VENUE GROUPCONTENTS NAME: UCAR Conference room Department of Nuclear Medicine, OUH

4 Program 71 Larsen Group

5 Meeting attendees 74 Meyer Group

7 Strategy 80 Nielsen

17 BRIDGE 83 Neuroepidemiology

22 Asgari Group 89 Neuroimmunology

27 BWK Brain Cancer Research Group 94 Neurosurgical research Group

31 Cellular Neurobiology 98 Owens Group

37 Child and Adolescent Psychiatric 103 Peripheral Neuropathy

41 The Danish Aging Research Center 108 T-Pemf and parkinsonism Group

45 Department of epilepsy genetics and 114 TRANSIC personalized medicine 123 Translational neuroscience Group 51 Finsen Group 128 UCAR 59 Focused Research Group in neurology 133 Posters 63 Gerlach Group

66 Lambertsen Group 4 VENUE PROGRAMGROUP NAME: JUNE UCAR 12TH Conference room Department of Nuclear Medicine, OUH

TIME

SESSION 1: INTRODUCTION – KIM BRIXEN, MEDICAL DIRECTOR, OUH 09:00-09:10

PRESENTER 09:10-09:20 Brain Cancer – Bjarne Winther Kristensen 09:20-09:30 Neuroimaging – Poul Flemming Højlund Carlsen and Albert Gjedde 09:30-09:40 Alcohol– Anette Søgaard Nielsen 09:40-09:50 Psychiatry - Tanja Michel

09:50-10:25 DISCUSSION PANEL Bjarne Winther Kristensen, Poul Flemming Højlund-Carlsen, Anette Søgaard Nielsen, Tanja Michel, Frantz Rom Poulsen, Albert Gjedde, Kate Lykke Lambertsen

10:25-10:35 BREAK

SESSION 2: INTRODUCTION - OLE SKØTT, DEAN HEALTH SCIENCE SDU 10:35-10:45

PRESENTER 10:45-11:00 Neuroinflammation - Trevor Owens 11:00-11:10 Stem cells and neurodegenerative diseases - Morten Meyer 11:10-11:20 Neuroepidemiology - David Gaist 11:20-11:30 Demyelinating diseases - Zsolt Illes

11:30-12:00 DISCUSSION PANEL Trevor Owens, Morten Meyer, David Gaist, Bente Finsen, Zsolt Illes, Åsa Fex-Svenningsen, Søren Sindrup, Kate Lykke Lambertsen

12:00-13:00 LUNCH AND POSTER SESSION 5 VENUE MEETINGGROUP NAME: ATTENDEES UCAR Conference room Department of Nuclear Medicine, OUH

THE LUNDBECK • Professor Kim Krogsgaard, Managing Director, The Brain Prize, FOUNDATION The Lundbeck Foundation • Dr. med. Sissel Vorstrup, Associate Director of Research, The Lundbeck Foundation • Ph.d. Line Vilbrad Knudsen, Science Liaison, The Brain Prize, The Lundbeck Foundation • Professor, Sir Colin Blakemore, University of London • Professor Martin Rossor, University College London

OUH, SDU AND • Professor Ole Skøtt, Dean at the Faculty of Health Sciences, SDU MENTAL HEALTH • Professor Kim Brixen, Medical Director, OUH SERVICES IN • Professor Kirsten Kyvik, Head of Department, Department of Clinical THE REGION Research, SDU OF SOUTHERN • Professor Uffe Holmskov, Head of Department, Department of Molecular DENMARK Medicine, SDU • Associate Professor Rikke Leth-Larsen, Head of Department, Department of Regional Health Research, SDU • MSc Marie Lund, Head of Department, Department of Quality, Research, Innovation and Education, OUH • Associate professor Kate Lykke Lambertsen, Lundbeck Brain Prize Council Representative at SDU

SESSION 1: • Professor Bjarne Winther Kristensen, Department of Pathology, OUH • Professor Poul Flemming Højlund Carlsen, Department of Nuclear Medicine, OUH • Professor Albert Gjedde, Department of Nuclear Medicine, OUH • Associate Professor Anette Søgaard Nielsen, Mental Health Services, Region of Southern Denmark • Professor Tanja Michel, Mental Health Services, Region of Southern Denmark • Professor Frantz Rom Poulsen, Department of Neurosurgery, OUH

SESSION 2: • Professor Trevor Owens, Department of Molecular Medicine, SDU • Associate Professor Morten Meyer, Department of Molecular Medicine, SDU • Professor David Gaist, Department of Neurology, OUH • Professor Zsolt Illes, Department of Neurology, OUH • Professor Bente Finsen, Department of Molecular Medicine, SDU • Associate Professor Åsa Fex-Svenningsen, Department of Molecular Medicine, SDU • Professor Søren Sindrup, Department of Neurology, OUH Neuroscience at the Faculty of Health Sciences, SDU, OUH and the Region of Southern Denmark 7

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

INTRODUCTION The University of Southern Denmark (SDU), Odense University Hospital (OUH) and the Region of Southern Denmark (RSD) wish to maintain and develop the region as an area with hospitals and a university that have a visible and decisive influence on research, the health care system and public health. We focus on translational research to facilitate interaction between basic health research and clinical practice. This is supported by strong collaborations between OUH, Mental Health Services (MHS) in RSD, institutes under the Faculty of Health Sciences, and the Faculty of Science, SDU.

When the New OUH is completed in 2022 it will be connected to the existing SDU by a new Faculty of Health Science. Translational research will enjoy extraordinarily good conditions in the close linkage between the university and the university hos- pital. The interaction between foundation-creating research subjects at SDU and the clinical subjects at OUH provides an example of translational research. New OUH/SDU will create synergies between the university and the university hospital, with the goal of creating even better research, better treatment and better edu- cation. Ultimately, it will also contribute to improving human health, which is the declared visionary goal of the Faculty of Health Sciences and futher the ambion of OUH - The Patient First.

The neuroscience at SDU, OUH, MHS and the regional hospitals is gathered together under the newly established BRIDGE initiative (Brain Research-Inter-Disciplinary Guided Excellence). BRIDGE was established with the aim of hosting a network of researchers with clinical expertise and scientific excellence in neuroscience. The center brings together the diverse research interests of members of a core research team who will work under the common umbrella of a neuroscience approach and neurobehavioral research methodologies. The vision of BRIDGE is to improve patient treatment and promote early intervention and the prevention of brain disorders patient by using translational research to harness the power of discovery science. We aim to establish a separate building for BRIDGE at the new university hospital. 8

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

INTERACTIONS Interactions between neuroscience researchers are facilitated by: • Communication of research ideas and findings facilitated by regular seminars within BRIDGE • An annual Neurotranslational meeting facilitating new collaborations and giving people from SDU, OUH, and RSD the opportunity to meet and discuss research. • Upcoming joint meetings for senior researchers within neuroscience at SDU, OUH, and RSD. The purpose is to facilitate and strengthen collaborations, to promote research strategies, and to discuss common applications. • Cross-affiliations and cross-appointments between OUH and SDU

INFRASTRUCTURE Our neuroscience infrastructure includes: • The Biomedical Laboratory (BL) is the central animal facility for Health Sciences, Natural Sciences and OUH. The department is involved in experimental biomedical research, surgical skills courses, training and research in labora- tory animal science at SDU, OUH and the regional hospitals. This is a world- class facility for animal research including rodents, rabbits, dogs, pigs and sheep and is headed by Associate Professor Peter Bollen together with veterinarian Louise Langhorn. • The IMM Flow Cytometry and Confocal Microscopy Core Facility serve all research groups at SDU and OUH as well as non-university users. • The Department of Human Genetics at OUH provides DNA and RNA sequencing and array screening services. • A small animal PET/CT scanner, which is part of the Danish Molecular Bioimaging Center (DaMBIC) at SDU, is operated in collaboration with the Biomedical Laboratory. • OPEN (Odense Patient data Explorative Network) offers access to databases, biobanks and use of registry data as well as general advice related to research projects. • Department of Nuclear Medicine, OUH, is an interdisciplinary clinical depart- ment serving almost all medical specialties and all departments at OUH and SDU. The department is equipped with gamma cameras, SPECT/CT scanners, and PET/CT scanners as well as its own Cyclotron and radiochemical laborato- ries for production and development of a variety of PET tracers. 9

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

NEUROSCIENCE The Department of Clinical Research is the largest department at The Faculty of AT OUH AND THE Health Sciences – but the entire department is physically located at OUH, where DEPARTMENT research and clinical experience are directly related. The Faculty of Health Sciences OF CLINICAL RESEARCH, SDU is thus essential for research at OUH, and the clinical environment is essential for the research. The Department of Clinical Research was established in 1989 and constitutes the university affiliation of the researchers and lecturers working at OUH. The Institute includes 42 research departments and is headed by Professor Kirsten Ohm Kyvik.

Strategy OUH and the Department of Clinical Research, SDU, have in collaboration prepared an ambitious research strategy for the period 2016-2020. A major focus in the strategy is involving patients and relatives in research. OUH's motto 'The Patient First' obliges in all respects - also in relation to research. Experience shows that involving patients and their relatives can give added value to research. We antici- pate that both the quality and the relevance of the research will be enhanced. If the research that is undertaken reflects patients’ needs and views on what needs to be researched, the results will be more readily implemented into clinical practice. Thus, since 2016 patients and relatives are members of Research Council at OUH. A further element of the strategy is to ensure that all OUH departments get experience of involving patients and/or relatives in the research process.

Structure Neuroscience at the Department of Clinical Research is responsible for neurological, neurosurgical and neurobiological research undertaken at OUH. Several departments and research groups are involved in the research and including researchers from neurology, neurosurgery, pathology, imaging, psychiatry, ophthalmology, infectious diseases and basic science. The cross- disciplinary research possibilities will expand the already established collaborative work at SDU and OUH with the aim of improving diagnosis and treatment of brain and mental disorders. Neurosciences at OUH form an important part of BRIDGE. The Department of Clinical Research acts by integrating all the research facilities at OUH. Professors and associate professors at the Department of Clinical Research 10

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

NEUROSCIENCE participate in course-based teaching, mainly to medical and biomechanical students. AT OUH AND THE Within each research unit, the distinct research group is led by a group leader who DEPARTMENT is a permanent faculty member at the professor level. In addition, researchers with OF CLINICAL independent funding from other research units at SDU contribute to neuroscience RESEARCH, SDU research at OUH and KI.

OUH Department of Mental Health clinical Resarch Services

Director Kim Brixen Head of department Director Anders Kirsten Kyvik Meinert

Dep. of Dep. of Ment. Health Dep. of Dep. of Dep. of Dep. of Services Nuclear Infect Ophthal- Pathology Medicine Neurology Neurosurgery diseases mology Prof. Tanja Prof. Niels Prof. Poul F. H. Prof. Søren Prof. Frantz R. Prof. Isik Prof. Jacob Michell Marcussen Carlsen Sindrup Poulsen Johansen Grauslund

NEUROSCIENCE AT The Department of Molecular Medicine (IMM) was formed in 2010 by a reorgani- THE DEPARTMENT zation of the Department of Medical Biology and the Medical Biotechnology Center, OF MOLECULAR under the directorship of Professor Uffe Holmskov. The Institute includes three MEDICINE, SDU research departments. Neuroscience is represented by the Department of Neuro- biology Research.

Strategy The strategy behind the formation of IMM in 2010 was to align university-based research with clinical hospital-based research, focusing on translational research to form a bridge between the clinically-oriented research environment at OUH and the more basic research-oriented environment at the Faculty of Natural Science. Re- search interests within Neurobiology can therefore be categorized by research topic and by disease focus, with intentional overlap between them. The goal is to enable high quality translational research in neuroscience and to train future researchers who will apply these principles and practice to understanding and treating neuro- logical disease. There is also a strong educational component and faculty members in Neurobiology participate with other IMM faculty in course-based teaching, main- ly to medical, biomedical and pharmaceutical students. Teaching of neuroanatomy is carried out in conjunction with the IMM Anatomy Department. 11

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

Structure There are currently 7 faculty members in IMM Neurobiology Research, 3 professors and 4 associate professors, all of them basic scientists, with Professor Trevor Owens as Research Leader. Five of them (Professor Owens and Finsen, Associate Professors Lambertsen, Meyer and Svenningsen) will form the nucleus for Neurobiology in the future integration of Health Sciences at the University campus, where there is currently an additional Associate Professor, with responsibility for Anatomy. Four clinical researchers who are embedded in IMM-based research programs are for- mally affiliated at the Professor or Associate Professor level to IMM-Neuro- biology (Illes and Hvilsted Nielsen from OUH Neurology, Asgari from the Insti- tute of Regional Health, and Sheldrick-Michel from OUH Psychiatry). Associate Kate Lambertsen is cross-appointed in OUH Neurology while Associate Professor Morten Meyer is affiliated to the Department of Neurology, Zealand University Hospital. Recruitment at all levels is ongoing or contemplated.

Research • Neuroinflammation is studied by Trevor Owens, Bente Finsen, Kate Lambertsen and Åsa Svenningsen with primary reference to CNS disorders multiple sclerosis, neuromyelitis optica spectrum disorders, stroke, spinal cord injury, and Alzheimer’s disease. Unifying features of these groups’ research are their interest in glial cells, glial-immune interactions and therapeutically-oriented regulatory mechanisms, using experimental animal and in vitro approaches. Principal clinical and basic collaborations are with colleagues in OUH Neuro- logy, Region Syddanmark Institute for Regional Health, SDU Centre for Clinical Proteomics, University of Miami USA, Lund University, and University Medical Centre Groningen (Netherlands). • Acute and chronic neurodegeneration are studied by Bente Finsen (Alzheimer’s disease, stroke), Kate Lambertsen (stroke and spinal cord injury), and Morten Meyer (Parkinson’s disease). Research approaches involve translation from animal studies to clinical (autopsy, CSF) material as well as disease modeling using patient-derived induced pluripotent stem cells (Meyer). Collaborations with OUH Neurology, Pathology, Glostrup Hospital, Dalhousie University Halifax Canada, University of Oxford, and the Buck Institute USA underpin these research programs. • Neurodevelopment has been represented by Professor Niels Aagaard Jensen’s research on genes that regulate cortical development, and extends to study of the role of the neurotransmitters GABA (Svenningsen) and dopamine 12

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

(Meyer), the cytokine TNF (Lambertsen) and microglial cells (Owens, Finsen) in regulation of developing neural networks and related Autism Spectrum Dísorders, combining in vitro work and behavioral studies in genetically-modified animals, with cohort-based analysis of patient groups. Key collaborations are with OUH Psychiatry, Aarhus University (DANDRITE, iPSYCH), Uppsala University Sweden, Autonomouse University of Barcelona, Bogazici University Turkey and UMCG in the Netherlands.

NEUROSCIENCE The Department of Clinical Health Research (IRS) is one of two clinical institutes at AT THE REGIONAL the Faculty of Health Science and is responsible for research and education at the HOSPITALS AND regional hospitals in the Region of Southern Denmark and Region of Zealand. The THE DEPARTMENT OF REGIONAL department is headed by Associate Professor Rikke Leth-Larsen. HEALTH RESEARCH, SDU The neuroscience research groups are physically placed at five different hospitals, but with collaboration between hospitals and between knowledge domains. The five hospitals are • The Hospital of Southern Jutland • Psychiatry in the Region of Southern Denmark, Aabenraa • Filadelfia • Naestved/Slagelse/Ringsted Hospital • Lillebaelt Hospital

Strategy IRS is strong in clinical research on selected frequent diseases with the aim of understanding biomedical foundations and treatment effect through a combination of basic research, health services research and clinical research, so that research results are brought to the patients by being applied in clinical practice. IRS facilitates the research through competent feedback on research processes, research politics, SDU infrastructure and services for researchers, and by facilitating and formalizing cooperation across the affiliated units.

Structure The center faculty infrastructure includes several senior researchers affiliated with 5 different hospitals under IRS, SDU. These groups include researchers from 13

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

neurology, psychiatry and basic science. Within each hospital, the distinct research group is led by a center leader, who is a permanent faculty member at either the professorial or associate professor level.

Hospitals Ind the Regions Dep. of Regional Health of Southern Denmark and Research, SDU Zealand Head of department Rikke Leth-Larsen

Centre for Dep.of Psychiatry, Dep. of Neurology, Dep. of epilepsy Neurological Reseach, Aabenrå Hosp. of southern genetics and pers. Naestved/ Slagelse/ Lillebælt Hospital Jutland med., Filadelfia Ringsted Hosp. Prof. Elsebeth Prof. Egon Ass. prof. Helle Jens J. E. Ass. prof. Jonna Stenager Stenager Hjalgrim Christensen Skov Madsen

NEUROSCIENCE Educational elements that include neurology at the Faculty of Health Sciences in- EDUCATION AT clude courses taught to pre- and postgraduate students in Medicine, Biomedicine, THE FACULTY OF Biomechanics, Pharmacy, Audiology and Logopedics, Psychology, Sports, Public HEALTH SCIENCES, SDU Health and Occupational Health. The educational program for the health sciences at SDU, include the following MEDICINE Bachelor's degree program • Module B9: The brain and the senses (15 ECTS) Master's degree program • Module K5: The nervous system, somatic and mental disorders (13 ECTS) • Module K8: Woman, mother, and child (13 ECTS) • Module K1 and K2: Skills Training (5 ECTS) • Clinical placement - Neurological department (6 ECTS) - for students who prioritize/choose this placement

MASTER’S DEGREE PROGRAM IN BIOMEDICINE: • SU810, Human patophysiology (15 ECTS) • SU803, Pharmacology (5 ECTS) • SU802, Medical Neurobiology (5 ECTS)

MASTER'S DEGREE PROGRAM IN PHARMACY • Included in one of the medical specialties in the module Clinical Pharmacology and Therapy A (10 ECTS) • Study placement - Neurological department (4 ECTS) - for students allocated to the department 14

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

CLINICAL BIOMECHANICS Bachelor's degree program • Module B9: The brain and the senses (15 ECTS) • Module B11: Orthopaedic and neurological examination (2 ECTS) Master's degree programme • Module K2 / K4: General diagnostics 3: Neurology (5 ECTS)

AUDIOLOGY AND LOGOPEDICS Bachelor's degree program • Anatomy and physiology (5 ECTS) • Neurobiology and neurology (7.5 ECTS)

PSYCHOLOGY Bachelor's degree program • Module B11: (Optional topic): Affective neuroscience (10 ECTS) • Module B05: Biological psychology - the biological and physiological basis of behaviour, including neurological processes (10 ECTS)

SPORTS Bachelor's degree program • FV2 Physical activity and cognition, including neurophysiology (10 ECTS) • BL1 Learning and cognition, cognition related to neuroscience (5 ECTS) • TS4 Targeted training in theory and practice, including neuromuscular function (10 ECTS)

PUBLIC HEALTH Bachelor's degree program • Pathology and public health, including neurological diseases (10 ECTS)

MASTER'S DEGREE PROGRAM IN OCCUPATIONAL HEALTH • Module 1: Motion Science Research on the newest rehabilitation regimes in neuro-rehabilitation is reviewed, with collaboration from staff at Hammel Neurocenter who present their research with relevance to occupational health. 15

Neuroscience at the Faculty of Health Sciences, VENUE SDU, OUHGROUP and the RegionNAME: of Southern UCAR Denmark Conference room Department of Nuclear Medicine, OUH

MASTER'S DEGREE IN HEALTH SCIENCES and MASTER'S PROGRAM IN CLINICAL NURSING, MIDWIFERY AND PHYSIOTHERAPY There is no systematic teaching within the neurological specialty.

PhD/RESEARCH EDUCATION • PhD students at the Faculty of Health Sciences can be enrolled under the Graduate Program in Neuroscience, which holds PhD courses and summer schools in the research area. About 40 PhD students are attached to the Graduate Program in Neuroscience (May 2017). • Graduate research year (Medical Masters) Medical students in the Faculty of Health Sciences have the opportunity to complete a pre-graduate research year in connection with a master's thesis. Research topics include neuroscience. The specific research topic and questions are planned in collaboration between the student and the main supervisor. External funding for pregraduate projects in basic science labs is available from the Danish Council for Independent Research Medical Sciences. • Masters research: MSc research projects under the auspices of the Department of Biochemistry and Molecular Biology, The Faculty of Natural Sciences, are also supervised within the Faculty of Health Sciences. • Sino-Danish Center (SDC): Faculty members in the Department of Neurobiology, Department of Molecular Medicine, participate in the SDC Masters program in Neuroscience and Neuroimaging through teaching courses in Beijing as well as supervision of students visiting Odense from China for short research exchanges. Neurobiology students can also apply to SDC PhD programs with exchange visits to China. • Summer School in Neuroscience 2017: "The Interdisciplinary Projects of the Future in Psychiatry, Neurology, Neurosurgery and Psychology" is a Residential Ph.D-course including lectures, group work, student presentations and social events. The course is directed at pre-graduates, Ph.D-students, senior scientists, Assistant Professors, Associate Professors and clinical practitioners in psychiatry, neurology, neurosurgery and psychology. BRIDGE Collaboration of SDU, OUH and Mental Health Services in the region of Southern Denmark 17

GROUPGROUP NAME: NAME UCAR GROUP LEADER BRIDGE Professor to be appointed

NUMBER OF 35 Professors, Post-docs. phD. Pregraduate students GROUP MEMBERS Full list of BRIDGE affiliated persons can be found at http://findresearcher.sdu.dk/ (AND THEIR TITLE) portal/da/organisations/bridge-brain-research-interdisciplinary-guided-excellen- ce(9a390ccf-6dbe-4842-b770-90e662e9950e)/persons.html?filter=current

DEPARTMENT & Collaboration of the University of Southern Denmark, Odense University Hospital UNIVERSITY/ and Psychiatry in the region of Southern Denmark HOSPITAL/OTHER

FUNDING SOURCES Main sources for the overall funding: Region of Southern Denmark, Psychiatric Re- search Fond, Odense University Hospital, University of Southern Denmark, Funding for single Projects within the BRDIGE: Alzheimer Foreningen, FSS, Lundbeckfonden

DESCRIPTION OF The Center for applied Neuroscience, “BRIDGE” is a joint initiative of the Odense RESEARCH University Hospital, the Psychiatry in the Region of Southern Denmark and the University of Southern Denmark to further excellence in neuroscience in the region of Southern Denmark. The aim of the research center is to ”bridge” the gap between clinical research and basic science in order to individualize treatment in psychiatry and neurology.

As a first step to this ambitious goal, we have built up well described (clinical) cohorts (epidemiology) for different brain disorders (autism, dementia, Multiple scleroris). Those will be clustered on the basis of their (single) clinical symptoms and their specific biomarkerprofile. This data will be analyzed utilizing a big data, bioinformatics approach. The clinical biomarkerprofile will be incorporating the different results from the use of cutting edge molecular methods (multiomics), psychology, neuroimaging, stem cell biology (bioengineering) to get multidimen- sional biomarkers for the diseases. This deep clinical biomarkerprofile will help to individualize treatment and by this a leap to the application of personalized medi- cine for brain disorders is expected. 18

GROUPGROUP NAME: NAME UCAR GROUP LEADER BRIDGE Professor to be appointed

Research is distributed into different workpackages: 1 Clinical epidemiology, 2 “Multi-omics” (Genomics, Epigenomics, Proteomics etc), 3 High resolution and multimodal Neuroimaging, 4 Neuropsychology 5 System bioinformatics (Big Data).

The center hosts around 35 Professors and a number of junior faculty members across all neurological disciplines and basic research. It spans from clinical research in Psychiatry, Psychology, Neurology, Neurosurgery, Sensory Disciplines (Ear nose and throat, Eye), Microbiology, to combination of these with basis science such as the one happening at the Institute for Molecular Medicine and also uses modern neuroimaging techniques such as molecular, func- tional and structural neuroimaging (at the Dept. for Neuroradiology and Nuclear Medicine respectively). It consists of the Research Departments investigating Neurobiology and Neuro- imaging. All in all 4 different University Institutes are involved (Institute for clinical Research, Institute for Psychology, Institute for Molecular Medicine and Institute for System Neuroscience), and two faculties are involved (Faculty for health scienc- es and mathematics and natural Science). It is located in Odense.

