
Merck Serono Nordic, Denmark, Norway
and Sweden
Biogen idec, Denmark and USA
Teva/Aventis, Israel and Denmark
Sanofi-aventis, Denmark
Bayer Schering, Germany
Genmab, Denmark
Genzymes, Holland
Glaxo Smith-Kline
Ovamed, Germany
Swedish Orphan, Sweden
Acknowledgements
Danish MS Society
Warwara Larsen Foundation
Rigshospitalets Scientific Board
The Johnsen Memorial Foundation
Fondsbørsvekselerer Henry Hansen
og Hustrus Legat
Danish Medical Research Council
EU Sixth Framework Programme
Brdr. Rønje Holding
Jeppe Juel Memorial Legacy
RoFar Foundation
Roche Denmark
The Danish Strategic Research Council
The Lounkær Foundation
Biogen idec
Sanofi-aventis
Merck Serono
Ejner Jonasson og Hustrus mindelegat
Publisher:
Danish Multiple Sclerosis Center
Photos:
Morten Blinkenberg, Dorthe Stauning Rasmussen
Editor:
Morten Blinkenberg
Proofreading:
Karen Schreiber
Authors:
Per Soelberg Sørensen, Morten Blinkenberg,
Finn Sellebjerg, Annette Oturai,
Helle Bach Søndergaard, Poul Erik H. Jensen
Concept, design, graphic ­production and print:
Datagraf Communications
St. Kongensgade 72, 1264 København K
Tlf. 33 13 73 83, www.datagraf.dk
DANISH Multiple sclerosis CENTER annual report 2013
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