KEY PUBLICATIONS Recent 15 publications

1. Mobarak-Abadi , P., Johansen, A., Godballe, C., Gerke, O., Høilund-Carlsen, P. F. & Thomassen, A. s18F-FDG PET/CT to differentiate malignant necrotic lymph node from benign cystic lesions in the neck. Annals of Nuclear Medicine 2017; 31, 2, s. 101-108 2. Lindgren Belal, S., Sadik, M., Kaboteh, R., Hasani, N., Enqvist, O., Svärm, L., Kahl, F., Simonsen, J., Poulsen, M. H., Ohlsson, M., Høilund-Carlsen, P. F., Edenbrandt, L. & Trägårdh, E. 3D skeletal uptake of 18F sodium fluoride in PET/ CT images is associated with overall survival in patients with prostate cancer. 2017 I : EJNMMI Research. 7, 8 s., 15

19

GROUPGROUP NAME: NAME UCAR GROUP LEADER BRIDGE Professor to be appointed

3. Liisberg, M., Diederichsen, A. C. & Lindholt, J. Abdominal ultrasound-scanning versus non-contrast computed tomography as screening method for abdominal aortic aneurysm: a validation study from the randomized DAN CAVAS study. BMC Medical Imaging 2017; 17, 8 s., 14 4. Nielsen, R. E., Lolk, A., Rodrigo-Domingo, M., Valentin, J. B. & Andersen, K. Antipsychotic treatment effects on cardiovascular, cancer, infection, and intentional self-harm as cause of death in patients with Alzheimer’s dementia. European Psychiatry 2017; 42, s. 14–23 5. Fernandez-García, C-E., Burillo, E., Lindholt, J. S., Martinez-Lopez, D., Pilely, K., Mazzeo, C., Michel, J-B., Egido, J., Garred, P., Blanco-Colio, L. M. & Martin- Ventura, J. L. Association of Ficolin-3 with abdominal aortic aneurysm presence and progression. Journal of Thrombosis and Haemostasis 2017; 15, 3, s. 575–585 6. Dyrvig, A-K., Yderstræde, K. B., Gerke, O., Jensen, P. B., Hess, S., Høilund-Carlsen, P. F. & Green, A. Cancer of unknown primary: Registered procedures compared with national integrated cancer pathway for illuminating external validity. Medicine (Philadelphia) 2017; 96, 16, 7 s., e6693 7. Venø, M. T., Venø, S. T., Rehberg, K., van Asperen, J. V., Clausen, B. H., Holm, I. E., Pasterkamp, R. J., Finsen, B. & Kjems, J. Cortical morphogenesis during embryonic development is regulated by miR-34c and miR-204. Frontiers in Molecular Neuroscience 2017; 10, 10 s., 31 8. Simão, S., Costa, M. Â., Sun, J. K., Cunha-Vaz, J., Simó, R. & European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Development of a Normative Database for Multifocal Electroretinography in the Context of a Multicenter Clinical Trial. Ophthalmic Research 2017; 57, 2, s. 107-117 9. Grauslund, J. & Blindbaek, S. L. Diabetic macular oedema: what to fear? How to treat? . Acta Ophthalmologica 2017; 95, 2, s. 117-118 10. Kristoffersen, J. H., Licht, R. W., Andersen, K., Stage, T. B., Nilsson, F. M., Stage, K. B., Valentin, J. B., bech, P. & Nielsen, R. E. Diagnostic conversion to bipolar disorder in unipolar depressed patients participating in trials on antidepres- sants. European Psychiatry 2017; 40, s. 76-81 11. Almeida, D. M., Skov, I., Silva, A., Vandin, F., Tan, Q., Röttger, R. & Baumbach, J. Efficient detection of differentially methylated regions using DiMmeR. Bioinfor matics 2017; 33, 4, s. 549-551 12. Holmager, P., Egstrup, M., Gustafsson, I., Schou, M., Dahl, J. S., Rasmussen, L. M., Møller, J. E., Tuxen, C. D., Faber, J. & Kistorp, C. M. N. Galectin-3 and fibulin-1 in systolic heart failure: relation to glucose metabolism and left ventricular contractile reserve. BMC Cardiovascular Disorders 2017; 17, 8 s. 22 20

GROUPGROUP NAME: NAME UCAR GROUP LEADER BRIDGE Professor to be appointed

13. Kristensen, K. L., Dahl, M., Rasmussen, L. M. & Lindholt, J. S. Glycated Hemo globin Is Associated With the Growth Rate of Abdominal Aortic Aneurysms: A Substudy From the VIVA (Viborg Vascular) Randomized Screening Trial. Arterio sclerosis, Thrombosis, and Vascular Biology 2017; 37, 4, s. 730-736 14. Emiliussen, J., Andersen, K. & Nielsen, A. S. How do older adults with very late-onset alcohol use disorder define alcohol problems?: Results from an interpretative phenomenological study. Alcoholism Treatment Quarterly 2017; 32, 2, s. 151-164 15. Gredal, H., Thomsen, B. B., Boza-Serrano, A., Garosi, L., Rusbridge, C., antho ny, D., Møller, A., Finsen, B., Deierborg, T., Lambertsen, K. L. & Berendt, M. IL-6 is increased in plasma and CSF of community-dwelling domestic dogs with acute ischaemic stroke. NeuroReport 2017; 28, 3, s. 134-140

The full list can be seen here: http://findresearcher.sdu.dk/portal/da/organi- sations/bridge-brain-research--interdisciplinary-guided-excellence(9a390c- cf-6dbe-4842-b770-90e662e9950e)/publications.html?filter=research&subfilter=- contributiontojournal

KEY Danish: COLLABORATIONS Statens Serum Institute, Cophenhagen. DTU. University of Cophenhagen University of Aalborg. University of Aarhus

International: Instite of Psychiatry, Kings College London, UK. Mount Sinai Hospital New York, USA. University of Cambridge. Max Planck Institute Goettingen and Homburg/Saar, Germany. Max Planck Institute Homburg/Saar, Germany. Charite Berlin, Germany University Bonn, Germany. University Cologne, Germany. University of Wuerzburg, Germany. Excellence Technical University Aachen, Germany. University of Zuerich, Switzerland. University of Wisconsin, USA. University of Sydney, Australia

INFRASTRUCTURE BRIDGE infra structure covers expertice, equipment and resources located within the affiliated research groups at SDU, OHU and Mental Health Services, SDU Asgari Group Department of Neurology, Naestved/Slagelse/Ringsted Hospital, & Department of Regional Health Research,SDU 22

GROUPGROUP NAME: NAME UCAR GROUP LEADER Asgari Group Nasrin Asgari

NUMBER OF Adj. Professor: Professor Brian Weinshenker, Mayo Clinic, USA GROUP MEMBERS PhD students: Kerstin Soelberg, Nikolaj Mads Olesen, Carsten Berg, (Co-supervisor) (AND THEIR TITLE) Marlene.T. Morch, (Co-supervisor)

DEPARTMENT & Dep. of Neurology, Slagelse, & Institute of Regional Health Research & UNIVERSITY/ Neurobiology, Institute of Molecular Medicine, University of Southern Denmark HOSPITAL/OTHER

FUNDING SOURCES Lundbeck Foundation, the Danish Multiple Sclerosis Society, The Region of Southern Denmark and The Danish Council for Independent Research, The Danish Foundation for Neurological Research,

DESCRIPTION OF Clinical and translational research on antibody-mediated inflammatory demyelin- RESEARCH ating diseases of the CNS, which include neuromyelitis optica spectrum disorder (NMOSD), and a subgroup of multiple sclero-sis (MS) as well as optic neuritis (ON) harboring IgG with specificities to aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG). A predominantly population-based cohort of patients with Systemic Lupus Erythematosus (SLE) has been evaluated focusing on the possible susceptibility for co-existence between antibody-mediated autoimmune diseases and neuropsychiatric SLE. Amyotrophic Lateral Sclerosis: this project aims to study a number of clinical, neuroinflammatory and immunogenetic aspects of ALS, contributing to the characterization of disease mechanisms. 23

GROUPGROUP NAME: NAME UCAR GROUP LEADER Asgari group Nasrin Asgari

KEY PUBLICATIONS 1. Asgari N, Lillevang ST, Skejoe HP, et al. A population-based study of neuromyelitis optica in Caucasians. Neurology 2011; 76: 1589-1595 2. Asgari N, Nielsen C, Stenager E, et al. HLA, PTPN22 and PD-1 associations as markers of autoimmunity in neuromyelitis optica. Multiple Sclerosis 2012; 18:23-30 3. Asgari N, Khorooshi R, Lillevang ST, Owens T. Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. J Neuroimmunology 2013 Jan 15;254(1-2):76-82. 4. Asgari N, Voss A, Steenstrup T, Kyvik KO, Stenager E, Lillevang ST. Interferon alpha association with neuromyelitis optica. Clin. Dev. Immunology 2013;2013:713519. 5. Asgari N, Henriksen TB, Petersen T, Lillevang ST and Weinshenker GB. Pregnancy outcomes in a wom-an with neuromyelitis optica, Neurology. 2014;83:1576-1577. 6. Asgari N, Berg CT, Mørch TM, Khorooshi R, Owens T. Cerebrospinal fluid aquaporin-4-immunoglobulin G disrupts blood brain barrier. Annals of Clinical and Translational Neurology. 2015. 2(8): p. 857-863. 7. Jarius S, Kleiter I, Ruprecht K, Asgari N, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome. Journal of neuroinflammation 2016;13:281. 8. Asgari N, Flanagan EP, Fujihara K, Kim HJ, Skejoe HPB, Wuerfel J, Kuroda H, Kim SJ, Maillart E, Mar-ignier R, Pittock SJ, Paul F, Weinshenker BG. Disruption of the leptomeningeal blood barrier in neuromy-elitis optica spectrum disorder. Neurology(R) neuroimmunology & neuroinflammation 2017;4:e343 Neurology(R) neuroimmunology & neuroinflammation 2017;4:e343 9. Asgari N, Jarius S, Laustrup H, Skejoe HPB, Lillevang ST, Weinshenker BG, Voss A. Aquaporin-4-autoimmunity in patients with systemic lupus erythematosus: A predominantly population-based study. Multiple Sclerosis (Houndmills, Basingstoke, England) 2017:1352458517699791. 10. Pache F, Zimmermann H, Mikolajczak J, chumacher S, Lacheta A, Oertel FC, Bellmann-Strobl J, Jarius S, Wildemann B, Reindl M, Waldman A, Soelberg K, Asgari N et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients. Journal of neuroinflammation 2016;13:282.

24

GROUPGROUP NAME: NAME UCAR GROUP LEADER Asgari group Nasrin Asgari

KEY Danish: COLLABORATIONS University of Southern Denmark, Inst. of Molecular Medicine, (Prof. T. Owens) Department of Ophthalmology, OUH (Prof. J. Grauslund) Clinical Immunology and Biochemistry, Vejle, (Prof. I. Brandslund) Clinical Immunology Department, OUH,( Associate Professor, Søren Thue Lillevang, M.D., Ph.D.) Rheumatology Department, OUH, Associate Professor, Consultant Anne Voss, M.D., Ph.D. Department of Oncology, SLB, Vejle,(Prof. A. Jacobsen) Institute for Medicine and Health Technology, Aalborg University (Prof. S. Nilesen) Department of Clinical Pathology, OUH ( Associate Professor,Martin Wirenfeldt Nielsen M.D., Ph.D.)

International: Mayo Clinic, Rochester MN, USA (Professors Brian Weinshenker, Vanda Lennon and Sean Pittock) NeuroCure Clinical Research Center, Charité University, Berlin, Germany (Professor Friedemann Paul) Department of Neurology, Research Institute and Hospital of National Cancer Cen- ter, Goyang, Korea (dr. Ho Jin Kim) Department of Multiple Sclerosis Therapeutics, Fukushima Medical University School of Medicine, Fuku-shima, Japan and Research Institute for Neuroscience, Koriyama, Japan (professor Kazuo Fujihara) Ophthalmology and Visual Sciences, University of Michigan Medical School, USA (Professor Terry J. Smith). Department of Neurology and Molecular Neuroimmunology, University of Heidel- berg, Heidelberg, Ger-many (Professor Sven Jarius) Mayo Clinic, Minnesota,USA University of Bern, Switzerland University of Colorado, USA

25

GROUPGROUP NAME: NAME UCAR GROUP LEADER Asgari group Nasrin Asgari

INFRASTRUCTURE Methods for biomarkers (identification of new autoimmune biomarkers in blood and spinal fluid) estab-lished and validated internationally. MRI methodology Optical coherence tomography (OCT) for quantification of damage to the optic nerve and retinal nerve cells Animal models for neurological inflammatory disease

BWK Brain Cancer Research Group Department of Pathology, OUH & Department of Clinical Research, SDU 27

GROUPGROUP NAME: NAME UCAR GROUP LEADER BWK Brain Cancer Research Group Bjarne Winther Kristensen

NUMBER OF Total 12; 1 post doc (50%), 2 PhD students, 2 MSc students, 5 pregraduate MSc/MD GROUP MEMBERS students, 1 technician (AND THEIR TITLE)

DEPARTMENT & Department of Pathology, OUH UNIVERSITY/ Department of Clinical Research, SDU HOSPITAL/OTHER

FUNDING SOURCES FSS, Novo Nordic Foundation, Danish Cancer Society and several private foundations

DESCRIPTION OF 1. Influence of tumor microenvironment on therapeutic resistance RESEARCH 2. Inlfuence of tumor-brain interaction on tumor development and therapeutic resistance 3. Identification of novel biomarkers by experimental discovery stragegies combined with studies in clinical patient cohorts 4. Integreated brain tumor diagnostics with microscopy, next-generation sequencing and genome-wide methylation profiling.

KEY PUBLICATIONS 1. S. Munthe, B. Halle, H.B. Boldt, H. Christiansen, S. Schmidt, V. Kaimal, J. Xu, S. Zabludoff, J. Mollenhauer, F.R. Poulsen, B.W. Kristensen. Shift of microRNA profile upon glioma cell mi-gration using patient-derived spheroids and se rumfree conditions. J Neurooncol 2017, Jan 13, Epub ahead of print. PMID: 28091986 2. H. Thisgaard*, B. Halle*, C. Aaberg-Jessen, B.B. Olsen, A.S. Therkelsen, J.H. Dam, N. Langkjær, S. Munthe, K. Någren, P.F. Høilund-Carlsen*, B.W. Kristensen*. Highly effective auger-electron therapy in an orthotopic glioblastoma xenograft model using convection-enhanced delivery. Theranostics 2016, Sep 29;6(12):2278-2291. (*Shared first and senior authorship). PMID: 27924163 28

GROUPGROUP NAME: NAME UCAR GROUP LEADER BWK Brain Cancer Research group Bjarne Winther Kristensen

3. S.S. Jensen, M. Meyer, S.A. Petterson, B. Halle, A.M. Rosager, C. Aaberg-Jessen, M. Thomassen, M. Burton, T.A. Kruse, B.W. Kristensen. Establishment and characterization of a tumor stem cell-based glioblastoma invasion model. PLoS One 2016, July 25;11(7). PMID: 27454178 4. S. Munthe, M.D. Sørensen, M. Thomassen, M. Burton, T.A. Kruse, J.D. Lathia, F.R. Poulsen, B.W. Kristensen. Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting. J Neurooncol. 2016, Oct;130(1):53-62. PMID: 27510953 5. B. Otvos, D.J. Silver, E.E. Mulkearns-Hubert, A.G. Alvarado, S.M. Turaga, M.D. Sørensen, P. Rayman, W.A. Flavahan, J.S. Hale, K. Stoltz, M. Sinyuk, Q. Wu, A. Jar rar, S.H. Kim, P.L. Fox, I. Nakano, J.N. Rich, R.M. Ransohoff, J. Finke, B.W. Kristensen, M.A. Vogelbaum, J.D. Lathia. Cancer stem cell-secreted macrophage migration inhibitory factor stimulates myeloid derived suppressor cell function and facilitates glioblastoma immune evasion. Stem Cells. 2016 Aug;34(8): 2026-39. PMID: 27145382 6. B. Halle, M. Thomassen, R. Venkatesan, V. Kaimal, E.G. Marcusson, S. Munthe, M.D. Sørensen, C. Aaberg-Jessen, S.S. Jensen, M. Meyer, T.A. Kruse, H. Christiansen, S. Schmidt, J. Mollenhau-er, M.K. Schulz, C. Andersen, B.W. Kristensen. Shift of microRNA profile upon orthothopic xenografting of glio blastoma spheroid cultures. J. Neurooncol 2016, July;128(3):395-404. PMID: 27063952 7. B. Halle, E. G. Marcusson, C. Aaberg-Jessen, S. S. Jensen, M. Meyer, M. K. Schulz, C. Andersen, B.W. Kristensen, Convection-enhanced delivery of an anti-miR is safe and causes effi-cient target de-repression – a proof of concept, J Neurooncol. 2016 Jan;126(1):47-55. PMID: 26428358 8. D. L. Schonberg, T. E. Miller, Q. Wu, W. A. Flavahan, N. K. Das, J. S. Hale, C. G. Hubert, S. C. Mack, A. M. Jarrar, R. T. Karl, A. M. Rosager, A. M. Nixon, P. J. Tesar, P. Hamerlik, B.W. Kristensen, C. Horbinski, J.R. Connor, P. L. Fox, J. D. Lathia, J. N. Rich, Preferential Iron Traffick-ing Characterizes Glioblastoma Stem-like Cells, Cancer Cell. 2015 Oct 12;28(4):441-55. PMID: 26461092 9. S. A. Petterson, R. H. Dahlrot, S. K. Hermansen, S. K. A. Munthe, M. T. Gundesen, H. Wohlle-ben, T. Rasmussen, C. P. Beier, S. Hansen and B.W. Kristensen. High levels of c-Met is asso-ciated with poor prognosis in glioblastoma, J Neurooncol. 2015 May;122(3):517-27. PMID: 25800004 10. J. D. Lathia M. Li, M. Sinyuk, A. G. Alvarado, W. A. Flavahan, K. Stoltz, A. M. Rosager, J. Hale, M. Hitomi, J. Gallagher, Q. Wu, J. Martin, J. G. Vidal, I. Nakano, R. H. Dahlrot, 9.S. Hansen, R. E McLendon, A. E. Sloan, S. Bao, A. B. Hjelmeland, 29

GROUPGROUP NAME: NAME UCAR GROUP LEADER BWK Brain Cancer Research group Bjarne Winther Kristensen

C. T. Carson, U. P. Naik, B. B.W. Kristensen, J. N. Rich. High-throughput flow cytometry screening reveals a role for junctional adhesion mol-ecule A as a cancer stem cell maintenance factor. Cell Rep. 2014 Jan 16;6(1):117-29. PMID: 24373972 11. S. K. Hermansen, R. H. Dahlrot, Boye S. Nielsen, S. Hansen, B.W. Kristensen, MiR- 21 expression in the tumor cell compartment holds unfavorable prognostic value in gliomas. J Neuroon-col. 2013 Jan;111(1):71-81. PMID: 23104517

KEY Danish: COLLABORATIONS Danish Cancer Society, Department of Psychology, University of Copenhagen; Department of Radiology, Odense University Hospital.

International: Multimodal Imaging Group, Norwegian Center for Mental Disorders Research (NORMENT), Oslo University Hospital Norway; Department of Neuroscience, Medical University of South Carolina, USA; LaPsyDÉ, CNRS, Université Paris Des- cartes, Université Caen Normandie, Institut Universitaire de France (IUF), Paris, France.

INFRASTRUCTURE Experimental facilities for conducting traditional experimental/neuropsychological investigations (measurement of reaction times, eye-tracking etc.) at the department.

Access to 3T MR-scanner (at Odense University Hospital) for doing fMRI/MR. Cellular Neurobiology Department of Molecular Medicine, SDU 31

GROUPGROUP NAME: NAME UCAR GROUP LEADER Cellular Neurobiology Åsa Fex Svenningsen

NUMBER OF Åsa Fex Svenningsen, associate professor, PhD, Simone Hjæresen PhD, Solveig Beck GROUP MEMBERS Nielsen PhD, Helle Vinsløv Jensen, tecnician (AND THEIR TITLE)

DEPARTMENT & Department of Molecular Medicine-Neurobiology Research UNIVERSITY/ University of Southern Denmark HOSPITAL/OTHER

FUNDING SOURCES Jascha Fonden, Lægevidenskabens fremme, Johansens og Hustrus mindelegat, Oda og Hans Svenningsens fond

DESCRIPTION OF The work focuses on neurological communication, and the molecules used by the RESEARCH different cells to understand each other when differentiating and growing. We investigate this mostly in vitro, in different types of cell culture, but also in vivo using a model for de and regeneration (the cuprizone model). A few years ago we made a proteomic screening of proteins in glia at different stages of development and found that a small, conserved protein Macrophage mi- gration inhibitory factor (MIF), was expressed in these cells but that the expression differed between the glial cells and between developmental stages. We have also made a 2-yeast hybrid screen for binding partners to MIF and verified three new such binding partner. A manuscript about the function of one such bind- ing partner, HTRA1 is right now accepted with minor revisions in the journal “Cel- lular and Molecular Life Science”. Since the function of MIF and its binding partner HTRA1 was little known in the nervous system we started to investigate MIF more and started several collaborations: The role of MIF in CNS development and regeneration: Resent studies have shown that MIF may be involved in several neurodegenerative diseases. Among them, Parkinson’s disease, multiple sclerosis and Alzheimers dis- eases. We are therefore trying to understand what MIF does in both development and regeneration in the CNS and PNS. The research is divided into 5 subprojects: 32

GROUPGROUP NAME: NAME UCAR GROUP LEADER Cellular Neurobiology Åsa Fex Svenningsen

A. The function of MIF in the CNS development and regeneration: We are inves- tigating the function of MIF in vitro in different types of cell culture. To date our preliminary data show that MIF is in fact involved in oligodendrocyte precursor pro- liferation, oligodendrocyte myelination and axonal growth, via different receptors. We have continued to investigate this in vivo in a model of de- and re-generation, though the study of this model has just started. B. The role of MIF in the generation of dopaminergic neurons from iPS cells. In collaboration with Dr. Morten Meyer we are also investigating the effect of MIF on neuronal stem cells. Interestingly, MIF increases the development of neuronal precusors to dopaminergic cells. We will continue investigating the mechanisms behind the increase in this pheno-type during 2017. C. The role of MIF in the regeneration of in the spinal cord: Together with Dr. James St John at Griffith University, Australia, we are investigating the function of MIF and HTRA1 in olfactory glia. The group of Dr. St John works with regeneration of the spinal cord using olfactory glia for the repair. In this project we have found that MIF positive olfactory glia are more prone to help the regeneration than the ones that do not express the molecule. The mechanisms behind this will be further investigated. D. The role of MIF in the regeneration in healthy and diabetic peripheral nerve. This is in collaboration with Professor Lars Dahlin at Lund University. We have found that MIF increases during the later stages of regeneration in the PNS, indicating that it may be in-volved in the start of the myelination process and/or the neuronal target recognition. Interestingly, Schwann cells have several types of MIF receptors and our preliminary data show that different receptors (involved in different functions) may be expressed during regeneration as well as during PNS development. E. The role of MIF and HTRA1 as diagnostic tools in MS. In collaboration with Professors Zsolt Illes and Jan Lycke, we are investigating MIF and HTRA1 in the serum and cerebrospinal fluid (CSF) of MS patients in different stages of disease. So far we have investigated patients during a relapse and in remission and compared to health controls. Interestingly, we have found that MIF decreases in the MS patients compared to control and that HTRA1 increases. The two proteins correlate well to each other suggesting the binding may be important in the disease. It also suggests that the two proteins may be used as biomarkers. We are at the moment analyzing serum and CSF from secondary progressive patients. 33

GROUPGROUP NAME: NAME UCAR GROUP LEADER Cellular Neurobiology Åsa Fex Svenningsen

KEY PUBLICATIONS 1. Opioid precursor protein isoform is targeted to the cell nuclei in the human brain. Ko-nonenko O, Bazov I, Watanabe H, Gerashchenko G, Dyachok O, Ver beek DS, Alkass K, Druid H, Andersson M, Mulder J, Svenningsen ÅF, Rajkowska G, Stockmeier CA, Krishtal O, Yakovleva T, Bakalkin G. Biochim Biophys Acta. Biochim Biophys Acta. 2017 Feb;1861(2):246-255. 2. Ellman DG, Degn M, Christiansen ML, Clausen BH, Novrup HG, Flæng SB, Jørgensen LH, Suntharalingam L, Brambilla R, Lambertsen KL (2016) Genetic ablation of soluble TNF does not affect lesion size and functional recovery after moderate spinal cord injury in mice. Mediators of Inflamm, 2016:2684098. doi: 10.1155/2016/2684098. 3. The Schizophrenia Susceptibility Gene ZNF804A is highly expressed during brain devel-opment, particularly in growth cones. Katja Hvid Hinna; Karen Rich; Åsa Fex-Svenningsen; Eirikur Benedikz PLoS One. 2015 Jul 6;10(7):e0132456. 4. GABA and its B-receptor are present at the node of Ranvier in a small population of sen-sory fibers, implicating a role in myelination. M. Corell, G. Wicher, K. J. Radomska, E. D. Dağlıkoca, R. Elberg Godskesen, R. Fredriksson, E. Benedikz, V. Magnaghi, Å. Fex Svenningsen. 2015 Feb;93(2):285-95. 5. Oxaliplatin-Induced Neuropathy in Colorectal Cancer: Many Questions With Few An-swers. H. Zedan, T. Frøstrup Hansen, A. Fex Svenningsen, O. J. Vilholm. Clinical Colo-rectal Cancer 2014 Jun;13(2):73-80. 6. Repair of the Peripheral Nerve—Remyelination that Works. Å. Fex Svennigsen, L. B Dahlin Brain Sci. 2013 Aug 2;3(3):1182-97. 7. MALDI mass spectrometry based molecular phenotyping of CNS glial cells for prediction in mammalian brain tissue. J. Hanrieder, G. Wicher, J. Bergquist, M. Andersson, A. Fex-Svenningsen. Analytical and Bioanalytical Chemistry 2011 Jul;401(1):135-47. 8. Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regula-tion of CYP7B1-mediated metabolism. A. Fex Svenningsen, G. Wicher, J. Lundqvist, H. Pettersson, M.l Corell, M. Norlin. Neurochemistry International 2011 May;58(6):620-4. 9. A low ethanol dose affects all types of cells in mixed long-term embryonic cultures of the cerebellum. C. Pickering, G. Wicher, S. Rosendahl, H. B Schiöth, A. Fex Svenningsen. Basic & Clinical Pharmacology & Toxicology 2010 Aug 15;88(11):2338-49. 34

GROUPGROUP NAME: NAME UCAR GROUP LEADER Cellular Neurobiology Åsa Fex Svenningsen

10. Optimization of chemically defined cell culture mediareplacing fetal bovine serum in mammalian in vitro methods. J van der Valk, D Brunner, K De Smet, A Fex Svenningsen, P Honegger, L E Knudsen, T Lindl, J Noraberg, A Price, M L Scarino, G Gstraunthaler. Toxicology in Vitro 2010 Jun;24(4):1053-63. 11. Spatiotemporal Distribution and Function of N-Cadherin in Postnatal Schwann Cells: A Matter of Adhesion? M. Corell, G. Wicher, C. Limbach, M. W. Kilimann, D. R Colman, A. Fex Svenningsen. Journal of Neuroscience Research 2010 Aug 1 5;88(11):2338-49. 12. In Vitro Neurotoxicity of PBDE-99: Immediate and Concentration-Dependent Effects on Protein Expression in Cerebral Cortex Cells. H. Alm, B. Scholz, K. Kultima, A. Nilsson, P. E. Andrén, M. M Savitski, A. Bergman, M. Stigson, A. Fex-Svenningsen, L. Dencker. Journal of Proteome Research 2010 Mar 5;9(3):1226-35. 13. MDMA (Ecstasy) decreases the number of neurons and stem cells in embryonic cortical cultures. Kindlundh-Högberg, C. Pickering, G. Wicher, D. Hobér, H. B. Schiöth, A. Fex Svenningsen. Cellular and Molecular Neurobiology. 2010 Jan;30(1):13-21. 14. Extracellular clusterin promotes neuronal network complexity in vitro. G. Wich er, A. Fex-Svenningsen, I. Velsecchi, Y. Charnay, H. Aldskogius. Neuroreport.2008 Oct 8;19(15):1487-91 15. 15. Environmental cues from CNS, PNS, and ENS cells regulate CNS progenitor differentiation K. Brännvall, M. Corell, K.Forsberg-Nilsson, A. Fex Svenningsen. Neuroreport. 2008 Aug 27;19(13) 16. Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex. H. Alm, K. Kultima, B. Scholz, A.Nilsson, P. E. An-drén, A. Fex-Svenningsen, L. Dencker, M. Stigson. Neurotoxicology. 2008 Jul;29(4):628-37. 17. Microfluidic high viability neural cell separation using viscoelastically tuned hydrody-namic spreading. Z. Wu, K. Hjort, G. Wicher, A. Fex Svenningsen. Biomed Microdevices. 2008 Oct;10(5):631-8. 18. The myelin membrane influences the organization of molecules on the axonal surface. L. Pedraza, J. K. Huang, A. F. Svenningsen, D. R. Colman Journal of Neurochemistry. 2008 June (81):68-68. 35

GROUPGROUP NAME: NAME UCAR GROUP LEADER Cellular Neurobiology Åsa Fex Svenningsen

SUBMITTED 1. Macrophage Migration Inhibitory Factor (MIF) Modulates Trophic Signaling Through Interaction With Serine Protease HTRA Åsa Fex Svenningsen, Svenja Löring, Anna Lahn Sørensen1, Ha Uyen Buu Huynh, Nellie Martin, Jesper Bonnet Moeller, Simone Hjæresen, Maria Louise Elkjær, Uffe Holmskov, Zsolt Illes, Malin Andersson, Solveig Beck Nielsen, Eirikur Bene Benedikz, dikz Sent: 2/3- 2017 to Cellular and Molecular Life Sciences. Was returned with revisions suggested by reviewers 15/4-2017. 2. Pecanex-like protein 4 (PCNXL4), a DISC1 and ZNF804A interacting protein, may play a role in neurodevelopment. Solveig Beck Nielsen, Daniel Jung Jensen, Åsa Fex Svenningsen, Eirikur Benedikz, Sent to BBRC 4/5-2017

KEY Danish: COLLABORATIONS Professor Zsolt Illes (OUH) Associate professor Morten Meyer (SDU) Professor Tanja Sheldrik Michel (OUH) Daniel Wustner (SDU) Winnie Svensdsen (DTU) International: Professor Lars Dahlin (Lund University, Sweden) Associate professor Malin Anderson (Uppsala University, Sweden) Professor Jan Lycke (Sahgrenska Akademy, Göteborg, Sweden) Associate professor Luca Colucci D´Amato (University dela Campaia, Napoli, Italien) Associate professor James St. John (Griffith University, Brisbane Australia)

• Primary cell culture: Neurons, all types of glial cells, separately and INFRASTRUCTURE together (from both PNS and CNS). Myelinating cultures (with oligodendrocytes and Schwann cells is a speciality) • The generation of human iPS cells (together with Tanja Sheldrik Michels group) • pPCR, western blott, Immunochmistry, ELISA , Mesoscale, 2yeast hybrid, MST. • Functional studies in vitro: studies of migration, proliferation apoptosis and neurite outgrowth • Cuprizone model (mice) Child and Adolescent Psychiatric Mental Health Services in the region of Southern Denmark & Department of Clinical Research, SDU 37

GROUPGROUP NAME: NAME UCAR GROUP LEADER Child and Adolescent Psychiatric Niels Bilenberg

NUMBER OF 3 Professors, 1 Ass. professor (MD,PhD), 3 Postdoc (MD, psychologists), GROUP MEMBERS 3 PhD-students, 3-5 Research ass. 1 Research nurse, 10-12 Clinicians (AND THEIR TITLE) (multi-professions), project-manager, datamagager

DEPARTMENT & Child and Adolescent Psychiatric Department, Psychiatric Hospital in Region of UNIVERSITY/ Southern Denmark, University of Southern Denmark (SDU) HOSPITAL/OTHER

FUNDING SOURCES Research fund at Psychiatic Hospital in Region of Southern Denmark, Tryg-fundation, Socialstyrelsen, Jascha fonden, a.o.

DESCRIPTION OF Center for NeuroDevelopmental Disorders (CNDD) is a research-intensive clinical RESEARCH unit in Child and Adolescent Psychiatric Department, Odense. The center engages clinicians and researchers side by side. We collaborate with the adult psychiatric research unit and a number of research units / departments at Odense University Hospital and at the University of Southern Denmark. In particular we have a very close collaboration with the Center for Brain Research (BRIDGE) (Brain Research - Interdisciplinary Guided Excellence - a collaboration between Psychiatry in Southern Denmark, Odense University Hospital and University of Southern Denmark).

CNDD follows four main paths; 1) epidemiology (birth cohort, clinical cohorts), 2) etiological research, 3) intervention research and 4) rehabilitation (integrated care). CNDD aim at being “Centers of Excellence” in 2-3 years - the first of its kind in Denmark - and a significant competitor in Danish and international Child and Adolescent Psychiatry.

Numerous of studies/protocols are running or in preparation. We recrute all children and adolescents referred for assessment and treatment in the clinical neuroteam (about 500 patients a year). 38

GROUPGROUP NAME: NAME UCAR GROUP LEADER Child and Adolescent Psychiatric Niels Bilenberg

KEY PUBLICATIONS 1. Nordenbaek C, Kyvik KO, Skytthe AE, Bilenberg N. Efficiency of a small size screening instrument in identifying children with autism spectrum disorders in a large population of twins. Epidemiology Research International 2011, ID 412150, 8p (http://www.hindawi.com/journals/eri/2011/412150/) 2. Rasmussen CS, Nielsen LG, Petersen DJ, Christiansen E, Bilenberg N. Adverse life events as risk factors for behavioural and emotional problems in a 7-year follow-up of a population-based child cohort. Nord J Psychiatry 2013 May 22. 3. Nordenbaek C, Jorgensen M, Kyvik KO, Bilenberg N. A Danish population-based twin study on autism spectrum disorders. Eur Child Adolesc Psychiatry 2013 May 10. 4. Mossin MH, Aaby JB, Dalgård C, Lykkedegn S, Christesen HT, Bilenberg N. Inverse associations between cord vitamin D and attention deficit hyper- activity disorder symptoms: A child cohort study. Australian & New Zealand Journal of Psychia-try. 2016 5. Hvolby A, Jorgensen J, Bilenberg N, Actigraphic and parental reports of sleep difficulties in children with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 2008; 162:323-329 6. Hvolby A, Jorgensen J, Bilenberg N. Parental rating of sleep in children with attention deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 2009; 18(7):429-38. 7. Bilenberg N, Hougaard D, Norgaard-Pedersen B, Nordenbaek CM, Olsen J. Twin study on transplacental-acquired anti-bodies and attention deficit/hyper- activity disorder - A pilot study. J Neuroimmunol 2011, 236:72-75 8. Madsen GF, Bilenberg N, Cantio C, Oranje B. Increased Prepulse Inhibition and Sensitization of the Startle Reflex in Autistic Children. Autism Res 2013 Oct 4;10. 9. Madsen GF, Bilenberg N, Jepsen JR, Glenthøj B, Cantio C, Oranje B. Normal P50 Gating in Children with Autism, Yet At-tenuated P50 Amplitude in the Asperger Subcategory. Autism Res. 2015 Jan 20. doi: 10.1002/aur.1452. 10. Cantio C, Jepsen JR, Madsen GF, Bilenberg N, White SJ. Exploring ‘The autisms’ at a cognitive level. Autism Res. 2016 Apr 19. doi: 10.1002/aur.1630. 11. Dam ME, Kolmos KK, Bilenberg N. Does Test Dose of Central Stimulant Influence Continuous Performance Test (CPT) and Activity in Boys with Attention Deficit Hyperactivity Disorder? Clinical Psychiatry (ISSN 2471-9854), 2016, Vol.2 No.3:13. 39

GROUPGROUP NAME: NAME UCAR GROUP LEADER Child and Adolescent Psychiatric Niels Bilenberg

12. Hvolby A, Bilenberg N. Use of Ball Blanket in attention-deficit/hyperactivity disorder sleeping problems. Nord J Psychiatry 2011 Apr; 65(2):89-94. Epub 2010 Jul 22. 13. Pagsberg AK, Jeppesen P, Klauber DG, Jensen KG, Rudå D, Stentebjerg-Olesen M, Jantzen P, Rasmussen S, Saldeen EA, Lauritsen MB, Bilenberg N, Stenstrøm AD, Pedersen J, Nyvang L, Madsen S, Lauritsen MB, Vernal DL, Thomsen PH, Paludan J, Werge TM, Winge K, Juul K, Gluud C, Skoog M, Wetterslev J, Jepsen JR, Correll CU, Fink-Jensen A, Fager-lund B. Quetiapine versus aripiprazole in children and adolescents with psychosis - protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial. BMC Psychiatry. 2014 Jul 11;14(1):199.

KEY Danish: COLLABORATIONS BRIDGE

International: KIND (Karolinska Institute NeuroDevelopment); Institute of Cognitive Neuroscience, (UCL) The Danish Aging Research Center Department of Public Health, SDU 41

GROUPGROUP NAME: NAME UCAR GROUP LEADER The Danish Aging Research Center Kaare Christensen

NUMBER OF Kaare Christensen, Professor; Bernard Jeune, Associate professor; Axel Skytthe, GROUP MEMBERS Senior data analyst; Lene Christiansen, Professor; James W. Vaupel, Professor; (AND THEIR TITLE) Matt McGue, Professor; Karen Andersen-Ranberg, Professor; Mikael Thinggaard, Assistant professor; Marianne Nygaard, Assistant professor; Signe Høi Rasmussen, Ph.D. student

DEPARTMENT & Department of Public Health, University of Southern Denmark, Odense, Denmark UNIVERSITY/ HOSPITAL/OTHER

FUNDING SOURCES Danish National Research Foundation; U.S. National Institute on Aging - National Institutes of Health [Grant PO1-AG08761]; Danish Health Insurance Foundation [Grant 2006B139]; Danish Agency for Science, Technology and Innovation; Danish Interdisciplinary Research Council; The Danish Council for Independent Researchǀ- Medical Sciences [Grant 09-070081 and 6110-00016]; The Lundbeck Foundation [R83-A8168]; The Novo Nordisk Foundation; The Clinical Institute of Research, University of Southern Denmark; The Health Foundation (Helsefonden) [Grant nr.16-B-0271]; U.S. National Institutes of Health [Grant UO1-AG023712]; U.S. National Institutes of Health [Grant PO1-AG031719]. The Danish Aging Research Center is supported by a grant from the Velux Foundation

DESCRIPTION OF Background RESEARCH There is a growing concern that the improved survival among elderly people will increase the proportion of oldest old with physical and cognitive impairments.

Overall aim for the previous and the ongoing studies To determine the health and cognitive and physical function of the population of long-lived individuals, and to investigate whether these improve, decrease or are stable over cohorts. And, moreover, to identify genetic and environmental determinants of exceptional functioning at the highest ages. 42

GROUP NAME GROUP LEADER The Danish Aging Research Center Kaare Christensen

Secular trends in the health and functioning of the very old Following the Danish 1905 Cohort from age 93 to 100 years, we found that the age trajectory of average cognitive and physical functioning is constant at the popu- lation level in this age range because of higher mortality among those with the lowest cognitive scores. This suggests that exceptional longevity is not associated with higher levels of cognitive impairment. We also found that 95-year olds born in 1915 performed better both in the cognitive tests and in the activities of daily living score compared to 93-year olds born in 1905. This indicates that more people are living to older ages with better overall functioning. We are currently investigating whether this improvement is also present among centenarians born 20 years apart.

Genetic studies of aging and cognitive function Twin and family studies indicate a moderate to substantial influence of genetic factors on survival probability and cognitive decline during aging. Our previous and ongoing genetic studies focus on investigating both common and rare variants in candidate genes (e.g. Apo-E), and we carry out genome-wide studies of common genetic variants and their influence on these age-related traits. Current studies also include epigenetic and gene expression studies.

KEY PUBLICATIONS 1. Rasmussen, S. H., Andersen-Ranberg, K., Thinggaard, M., Jeune, B., Skytthe, A., Christiansen, L., ... & Christensen, K. (2017). Cohort Profile: The 1895, 1905, 1910 and 1915 Danish Birth Cohort Studies-secular trends in the health and functioning of the very old. International journal of epidemiology. 2. Petersen, I., McGue, M., Tan, Q., Christensen, K., & Christiansen, L. (2016). Change in depression symp-tomatology and cognitive function in twins: a 10-year follow-up study. Twin Research and Human Genet-ics, 19(02), 104-111. 3. Mengel-From, J., Soerensen, M., Nygaard, M., McGue, M., Christensen, K., & Christiansen, L. (2016). Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 71(9), 1151-1159. 4. Christensen, K., Thinggaard, M., Oksuzyan, A., Steenstrup, T., Andersen-Ranberg, K., Jeune, B., ... & Vaupel, J. W. (2013). Physical and cognitive functioning of people older than 90 years: a comparison of two Danish cohorts born 10 years apart. The Lancet, 382(9903), 1507-1513. 43

GROUPGROUP NAME: NAME UCAR GROUP LEADER The Danish Aging Research Center Kaare Christensen

5. Lindahl-Jacobsen, R., Tan, Q., Mengel-From, J., Christensen, K., Nebel, A., & Christiansen, L. (2013). Effects of the APOE ε2 allele on mortality and cognitive function in the oldest old. The Journals of Ger-ontology Series A: Biological Sciences and Medical Sciences, 68(4), 389-394. 6. Christensen, K., McGue, M., Petersen, I., Jeune, B., & Vaupel, J. W. (2008). Exceptional longevity does not result in excessive levels of disability. Proceedings of the National Academy of Sciences, 105(36), 13274-13279. 7. Engberg, H., Christensen, K., Andersen-Ranberg, K., & Jeune, B. (2008). Cohort changes in cognitive function among Danish centenarians. Dementia and geriatric cognitive disorders, 26(2), 153-160. 8. Lachine, I., Skytthe, A., Vaupel, J. W., McGue, M., Koskenvuo, M., Kaprio, J., ... & Christensen, K. (2006). Genetic influence on human lifespan and longevity. Human genetics, 119(3), 312-321. 9. McGue, M., & Christensen, K. (2002). The heritability of level and rate-of-change in cognitive function-ing in Danish twins aged 70 years and older. Experimental aging research, 28(4), 435-451

KEY Danish: COLLABORATIONS Univeristy of Copenhagen, Aarhus University and Odense University Hospital, Odense.

International: Max-Planck Institute for Demographic Research, Rostock, Germany Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.

INFRASTRUCTURE The group includes participants with expertise in epidemiology, genetics, statistics, and bioinformatics.

Technical resources include: • Hand Dynamometer: Equipment to measure hand grip strenght • Peak flow meter and Spirometer: Equipment to measure lung function • Electrocardiograph: Equipment to obtain an electrocardiogram (ECG) • Within our domestic laboratory facilities at department of Clinical Genetics, Odense University Hospital, we have access to the equipment and expertise necessary for carrying out medium and high-through-put genetic variation and gene expression studies. Department of epilepsy genetics and personalized medicine Danish Epilepsy Centre & Department of Regional Health Research, SDU 45

GROUP NAME GROUP LEADER DepartmentGROUP of NAME: epilepsy genetics UCAR and Rikke Steensbjerre Møller personalized medicine

NUMBER OF 12 members: 2 neurologists (1 professor and 1 associate professor), GROUP MEMBERS 2 padiatricians (one associate professor), 3 molecular geneticists, 1 Post Doc. (AND THEIR TITLE) 1 Phd-student, 2 medical students, 1 Research nurse

DEPARTMENT & Danish Epilepsy Centre, Institute for Regional Health Services, University of UNIVERSITY/ Southern Denmark HOSPITAL/OTHER

FUNDING SOURCES Our reseach is mainly internally funded, funded from revenue from our gene panel analysis or funded by internationally multicenter collaborations

DESCRIPTION OF During the last decade, next-generation sequencing (NGS) technologies such as RESEARCH targeted gene panels and whole-exome sequencing have led to an explosion of gene identifications in monogenic epilepsies. In the short term, these findings will help with genetic counseling by providing information on prognosis and recurrence risks for patients and by providing families with a definitive diagnosis. In the long term, these discoveries may allow us to develop more effective treatments that can be targeted to the individual patient based on his/her genetic profile instead of empiric trials of medications broadly indicated for epilepsy. Monogenic epilepsies offer an excellent opportunity to achieve targeted treatments, also referred to as precision medicine, mainly because of the ongoing explosion in gene discovery, the existence of good animal and in vitro models, in which targeted medications can be developed, and the ability to assess the efficacy of experimental targeted treat- ments in small clinical trials.

Our main research topics includes: Identification of candidate genes involved in brain development and epilepsy using next generation sequencing (whole exome sequencing or targeted arrays) Genotype-phenotype correlation studies, including electroclinical charaterizations of the different genetic epilepsy syndromes, fuctional studies of the specific muta- 46

GROUP NAME GROUP LEADER DepartmentGROUP of NAME: epilepsy genetics UCAR and Rikke Steensbjerre Møller personalized medicine

tions in cell systems, and evaluation of treatment response. Grouping patients with different epilepsy syndromes eg syndromes due to mutations in voltage-gated sodium channel genes and grouping different anti-epileptic drugs based on their joint function such as e.g. sodium-channel blockers is somewhat hypothesis-driven and imprecise. However, it provides an interesting approach to overcome the vast genetic heterogeneity in some neurodevelopmental disorders and gives a useful template on how we can approach the genetic heterogeneity in other conditions.

KEY PUBLICATIONS We have (within the last 10 years) published more than 100 peer-reviewed papers within the area of epilepsy genetics. I have highligthed the following 12 publications

1. Wolff M, Johannesen KM, Hedrich UB, Masnada S, Rubboli G, Gardella E, Lesca G, Ville D, Milh M, Villard L, Afenjar A, Chantot-Bastaraud S, Mignot C, Lardennois C, Nava C, Schwarz N, Gérard M, Perrin L, Doummar D, Auvin S, Miranda MJ, Hempel M, Brilstra E, Knoers N, Verbeek N, van Kempen M, Braun KP, Mancini G, Biskup S, Hörtnagel K, Döcker M, Bast T, Loddenkemper T, Wong-Kisiel L, Baumeister FM, Fazeli W, Striano P, Dilena R, Fontana E, Zara F, Kurlemann G, Klepper J, Thoene JG, Arndt DH, Deconinck N, Schmitt-Mechelke T, Maier O, Muhle H, Wical B, Finetti C, Brückner R, Pietz J, Golla G, Jillella D, Linnet KM, Charles P, Moog U, Õiglane-Shlik E, Mantovani JF, Park K, Deprez M, Lederer D, Mary S, Scalais E, Selim L, Van Coster R, Lagae L, Nikanorova M, Hjalgrim H, Korenke GC, Trivisano M, Specchio N, Ceulemans B, Dorn T, Helbig KL, Hardies K, Stamberger H, de Jonghe P, Weckhuysen S, Lemke JR, Krägeloh-Mann I, Helbig I, Kluger G, Lerche H, Møller RS. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain. 2017 Mar 4. 2. Møller RS, Wuttke TV, Helbig I, Marini C, Johannesen KM, Brilstra EH, Vaher U, Borggraefe I, Talvik I, Talvik T, Kluger G, Francois LL, Lesca G, de Bellescize J, Blichfeldt S, Chatron N, Holert N, Jacobs J, Swinkels M, Betzler C, Syrbe S, Nikanorova M, Myers CT, Larsen LHG, Vejzovic S, Pendziwiat M, von Spiczak S, Hopkins S, Dubbs H, Mang Y, Mukhin K, Holthausen H, van Gassen KL, Dahl HA, Tommerup N, Mefford HC, Rubboli G, Guerrini R, Lemke JR, Lerche H, Muhle H, Maljevic S. Neurology. From febrile seizures to epileptic encephalopathies. Mutations in GABRB3: 2017 Jan 31;88(5):483-492. 47

GROUP NAME GROUP LEADER DepartmentGROUP of NAME: epilepsy genetics UCAR and Rikke Steensbjerre Møller personalized medicine

3. Johannesen KM, Marini C, Pfeffer S, Møller RS, Dorn T, Niturad CE, Gardella E, Weber Y, Søndergård M, Hjalgrim H, Nikanorova M, Becker F, Larsen LH, Dahl HA, Maier O, Mei D, Biskup S, Klein KM, Reif PS, Rosenow F, Elias AF, Hudson C, Helbig KL, Schubert-Bast S, Scordo MR, Craiu D, Djémié T, Hoffman-Zacharska D, Caglayan H, Helbig I, Serratosa J, Striano P, De Jonghe P, Weckhuysen S, Suls A, Muru K, Talvik I, Talvik T, Muhle H, Borggraefe I, Rost I, Guerrini R, Lerche H, Lemke JR, Rubboli G, Maljevic S. Neurology. From generalized epilepsies to severe epileptic encephalopathies. Phenotypic spectrum of GABRA1: 2016 Sep 13;87(11):1140-51 4. Møller RS, Larsen LH, Johannesen KM, Talvik I, Talvik T, Vaher U, Miranda MJ, Farooq M, Nielsen JE, Svendsen LL, Kjelgaard DB, Linnet KM, Hao Q, Uldall P, Frangu M, Tommerup N, Baig SM, Abdullah U, Born AP, Gellert P, Nikanorova M, Olofsson K, Jepsen B, Marjanovic D, Al-Zehhawi LI, Peñalva SJ, Krag-Olsen B, Brusgaard K, Hjalgrim H, Rubboli G, Pal DK, Dahl HA. Mol Syndromol. Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies 2016 Sep;7(4):210-219. 5. Bayat A, Hjalgrim H, Møller RS. Epilepsia. The incidence of SCN1A-related Dravet syndrome in Denmark is 1:22,000: a population-based study from 2004 to 2009. 2015 Apr;56(4):e36-9 6. Møller RS, Heron SE, Larsen LH, Lim CX, Ricos MG, Bayly MA, van Kempen MJ, Klinkenberg S, Andrews I, Kelley K, Ronen GM, Callen D, McMahon JM, Yendle SC, Carvill GL, Mefford HC, Nabbout R, Poduri A, Striano P, Baglietto MG, Zara F, Smith NJ, Pridmore C, Gardella E, Nikanorova M, Dahl HA, Gellert P, Scheffer IE, Gunning B, Kragh-Olsen B, Dibbens LM. Epilepsia. Mutations in KCNT1 cause a spectrum of focal epilepsies. 2015 Sep;56(9):e114-20 7. Gardella E, Becker F, Møller RS, Schubert J, Lemke JR, Larsen LH, Eiberg H, Nothnagel M, Thiele H, Altmüller J, Syrbe S, Merkenschlager A, Bast T, Steinhoff B, Nürnberg P, Mang Y, Bakke Møller L, Gellert P, Heron SE, Dibbens LM, Weckhuysen S, Dahl HA, Biskup S, Tommerup N, Hjalgrim H, Lerche H, Beniczky S, Weber YG. Ann Neurol. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation 2016 Mar;79(3):428-36 8. Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, Depienne C, Brilstra E, Mang Y, Nielsen 8.JE, Kirkpatrick M, Goudie D, Goldman R, Jähn JA, Jepsen B, Gill D, Döcker M, Biskup S, McMahon JM, Koeleman B, Harris M, Braun K, de Kovel CG, Marini C, Specchio N, Djémié T, Weckhuysen S, Tommerup N, Troncoso M, Troncoso L, Bevot A, Wolff M, Hjalgrim H, Guerrini R, Scheffer IE, Mefford HC, Møller RS Neurology. The phenotypic spectrum of SCN8A encephalopathy. 2015 Feb 3;84(5):480-9 48

GROUP NAME GROUP LEADER DepartmentGROUP of NAME: epilepsy genetics UCAR and Rikke Steensbjerre Møller personalized medicine

9. Am J Hum Genet. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. EuroEPINOMICS-RES Consortium.; Epilepsy Phenome/Genome Project.; Epi4K Consortium. 2014 Oct 2;95(4):360-70 10. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. International League Against Epilepsy Consortium on Complex Epilepsies. Lancet Neurol. 2014 Sep;13(9):893-903 11. Møller RS, Jensen LR, Maas SM, Filmus J, Capurro M, Hansen C, Marcelis CL, Ravn K, Andrieux J, Mathieu M, Kirchhoff M, Rødningen OK, de Leeuw N, Yntema HG, Froyen G, Vandewalle J, Ballon K, Klopocki E, Joss S, Tolmie J, Knegt AC, Lund AM, Hjalgrim H, Kuss AW, Tommerup N, Ullmann R, de Brouwer AP, Strømme P, Kjaergaard S, Tümer Z, Kleefstra T. Hum Genet. X-linked congenital ptosis and associated intellectual disability, short stature, microcephaly, cleft palate, digital and genital abnormalities define novel Xq25q26 duplication syndrome. 2014 May;133(5):625-38 12. Møller RS, Kübart S, Hoeltzenbein M, Heye B, Vogel I, Hansen CP, Menzel C, Ullmann R, Tommerup N, Ropers HH, Tümer Z, Kalscheuer VM. Am J Hum Genet. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. 2008 May;82(5):1165-70

KEY Danish: COLLABORATIONS We have a very close collaboration with the private company Amplexa Genetics- Furthermore we have a similarly close collaboration with clinicians all over Denmark

International: we are members of several international consortia including: EuroEPINOMICS: European epilepsy genetics network EpiPGX - a research initiative to identify biomarkers for drug response and adverse drug reactions in epilepsy treatment, funded by the European Commission’s Re- search Framework Program International League Against Epilepsy Consortium on Complex Epilepsies: The driving principle behind the Consortium is that through collaboration and synergy, we will make more progress towards fully understanding the inherited compo- nents of epilepsy than can be achieved by individual groups. 49

GROUP NAME GROUP LEADER DepartmentGROUP of NAME: epilepsy genetics UCAR and Rikke Steensbjerre Møller personalized medicine

EPI25: The Epi25k Consortium represents the unification of various consortia dedicated to the study of epilepsy, including Epi4K, EPIGEN, EuroEPINOMICS, the Epilepsy Phenome/Genome Project, EpiPGX, SANAD, and EpiCURE. Each of these large, multinational projects maintains a DNA repository. The objective of this col- laboration is to combine genotype, phenotype, and genomic sequencing data from Epi25K GWAS and genome sequencing (WES and WGS) studies, and to perform joint analyses of these datasets.

INFRASTRUCTURE We have expertise in all aspects of epilepsy (clinical charaterization and neurophysiology), epilepsy treatment and epilepsy genetics (including gene discoveries, clinical charaterization of rare genetic epilepsies, genetic testing, genetic counselling etc) Equipment for genetics testing – including equipment for next generation sequencing Finsen Group Department of Neurobiology Research Department of Molecular Medicine SDU 51

GROUPGROUP NAME: NAME UCAR GROUP LEADER Finsen Group Bente Finsen

NUMBER OF 3 PhD students, 1 postdoc, and 2 parttime technicians GROUP MEMBERS (AND THEIR TITLE) DEPARTMENT & Department of Neurobiology Research, Institute of Molecular Medicine, SDU UNIVERSITY/ HOSPITAL/OTHER

FUNDING The Danish Multiple Sclerosis Society, The Danish Alzheimer Society, The Velux- SOURCES foundation, The Danish Research Agency, The Lundbeckfoundation, SDU2020

MAIN PROJECTS Our research aim is to understand how our immune system, particularly the innate microglia, contributes to protect and strengthen the neuronal network in acute and chronic CNS-disease. 1. Neuro-glial interactions in Alzheimer’s disease (AD). We wish to understand why microglia fail to clear Aßβin AD, and whether this relates to microglial dysfunction/degeneration. Microglial failure in AD may involve both glial- and neuronally-expressed signaling molecules, such as TNF and IL-1, as well as the neurotransmitter serotonin (5-HT), which promotes microglial process motility and upregulates expression of Aßββ-degrading enzymes. In the case of TNF and IL-1, data are currently being extracted from cytokine knocked-out APP/PS1 mice and controls. In the case of 5-HT, we have characterised the expression of 5-HT receptors on primary microglia cells, and are now examining molecular signaling pathways downstream of the 5-HT2a/b-receptors in Aßβ-stimulated microglia, followed by functional studies. Studies on the effects of selective 5-HT reuptake inhibitors and genetic inactivation of tryptophan hydroxylase-2 on Aßβload in APP/PS1 mice are nearing completion. 2. Proteomic profiling of AD and non-AD brain and APP/PS1 mouse brain. Proteomics suggest that an astrocyte-produced cytokine/growth factor, along with IgG are particularly abundant in the neocortex from AD cases. These findings are being validated by immunohistochemistry in AD and non-AD tissue. Findings of Tau hyperphosphorylation at pSer404 by proteomics in APP/PS1 cortical tissue are currently 52

GROUPGROUP NAME: NAME UCAR GROUP LEADER Finsen-Group Bente Finsen

being evaluated to decipher the role of Aβ as a driver of Tau-pathology. In addition, proteomic studies of tissue from APP/PS1 transgenics treated with bacterially-de- rived lipopolysaccharide (LPS) have indicated that LPS stimulates the complement pathways, an observation that might underlie the observed reduction in Aβ-load in the neocortex of the same animals. 3. Regulation of microglial cytokine production. Microglial cells are heterogeneous in terms of their production of the functionally important cytokines TNF, IL-1ßβ, and L1Ra. Cytokines, such as TNF and IL-1Ra, and potentially IL-6, which have neuroprotec- tive and pro-regenerative functions in stroke, have been shown also to have complex functions in AD and multiple sclerosis (MS). Work in progress focuses on the post- transcriptional regulation of TNF in an MS-context. These studies involve RNA-Seq on IFN stimulated microglia for circular, linear, and microRNA, followed by functional analysis and in vivo validation in brain tissue from MS models and patients with MS. 4. Myelination/remyelination. We have a long-standing interest in understanding how myelin-reactive T-cells appear to stimulate the remyelination of denuded axons by stimulating the oligodendrocyte precursor cells (OPCs). We have identi- fied a set of genes, which we show are expressed in OPCs in vivo. We now study the role of one of the identified genes in OPC differentiation and myelination processes. Moreover, we have identified the genome-wide active binding sites in OPCs and oligodendrocytes of the transcription factor Nkx2.2, which has a well-defined role in myelination. These studies involved ChIP-seq and transcript profiling of Nkx2. 2-/- mice, and siRNA-knock down of Nkx2.2 in rat OPC, and are in the pipeline for publication. The projects outlined above heavily depend on both national and international collaborations.

KEY PUBLICATIONS Neuro-glial interactions in AD (incl. microglial cell dynamics) 1. Wirenfeldt M, Dissing-Olesen L, Babcock AA, Nielsen M, Meldgaard M, Zimmer J, Azcoitia I, Leslie RGQ, Dag-næs-Hansen F, Finsen B (2007) Population control of resident and immigrating microglia by mitosis and apopto-sis. Am J Pathol 171:1-31. 2. Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS (2013) Alternative polyad enylation and miR-34 family members regulate Tau expression. J Neurochem 127:739-49. 53

GROUPGROUP NAME: NAME UCAR GROUP LEADER Finsen-Group Bente Finsen

3. Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A (2014) Accelerated microglial pathology is asso-ciated with Aβ plaques in mouse models of Alzheimer’s disease. Aging Cell 13:584-95. 4. Khan AM, Babcock AA, Saeed H, Myhre CL, Kassem K, Finsen B (2015) Telomere dysfunction reduces microg-lial numbers without fully inducing an aging phenotype. Neurobiol Aging 36:2164-75. 5. Babcock AA, Ilkjær L, Clausen BH, Villadsen B, Dissing-Olesen L, Bendixen ATM, Lyck L, Lambertsen KL, Finsen B (2015) Cytokine-producing micro- glia have an altered beta-amyloid load in aged APP/PS1 Tg mice. Brain Beh Immun. 48:86-101. 6. Olesen LØ, Bouzinova E, Severino M, Sivasaravanaparan M, Hasselstrøm JB, Finsen B*, Wiborg O* (2016) Be-havioural phenotyping of APPswe/PS1dE9 mice: Age-related changes and effect of long-term paroxetine treatment. PLoS One. 11(11):e0165144. 7. Metaxas A, Vaitheeswaran R, Jensen KT, Darvesh S, Finsen B. Reduced serotonin transporter levels and in-flammation in the midbrain raphe of APP/ PS1 mice, without local deposition of plaques or tangles. In submission. 8. Olesen LØ, Sivasaravanaparan M, Severino M, Babcock AA, Bouzinova EV, West MJ, Wiborg O*, Finsen B* (2017) Neuron number and neurogenesis in the dentate gyrus of aged APPswe/PS1dE9 transgenic mice: Effect of long-term treatment with paroxetine. Neurobiol. Aging. PMID: 28461249. 9. Von Linstow CU, Severino M, Metaxas A, Waider J, Lesch KP, Gramsbergen JB, Finsen B (2017) Effect of age-ing and Alzheimer’s disease-like pathology on brain monoamines in mice. Neurochem. Int. PMID: 28414094. 10. Von Linstow CU, Waider J, Grebing M, Metaxas A, Lesch KP, Finsen B. Serotonin augmentation therapy by escitalopram has subtle or no effect on amyloid-β levels in early stage Alzheimer’s-like disease in mice. In sub-misssion/revision. 11. Babcock AA, Ilkjær L, Wirenfeldt M, Krøigård T, Myhre CL, Khan AM, Dissing-Olesen L, Darvesh S, Jensen MS, West MJ, Finsen B. Beta-amyloid induces apoptosis of phagocytic microglia and macrophages. In submisssion/ revision.

Proteomic profiling in AD and AD mouse models 12. Lyck L, Dalmau Santamaria I, Pakkenberg B, Chemnitz J, Schrøder HD, Finsen B*, Gundersen HJG (2009) An empirical analysis of the precision of estimating the numbers of neurons and glia in human neocortex using a fractionator- design with sub-sampling. J Neurosci Meth 182:143-856. *Corresponding author 54

GROUPGROUP NAME: NAME UCAR GROUP LEADER Finsen-Group Bente Finsen

13. Kempf SJ, Metaxas A, Ibáñez-Vea M, Darvesh S, Finsen B, Larsen MR (2016) An integrated proteomics ap-proach shows synaptic plasticity changes in an APP/ PS1 Alzheimer´s mouse model. Oncotarget 7:33627-48. 14. Jensen P, Myhre CL, Lassen P, , Khan AM, Babcock AA, Finsen B*, Larsen MR*, Kempf SJ. Elucidation of the molecular network of TNF in neurons in neuroin- flammation and neural plasticity. Oncotarget. In revision.

Regulation of microglial (neuroprotective) cytokine production Cerebral Ischemia/Stroke 15. Clausen BH*, Lambertsen KL*, Babcock AA, Holm T, Dagnaes-Hansen F, Finsen B (2008) Interleukin-1β and tumor necrosis factor-a are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. J Neuroinflam. 5:46. *Shared 1st authorship. 16. Lambertsen KL, Clausen BH, Babcock A, Gregersen R, Fenger C, Nielsen HH, Haugaard LS, Wirenfeldt M, Niel-sen M, Dagnaes-Hansen F, Bluethmann H, Færgeman NJ, Meldgaard M, Deierborg T, Finsen B (2009) Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci 29:1319-1330. 17. Lambertsen KL, Deierborg T, Gregersen R, Clausen BH, Wirenfeldt M, Nielsen HH, Dalmau I, Diemer NK, Dag-naes-Hansen F, Johansen FF, Keating A, Finsen B (2011) Differences in origin of reactive microglia in bone mar-row chimeric mouse and rats after transient global ischemia. J Neuropathol Exp Neurol 70:481-494. 18. Clausen BH, Lambertsen KL, Dagnæs-Hansen F, Babcock AA, von Linstow CU, Meldgaard M, Kristensen BW, Deierborg T, Finsen B (2016) Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke. Acta Neuropathol. 131:775-91. 19. Madsen PM, Clausen BH, Degn M, Thyssen S, Kristensen LK, Svensson M, Ditzel N, Finsen B, Deierborg T, Brambilla R, Lambertsen KL (2015) Genetic ablation of soluble tumor necrosis factor with preservation of mem-brane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia. J Cereb Blood Flow Metab. Oct 19. pii: 0271678X15610339. 20. Clausen B, Degn M, Martin N, Couch Y, Karimi L, Ormhøj M, Mortensen ML, Gredal H, Gardiner C, Sargent II, Szymkowski DE, Petit GH, Deierborg T, Finsen B, Anthony D, Lambertsen K (2015) Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. J Neu roinflam 11:203. 55

GROUPGROUP NAME: NAME UCAR GROUP LEADER Finsen-Group Bente Finsen

21. Gredal H, Thomsen BB, Boza-Serrano A, Garosi L, Rusbridge C, Anthony D, Møller A, Finsen B, Deierborg T, Lambertsen KL, Berendt M (2016) Interleukin-6 is increased in plasma and cerebrospinal fluid of community dwell-ing domestic dogs with acute ischaemic stroke. NeuroRep 28:134-140. 22. Grønhøj MH, Clausen BH, Fenger C, Lambertsen KL, Finsen B. Intravenously administered IL-6 improves func-tional outcome after experimental stroke in C57BL/6 mice and is neuroprotective in IL-6 knock out mice. Brain Beh. Immun. In press.

Posttranscriptional regulation 23. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495:384-8. 24. Venø MT, Hansen TB, Venø ST, Clausen BH, Grebing M, Finsen B, Holm IE, Kjems J (2015) Spatio-temporal regulation of circular RNA expression during porcine embryonic brain development. Genome Biol. 16:245. 25. Venø MT, Venø ST, Rehberg K, van Asperen J, Clausen BH, Holm IE, Pasterkamp I, Finsen B, Kjems J (2017) Cortical morphogenesis during embryonic develop ment is regulated by miR-34c and miR-204. Feb 9;10:31.

Myelination/remyelination & multiple sclerosis 26. Nielsen HH, Ladeby R, Fenger C, Toft-Hansen H, Babcock AA, Owens T, Finsen B (2009) Enhanced microglial clearance of myelin debris in T cell infiltrated central nervous system. J Neuropathol Exp Neurol 68:845-856. 27. Drøjdahl N*, Nielsen HH*, Gardi J, Wree A, Peterson AC, Nyengaard JR, Eyer J, Finsen B (2010) Axonal plastici-ty elicits long-term changes in oligodendroglia and myelinated fibers. Glia 58:29-42. *Shared 1st authorship. 28. Nielsen HH, Toft-Hansen H, Lambertsen KL, Owens T, Finsen B (2011) Stimu- lation of adult oligodendrogenesis by myelin specific T-cells. Am J Pathol 179:2038-41. 29. Grebing MM, Nielsen HH, Fenger CD, Jensen KT, von Linstow CU, Clausen BH, Söderman M, Lambertsen KL, Thomassen M, Kruse TA, Finsen B (2016) Myelin specific T cells induce interleukin-1beta expression in activated microglia in zones of axonal degeneration. Glia 64:407-24. 56

GROUPGROUP NAME: NAME UCAR GROUP LEADER Finsen-Group Bente Finsen

30. Dionne N, Dib S, Finsen B, Denarier E, Tanja Kuhlmann T, Drouin R, Kokoeva M, Hudson TJ, Kathy Siminovitch K, Friedman HC, Peterson AC (2016) Functional organization of an mbp enhancer exposes striking transcriptional regulatory diversity within myelinating glia. Glia 64:175-94. 31. Fenger CD, Thomassen M, Abdulla SA, Larsen M, Kuhlmann T, Kotter MR, Kruse TA, Emery B, Finsen B. Ge-nome-wide identification of Nkx2.2 targets in oligodendrocyte-lineage cells reveals numerous novel target genes involved in a broad range of cellular activities. In submission/revision.

KEY Danish: COLLABORATIONS Prof. Martin Røssel Larsen, Ctr. Proteomics, Inst. Biochem. & Mol. Biol., SDU (proteomics) Prof. Jørgen Kjems, iNano, Inst. Mol. Biol., Aarhus University (AaU), Aarhus (RNAomics) Prof. Torben Kruse, Human Genetics, Odense University Hospital (OUH), Odense (array analysis) Prof. Poul Hyttel, Veterinary Medicine, Dpt. Anat, Physiol., Biochem., Copenhagen Univ. (AD, stem cell biol.) Senior scientist, Ove Wiborg, CFIN, Aarhus Univ. Hospital, Aarhus (AD, small animal behavior) Chief consultant, PhD Helle Klingenberg Iversen, Rigshospitalet, Glostrup Hospital (stroke)

International: Prof. Klaus-Peter Lesch, Dpt. Psych., Würzburg Univ. Hospital, Würzburg, Germany (5-HT biology) Prof. Sultan Darvesh, Dalhousie Univ., & The Maritime Brain Tissue Bank, Halifax, Canada (AD) Prof. Tanja Kuhlmann, Dpt. Neuropath., Münster Univ. Hospital, Münster, Germany (MS) Prof. Jessica Teeling, Southampton Univ., Southampton, United Kingdom (neuroinflammation in AD) Assoc. prof. Ben Emery, Dpt. Anat. & Neurosci. Univ. Melbourne, Melbourne, Australia 57

GROUPGROUP NAME: NAME UCAR GROUP LEADER Finsen-Group Bente Finsen

INFRASTRUCTURE From originally being an entirely histology- and morphometry-based laboratory, my research group today uses integrated approaches that include different types of molecular biology and protein chemical techniques, cell cultivation-, isolation-, and characterization-techniques, pharmacology (ligand binding), high resolution anatomy, as well as rodent behavior. The laboratory has outstanding expertise in in situ hybridization techniques. Proteomics and RNAomics are performed on a collaborative basis.

Facilities available to the research group: EM-microscopy (Dpt. Pathology, OUH), Confocal microscopy (IMM, assoc. prof. S. Moestrup), Small animal behavioral suite (IMM, assoc. prof. KL Lambertsen), Flowcytometry (IMM, assoc. prof. S Hansen), Array Ctr. (Human Genetics, OUH (prof. T Kruse), Radioactivity lab (IMM, Autoradiography/cell harvester, Seniorpostdoc. A Metaxas). Focused Research in Neurology Department of Neurology, Hospital of Southern Jutland & Department of Regional Research SDU 59

GROUPGROUP NAME: NAME UCAR GROUP LEADER Focused Research Group in neurology Egon Stenager

NUMBER OF Associate Professor Michael Binzer, adj. Professor Ulrik Dalgas, adj. Professor Nete GROUP MEMBERS Munk Nielsen, Clinical associate professors: 2 Guest reasearchers: 6 (previous PhD (AND THEIR TITLE) students), Current PhD students: 4 Up-coming PhD students: 2, Research nurses: 3

DEPARTMENT & Institute of Regional Research, University of Southern Denmark and Department of UNIVERSITY/ Neurology, Hospital of Southern Jutland. HOSPITAL/OTHER

FUNDING Public and private funding SOURCES Participation in international multicenter studies

DESCRIPTION OF 1. Clinical epidemiological studies (primarily demyelinating CNS disorders) RESEARCH 2. Register-based epidemiological studies 3. Studies on the pathological and physiological basis of effect of rehabilitation 4. Neuro-psychiatric studies 5. Genetic studies (primarily in demyelinating disorders) 6. Biomarkers in L-DOPA induced dyskinesia in Parkinson´s disease 7. International multicenter studies (Phase 2, 3 and 4)

KEY PUBLICATIONS 1. Andersen AD, Blaabjerg M, Binzer M, Kamal A, Thagesen H, Kjær T, Stenager E, Gramsbergen JB. Cerebrospinal fluid levels of catecholamines and its metab olitesin Parkinson´s disease: Effect of L-DOPA treatment and changes in levodopa-induced dyskinesia. J. Neurochem 2017 Feb 28. doi: 10.1111/jnc.13997 2. Nielsen NM, Munger K, Koch-Henriksen N, Hougaard D, Magyari M, Jørgensen KT, Lunqvist M, Simonsen J, Jess T, Cohen A, Stenager E, Ascherio A. Neonatal vitamin D and risk of multiple sclerosis. A population-based case-control study. Neurology. 2017 Jan 3;88(1):44-51 3. Andersen AD, Binzer M, Stenager E, Gramsbergen JB. Cerebrospinal fluid biomarkers for Parkinson´s disease – a systematic review. Acta Neurol Scand 2017 Jan;135(1):34-56. 60

GROUP NAME GROUP LEADER Focused Research group in neurology Egon Stenager

4. Nielsen NM, Harpsøe M, Simonsen J, Stenager E, Magyari M, Koch-Henriksen N, Sørensen TIA, Hjalgrim H, Frisch M, Bager P. Age at menarche and risk of multiple sclerosis. A retrospective cohort study based on the Danish Birth Cohort. Am J Epidemiol. 2017 Mar 25:1-8. 5. Huong Hoang, Stenager EN, Laursen B, Stenager E. Psychiatric co-morbidity in multiple sclerosis: The risk of depression and anxiety before and after MS diagnosis. Multiple Sclerosis Journal 2016;22(3):347-353 6. Binzer S, Stenager E, Binzer M, Kyvik KO, Hillert J, Imrell K. Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene Mult Scler Jr 2016;22(6):733-40. 7. Dalgas U, Stenager E, Sloth M, Stenager EN. The effect of excercise on depressive symptoms in multiple sclerosis based on meta-analysis and critical review of literature. Eur J Neurol. 2015 Mar;22(3):443-e34 8. Jensen HB, Ravnborg M, Mamoei S, Dalgas U, Stenager E. Changes in cognition, arm function and lower body function after Slow-Release Fampridine treat- ment .Mult Scler. 2014;20:1872-1880. 9. Yu F, Bilberg A, Stenager E, Rabotti C, Zhang B, Mischi M. Wireless body measurement system to study fatique in multiple sclerosis. Physiol Meas 2012;33:2033-48 10. Dalgas U, Stenager E. Exercise and disease progression in multiple sclerosis – can exercise slow down the progression of multiple sclerosis? Therapeutic Advances in Neurological Disorders. 2012;5:81-95 11. Sørensen PS, Lycke J, Erälinna J-P, Edland A, Wu X, Frederiksen JL, Oturai A, Malmestöm C, Stenager E, Sellebjerg F, Søndergaard HB, Sperling B for the SIMCOMBIN Investigators. Simvastatin as add-on therapy to interferon-beta-1a for relapsing-remitting multiple sclerosis. (SIMCOMBIN Study): a placebo- controlled randomised phase 4 trial. Lancet Neurology 2011:10;691-701. 12. Asgari N, Lillevang ST, Skejø HPB, Falah M, Stenager E, Kyvik KO. Occurrence of neuromyelitis optica (NMO) in Caucasians. A population-based study. Neuro- logy 2011;76:1581-88 13. U Dalgas, E Stenager, J Jakobsen, T Petersen, HJ Hansen, C Knudsen, K Overgaard, T Ingemann-Hansen. Resistance training improves muscle strength and functional capacity in multiple sclerosis. Neurology 2009;73:1478-84 14. McCombe P, Stenager E. Editorial: Female infertility and multiple sclerosis: is this an issue? Mult Scler J 2015 Jan;21(1):5-7. 61

GROUP NAME GROUP LEADER Focused Research group in neurology Egon Stenager

KEY Danish: COLLABORATIONS All departments in the Region of Southern Denmark and all MS clinics in Denmark. Department of Sport, Aarhus University Department of Clinical Genetics, OUH. SSI, Denmark MS registry, Copenhagen

International: Professor Alberto Acherio, Harvard Professor Chris Heesen, Hamburg Professor Jan Hillert, Karolinske, Stockholm Senior Researcher Jon Stone, Edinburgh Professor Peter Feys, Hasselt, Belgium And several others. Please, consult publication list

INFRASTRUCTURE Access to exercise measurements. Neuro-epidemiology. Gerlach Group Department of Psychology University of Southern Denmark 63

GROUPGROUP NAME: NAME UCAR GROUP LEADER Gerlach Group Christian Gerlach

NUMBER OF Total 3: Christian Gerlach (Prof. MSO), Solja K. Klargaard (ph.d-student), GROUP MEMBERS Christina Desireé Kühn (ph.d-student) (AND THEIR TITLE)

DEPARTMENT & Department of Psychology, University of Southern Denmark UNIVERSITY/ HOSPITAL/OTHER

FUNDING SOURCES DFF | Humanities

DESCRIPTION OF Experimental psychology, neuropsychology and neuroimaging focussing on: RESEARCH • Face recognition (in congenital/developmental prosopagnosics and normal participants) • Visual object recognition (mainly in normal participants but also in brain damaged patients) • Word recognition (in dyslexia, alexia)

KEY PUBLICATIONS 1. Gerlach, C. (2009). Category-specificity in visual object recognition. Cognition 111(3), 281-301. doi: 10.1016/j.cognition.2009.02.005. 2. Gerlach, C., and Gainotti, G. (2016). Gender differences in category-specificity do not reflect innate dispositions. Cortex 85, 46-53. doi: 10.1016/j.cortex. 2016.09.022. 3. Gerlach, C., Klargaard, S.K., and Starrfelt, R. (2016). On the Relation between Face and Object Recognition in Developmental Prosopagnosia: No Dissociation but a Systematic Association. PLoS One 11(10), e0165561. doi: 10.1371/journal. pone.0165561. 4. Gerlach, C., Zhu, X., and Joseph, J.E. (2015). Structural similarity exerts opposing effects on perceptual differentiation and categorization: an FMRI study. Journal of Cognitive Neuroscience 27(5), 974-987. doi: 10.1162/jocn_a_00748. 64

GROUPGROUP NAME: NAME UCAR GROUP LEADER Gerlach Group Christian Gerlach

5. Klargaard, S.K., Starrfelt, R., Petersen, A., and Gerlach, C. (in press). Topographic processing in Developmental Prosopagnosia: preserved perception but impaired memory of scenes. Cognitive Neuropsychology. 6. Starrfelt, R., Habekost, T., and Gerlach, C. (2010). Visual processing in pure alexia: a case study. Cortex 46(2), 242-255. doi: 10.1016/j.cortex.2009.03.013.

KEY Danish: COLLABORATIONS Department of Psychology, University of Copenhagen; Department of Radiology, Odense University Hospital.

International: Multimodal Imaging Group, Norwegian Center for Mental Disorders Research (NORMENT), Oslo University Hospital; Department of Neuroscience, Medical Uni- versity of South Carolina, USA; LaPsyDÉ, CNRS, Université Paris Descartes, Univer- sité Caen Normandie, Institut Universitaire de France (IUF), Paris, France.

INFRASTRUCTURE Experimental facilities for conducting traditional experimental/neuropsychological investigations (measurement of reaction times, eye-tracking etc.) at the department.

Access to 3T MR-scanner (at Odense University Hospital) for doing fMRI/MR. Lambertsen Group Department of Neurobiology Research, Department of Molecular Medicine, SDU Denmark, & Department of Neurology, OUH 66

GROUPGROUP NAME: NAME UCAR GROUP LEADER Lambertsen Group Kate Lykke Lambertsen

NUMBER OF GROUP Postdocs: 2, PhD students: 3, Medical students: 3, Master students: 4, Technicians: 2 MEMBERS (AND THEIR TITLE)

DEPARTMENT & Department of Neurobiology Research, Institute of Molecular Medicine, University UNIVERSITY/ of Southern Denmark and Department of Neurology, Odense University Hospital HOSPITAL/OTHER

FUNDING The Lundbeck Foundation, The Danish Council for Independent Research, Medical SOURCES Research, The Danish Multiple Sclerosis Society, The Danish Victims Fund

DESCRIPTION OF In our laboratory we are studying cerebrovascular diseases of and trauma to the RESEARCH central nervous system (CNS), such as stroke and spinal cord injury (SCI), to try to understand the cellular and molecular mechanisms that contribute to inflam- mation and secondary neuronal cell death. We have primarily one main research objective, which is to study the neuro-inflammatory response that occurs following stroke and SCI with the aim to contribute to the development of novel therapies for stroke and SCI patients. To determine what role inflammation plays following CNS injury we use transgenic mouse models and other molecular approaches to study the central but complex role of the pleiotrophic cytokine tumor necrosis factor (TNF) for neuronal survival/ death. We specifically use conventional and conditional knock out models in which TNF and/or its receptors can be manipulated in all cells or in tissue specific cells, in- cluding microglia, leukocytes, oligodendrocytes and neurons. We also use a variety of anti-TNF drugs targeting both the transmembrane and the soluble forms of TNF in order to elucidate the very complex role of this signaling molecule in modulating neuroinflammation following CNS injury.

We hope to be be able to contribute to identifying novel neuroprotective therapeu- tics for treatment in stroke and SCI. 67

GROUP NAME GROUP LEADER Lambertsen lab Kate Lykke Lambertsen

KEY PUBLICATIONS Selected 10 publications: 1. Lambertsen KL, Clausen BH, Babcock AA, Gregersen R, Nielsen M, Wirenfeldt M, Haugaard LS, Færgemann NJ, Dagnaes-Hansen F, Bluethmann H, Meldgaard M, Deierborg T, Finsen B (2009) Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J Neurosci, 29:1319-1330. 2. Novrup HG, Bracchi-Ricard V, Ellman DG, Ricard J, Jain A, Runko E, Lyck L, Yli-Karjanmaa M, Szymkowski DE, Pierce DD, Lambertsen KL*, Bethea JR* (2014) Central versus peripheral administration of XPro1595 is therapeutic following moderate spinal cord injury. (*Co-corresponding and shared authors) J Neuroin flam 11:159. 3. Clausen BH, Degn M, Martin NA, Couch Y, Karimi L, Ormhøj M, Schmidt M-LB, Gredal HB, Gardiner C, Sargent IIL, Szymkowski DE, Petit G, Deierborg T, Finsen B, Anthony DC, Lambertsen KL (2014) Peripherally administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. J Neuroinflam 11:203. 4. Madsen PM, Clausen BH, Degn M, Thyssen S, Svensson M, Ditzel N, Finsen B, Deierborg T, Brambilla R, Lambertsen KL (2016) Genetic ablation of soluble TNF is associated with neuroprotection after focal cerebral ischemia. J Cereb Blood Flow Metab 36(9): 1553-1569. 5. Martin NA, Bonner H, Elkjær ML, D’Orsi B, Chen G, König HG, Svensson M, Deierborg T, Pfeiffer S, Prehn J, Lambertsen KL (2016) Deficiency of BID is partially neuroprotective in oxygen-glucose deprived organotypic hippocampal slice cultures, but not in a transient experimental stroke model. Front Cell Neurosci, Feb 3;10:14. doi: 10.3389/fncel.2016.00014. 6. Clausen BH, Lambertsen KL, Dagnaes-Hansen F, Babcock AA, von Linstow C, Meldgaard M, Kristensen BW, Wieloch T, Deierborg T, Finsen B (2016) Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke. Acta Neu ropathol 131(5):775-91. 7. Madsen PM, Mottie D, Karmally S, Szymkowski DE, Lambertsen KL, Bethea JR, Brambilla R (2016) Oligodendroglial TNFR2 mediates membrane TNF-depen- dent repair in neuroimmune disease by promoting oligodendrocyte differentia- tion and remyelination. J Neurosci 36:5128-5143. 8. Clausen BH, Degn M, Sivasaravanaparan M, Fogtmann T, Andersen MG, Trojanowsky M, Gao H, Hvidsten S, Baun C, Deierborg T, Finsen B, Kristensen BW, Bak S, Meyer M, Lee J, Nedospasov SE, Brambilla R, Lambertsen KL (2016) Conditional deletion of myeloid increases neuronal sensitivity to focal cerebral ischemia. Sci Rep, 6, 29291; doi: 10.1038/srep29291. 68

GROUP NAME GROUP LEADER Lambertsen lab Kate Lykke Lambertsen

9. Ellman DG, Degn M, Christiansen ML, Clausen BH, Novrup HG, Flæng SB, Jørgensen LH, Suntharalingam L, Brambilla R, Lambertsen KL (2016) Genetic ablation of soluble TNF does not affect lesion size and functional recovery after moderate spinal cord injury in mice. Mediators of Inflamm, 2016:2684098. doi: 10.1155/2016/2684098. 10. Gao H, Danzi M, Choi C, Taherian M, Hansen CD, Ellman D, Madsen PM, Lemmon V, Lambertsen KL, Brambilla R. Opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of experimental autoimmune encephalomyelitis. Cell Reports, Jan 3;18(1):198-212. doi: 10.1016/j. celrep.2016.11.083..

Other outputs e.g. patents, novel therapies etc: 1. Lambertsen KL, Novrup HG, Bethea J, Bracchi-Ricard V (equal contributors) (2015) Methods of treating spinal cord injury. Patent No: WO/2016/040581, PCT/ US2015/049360. 2. Lambertsen KL, Clausen BH, Finsen B, Nielsen HH, Finsen B (equal contributors) (2015) Fumaric acid derivatives for medical use. Patent No: WO2016074684 A1, PCT/DK2015/050344 3. Lambertsen KL, Clausen BH, Meyer M (equal contributors) (2015) Tnf-alpha inhibitor for treating stroke. Patent No: WO2016078672 A1, PCT/DK2015/050358.

KEY Danish: COLLABORATIONS Dr. Anders Bach, Department of Medicinal Chemistry, University of Copenhagen "DR. LARS HENRIK Dr. Petrine Wellendorf, Experimental Pharmacology, University of Copenhagen FRICH, DEPARTMENT OF Dr. Karin Lykke-Hartmann, Department of Biomedicine, University of Aarhus ORTHOPEDIC Dr. Allan Stensballe, Department of Health Science and Technology, Aalborg RESEARCH, OUH" University, Dr. Lars Henrik Frich, Department of Orthopedic Research, OUH Dr. Søren Nielsen, Department of Health Science and Technology, Aalborg University

International: Dr. Roberta Brambilla, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine. Dr. Tomas Deierborg, Neuroinflammation, Lund University Dr. Daniel Anthony, Department of Pharmacology, University of Oxford Dr. Mathias Gelderblom, Department of Neurology, Hamburg University 69

GROUP NAME GROUP LEADER Lambertsen lab Kate Lykke Lambertsen

INFRASTRUCTURE The Lambertsen lab is fully equipped to perform animal models of spinal cord injury and stroke, including behavioral analysis, stereological, immunohistochemical, molecular and biochemical analyses, with specific focus on analysis of inflamma- tory pathways following CNS injury. Larsen Group Center for Clinical Proteomics, Department of Biochemistry and Molecular Biology, SDU 71

GROUP NAME GROUP LEADER Larsen Group Martin R. Larsen

NUMBER OF GROUP 4 postdocs, 4 PhD students, 5 project students and one Academic technician (A-TAP). MEMBERS (AND THEIR TITLE)

FUNDING 2014-17: NNF: glucose signalling in beta cells. 1.200.000 Kr SOURCES 2014-17: Kræftens bekæmpelse: sialyltransferases in cancer. 1.250.000 Kr 2014-17: Danish Diabetes Academy postdoc: Free radical modifications. 1,800,000 Kr 2014-16: FNU: Sialic acid modifications. 2.470.176 Kr 2014-16: FSS: signalling in beta cells from normal and db / db mice. 2.470.176 Kr 2014-17: Danish Elite Research Award.1.200.00 Kr 2014-: LF: RIMMI partner 45 million Kr 2014-18: VILLUM Center for Bioanalytical Sciences. 60 million Kr 2016-18: FTP: Proline isomerization in signalling in neurons. 2.239.200 Kr 2017-19: FNU: Novel signalling mechanisms in nerve terminals. 2.239.200 Kr 2017-19: NNF: ROS-mediated beta-cell damage. 1.396.500 Kr

DESCRIPTION OF The group of Martin R. Larsen is focusing on the application of biological mass RESEARCH spectrometry in proteomics, especially the characterization of post-translational modifications in proteins and their influence on biological system and their cross- talk in cellular signaling. Selected projects: 1. Characterization of depolarization-dependent PTM signaling in nerve terminals after ultra-short time stimulation The role of phosphorylation, sialylation and acetylation in nerve-terminal biology. 2. Proteomics and PTMomics analyses of human stem cell-derived neurons in vari- ous settings (characterization of protein mutations in Alzheimer´s Disease and Parkinson´s Disease, sAPPalpha signaling in neurons, TNF signaling in neurons etc.). 3. Proteomics and phosphoproteomic changes of the post-synaptic density during inhibitory avoidance learning. 4. Characterization of phosphorylation-dependent signaling events in pancreatic betacells; Glucose induced Insulin secretion, Free radical signaling in beta cells, Beta cell signaling in Islet of Langerhans from db/db mice). 5. Characterization of altered glycosylation (i.e., sialylation) on surface proteins of cancer cells and their influence on metastasis. 6. Biomarker discovery, with the focus on glycosylated proteins in various body-fluids such as plasma, serum and cerebrospinal fluid (type 2 diabetes related diseases, Alzheimer´s Disease and other CNS diseases). 7. Proteomics and PTMomics characterization of immune cells in relation to Regional Immune-Modulation of Mucosal Inflammation (RIMMI). 72

GROUP NAME GROUP LEADER Larsen Group Martin R. Larsen

KEY PUBLICATIONS Lassen PS, et al. J Proteomics. 2017 Apr 8, Berchtold MW, et al. J Biol Chem. 2016 Dec (LAST 10 YEARS) 23;291(52):26636-26646, Boysen A, et al. Sci Rep. 2016 Aug 26;6:32016, Alves MJ, et al. J Proteomics. 2017 Jan 16;151:182-192, Kempf SJ, et al. Oncotarget. 2016 Nov 1;7(44):71817-71832, Kempf SJ, et al. Oncotarget. 2016 Jun 7;7(23):33627-48, Huang H, et al. Mol Cell Proteomics. 2016 Oct;15(10):3282-3296, Kulej, K., et al. EuPA Proteomics Journal, Volume 8, September 2015, Pages 55–67, Heegaard NH, et al. Proteomics Clin Appl. 2015 Feb;9(1-2):235-52, Melo-Braga MN, et al. Proteomics. 2015 Feb;15(4):656-74. Parker BL, et al. J Biol Chem. 2014 Sep 12;289(37):25890-906, Edwards AV et al. J Proteomics. 2014 Apr 14;101:77-87, Melo-Braga MN, et al. Mol Cell Proteomics. 2014 Jan;13(1):311-28, Edwards AV, et al. J Proteome Res. 2014 Jan 3;13(1):260-7, Engholm- Keller, K., et al. J Proteomics. 2012 Oct 22;75(18):5749-61, Palmisano G, et al. Mol Cell Proteomics. 2012 Nov;11(11):1191-202,Palmisano, G., et al. J Proteome Res. 2012 Mar 2;11(3):1949-57

Other outputs e.g. patents, novel therapies etc: 1. Patent Number: US 2010/0207051 A1 2. Patent Number: US 7,915,008 B2 3. Patent Number: WO 2015/1554783 A1

INFRASTRUCTURE The protein research group at department of Biochemistry and Molecular Biology at SDU, where the Larsen group is located, is one of the largest proteomics groups in Europe with a large variety of mass spectrometers, protein chemistry methods and unique methods for assessment of multiple PTMs, developed in the Larsen group. Through the Center for Bioanalytical Sciences (Financed by the Villum foundation) we have access to state-of-the-art instrumentation for proteomics, including two Orbitrap Lumos instruments and 3 Q-Exactive HF instruments, with novel nano-LC systems. In addition, we have advanced cell laboratory facili- ties (class 1 and 2) ena-bling manipulation of various cell lines and animal tissues. Furthermore, we have several path-way analysis programs and in-house developed software for bioinformatics data handling and storage. Meyer Group Department of Neurobiology Research, Department of Molecular Medicine, SDU 74

GROUPGROUP NAME: NAME UCAR GROUP LEADER Meyer Group Morten Meyer

NUMBER OF 1 Research assistant, 4 Ph.D. students, 1 Technician, GROUP MEMBERS (B.Sc. and M.Sc. students not included) (AND THEIR TITLE)

DEPARTMENT & Department of Neurobiology Research of Molecular Medicine, SDU UNIVERSITY/ HOSPITAL/OTHER

FUNDING SOURCES Den A.P. Møllerske Støttefond Grosserer, L.F Foghts foundation, Jascha foundation, Odense University Hospital, University of Southern Denmark

DESCRIPTION OF Our research group is a subgroup within a larger, internationally recognized re- RESEARCH search unit, with strong international and industrial relations, focusing on injury, protection and repair of CNS nerve cells and glial cells using in vitro and animal models of disease.

The major effort of our group is devoted to harnessing and manipulating the differentiation potential of human neural stem cells and induced pluripotent stem cells. Our research program is focused on identifying molecular and biochemical signals regulating cell fate decisions. We place particular emphasis on formation of functional dopaminergic neurons with midbrain characteristics - the cell type that degenerates in Parkinson’s disease.

Using stem cells and dopaminergic neurons derived from developing human brain tissue (neural stem cells) and patients with sporadic or familial Parkinson’s disease (induced pluripotent stem cells), our main current effort is on:

a) investigation of the early cellular changes that underlie the onset of neurode generation in familial Parkinson’s disease (cells with and without PARK2 muations). This includes the use of isogenic stem cells in combination with molecular assays and advanced mass spectometry-based methods (proteomics, metabolomics and lipidomics - including post-translational modifications). 75

GROUPGROUP NAME: NAME UCAR GROUP LEADER Meyer Group Morten Meyer

b) validation of stem cell-derived human dopaminergic neurons in a hemipar- kinsonian rat model of Parkinson’s disease. This includes long-term survival of transplanted cells to assess cell fate, maturation and integration, as well as functional behavioural assessment for graft function.

Our general ambitions are to advance the understanding of the molecular mechanisms underlying Parkinson’s disease and to contribute to the development of a potential future stem cell therapy.

KEY PUBLICATIONS 1. Jensen P., Bauer M., Jensen C.H, Widmer H.R., Gramsbergen J.B., Blaabjerg M., Zimmer J., Meyer M. (2007) Expansion and characterization of ventral mesencephalic precursor cells: Influence of mitogens and investigation of FA1 as a potential dopaminergic marker (J. Neurosci. Research 85: 1884-1893). 2. Andersen R. K., Johansen M., Blaabjerg M., Zimmer J., and Meyer M. (2007) Neural tissue-spheres: A microexplant culture method for propagation of precursor cells from the rat forebrain subventricular zone (Journal of Neuroscience Methods 165: 55-63). 3. Anwar M.R., Andreasen C.M., Lippert S.K., Zimmer J., Martinez-Serrano A., Mey er M. (2008) Dopami-nergic differentiation of human neural stem cells mediated by cocultured rat striatal brain slices (Journal Neurochemistry 105: 460-470). 4. Andersen R. K., Zimmer J., Wahlberg L. U., Meyer M. (2008) Effect of leukemia inhibitory factor on long-term propagation precursor cells derived from rat forebrain subventricular zone and ventral mesencepha-lon (Experimental Neurology 211: 301-310). 5. Jensen P., Pedersen E.G., Zimmer J., Meyer M. (2008) Functional effect of FGF2- and FGF8-expanded ventral mesencephalic precursor cells in a rat model of Parkinson’s disease (Brain Research 1218: 13-20). 6. Krabbe C., Courtois E., Jensen P., Jørgensen J. R., Zimmer J., Martínez-Serrano A., Meyer M. (2009) En-hanced dopaminergic differentiation of human neural stem cells by synergistic effect of Bcl-xL and reduced oxygen tension (Journal of Neurochemistry 110: 1908-1920). 76

GROUPGROUP NAME: NAME UCAR GROUP LEADER Meyer Group Morten Meyer

7. Tanvig M., Blaabjerg M., Andersen R.K, Villa A., Rosager A.M., F.R. Poulsen, Martinez-Serrano A., Zim-mer J., Meyer M. (2009). A brain slice culture model for studies of endogenous and exogenous precursor cell migration in the rostral migratory stream (Brain Research 1295: 1-12). 8. Andersen, R.K., Widmer, H. R., Wahlberg L. U., Zimmer, J., Meyer, M. (2009) Leukemia inhibitory factor induces tyrosine hydroxylase expression in long-term propagated human midbrain precursor cells (Neuroscience Letters 464: 203-208). 9. Jensen P., Gramsbergen J.B., Zimmer J., Widmer H.R., Meyer M. (2011). Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension (Exp. Cell Research 317: 1649-1662). 10. Jensen P.S., Lyck L., Jensen P., Zimmer J., Meyer M. (2012). Characterization of porcine ventral me-sencephalic precursor cells following long-term propagation in 3D culture (Stem Cells Int. 2012: 761843). 11. Jensen P., Heimberg M., Ducray A.D., Widmer H.R., Meyer M. (2013). Expression of Trefoil factor 1 in the developing and adult rat ventral mesencephalon (PLoS ONE, DOI 10.1371/journal.pone.0076592). 12. Krabbe C., Thornby Bak S., Linstow C.U., Jensen P., Martinez-Serrano A., Hansen C., Meyer M. (2014). Influence of oxygen tension on dopaminergic differentiation of human fetal stem cells of midbrain and forebrain origin (PLoS ONE. DOI 10.1371/journal.pone.0096465). 13. Erichsen J.L., Blaabjerg M., Bogetofte H., Martinez Serrano A., Meyer M. (2015). Group I Metabotropic Glutamate Receptors: A Potential Target for Regulation of Proliferation and Differentiation of an Immor-talized Human Neural Stem Cell Line (Basic & Clinical Pharmacology & Toxicology, 116, 4, 329-336). 14. Jensen P., Ducray A.D., Widmer H.R., Meyer M. (2015). Effects of forskolin on trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons (Neuroscience: DOI 10.1016/ j.neuroscience. 2015.10.010). 15. Momcilovic O., Sivapatham R., Oron T.R., Meyer M., Mooney S.D., Rao M., Zeng X. (2016). Derivation, characterization, and neural differentiation of integrationfree induced pluripotent stem cell lines from Parkinson’s disease patients carrying SNCA, LRRK2, PARK2, and GBA mutations (PLoS ONE, DOI 10.1371/journal.pone.0154890). 77

GROUPGROUP NAME: NAME UCAR GROUP LEADER Meyer Group Morten Meyer

15. Holmqvist S., Lehtonen Š., Chumarina M., Puttonen K.A., Azevedo C., Lebedeva O., Ruponen M., Oksanen M., Dejlloul M., Collin A., Goldwurm S., Meyer M., Lagarkova M., Kiselev S., Koistinaho J., Roybon L. (2016). Creation of a library of induced pluripotent stem cell models from Parkinsonian patients (NPJ Parkinson’s Disease, DOI 10.1038/npjparkd.2016.9). 16. Zhang Y., Schmid B., Nikolaisen N.K., Rasmussen M.A., Aldana B.I., Agger M., Calloe K., Stummann T.C., Larsen H.M., Nielsen T.T., Huang J., Xu F., Liu X., Bolund L., Meyer M., Bak L.K., Waagepetersen H.S., Lou Y., Nielsen J.E., Thre FReJA Consortium, Holst B., Clausen C., Hyttel P., Freude K.K (2017). Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B (Stem Cell Reports, DOI: http://dx.doi.org/10.1016/j. stemcr.2017.01.012). 17. Perez-Bouza, A., Di Santo, S., Seiler, S., Meyer, M., Andereggen, L., Huber, A., Guzman, R., Widmer, H. R. (2017). Simultaneous transplantation of fetal ventral mesencephalic tissue and encapsulated genetically modified cells releasing GDNF in a hemi-parkinsonian rat model of Parkinson’s disease (Cell Transplantation, DOI: 10.3727/096368917X694679). 18. Lambertsen KL, Clausen BH, Meyer M (equal contributors) (2015) Tnf-alpha inhibitor for treating stroke. Patent No: WO2016078672 A1, PCT/DK2015/050358.

KEY Danish: COLLABORATIONS Drs. Poul Hyttel, Kristine Freude, Vanessa Jane Hall, University of Copenhagen. Drs. Karina Fog, Tina Charlotte Stummann, H. Lundbeck A/S. Dr. Morten Blaabjerg, University Hospital Zealand. Dr. Poul Henning Jensen, Aarhus University. Drs. Frantz R. Poulsen, Bjarne Winther Kristensen, Lene Wermuth, Odense University Hospital. Drs. Kate Lykke Lambertsen, Åsa Fex Svenningsen, University of Southern Denmark. Drs. Martin Røssel Larsen, Nils J. Færgeman, Christer Ejsing, University of Southern Denmark. 78

GROUPGROUP NAME: NAME UCAR GROUP LEADER Meyer Group Morten Meyer

International: Drs. Richard Wade-Martins, Brent Ryan, Oxford University, UK. Dr. Laurent Roybon, Lund University, S. Dr. Xianmin Zeng, Buck Institute, USA. Dr. Alberto Martinez-Serrano, Autonomous University of Madrid, E. Dr. Hans R. Widmer, University Hospital of Bern, CH. Dr. Raphael Guzman, University Hospital Basel, CH.

INFRASTRUCTURE Human neural stem cell lines (forebrain, midbrain). Induced pluripotent stem cell lines (Parkinson patient/controls). Isogenic induced pluripotent stem cell lines (PARK2 mutation vs. control). Human brain tissue (sporadic Parkinson’s disease, healthy fetal and adult) 3-D neurosphere cultures (forebrain subventricular zone). Organotypic brain slice cultures (ventral mesencephlon, striatum, hippocamus). Microtransplantation of brain slice cultures (in vitro model of cell grafting) Animal model of Parkinson’s disease (6-OHDA), stereotactic cell transplantation, behavioral analyses (motor assessment and cognition). Various histological, immunological and biochemical techniques (e.g. cytochemis- try, imunocyto-chemistry, in situ hybridization, Western blotting, enzyme assays, HPLC analysis, multiplex cytokine arrays, calcium imaging). Nielsen Department of Neurology, OUH & Department of Molecular Medicine, SDU 80

GROUPGROUP NAME: NAME UCAR GROUP LEADER Nielsen Helle Hvilsted Nielsen

NUMBER OF Helle Hvilsted Nielsen, Senior Consultant PhD and Associate Professor, GROUP MEMBERS Katrine Tækker Jensen, PhD student, Laura Davidsen, ITEK student, (AND THEIR TITLE) Minna Lund, PhD student

DEPARTMENT & UNIVERSITY/ Department of Neurology. Odense University Hospital HOSPITAL/OTHER

FUNDING SOURCES Danish Society for Multiple Sclerosis

DESCRIPTION OF • Clinical and paraclinical research in neuromyelitis optica and multiple sclerosis RESEARCH • Pathogenic mechanisms in neuroinflammatory disorders

KEY PUBLICATIONS 1. Gebregiworgis T, Nielsen HH et al. (2016): A Urinary Metabolic Signature for Multiple Sclerosis. J Proteome 2. Res Waters P, Reindl M, Saiz A, Schanda K, Tuller F, Kral V, Nytrova P, Sobek O, Nielsen HH et al. (2016): Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica. J Neurol Neurosurg Psychiatry. 3. Nielsen HH et al. (2015): The Urine Proteome Profile is Different in Neuromyelitis Optica Com-pared to Multiple Sclerosis. PlosOne 4. Grebing MM, Nielsen HH et al (2015): Myelin Specific T Cells Induce Interleukin-1beta Expres-sion in Lesion-Reactive Microglia in Zones of Axonal Degeneration. In press. 5. GLIA Nielsen HH, et al. (2014): Diagnostik og behandling af Neuromyelitis Optica. Ugeskr Laeger. 6. Banati M, Csecsei P, Koszegi E, Nielsen HH et al. (2013): Antibody response against gastroin-testinal antigens in demyelinating diseases of the central nervous system. Eur J Neurol. 7. Nielsen HH et al. (2012): Treatment of Helicobacter Pylori and risk of developing Parkinson’s disease in Denmark. Eur J Neurol. 81

GROUP NAME GROUP LEADER Nielsen Helle Hvilsted Nielsen

8. Nielsen HH et al. (2011): Stimulation of adult oligodendrogenesis by myelin specific T-cells. Am J Pathol. 9. Nielsen HH et al. (2009): Enhanced microglia clearance of myelin debris in T-cell i nfiltrated central nervous system. J Neuropathol Exp Neurol. 10. Drøjdahl N*, Nielsen HH* et al. (2010): Axonal plasticity elicits longterm changes of oligoden-droglia and myelinated fibres. Glia. (*equal contribution) 11. Nielsen HH et al. (2006): Axonal Degeneration Stimulates the Formation of NG2+ Cells and Oli-godendrocytes in the Mouse. Glia

Other outputs e.g. patents, novel therapies etc: Fumaric acid derivatives for medical use: SDU ref.: 14/5668; P&V ref.: 54985US01

KEY Danish: COLLABORATIONS Dept of Neurology, OUH: Prof Zsolt Illes, David Gaist Center for Clinical Proteomics, OUH: Prof Niels Heegaard Dept of Orhtopedic Surgery, OUH: Ass Prof Lars Henrik Frich Dept of Opthalmology: Prof. Jakob Grauslund Dept. of Reumatology: Consultant Keld-Erik Byg Institute of Molecular Medicine: Prof Bente Finsen, Ass prof Kate Lambertsen

International: University of Miami: Ass Prof Roberta Bramilla

INFRASTRUCTURE Patients with inflammatory disorders of the CNS, including clinical database and biobank with couples samples of urine, plasma, sera, CSF, RNA and DNA Neuroepidemiology Department of Neurology, OUH & Department of Clinical Research, SDU 83

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroepidemiology David Gaist

NUMBER OF Total 8 members: David Gaist, PhD, Professor Emil A. Pedersen, MD, PhD, post doc GROUP MEMBERS Toke de K. Svendsen, MD, PhD stud, Sidsel Arnspang, MD, PhD student Stine Munk (AND THEIR TITLE) Hald, MD Christine Kring Sloth, MD, Sabine Morris Hey, MD, Charlotte Madsen, MD

DEPARTMENT & Department of Neurology, Odense University Hospital & Neurology Research Unit, UNIVERSITY/ Department of Clinical Research, Faculty of Health Sciences, University of Southern HOSPITAL/OTHER Denmark

FUNDING Hospital and regional research funds, Danish Cancer Society, Fonden til Læge- SOURCES videnskabens Fremme A.P, Møller & Hustru Chastine Mc-Kinney Møllers Fond til Almene Formaal, Lundbeck Foundation, Fabrikant Vilhelm Pedersen and Hustru legat.

DESCRIPTION OF The principal research areas of the group are: (i) the epidemiology of neurological RESEARCH disorders, particularly associations of these disorders with use of drugs, and (ii) longterm effects of migraine on brain structure and health. Randomized clinical trials (RCTs) are the gold standard for proving drug efficacy. However, RCTs also leave many questions unanswered, e.g., regarding populations not studied in trials, interactions with other drugs or patient characteristics, and long-term effects of drugs beyond the typical trial duration. To bridge this knowledge gap, our group uses realworld data to study potential benefits and adverse effects of drugs on risk or prognosis of neurological disorders. Additionally, non-neurological effects of drugs that are used to treat or prevent neurological dis-orders are also investigated. The long-term goal is to provide evidence that will enhance physi-cians’ ability to individualize drug treatment for patients with neurological disorders, and, possibly, to identify hitherto unrecognized preventive effects of drugs against neurological disorders. Migraine is the most prevalent of neurological disorders. Several studies have raised concerns about potential longterm health consequences of migraine, 84

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroepidemiology David Gaist

particularly migraine with aura. Further, some studies have indicated that migraine may be linked to structural changes in the brain. Using comprehensive high-quality data collected in population-based studies, our group aims at exploring hypothe- ses on migraine aura and its purported relations to brain structure and longterm health effects.

Main current projects We believe the studies below will provide answers to questions of major clinical and public health significance. The disorders investigated in these projects afflict millions of patients worldwide. The majority of projects are based on linkage of several Danish nationwide or regional registries, and some of the studies are supplemented with additional detailed clinical data extracted from medical records and brain imaging studies. In some projects, registries are used as a source to screen and recruit subjects for participation in observational studies involving extensive testing, e.g. MRI of the brain.

• Subdural haemorrhage (SDH) epidemiology Aim: to ascertain the impact of increased use of antithrombotic drugs in more recent years on the incidence of SDH; to investigate the impact of antithrom botic drug use on risk or longterm prognosis of SDH. • Association of common drugs with intracerebral haemorrhage (ICH) Aim: To evaluate the risk of ICH associated with commonly used drugs with particular focus on concurrent use of multiple drugs (hypothesis driven analyses); further to screen for hither-to unrecognized drug-induced ICH (data driven analyses). • Use of common drugs and risk or prognosis of glioma Aim: To evaluate chemopreventive or adverse effects of common drugs on the risk of glioma and to identify the effect of commonly used drugs on glioma prognosis. This project will form the basis for a Nordic study. • Myasthenia gravis epidemiology Aim: To describe the incidence of myasthenia, explore the suggested relation ship of myasthenia to extrathymic cancer, and to describe trends in myasthenia treatment in Denmark. 85

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroepidemiology David Gaist

• Drugs used in secondary cerebrovascular prevention and risk of skin cancer Aim: To investigate whether drugs used for secondary prevention of cerebro- vascular disorders, e.g. antihypertensive drugs, and statins, influence the risk of melanoma or non-melanoma skin cancer. • Use of statins and risk of polyneuropathy: An evaluation based on pharma- coepidemiological and clinical epidemiological data Aim: To investigate whether statin use is associated with increased risk of polyneuropathy. • Register-based studies of dementia risk factors and prognosis with focus on medication use. Aim: To evaluate chemopreventive or adverse effects of common drugs on the risk of dementia and to identify the effect of commonly used drugs on dementia prognosis. • Migraine with aura and structural brain changes Aim: To investigate whether migraine with aura is related to increased burden of white matter hyperintensities, silent brain infarcts, or other structural brain changes as compared with individuals without migraine of any type.

KEY PUBLICATIONS 1. Gaist D, García-Rodríguez LA, Hellfritzsch MS, Poulsen FR, Halle B, Hallas J, Pottegård A. Association of antithrombotic drug use with subdural hematoma risk. JAMA 2017; 317: 836-46. 2. Svendsen TK, Hansen PN, García Rodríguez LA, Andersen L, Hallas J, Sindrup SH, Gaist D. Statins and polyneuropathy revisited: a case-control study in Denmark, 1999-2013. Br J Clin Pharmacol 2017 Apr 1. doi: 10.1111/bcp.13298. 3. Gaist D*, Garde E*, Blaabjerg M, Nielsen N, Krøigaard T, Østergaard K, Møller H, Hjelmborg J, Madsen CG, Iversen P, Kyvik KO, Siebner HR, Ashina M. Migraine with au-ra and risk of white matter hyperintensities and silent brain infarcts: an MRI-study. Brain 2016; 139: 2015-23. *shared first authorship 4. Pottegård A, García-Rodríguez LA, Rasmussen L, Friis S, Damkier P, Gaist D. Use of tri-cyclic antidepressants and risk of glioma: a nationwide case-control study Br J Cancer 2016; 114: 1265-8 5. Pottegård A, García-Rodríguez LA, Poulsen FR, Hallas J, Gaist D. Antithrombotic drugs and subarachnoid hemorrhage risk: a nationwide case-control study in Denmark. Thrombosis and Haemostasis 2015; 114: 1064-75 86

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroepidemiology David Gaist

6. Andersen L, Friis S, Hallas J, Ravn P, Kristensen BW, Gaist D. Hormonal contraceptive use and risk of glioma among younger women: a nationwide casecontrol study. Br J Clin Pharmacol 2015; 79: 677-84 7. Pedersen AG, Pottegård A, Hallas J, Friis S, Hansen K, Hyldgaard Jensen PE, Gaist D. Myasthenia and risk of cancer: a population-based case control study. Eur J Neurol 2014; 21: 773-8 8. Pedersen AG, Hallas J, Hansen K, Hyldgaard Jensen PE, Gaist D. Late-onset myasthenia gravis not on the increase: A nationwide register study in Denmark, 1996-2009. Eur J Neurol 2013; 20: 309-14 9. Gaist D, Andersen L, Hallas J, Sørensen HT, Schrøder HD, Friis S. Statins and risk of glioma: a nationwide case-control study in Denmark. Br J Cancer 2013; 108: 715-20 10. García-Rodríguez LA, Gaist D, Morton J, Cookson C, González-Pérez A. Anti thrombotic drugs and risk of haemorrhagic stroke in the general population. Neurology 2013; 81:566-74

KEY Danish: COLLABORATIONS Danish Headache Center, Rigshospitalet Glostrup, Copenhagen Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital, Hvidovre Danish Cancer Society Center, Danish Cancer Society, Copenhagen Department of Neurology, Rigshospitalet, Copenhagen Unit for Psychiatric Research, Department of Psychiatry, Aalborg University Hospital, Aalborg Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus Clinical Pharmacology, Department of Public Health, University of Southern Denmark The Danish Twin Registry, University of Southern Denmark Peripheral Neuropathy Group at Neurology Research Unit at SDU (Søren Sindrup’s group) Research Units at departments of Neurosurgery, Psychiatry, Pathology, Haematology, and Gynaecology at Odense University Hospital 87

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroepidemiology David Gaist

International: Spanish Centre for Pharmacoepidemiologic Research, CEIFE, Madrid, Spain Department of Biomedical Sciences, School of Medicine and Health Sciences, University of Alcalá, & Unit of Clinical Pharmacology, University Hospital “Príncipe de Asturias”, Madrid, Spain

INFRASTRUCTURE Extensive experience with design, conduct, and analyses of epidemiological and clinical epidemiological projects, surveys, and validation studies. Expertise in handling large data sets from multiple registries; in depth knowledge of key medical registries in Denmark, and; experience in utilizing electronic data capture technologies to enrich medical register data with detailed clinical information. Neuroimmunology Department of Neurology OUH, & Clinical Research, SDU 89

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroimmunology Zsolt Illes

NUMBER OF Zsolt Illes MD, PhD, DSc, Nellie A. Martin MSc, PhD student, Maria L. Elkjaer MSc, GROUP MEMBERS PhD student, Tobias Sejbaek MD, PhD student, Tobias Frisch MSc, PhD student (AND THEIR TITLE) (co-supervisor), Viktoria Papp MD, PhD student (co-supervisor), Malte Roar, mediacl student, Kirsten Hyrlov BSc student, Helle H. Nielsen MD, PhD, Morten Blaabjerg MD, PhD

DEPARTMENT & Department of Neurology, OUH. Institute of Molecular Medicine, SDU. Institute UNIVERSITY/ of Clinical Research, SDU. BRIDGE, Brain Research - Interdisciplinary Guided HOSPITAL/OTHER Excellence, SDU

FUNDING SOURCES Lundbeckfonden, Scleroseforeningen, Region Syddanmark, Odense University Hos- pital, Biogen-Idec, Merck-Serono, Sanofi-Genzyme, Direktør Ejnar Jonasson kaldet Johnsen, og Hustru’s Mindelaget, University of Southern Denmark, Jascha Fonden, Hungarian National Research Fund OTKA, Fonden for Lægevidenskabensfremme, The Foundation for the Advancement of Medical Science and Brogaards Memorial Grant, Dir. Leo Nielsens Foundation

DESCRIPTION OF 1. We use the cuprizone (CPZ) model of experimental de- and remyelination to RESEARCH examine (i) microRNA, (ii) transcriptome, (iii) and proteome/post-translational proteome of de- and remyelination in the brain. By using these databases, we found that absence of miR-146a protects against demyelination and increases microglia function. We identified homologous genes in multiple sclerosis (MS) lesions related to de- and remyelination by overlapping transcriptome of MS lesions with the CPZ transcriptomes. We quantified 130 peptides of these genes in the 97 CSF by targeted proteomics, and identified 4 proteins differentially regulated between progressive and relapsing MS: all expressed during acute remyelination and correlate negatively pro-inflammatory responses. (manu-scripts in prep) 90

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroimmunology Zsolt Illes

2. We performed next-generation RNA sequencing of 73 brain lesions of progres- sive MS that covers the different phases of lesion evolution, and 25 contols brain areas. We established the transcriptome signature of MS lesion evolution, and look for endogeneous and exogeneous viral sequences. We link these data to genome-wide DNA methylation and proteome/metabolome of the same MS lesions in order to examine epigenetic effect of viral sequences and their association with lesion evolution. We also plan to examine if these transcrip- tome signatures are differentially regulated in the CSF proteome of relapsing versus progressive MS as potential composite biomarkers predicting disease progression. 3. In our prospective ProActive study, we examined social cognition and emotion recognition in 85 MS patients and correlate data with eye motion, cognition, optical coherence tomography (OCT) and clinical outcomes. We also examine biomarkers related to axonal damage and neuroinflammation in the CSF of MS patients after a novel oral treatment in our prospective , ongoing TREMEND trial. We also used frequent MRI combined with protein array, proteomics and endothelial-microvesicle array to examine pathogenesis and biomarkers related to inflammatory blood-brain barrier disruption (manuscripts partly in prep) 4. We compared the urine proteome and metabolome of patients with neuromyelitis optica spectrum disorders (NMOSD) and MS. We examine, if pathological antibody responses are reflected by urine immunoglobulins, and can be used as diagnostic tools in suspected antibody-mediated diseases, when antibodies are not known. We compare the nationwide epidemiology of NMOSD in Denmark versus Hungary, and collect blood samples for antibody studies. 5. We examine the pathogenesis of rare neuroimmunological diseases. By using 7T MRI and brain samples, we showed that CLIPPERS is characterized by diffuse brain inflammation. Our recent proteome data of CLIPPERS CSF have been validated by brain histology and protein arrays, and identified complement activation as a major pathway and 4 biomarkers differentiating CLIPPERS from MS (manuscripts partly in prep). 91

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroimmunology Zsolt Illes

KEY PUBLICATIONS 1. Palotai M…Illes Z, Guttmann RCG (eqaully contributed). 2017. Changes to the septo-fornical area might play a role in the pathogenesis of anxiety in multiple sclerosis. Multiple Sclerosis, in press 2. Blaabjerg M, … Illes Z. 2016. Wide-spread inflammation in CLIPPERS syndrome indicated by autopsy and ultra high field 7T MRI. Neurology: Neuroimmunol Neuroinflam, 3:e226. 3. Herwerth M, … Illes Z, … Hemmer B. 2016. In vivo imaging of axon damage in a model of neuromyelitis optica-related pathology. Ann Neurol, Mar 6. doi: 10.1002/ana.24630. 4. Zeka B, …Illes Z, … Bradl M. 2015. Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS. Acta Neuropathol. 130:783. 5. Nielsen HH, …Illes Z. 2015. The urine proteome profile is different in neuromyelitis optica compared to MS. PLoS One. PLoS One. 2015;10:e0139659. 6. Massilamany C, … Illes Z, Reddy J. 2014. SJL mice infected with Acanthamoeba castellanii develop central nervous system autoimmunity through the generation of cross-reactive T cells for myelin antigens. PLoS One. 9:e98506. 7. Mike A, … Illes Z. 2013. Disconnection mechanism and regional cortical atrophy contribute to impaired processing of facial expressions in multiple sclerosis: a structural MRI study. PLoS One. 8:e8242 8. Kalluri SR, Illes Z, … Hemmer B. 2010. A novel bioassay to quantify and functionally characterise antibod-ies to native aquaporin-4 in neuromyelitis optica. Arch Neurol. 67:1201. 9. Veto S, … Illes Z. 2010. Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendro-cyte death. Brain. 133:822 10. Banati M, … Illes Z. 2010. Social cognition and Theory of Mind in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 17:426.

Submitted: 11. Blaabjerg M…Illes Z. 2017. Omics-based approach reveals complement- mediated inflammation in CLIPPERS (submitted to Ann Neurol) 12. Martin NA…Illes Z. 2017. MicroRNA-146a deficiency protects against cuprizone-induced demyelination (submitted to J Neurosci) 13. Nielsen HH…Illes Z. 2017. Integrin and IL-16/Th17 biomarker cluster differentiate AQP4-IgG+ NMO spectrum disorders, relapsing-remitting MS and healthy controls (submitted to Mult Scler) 14. Martin NA…Illes Z. 2017. Translational mult-omics identifies biomarkers related to acute remyelination in the CSF of multiple sclerosis patients (submitted toBrain) 92

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neuroimmunology Zsolt Illes

Submitted patents: 1. Gallyas F…Illes Z. 2009. Combination of a PARP inhibitor and an AKT kinase activating compound. NSZO: A61K 45/06, PCT/HU2009/000055 esp@cenet link; Submitted: 2008, Hungary (NoP0800414); Public:2009 2. Powers R…Illes Z. Biomarkers used to detect and monitor neurological autoim- mune diseases. 2014. Pub. No.: US 2014/0045197 Al. Pub. Date: Feb. 13,2014. 3. Lambertsen KL, Clausen BH, Finsen B, Nielsen HH, Finsen B (equal contributors) (2015) Fumaric acid derivatives for medical use. Patent No: WO2016074684 A1, PCT/DK2015/050344

KEY Danish: COLLABORATIONS Finn Sellebjerg (CU), Thor Petersen (AU), Peter Garred (CU), Allan Stensballe (AAU), Torben Kruse (SDU), Mads Thomassen (SDU), Jan Baumbach (SDU), Martin R. Lars- en (SDU), Trevor Owens (SDU), Asa Fex-Svenningsen (SDU)

International: Charles Guttmann (Harvard Medical School), Richard Reynolds (Imperial College, UK), Bernhard Hemmer (Technische Universitat, Munich), Hans Lassmann (Medical University of Vienna), Friedemann Paul (Charite, Berlin), Jacqueline Palace (Oxford University), Francois Cotton and Romain Marignier (University Lyon)

INFRASTRUCTURE Cuprizone and EAE model of MS, Mesoscale array (neurofilament, inflammation), microglia-related in vitro assays, cellular immunology, working with KO and trans- genic mice, RNA sequencing, real-time PCR, apoptosis, cognition, clinical trials Neurosurgical Research Group OUH & Department of Clinical research, SDU 94

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neurosurgical research Group Frantz Rom Poulsen

NUMBER OF 5 MD, PhD’s including one professor and 2 associate professors GROUP MEMBERS (AND THEIR TITLE) DEPARTMENT & Department of Neurosurgery, Odense University Hospital and University UNIVERSITY/ of Southern Denmark HOSPITAL/OTHER

FUNDING SOURCES External funds, Region Syddanmark, Odense University Hospital

DESCRIPTION OF • Neurosurgical oncology: improving surgical techniques (intraoperative RESEARCH fluorescense and MR), studies on brain cancer tumor heterogenicity including identification of new molecular markers as potential targets for treatment and as possible predictors of tumor recurrence. • Head trauma: risk factors for developing subdural hematomas, optimizing treatment of chronic subdural hematomas, participant in CenterTBI (a multicentre study on traumatic brain injury) • Vascular: Outcome after aneurism surgery or endovascular treatment. Predictors of aneurism rupture • Cerebral metabolism and mitochondrial dysfunction under pathological conditions (subarachnoidal hemorhage, severe bacterial meningitis) • Spine: conservative management of cervical spine fractures, classification and outcome

KEY PUBLICATIONS 1. Gaist D, García Rodríguez LA, Hellfritzsch M, Poulsen FR, Halle B, Hallas J, Pottegård A. Association of Antithrombotic Drug Use With Subdural Hematoma Risk. JAMA. 2017 Feb 28;317(8):836-846. doi: 10.1001/jama.2017.0639. 2. Munthe S, Halle B, Boldt HB, Christiansen H, Schmidt S, Kaimal V, Xu J, Zabludoff S, Mollenhauer J, Poulsen FR, Kristensen BW. Shift of microRNA profile upon glioma cell migration using patient-derived spheroids and serum-free conditions. J Neurooncol. 2017 Mar;132(1):45-54. 95

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neurosurgical research group Frantz Rom Poulsen

3. Larsen L, Poulsen FR, Nielsen TH, Nordström CH, Schulz MK, Andersen ÅB. Use of intracranial pressure monitoring in bacterial meningitis: a 10-year follow up on outcome and intracranial pressure versus head CT scans. Infect Dis (Lond). 2017 May;49(5):356-364. 4. Poulsen FR, Schulz M, Jacobsen A, Andersen ÅB, Larsen L, Schalén W, Nielsen TH, Nordström C-H: Bedside evaluation of cerebral energy metabolism in severe community-acquired bacterial meningitis. Neurocrit Care. 2014 Aug 21 5. Poulsen FR, Halle B, Pottegård A, García Rodríguez LA, Hallas J, Gaist D. Subdural hematoma cases identified through a Danish patient register: diagnosis validity, clinical characteristics, and preadmission antithrombotic drug use. Pharmacoepidemiol Drug Saf. 2016 Nov;25(11):1253-1262. 6. Munthe S, Sørensen MD, Thomassen M, Burton M, Kruse TA, Lathia JD, Poulsen FR, Kristensen BW. Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting. J Neu-rooncol. 2016 Oct;130(1):53-62. 7. Andersen-Ranberg NC, Poulsen FR, Bergholt B, Hundsholt T, Fugleholm K. Bilateral chronic subdural hematoma: unilateral or bilateral drainage? J Neurosurg. 2016 Jul 8:1-7. 8. Thisgaard H, Halle B, Aaberg-Jessen C, Olsen BB, Therkelsen AS, Dam JH, Langkjær N, Munthe S, Någren K, Høilund-Carlsen PF, Kristensen BW. Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xeno graft Model using Convection-Enhanced Delivery.Theranostics. 2016 Sep 29;6(12):2278-2291 9. Halle B, Marcusson EG, Aaberg-Jessen C, Jensen SS, Meyer M, Schulz MK, Andersen C, Kristensen BW. Convection-enhanced delivery of an anti-miR is well-tolerated, preserves anti-miR stability and cau-ses efficient target derepression: a proof of concept. J Neurooncol. 2016 Jan;126(1):47-55 10. Mölström S, Nielsen TH, Andersen C, Nordström CH, Toft P. Bedside Monitoring of Cerebral Energy State During Cardiac Surgery-A Novel Approach Utilizing Intravenous Microdialysis. J Cardiothorac Vasc Ane-sth. 2016 Nov 2 11 .Jacobsen A, Nielsen TH, Nilsson O, Schalén W, Nordström CH. Bedside diagnosis of mitochondrial dys-function in aneurysmal subarachnoid hemorrhage. Acta Neurol Scand. 2014 Sep;130(3):156-63 12. Thuesen AD, Lyngsø KS, Rasmussen L, Stubbe J, Skøtt O, Poulsen FR, Pedersen CB, Rasmussen LM, Hansen PB. P/Q-type and T-type voltage-gated calcium channels are involved in the contraction of mam-mary and brain blood vessels from hypertensive patients. Acta Physiol (Oxf). 2017 Mar;219(3):640-651. 96

GROUPGROUP NAME: NAME UCAR GROUP LEADER Neurosurgical research group Frantz Rom Poulsen

13. Munthe S, Petterson SA, Dahlrot RH, Poulsen FR, Hansen S, Kristensen BW. Glioma Cells in the Tumor Periphery Have a Stem Cell Phenotype. PLoS One. 2016 May 12;11(5) 14. Dahlrot RH, Poulsen FR, Nguyen NN, Kristensen BW, Hansen S, Holm NV; Academy of Geriatric Cancer Research Trends in tumors in the central nervous system in elderly in Denmark, 2008-2012. (AgeCare) Acta Oncol. 2016;55 Suppl 1:91-7. 15. Poulsen FR, Munthe S, Søe M, Halle B: Perindopril and residual chronic subdural hematoma volume six weeks after burr hole surgery: A randomized trial. Clin Neurol and Neurosurg. 123 (2014) 4-8

KEY Danish: COLLABORATIONS Departments of Neuropathology, Neurology, Infectious Medicine, Nuclear Medicine, Radiology, Oncology, Biochemistry and Genetics at Odense University Hospital. Departments of Neurosurgery, Aalborg, Aarhus and Copenhagen. Basic research groups at University of Southern Denmark

International: Department of Neurosurgery, Regensburg, Germany

INFRASTRUCTURE We are specialists in Neurosurgery and we have the possibility to use intraoperative low field MR and intraoperative fluorescense. We have close collaborations with many medical specialities (see above) and their location in the immediate vicinity makes clinical and paraclinical studies more feasible. This includes proteome and genome analysis of freshly harvested tumor samples Owens group Department of Neurobiology Research, Department of Molecular Medicine, SDU 98

GROUPGROUP NAME: NAME UCAR GROUP LEADER Owens Group Trevor Owens

NUMBER OF 1 assoc prof/ATAP, 1 clinical assoc prof. 2 postdocs. 4 PhD students, 2 masters GROUP MEMBERS students, 2 technicians, 3 project students (number varies) (AND THEIR TITLE)

DEPARTMENT & Neurobiology, IMM, SDU UNIVERSITY/ HOSPITAL/OTHER

FUNDING SOURCES Scleroseforeningen, Lundbeckfonden, FSS, NovoNordiskFonden, RegionSyddanmark, ECTRIMS

DESCRIPTION OF Innate regulation of neuroinflammation RESEARCH We study CNS-endogenous mechanisms for regulation of inflammation, using EAE in mice as an MS-relevant model. We find that innate signaling receptors normally considered to operate in context of infection or tissue damage, induce production of anti-inflammatory cytokines, particularly Type I interferons and interleukin-10. Experimental ligation of these receptors can suppress EAE. Our research leads to questions about the myeloid cells that initiate these responses, including microglia, their location in the CNS and their migration to and interaction with elements of the immune response.

Antibody-mediated pathology in CNS Autoantibodies are speculated to contribute to demyelinating pathology in MS and are known to mediate astrocytopathology in the related disease Neuromy- elitis Optica (NMO). We have published adoptive transfer models for NMO using patient-derived IgG and we recently developed stereotactic models for focal white matter demyelination. Antibody+complement-mediated pathologies are depen- dent on Type I IFN, which is nevertheless beneficial for MS. We are investigating the differential effect of IFN signaling (both Type I and II) on antibody+complement versus cellular cytotoxic mechanisms of demyelination, as well as the role of innately-triggered IL-10 in alleviating NMO-like pathology. 99

GROUPGROUP NAME: NAME UCAR GROUP LEADER Owens group Trevor Owens

Microglial subsets in developing and adult CNS Microglia are CNS-resident myeloid cells, equivalent to tissue macrophages. We study their heterogeneity and their role in regulation of inflammation as well as in development. Transcriptomic analysis shows that neonatal microglia are distinct from adult, and a subset that express the integrin complement receptor CD11c are particularly important for primary myelination as well as regulation of EAE. Cells with a distinct phenotype corresponding to microglial precursors are located in the placenta and we study whether they may be responsible for pregnancy-associated remission from MS.

KEY PUBLICATIONS 1. Remington, L.T., Babcock, A.A., Zehntner, S.P., and Owens, T. 2007. Microglial Recruitment, Activation and Proliferation in Response to Primary Demyelination. Am. J. Pathol. 170:1713-1724. 2. Millward, J. M., M. Caruso, I. L. Campbell, J. Gauldie, and T. Owens. 2007. IFN-{gamma}-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Cen-tral Nervous System. J Immunol 178:8175-8182. 3. Babcock, A.A., Toft-Hansen, H. and Owens, T. 2008. Signaling Through MyD88 Regulates Leu-kocyte Recruitment After Brain Injury. J. Immunol. 181: 6481-6490. 4. Füchtbauer, L, Toft-Hansen, H., Khorooshi, R., and Owens T. 2010. Expression of astrocytic type 2 angiotensin receptor in CNS inflammation correlates with blood-brain barrier break-down. J. Mol. Neurosci. 42:89-98. 5. Khorooshi, R. and Owens, T. 2010. Injury-induced type I interferon signaling regulates inflam-matory responses in the CNS. J. Immunol. 185: 1258-1264. 6. Millward, J.M., Løbner, M., Wheeler, R.D. and Owens, T. 2010. Inflammation in the central ner-vous system and Th17 responses are inhibited by interferon-gamma-induced interleukin-18 binding protein. J. Immunol. 185:2458-2466. 7. Toft-Hansen, H., Füchtbauer, LM, and Owens, T. 2011. Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease. Glia 59:166-176. 8. Salem, M., J. T. Mony, M. Løbner, R. Khorooshi, and T. Owens. 2011. Interferon regulatory fac-tor-7 modulates inflammatory responses in experimental auto immune encephalomyelitis in mice. J. Neuroinflamm. 8:181-189. 100

GROUPGROUP NAME: NAME UCAR GROUP LEADER Owens group Trevor Owens

9. Holm, TH, D. Draeby, and T. Owens. 2012. Microglia are required for astroglial Toll-like recep-tor 4 response, and for optimal Toll-like receptor 2 and 3 response. Glia 60:630-638. 10. Reinert, L. S., Harder, L., C.K., H., Iversen, M. B., Horan, K. A., Dagnæs-Hansen, F., Ulhøi, B. P., Holm, T. H., Mogensen, T. H., Owens, T., Nyengaard, J. R., Thomsen, A. R. & Palu-dan, S. R. 2012. TLR3-deficiency renders astrocytes permissive to HSV infection and fa-cilitates establishment of CNS infection in mice. Journal of Clinical Investigation 122:1368-76. 11. Asgari, N., R. Khorooshi, S. Lillevang, & T. Owens. 2013. Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. J. Neuroimmunol. 254:76-82. 12. Khorooshi, R., A. Wlodarczyk, N. Asgari, & T. Owens. 2013. Neuromyelitis optica-like patholo-gy is dependent on type I interferon response. Exp Neurol 247: 744-747. 13. Mony JT, Khorooshi R, Owens T. 2014. Chemokine receptor expression by inflammatory T cells in EAE. Front Cell Neurosci. 8:187. IF 4,18 14. Cédile, O, Løbner, M, Toft-Hansen, H, Frank, I, Wlodarczyk, A, Irla, M, & Owens, T. 2014 Thymic CCL2 influences induction of T-cell tolerance. J Autoimmun 55:73-85. IF 7,02 15. Khorooshi, R., Mørch, M, Berg, CT, Holm, TH, Dieu, RT, Dræby, D, Issazadeh- Navikas, S, Weiss, S, Lienenklaus, S and Owens, T. 2015. Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune en-cephalomyelitis. Acta Neuropathologica, 130:107-118. 16. Wlodarczyk, A, Cédile, O, Jensen, KN, Jasson, A, Mony, JT, Khorooshi, R, and Owens, T. 2015. Pathologic and protective roles for microglial subsets and bone marrow- and blood-derived myeloid cells in central nervous system inflammation. Frontiers in Immunology 6:463 doi: 10.3389/fimmu.2015.00463

Submitted papers 1. Wlodarczyk A, Holtman IR, Krueger M, Yogev N, Bruttger J, Khorooshi, R, Benmamar-Badel, A, de Boer-Bergsma JJ,, Martin,NA, Karram K, Kramer, I, Boddeke EWGM, Waisman A, Eggen BJL and Owens T.. A novel microglial subset plays a key role in myelinogenesis in developing brain 2. Cédile, O, Wlodarczyk, A, and Owens T. CCL2 recruits T cells into the brain in a CCR2-independent manner 101

GROUPGROUP NAME: NAME UCAR GROUP LEADER Owens group Trevor Owens

3. Cédile, O, Østerby Jørgensen, L, Frank, I, Wlodarczyk, A and Owens, T. The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis 4. Berg, CT, Khorooshi R, Asgari N, Owens, T. Influence of Type I IFN signalling on anti-MOG-mediated demyelination.

KEY Danish: COLLABORATIONS Søren Paludan, Aarhus University (AU) – interferon induced genes in CNS Lisbeth Laursen, AU – antibody+complement-mediated oligodendrocyte pathology and effects of IFN signaling Ulrike Muscha Steckelings, SDU – Angiotensin II Type 2 receptor in regulation of neuroinflammation Bente Finsen (SDU), Anders Nykjær and Simon Glerup Pedersen (AU) – microglia in regulation of synaptopathies in developing and adult brain

International: Bart Eggen, UMC Groningen, Netherlands – transcriptomic analysis of mouse microglia Ari Waisman, Mainz, Germany – depletion and repopulation of microglial subsets in mouse brain Gill Webster, Auckland, New Zealand – innate triggers for tolerogenic myeloid cells in CNS Martin Krueger, Leipzig University, Germany – myelin pathology in developing brain Peripheral Neuropathy Department of Neurology, OUH & Department of Clinical Research, SDU 103

GROUPGROUP NAME: NAME UCAR GROUP LEADER Peripheral Neuropathy Søren Hein Sindrup

NUMBER OF Søren Sindrup, Dr Med Sci, Professor, Jakob Holbech, PhD, Ass. Professor, Thomas GROUP MEMBERS Krøigård, PhD student, Mimmi Forsberg-Gilving, PhD stud. Mustapha Itani, PhD (AND THEIR TITLE) student, Thomas Gaist, medical student, Laura Brok-Lauridsen, medical stud.

DEPARTMENT & Department of Neurology and Neurology Research Unit UNIVERSITY/ Odense University and University of Southern Denmark HOSPITAL/OTHER

FUNDING SOURCES Hospital research funds, Danish Cancer Society (KB), EU Innovative Medicines Initiative (IMI), Novo Nordisk Challenge Fund, Regionernes Medicinpulje, Danish Movement Disorder Society (DANMODIS), Novo Nordisk Foundation scolarstipendium, Lundbeck Foundation scolarstipendium in neurology, Danish Immune Neuropathy Group, drug companies.

DESCRIPTION OF Peripheral neuropathy RESEARCH The research focuses on diseases or lesions of the peripheral somatic and autonomic nervous system. A. Diagnosis and etiology A research database on patients evaluated for suspected polyneuropathy has been established and has included patients since january 2016. Data from this database will evaluate the role of different diagnostic procedures such as nerve conduction, and nerve fibre density in skin biopsies and on the cornea by in-vivo confocal microscopy. The pattern of peripheral nerve affection will be compared between different etiologies of polyneuropathy. The data from the database will also be used to develop procedures to reduce the number of patients in which the etiology of polyneuropathy cannot be determined. Further, the purpose of the database is also to establish a cohort of well characterised patients which can be re-evaluated later. A large cross-sectotional study on polyneuropathy in patients with type 2 diabetes is being performed in order to determine pathophysiological 104

GROUPGROUP NAME: NAME UCAR GROUP LEADER Peripheral Neuropathy Søren Hein Sindrup

mechanisms and risk factors. In collaboration with researchers at the Danish Pain Research Center in Aarhus we will examine in total 600 patients with type 2 diabetes and 100 healthy controls. Other clinical studies focus on development of peripheral neuropathy due to treatment with oxaliplatin (chemotherapy), statins (cholesterol lowering drugs), and other drugs. We are also studying patients with newly diagnosed Parkinson’s disease to test if there is peripheral nerve affection in relation to this neurodegenerative disease and if peripheral nerves may be involved in the patogenesis of the disease via synuclein deposits in relation to peripheral nerve structures. B. Pharmacological treatment of peripheral neuropathic pain Pharmacological treatment of peripheral neuropathic pain has for many years been an important area for the research group and we have performed numerous controlled clinical trials to improve treatment outcome and to search for relations between drug actions and mechanisms of pain. In the EuroPain collaboration (EU Innovative Medicines Innitiative) we contributed a large study clinical trial using patient stratification by pain phenotype as determined by an extensive quantitative sensory testing protocol. We were able to demontrate that the effect of a sodium channel blocking drug depended on pain phenotype. This study is recoqnized as the first step towards mechanism-based treatment of peripheral neuropathic pain, which has for decades been a goal within this area. Present clinical studies are looking further into the mechanism-based pain treatment and are testing drugs targeting other potential pain mechanisms than the currently used drugs. C. Treatment of immune mediated peripheral neuropathies. The first choice treatment for immune mediated peripheral neuropathies is immunoglobulins given intravenously or subcutaneously. We have been engaged in a number of clinical trials headed by the Danish Immune Neuro- pathy Group on the initiative of group members from the Neurology Department at Aarhus University Hospital. Further studies have been planned by this research collaboration. Our group has developped a new method to test physical function in patients with immune neuropathies and we plan to perform a study with a drug with a mechanism of action completely different from the supposed mechanism of action of immunoglobulins. 105

GROUPGROUP NAME: NAME UCAR GROUP LEADER Peripheral Neuropathy Søren Hein Sindrup

D. Guillain Barré Syndrome During the past 5 years we have participated in the International Guillain Barré syndrome outcome study (IGOS). We have at our research unit contributed more than 50 patients to the database and more than 100 Danish patients have been enrolled. Researchers from both Aarhus and our group plan to do studies based on data from the international database which currently comprise more than 1500 patients.

KEY PUBLICATIONS 1. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain 2010;150:573-81. 2. Demant DT, Lund K, Vollert J, Maier C, Segerdahl M, Finnerup NB, Jensen TS, Sindrup SH. The effect of oxcarbazepine in peripheral neuropathic pain depends on pain pheno-type. A randomized, double-blind, placebo-controlled and phenotype-stratified study. Pain 2014; 155:2263-2273. 3. Krøigård T, Schrøder HD, Qvortrup C, Eckhoff L, Pfeiffer P, Gaist D, Sindrup SH. Char-acterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduc-tion studies. Eur J Neurol. 2014;21:623-9 4. Holbech JV, Bach FW, Finnerup NB, Brøsen K, Jensen TS, Sindrup SH. Imipramine and Pregabalin Combination for Painful Polyneuropathy. A Randomized Controlled Trial. Pain. 2015;156:958-66 5. Holbech JV, Bach FW, Finnerup NB, Jensen TS, Sindrup SH. Pain phenotype as a predictor for drug response in painful polyneuropathy A retrospective analysis of data from controlled clinical trials. Pain 2016;157:1305-13 6. Markvardsen LH, Sindrup SH, Christiansen I, Olsen NK, Jakobsen J, Andersen H; Danish CIDP and MMN Study Group. Subcutaneous immunoglobulin as firstline therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: ran-domized controlled trial study. Eur J Neurol. 2017;24:412-418 7. Sindrup SH, Holbech JV, Bach FW, Finnerup NB, Brøsen K, Jensen TS. The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin and their Combina-tion in Painful Polyneuropathy. Clin J Pain. 2017 Mar 7. doi: 10.1097/AJP.0000000000000497. 106

GROUPGROUP NAME: NAME UCAR GROUP LEADER Peripheral Neuropathy Søren Hein Sindrup

KEY Danish: COLLABORATIONS Danish Pain Research Center, Aarhus University Danish Immune Neuropathy Group (neurology departments at university hospitals in Denmark) Neuroepidemiology Group at Neurology Research Unit at SDU (David Gaist’s group) Neuropathology and Oncology Research Units at SDU.

International: EuroPain Collaboration on Chronic Pain (researchers from UK, Germany, Spain and Denmark. Funded by EU Innovative Medicines Innitiative) International Diabetic Neuropathy Consortium (researchers from UK, US, and Denmark. Funded by Novo Challenge Fund). International Guillain Barré Study Group (world wide research collaboration).

INFRASTRUCTURE Clinical research, controlled clinical drug trials, clinical evaluation of physical function in relation to peripheral nerve diseases, peripheral nerve conduction (NC), quantitative sensory testing (QST), confocal microscopy of cornea (CCM) for determination of nerve fibre density and length, skin biopsy for determination of intra-epidermal nerve fibre density (IENFD), treshold tracking in peripheral nerves to evaluate ion channel function, testing of the autonomous nervous system (sweat secretion with QSweat, heart rate variablity on deep breathing, valsalva, and tilt table procedure with TestWorks). T-Pemf and parkinsonism group Department of Neurology OUH & Department of clinical Research, SDU 108

GROUP NAME GROUP LEADER GROUP NAME: UCAR Lene Wermuth, Bente R Jensen, T-Pemf and parkinsonism Group Ole Gredal & Per Back

NUMBER OF Lene Wermuth, MD, Consultant, Ass. Prof. Bente R Jensen, Phd, Professor, GROUP MEMBERS Ole Gredal, MD, Consultant, Per Bech, MD, Professor, Bo M Morberg, MD, Phd. (AND THEIR TITLE) student, Anne Sofie B Malling, M.Sc. Phd student

DEPARTMENT & Department of Neurology, Odense University Hospital, University of Southern UNIVERSITY/ Denmark, Odense, Denmark HOSPITAL/OTHER

FUNDING SOURCES Den A.P. Møllerske Støttefond Grosserer, L.F Foghts foundation, Jascha foundation, Odense University Hospital, University of Southern Denmark

DESCRIPTION OF Parkinsonism (PD) is a common progressive neurodegenerative disorder charac- RESEARCH terized by tremor, bradykinesia, rigidity and postural instability. Treatment with bi- polar pulsed electromagnetic (PEMF) stimulations is a non-invasive rapidly emerg- ing method. The PEMF technique has been successfully applied to stimulate nerve growth and attenuate nerve abnormalities. Application of the technique seems to enhance cellular activity and stimulate growth related responses and regeneration. Project part 1: The Effects of Transcranial Pulsed Electromagnetic Field stimu- lation on disease severity, non-motor symptoms, motor function and quality of life in Parkinson’s Disease. Project part 2: Effects of longterm treatment with bipolar pulsed electromagnetic stimula-tion on disease severity, cerebrospinal fluid growth factors, tremor, muscle activation and brain glucose metabolism in persons with Parkinsonism

KEY PUBLICATIONS 1. Wermuth L, Bech S, Skaalum M, Joensen P, Weihe P, Grandjean P. The ep idemiology of Parkinson’s disesase in the Faroe Islands. Acta Neurol Scand 2008;118(2):126-31. 2. Petersen MS, Halling J, Bech S, Wermuth L, Weihe P, Nielsen F, Jørgensen PJ, Budtz-Jørgensen E, Grandjean P. Impact of dietary exposure to food contaminants on the risk of Parkinson’s disease. NeuroTox. 2008;29:584-590. 109

GROUP NAME GROUP LEADER GROUP NAME: UCAR Lene Wermuth, Bente R Jensen, T-Pemf and parkinsonism group Ole Gredal & Per Back

3. Manthripragada AD, Schernhammer E, Qiu J, Friis S, Wermuth L, Olsen JH, Ritz B.Non-steroidal Anti-inflammatory Drug use and the risk of Parkinson’s Disease. Neuroepidemiology 2011; 36: 155-61. 4. Schernhammer E, Hansen J, Rugbjerg K, Wermuth L, Ritz B. Diabetes and the risk of developingParkinson’s Disease in Denmark. Diabetes Care 2011; 34: 1102-8. 5. Ritz B, Manthripragada AD, Qian L, Schernhammer E, Wermuth L, Olsen J, Friis S. Statin Use and Parkinson’s Disease in Denmark. Movement Disorders 2010;25(9):1210-1216. 6. Martiny K, Lunde M, Bech P. Transcranial Low Voltage Pulsed Electromagnetic Fields in Patients with Treatment-Resistant Depression. Biol Psychiatry 2010;68(2):163-9 7. Rose MH, Lokkegaard A, Sonne-Holm S, Jensen BR. Isometric Tremor Irregularity, Torque Steadiness and Rate of Force Devel-opment in Parkinson’s Disease. Motor Control 2012. 8. Nielsen HH, Qiu J, Friis S, Wermuth L, Ritz B. Treatment for Helicobacter pylori infection and risk of Parkinson’s disease in Denmark. European J of Neurol. 2012 19(6):864-9. 9. Wermuth L, Lassen CF, Himmerslev L, Olsen J, Ritz B. Validation of hospital register-based diagnosis of Parkinson’s disease. Dan Med J 2012;59(3);A4391 Resume af originalartikel i Ugeskrift for læger 2012;174:641 10. Rose MH, Lokkegaard A, Sonne-Holm S, Jensen BR. Tremor irregularity, torque steadiness and rate of force development in Parkinson’s disease. Motor Control 2013; 17:203-216. 11. Rose MH, Lokkegaard A, Sonne-Holm S, Jensen BR. Effects of training and weight support on muscle activation in Parkinson’s disease. J Electromyogr Kinesiol 2013; 23:1499-1504. 12. Rose MH, Lokkegaard A, Sonne-Holm S, Jensen BR. Improved clinical status, quality of life, and walking capacity in Parkin-son’s disease after body weight-supported high-intensity locomotor training. Arch Phys Med Rehabil 2013; 94:687-692. 13. Schernhammer E, Qiu J, Wermuth L, Lassen CF, Friis S, Ritz B. Gout and the risk of Parkinson’sdisease in Denmark. Eur J Epidemiol 2013;28:359-60 14. Nielsen M, Hansen J, Ritz B, Nordahl H, Schernhammer E, Wermuth L, Hulvej Rod N. Cause-Specific Mortality Among Spouses of Parkinson Disease Patients. Epidemiology 2014;25(2):225-32. 110

GROUP NAME GROUP LEADER GROUP NAME: UCAR Lene Wermuth, Bente R Jensen, T-Pemf and parkinsonism group Ole Gredal & Per Back

15. Morberg M.B, Jensen J, Bode M, Wermuth L. The impact of high intensity physical training on motor and non-motor symptoms in patients with Parkinson’s disease(PIP): A preliminar study. Neurorehabilisation 35(2014)291-298. 16. Straasø B, Lauritzen L, Lunde M, Vinberg M, Lindberg L, Larsen ER, Dissing S, Bech P. Dose-remission of Pulsating Electro-Magnetic Fields as augmentation in therapy-resistant depression. A randomized, double-blind controlled study. Acta Neuropsy-chiatrica 2014;5:272-279 17. Kroigaard T, Christensen J, Wermuth L, Ritz B, Lassen CF. The use of antide pressant medication in Parkinson’s disease patients is not affected by the type of antiparkinson medication. J Parkinson’s Dis.2014;4(3):327-30. 18. Kenborg L, Lassen CF, Ritz B, Andersen KK, Christensen J, Schernhammer ES, Hansen J, Wermuth L, Rod NH, Olsen JH. Lifestyle, family history, and risk of idiopathic Parkinson’s disease: a large Danish case-control study. Am J Epidmi ol. 2015 May 15;181(10):808-16. 19. Wermuth L. Demens – nu og i fremtiden. Ugeskr Laeger. 2015 May 25;177(22):V67001. 20. Bech P, Lindberg L, Straasø B, Larsen ER. A two-year follow-up study of patients participating in our transcranial pulsating electromagnetic fields (T-PEMF) augmentation in treatment-resistant depresssion. Acta Neuropsychiatrica 2015; 2:119-125. DOI: 10.1017/neu.2014.44 21. Malling AS, Jensen BR. Motor intensive anti-gravity training improves performance in dynamic balance related tasks in persons with Parkinson’s disease. Gait Posture 2016; 43:141-147. 22. Hoffmann K, Sobol NA, Frederiksen KS, Beyer N, Vogel A, Vestergaard K, Brændgaard H, Gottrup H, Lolk A, Wermuth L, Jacobsen S, Laugesen LP, Gerge lyffy RG, Høgh P, Bjerregaard E, Andersen BB, Siersma V, Johannsen P, Cotman CW, Waldemar G, Hasselbalch SG. Moderate-to-High Intensity Physical Exercise in Patients with Alzheimer’s Disease: A Randomised Controlled Trial. Journal of Alzheimers Disease. 50(2016)443-453. 23. Wermuth L, Cui X, Greene N, Schernhammer E, Ritz B. Medical Record Review to Differentiate between Idiopathic Parkinsons’s Disease (IPD) and Parkinsonism: A Danish Record Linkage Study with 10 Years of Follow-up. Parkinson’s Disease 2015; Article ID 781479, 9 pages. 111

GROUP NAME GROUP LEADER GROUP NAME: UCAR Lene Wermuth, Bente R Jensen, T-Pemf and parkinsonism group Ole Gredal & Per Back

24. Sobol NA, Hoffmann K, Frederiksen KS, Vogel A, Vestergaard K, Brændgaard H, Gottrup H, Lolk A, Wermuth L, Jacobsen S, Laugesen L, Gergelyffy R, Høgh P, Bjerregaard E, Siersma V, Andersen BB, Johannsen P, Waldemar G, Hasselbalch SG, Beyer N. Effect of aerobic exercise on physical performance in patients with Alzheimer’s disease. Alzheimers Dement. 2016;12(12):1207-1215. 25. Jensen CS, Portelius E, Siersma V, Høgh P, Wermuth L, Blennow K, Zetterberg H, Waldemar G, Hasselbalch SG, Simonsen AH. Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Modorate- to High-Intensity Psysical Exercise in Patients with AlzheimerDisease. Dementia and Geriatr Cogn Disord 2016;42:146-158. 26. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth L. Parkinson’s disease and transcranial pulsed electromagnetic fields: A randomized clinical trial. Movement Disorders 2017 ,32(4):625-626. doi: 10.1002/mds.26927J 27. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth L. The effects of transcranial pulsed electromagnetic fields in the treatment of Parkinson’s disease. 2nd. International Brain Stimulation Conference, Spain 2017 (abstract) 28. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth . Treatment of Parkinson’s disease with pulsed elec-tromagnetic fields; a randomized clinical trial. The 13th International Conference on Alzheimer’s & Parkinson’s, Vien 2017 (abstract) 29. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth . Treatment with transcranial pulsed electromagnetic fields (T-PEMF) alters power distri bution og resting hand tremor frequencies in Parkinson’s disease. The 13th International Con-ference on Alzheimer’s & Parkinson’s, Vien 2017 (abstract) 30. Morberg BM, Malling AS, Jensen BR, Gredal O, Bech P, Wermuth . Associations between measured motor function and UPDRS motor score. The 13th International 114.Conference on Alzheimer’s & Parkinson’s, Vien 2017 (abstract) 31. Malling ASB., Morberg, BM, Wermuth, L, Gredal, O. Bech, P, Jensen, BR. Treatment with transcranial pulsed electromagnetic fields enhanges functional rate of force development during chair rise in persons with Parkinson disease. 2nd. International Brain Stimulation Conference, S pain 2017 (abstract) 112

GROUP NAME GROUP LEADER GROUP NAME: UCAR Lene Wermuth, Bente R Jensen, T-Pemf and parkinsonism group Ole Gredal & Per Back

KEY Danish: COLLABORATIONS Assoc. Prof. Morten Meyer, Neurobiologisk forskning, SDU. Professor Poul Flemming Høilund Carlsen, Nuclear Med. Afd, OUH.

International: Prof. Madeleine M. Lowery and Matt W Flood, School of electrical & electronic Engineering, University college Dublin, Ireland. Equipment/expertise within: transcranial pulsed electromagnetic stimulation. Electromyography/analysis, tremor measurements and analysis, force measurements and analysis. PET/CT. Biomarkers

INFRASTRUCTURE Equipment/expertise within: transcranial pulsed electromagnetic stimulation. Elec- tromyography/analysis, tremor measurements and analysis, force measurements and analysis.PET/CT. Biomarkers TRANSIC Department of Nuclear Medicine, OUH & Department of Clinical Research, SDU 114

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

NUMBER OF 12 Profs. (AG, BF, TO, ZI, FRP, TM, HBN, HM, TK, BWK, KB, PFHC) covering in one GROUP MEMBERS place: Pharmacy, Physiology, Molecular Medicine, Neurology, Neurosurgery, (AND THEIR TITLE) Psychiatry, Pathology, Nuclear Medicine, Molecular Imaging, PET/CT and PET/MRI, Medical Physics, Clinical Physiolgy and Nuclear Medicine, 3 Assoc. Profs. (KL, MSV, PB) covering Molecular Medicine, PET/CT and MRI, Biomed Lab (animal experiments), 1 PhD student + expected 9, 1 PostDoc + expected 3, 2 Cell biologists, 3 Hospital Physicists, 3 Radiochemists, 1 Biostatistician, 6 Undergraduate students, 1 Small animal technician, 2-4 Medical doctors International Associates: Please see below

DEPARTMENT & Translational research center under establishment, hosted by the Dept. of Nuclear UNIVERSITY/ Medicine, OUH. HOSPITAL/OTHER Close collaboration with 6 OUH departments: Neurology (Dementia Clinic included), Neurosurgery, Oncology, Occupational Medicine, Psychiatry, Pathology. Existing or planned collaborations with another 6 OUH departments: Anaesthe- sia, Endocrinology, Cardiology, Clinical Genetics, Clinical Microbiology, Infectious diseases. Existing collaboration with 16 other OUH departments on applied molecular imaging science, some of which are poised to become partners. Collaboration with SDU departments: Nucleic Acid Center, Single Particle Physics and Engineering, Biomed. Lab, several Molecular Medicine departments and other departments under the Dept. of Clinical Research, SDU. Planned collaboration on mulitcenter studies with sister departments in Vejle and Esbjerg and with selected foreign Nuclear Medicine Departments. 115

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

FUNDING SOURCES Part of project 1 is financed be internal and external grants; project 2 is partly funded by interal grants; part of project 3 is funded by the Psychiatry Fund of RSD; a small part of T3DMAD is funded by the Danish Alzheimer Foundation.

DESCRIPTION OF Clinical brain research, and in particular applied molecular imaging science, is RESEARCH under expansion at OUH and in RSD. A unifying approach to brain disorders mani- fested by deficient brain energy metabolism and glucose consumption is the claim that both information processing and energy metabolism are concentrated in the proximity of the synaptic densities of dendritic spines of neurons where presynaptic terminals, monoaminergic varicosities and astroglial processes congregate. The resulting interactions can be imaged and monitored in vivo. This is emphasized by the decision to (i) establish cyclotron #2 in Odense to secure isotope supply and production of special radioactive isotopes, incl. Auger-emitters for therapy, and (2) install a new generation PET/MRI scanner (GEHC Signa, the world’s best right now), which, due to new technology has double sensitivity with correspondingly lower radiation, allowing repeat patient studies and examination of children. This phase of establishment explains that some elements exist while others are being planned. Almost all necessary equipment and methodologies are present, translational and international research collaboration is there. Shortcomings exist primarily in terms of space, infrastructure, certain key persons, and funding.

1. Auger-emitter therapy. A main research area of the Dept. of Nuclear Medicine is targeted radionuclide therapy of cancers, not so much with 90Y or 177Lu, which are more common, but not curative, but with Auger-electron emitters, which have significant advantages, and has given promising preclincal results (Project GLITZ) in animal models of glioblastomas (ref. HC3). This line of research has many partners and continues also in prostate, lung, and breast cancer.

2. QUAD = Quantification of diaschisis with FDG-PET/CT. Ongoing PhD project by stud.med. Eivind Segtnan, has so far resulted in 3 peer-review publications (cf. HC2) and over 15 abstracts of which 11 were published internationally. Several papers and abstracts are in the pipeline. Commercially available and locally established processing algorithms are being tested. 116

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

3. ASDPET = Neurobiology of autism spectrum disorders revealed by in vivo PET. Accepted PhD project by DVM, MD Lotte Bo Petersen. Cerebral glucose and fat metabolism in ASD patients and matched controls assessed by PET/MRI. Scheduled to start when the PET/MR scanner is up and running.

4. Neuro-WAD = Neurobiological effects of work-related adjustment disorder. Applied for PhD Project by MSc Saga S. Madsen that starts as soon as the PET/ MR scanner is ready. Addresses a major societal burden aiming to provide objective evidence for cerebral pathology in patients exposed to occupational stress. We hypothesize that PET by FDG, [11C]raclo-pride and/or [11C]FLB 457 can detect and quantify pathology in specific brain areas and connections in patients with work related adjustment disorder.

5. SYNAPDIN = Brain synaptic density and network activity in neuropsychiatric and neurodegenerative disorders. Major prospective project by prof. Gjedde. The goal is to determine how brain regions with high functional connectivity density (FCD) determined by fMRI, such as the default mode network (DMN), become vulnerable in aging, dementia, and psychiatric conditions including autism spectrum disorder, Alzheimer’s disease and schizophrenia (ASD-AD-S). This is done by measuring glutamatergic and GABAergic (i.e., total) signaling and associated energetics using calibrated fMRI to confirm that high FCD regions have highly correlated neuronal activity. A novel PET method uses a radioligand (11C-UCB-J) of synaptic vesicle glyco protein 2A (SV2A) to measure synaptic density. We first validate these methods in animal models of ASD-AD-S against traditional electrophysiological recordings and immunohi-stochemistry, and then we apply the validated method to human studies in healthy controls and patients with ASD-AD-S disorders. To determine the factors that make high FCD regions such as DMN vulnerable to disease, we put together a multi-disciplinary team of experts in MRS, fMRI, PET, metabolism, and electrophysiology, and collaborators who are experts in ASD-AD-S and use R-fMRI to study these disorders.

6. T3DMAD = Defective aerobic glycolysis: the link between diabetes and Alz hei-mers disease? It has been proposed that impairments in brain insulin/ insulin-like growth factor (IGF) signaling is associated with increased accumula- tion of A�, hyperphosphorylated tau, reactive oxygen/nitrogen species, and 117

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

pro-≠≠inflammatory and pro-apoptotic molecules. Both restoration of insulin responsiveness and use of insulin therapy can improve cognitive performance. The role of altered glucose metabolism in diabetes type 2 and hyperglycemia has been further documented by Gejl et al. (cf. AG 3,9). The authors demon- strated that glucagon-like peptide-1 (GLP1) decreases intracerebral glucose content during hyperglycemia and diabetes type 2. We hypothesize that insulin resistance manifests itself as reduction in regional cerebral glucose metabolism, aerobic glycolysis, lactate, and cerebral blood flow in patients with diabetes 2, with increased risk of developing AD. To test this hypothesis, including the hypothetical association with brain levels of lactate in the healthy population and in AD patients with and without diabetes, we will use PET to compare the changes of brain energy metabolism and perfusion with the load of ß-am yloid peptide in the brain of elderly healthy volunteers and patients with AD with and without diabetes, and we will use MR spectroscopy to measure lactate levels. We have designed the studies specifically to reveal the role of defective glucose-energy metabolism and aerobic glycolysis in the link between AD and diabetes type 2.

7. ADMAC = Alzheimer’s and molecular carotid artery calcification. The above project will be conducted in consert with and in the same cohort of patients as a prospective longitudinal study (by prof. Høilund-Carlsen et al.) on molecular arterial (cardiac, aortic, carotid) calcification in patients referred to the Dept. of Endocrinology, OUH, on suspicion of DM1 or DM2. These paients are screened on entrance by all available and feasible methods meaning that all relevant additional data will be made available to both subprojects. The hypothesis of the current project is that molecular arterial calcification can be detected with PET/CT using sodium flouride (NaF) as tracer in diabetic patients, years or decades before otherwise possible (cf. HC1). If correct, this finding will potentially open for early and likely more effective prevention measures and/or therapy of diabetics, most of whom will die prematurely due to events secondary to arterial arteriosclerosis (acute myocardial infarction, apoplexia, renal failure). 118

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

Other: Additional projects applying PET tecnique are under consideration, e.g., projects focusing on Consciousness/Unconscoiusness; Normal pressure hydrochep- halus; Transcranial pulsed electromagnetic fields in Parkinson’s disease; Schizo- phrenia; Integrative medicine for treatment of Alzheimer’s disease; Global and re- gional cerebral metabolism following electrocon-vulsive therapy (formerly known as electroshock therapy); Chemobrain (brain metabolism dur-ing and following chemotherapy); and the following acute conditions: Acute psychosis; Acute stroke; Acute injury (trauma, car accident, sports).

KEY PUBLICATIONS Selected Gjedde publications: 1. Rodell AB, O’Keefe G, Rowe CC, Villemagne VL, Gjedde A. Cerebral Blood Flow and Aβ-Amyloid Estimates by WARM Analysis of [11C]PiB Uptake Distinguish among and between Neurodegenerative Disorders and Aging. Front Aging Neurosci 2017;8:321. 2. Aanerud J, Borghammer P, Rodell A, Jónsdottir KY, Gjedde A. Sex differences of human cortical blood flow and energy metabolism. J Cereb Blood Flow Metab 2016:271678X16668536. 3. Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Vang K, Rodell A, Brændgaard H, Gottrup H, Schacht A, Møller N, Brock B, Rungby J. In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci 2016;8:108. 4. Stender J, Mortensen KN, Thibaut A, Darkner S, Laureys S, Gjedde A, Kupers R. The Minimal Energetic Re-quirement of Sustained Awareness after Brain Injury. Curr Biol 2016;26(11):1494-9. 5. Hyder F, Herman P, Bailey CJ, Møller A, Globinsky R, Fulbright RK, Rothman DL, Gjedde A. Uniform distribu-tions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis. J Cereb Blood Flow Metab 2016;36(5):903-16. 6. Nahimi A, Jakobsen S, Munk OL, Vang K, Phan JA, Rodell A, Gjedde A. Mapping α2 adrenoceptors of the human brain with 11C-yohimbine. J Nucl Med 2015 Mar;56(3):392-8. 7. Phan JA, Landau AM, Wong DF, Jakobsen S, Nahimi A, Doudet DJ, Gjedde A. Quantification of [(11)C]yohimbine binding to α2 adrenoceptors in rat brain in vivo. J Cereb Blood Flow Metab 2015;35(3):501-11. 119

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

8. Stender J, Kupers R, Rodell A, Thibaut A, Chatelle C, Bruno MA, Gejl M, Bernard C, Hustinx R, Laureys S, Gjedde A. Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients. J Cereb Blood Flow Metab 2015;35(1):58-65. 9. Iversen P, Mouridsen K, Hansen MB, Jensen SB, Sørensen M, Bak LK, Waagepetersen HS, Schousboe A, Ott P, Vilstrup H, Keiding S, Gjedde A. Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [(11)C]acetate in humans. Front Neurosci. 2014 Nov 3;8:353. 10. Gejl M, Lerche S, Egefjord L, Brock B, Møller N, Vang K, Rodell AB, Bibby BM, Holst JJ, Rungby J, Gjedde A. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain. Front Neuroenergetics. 2013 Mar 27;5:2. doi: 10.3389/fnene.2013.00002. 11. Gjedde A, Aanerud J, Braendgaard H, Rodell AB. Blood-brain transfer of Pittsburgh compound B in humans. Front Aging Neurosci. 2013;5:70. 12. Gjedde A, Aanerud J, Peterson E, Ashkanian M, Iversen P, Vafaee M, Møller A, Borghammer P. Variable ATP yields and uncoupling of oxygen consumption in human brain. Adv Exp Med Biol. 2011;701:243-8. 13. Gjedde A, Keiding S, Vilstrup H, Iversen P. No oxygen delivery limitation in hepatic encephalopathy. Metab Brain Dis. 2010 Mar;25(1):57-63. 14. Gjedde A, Kumakura Y, Cumming P, Linnet J, Møller A. Inverted-U-shaped correlation between dopamine re-ceptor availability in striatum and sensation seeking. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3870-5. 15. Gjedde A, Geday J. Deep brain stimulation reveals emotional impact processing in ventromedial prefrontal cor-tex. PLoS One. 2009 Dec 7;4(12):e8120.

Recent Høilund-Carlsen publications: 1. Blomberg BA, de Jong PA, Thomassen A, Lam MG, Vach W, Olsen MH, Mali WP, Narula J, Alavi A, Høilund-Carlsen PF. Thoracic aorta calcification but not inflammation is associated with increased cardiovascular disease risk: results of the CAMONA Study. Eur J Nucl Med Mol Imaging 2017; 44(2): 249-58. 2. Segtnan EA, Grupe P, Jarden JO, Gerke O, Ivanidze J, Christlieb SB, Constantinescu C, Pedersen JE, Housh-mand S, Hess S, Zarei M, Gjedde A, Alavi A, Høilund-Carlsen PF. Prognostic implications of total hemispheric glucose metabolism ratio in cerebrocerebellar diaschisis. J Nucl Medk 2017; 58(5): 768-773. 120

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

3. Thisgaard H, Halle B, Aaberg-Jessen C, Olsen BB, Therkelsen ASN; Dam JH, Langkjær N, Munthe S, Någren K, Høilund-Carlsen PF, Kristensen BW. Highly effective auger-electron therapy in an orthotopic glioblastoma xeno-graft model using convection-enhanced delivery. Theranostics 2016; 6(12): 2278-91. 4. Hildebrandt MG, Gerke O, Baun C, Falch K, Hansen JA, Farahani ZA, Petersen H, Larsen LB, Duvnjak S, Buskevica I, Bektas S, Søe K, Jylling AM, Ewertz M, Alavi A, Høilund-Carlsen PF. [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in suspected recurrent breast cancer: a prospective comparative study of dual-time-point FDG-PET/CT, contrast-enhanced ct, and bone scintigraphy. J Clin Oncol 2016;34(16):1889-97. 5. Petersen H, Holdgaard PC, Madsen PH, Knudsen LM, Gad D, Gravergaard AE, Rhode M, Godballe C, Engelmann BE, Bech K, Theilmann-Jørgensen D, Mogensen O, Karstoft J, Johansen J, Christensen JB, Johansen A, Høi-lund-Carlsen PF; PET/CT Task Force of the Region of Southern Denmark. FDG PET/CT in cancer: comparison of actual use with literature-based recommendations. Eur J Nucl Med Mol Imaging 2016; 43(4): 695-706.

Other outputs e.g. patents, novel therapies, etc.: One patent in Auger-emitter therapy of glioblastomas, one biotech company (GlioPharma) established in RSD.

KEY Danish: COLLABORATIONS The main Danish collaborators are mentioned above.

International: General Electric Healthcare (Bich Lee, Global Manager PET/CT and Lars Kervefelt, Segment Leader Molecular Imaging Nordic). Long-term cooperation (without sponsor-ship). Our department is GE Healthcare’s largest customer in the Nordic region. Bich Lee wants PFHC as head of advisory board regarding molecular arterial calcification and cancer. Gothenburg and Lund-Malmö Universities (Prof. Lars Edenbrandt). Longterm collaboration on intelligent computer technology to support the interpretation of gamma camera and PET studies. Valuable in assessing myocardial perfusion and cancer spread to the bones.Uppsala University (Prof. Vladimir Tolmachev). Collaboration on highly promising new PET traces for diagnostics and also radioisotope treatment of prostate and other cancers. 121

GROUPGROUP NAME: NAME UCAR GROUP LEADER TRANSIC Poul F. Høilund-Carlsen

TracerPharma and GlioPharma (CEO John Bo Jacobsen and CFO Jette Breum). These two Danish companies are mentioned here because of their many international contacts. Our research concerns on brain tumors together with Pathology and Neurosurgery, OUH, have resulted in the creation of a biotech company (GlioPharma) in the RSD. University of Pennsylvania, Philadelphia, PA, USA (Prof. Abass Alavi). Since 2011 of great importance to us (and OUH). At the Society of Nuclear Medicine’s Annual 2017 Meeting in Denver in June this year, PENN and NMA are the two departments with the highest number of accepeted abstracts. At the forthcoming World Congress in Molecular Imaging in Philadelphia later this year and the forthcoming European Association of Nuclear Medicine Congress in October in Vienna, NMA also expects to be among top 3 in terms of number of abstracts. Geneva University, Geneva, Switzerland (Prof. Habib Zaidi). Advanced coope- ration on especially technical aspects of clinical PET/CT, PET/MR and preclinical PET/ CT/SPECT and PET/MR in animals. John Hopkins University and Medical Institutions, Baltimore, MD, USA (Prof. Dean F. Wong). Leader in the study of neurotransmission and the effect of CNS drugs. Yale University, New Haven, CT, USA (Prof. Fahmeed Hyder). Initial cooperation in neuroscience focusing on PET/MRI and mapping of brain energy conversion. Karolinska Instituttet, Stockholm (Prof. Christer Halldin). Potential collaboration on brain tracers. Shahid Besheshti University, Tehran, Iran (Prof. Mojtaba Zarei). Prof. Høilund- Carlsen is an adjunct professor at this university, who is currently setting up a large PET center with the same PET/MRI scanner as in Odense. Students from here are expected to solve several demanding mathematical-physical research tasks for the clinical use of PET/MR. Tabriz University of Medical Sciences, Tabriz, Iran (Chancellor Somi, Dean Shakouri). Cooperation on PhD education and aging science (brain, cardiovascular and musculoskeletal diseases).

INFRASTRUCTURE As mentioned, with few exceptions, almost all types of equipment, know-how, experience and standardized routines in basic, preclinical and clinical examinations involved in the above studies are available in Odense at OUH and SDU. This includes also experience with study designs, database administration, and publication. Exceptions are specific exepertises in MRI, additional space, additional manpower, and additional funding. Translational neuroscience group Mental Health Services, Region of Southern Denmark & Department of Clinical Research, SDU 123

GROUPGROUP NAME: NAME UCAR GROUP LEADER Translational neuroscience Group Tanja Maria Sheldrick-Michel

NUMBER OF 1 Full Professor, 1 Associate Professor, 3 post-doc fellows, 2 Ph.D. students, GROUP MEMBERS 3 Pre-graduate students (AND THEIR TITLE)

DEPARTMENT & Dept. Psychiatry, Clinical Research Inst. University of Southern Denmark, Nuclear UNIVERSITY/ Medicine Dept. Odense University Hospital HOSPITAL/OTHER

FUNDING SOURCES Region of Southern Denmark, Psychiatric research fund, Odense University Hospital, University of Southern Denmark

DESCRIPTION OF 1. We have established a well characterised clinical cohort of patients that have RESEARCH been diagnosed with autism within the last 20 years in the former Fyns Amt (600 individuals, Fynen autism cohort). 2. We established a biobank of different tissue types of the Fynen autism cohort/ matched healthy controls. We will combine our available re-soursces (OPEN) with newly developed cutting-edge techniques from stem cell biology and tissue engineering, nanotechnology,proteomics and computational biology to analyse the samples. 3. We investigate the impact of cellular damage in autism. We analyse the whole proteome, but put a special focus on oxidative stress, due to free radicals. For this, we measure the concentration of anti-oxidants and free radical scavengers in tissue of patients and compare them to age and gender matched healthy controls. 4. As one of the first groups in Denmark, and one of the few in the world, we develop three dimensional neuronal stem-cell models (organoids, mini-brains) to investigate the mechanism of embrionic development in autism. We apply the cutting edge technology on the basis of pattients/controls derived induced pluripotent stemcell (iPSC), in a the new concept to create discrete 3D brain structures in vitro named “mini-brain” that can be used for disease modeling, diagnosis, and therapy 124

GROUPGROUP NAME: NAME UCAR GROUP LEADER Translational neuroscience group Tanja Maria Sheldrick-Michel

5. We want to monitor the cellular damage/processess in vivo employing the newest state of the art PET/MRI scanner to investigate the glucose metabolism, blood flow and fatty acid metabolism in their brains and compared them with the population of healthy subjects. We hope by this comparison we will get a clear idea about the functional differences of brains of ASD patients compared with healthy subjects. 6. In collaboration with the Dept of Bioinformatics, the different data-sets will be collected and analysed and compared to other clinical cohortes in order to find individual biomarker clusters for the distinct clinical conditions versus unaffected healthy individuals (e.g. autism, high risk for schizophrenia, healthy individuals). This aims to individualize autism (and psychiatric) treatment in the future.

KEY PUBLICATIONS 1. Ilieva M, Thorsen MB, Michel TM (2017) Brain organoids- from personalized in vitro model to precision treatment of autism. Under editorial decision, Biological Psychiatry 2. Forsberg LS, Ilieva M, Michel TM (2017) Epigenetics and Cerebral Organoids: Proising directions in Autism Spectrum Disorders (under review, Molecular Psychiatry 3. Andablib S, Vafaee MS, Michel TM (2017) Maternal exposure increases the risk of autis-tic offspring: A meta-analys and systematic review (under review European Psychiatry 4. Van der Steen Y, Gimpel-Drees J, Lataster T, Viechbauer W, Simons CJP, Lardinois M, Michel TM et al., (2017) Clinical high risk for psychosis: the association between mo-mentary stress, affective and psychotic symptoms Acta Psychiatr Scand. 2017 Mar 5. 5. Kaestner A, Begemann M, Michel TM, Everts S, Stepniak B, Bach C, Poustka L, Becker J, Banaschewski T, Dose M, Ehrenreich H (2015) Autism beyond diagnostic categories: characterization of autistic phenotypes in schizophrenia. BMC Psychiatry 15:115 6. Derntl B*, Michel TM* (shared first author), Prempeh P, Backes V, Finkelmeyer A, Schneider F, Habel U (2015) Empathy in individuals clinically at risk for psychosisi: brain and behaviour. Br. J Psychiatry 207: 407-13; e-pub: 20 August 125

GROUPGROUP NAME: NAME UCAR GROUP LEADER Translational neuroscience group Tanja Maria Sheldrick-Michel

7. Zink M, Schirmbeck F, Rausch F, Eifler S, Elkin H, Solojenkina X, Englisch S, Wagner M, Maier W, Lautenschlager M, Heinz A, Gudlowski Y, Janssen B, Gaebel W, Michel TM, et al., (2014). Obsessive-compulsive symptoms in at-risk mental states for psychosis: as-sociations with clinical impairment and cognitive function. Acta Psychiatr Scand. 8. Abdalla M, Michel TM (2013) Matrix metalloproteinases in Autism Spectrum Disorders. J Molecular Psychiatry 1:16 (open access e-journal) 9. Schneider K, Regenbogen C Pauly KD, Gossen A, Schneider DA, Mevissen L, Michel TM, Gur RC, Habel U, Scheider F (2013) Evidence for Gender-Specific Endophenotypes in High-Functioning Autism spectrum disorder during empathy. Autism Res. 6:506-21 10. Ngounou Wetie GA, Sokolowska I, Wormwood K, Beglinger K, Michel TM, Thome J, Darie CC, Woods AG (2013). Mass spectrometry for the detection of potential psychiatric biomarkers. J Mol Psychiatry 1:8 (open access e-journal) 11. Woods AG, Wetie AG, Sokolowska I, Russell S, Ryan JP, Michel TM, Thome J, Darie CC (2013) Mass spectrometry as a tool for studying autism spectrum disorder Journal of Molecular Psychiatry – open access, 1:6 (21 May 2013) open access 12. Michel TM, Pülschen D, Thome J (2012). The role of free radicals in depression. Curr. Pharmac. Design 18:5890-9 13. Schneider K, Mevissen L, Michel TM, Gur R, Habel F, Schneider F (2013) Neural Corre-lates of Moral Reasoning in Autism Spectrum Disorders. Social Cognitive and Affective Neuroscience 8:702-10 14. Nickl-Jockschat T, Habel U, Michel TM, Manning J, Laird A, Fox PT, Schneider F, Eick-hoff SB (2011) “Brain structure anomalies in autism spectrum disorder (ASD) - a meta-analysis of VBM studies using anatomic likelihood estimation (ALE). HBM (Human Brain Mapping) 33:1470-89 15. Nickl-Jockschat T, Michel TM (2011) Neurotrophic factors in autism. Molecular Psychiatry 16:478-490 16. Michel TM, Sheldrick AJ, Camara S, Schneider F, Grünblatt E, Riederer P (2011) Altera-tion of the pro-oxidant xanthine oxidase (XO) in the thalamus and the cerebral cortex of patients with schizophrenia. World J Biol Psychiatry 12:588-97 17. Ettinger U, Williams SC, Patel D, Michel TM, Nwaigwe A, Caceres A, Mehta MA, Anilku-mar AP, Kumari V (2009). Effects of acute nicotine on brain function in healthy smokers and non-smokers: Estimation of inter-individual response heterogeneity. Neuroimage 45:549-561 126

GROUPGROUP NAME: NAME UCAR GROUP LEADER Translational neuroscience group Tanja Maria Sheldrick-Michel

KEY Danish: COLLABORATIONS Odense University Hospital, Århus University Hospital, University Hospital Ålborg, Statens Serum Insitute, Cophenhagen

International: Montreal Neurological Inst., John´s Hopkins University, Dept. Nuclear Medicine, Max Planck Institute Goettingen, Germany, Excellence University Aachen, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, UK, Mount Sinai Hospital New York, USA; University of Zuerich, University of Sydney, Australia

INFRASTRUCTURE We have a new established laboratory for stem-cell research in Psychiatry, with new cutting edge technology with cutting edge technologyies such as e.g. the IncuCyte live cell imaging system (Essens) microscope and the Amaxa Nucleofector. We have access to modern neuroimaging facilities at the Center for Nuclear Medicine (6PET CT, state of the art PET-MRI We have the right to use to a “super Computer “Abacus” for “big data” analysis and system neurobiology/bioinformatics. UCAR Mental Health Services, Region of Southern Denmark & Department of Clinical Research SDU 128

GROUPGROUP NAME: NAME UCAR GROUP LEADERS UCAR Annette Søgaard Nielsen & Bent Nielsen

NUMBER OF Associate Professor: Anette Søgaard Nielsen GROUP MEMBERS Professor: Bent Nielsen (AND THEIR TITLE) Professor: Kjeld Andersen Professor: Jes Søgaard Assistant Professor: Randi Bilberg PhD-students: Angelina Mellentin, Lotte Kramer Schmidt, Jakob Emiliussen, Kristine Hindkjær Tarp, Morten Hell, Anne-Sophie Schwarts, Sengül Sari, Dorthe Nielsen, Scientific Assistants: Anna Mejldal, Birgit Jensen

DEPARTMENT & Psychiatric Hospital, Region Southern Denmark & Clinical Institute, University of UNIVERSITY / Southern Denmark HOSPITAL / OTHER

FUNDING Lundbeckfonden, Trygfonden, Region of Southern Denmark, University of SOURCES Southern Denmark

DESCRIPTION OF The Unit of Clinical Alcohol Research UCAR has specialized in clinically relevant RESEARCH research that has a direct impact on the quality and effectiveness of the treatment delivered to the patients with alcohol use disorder. UCAR carries out its research together with operating treatment institutions and hospitals. In particular, UCAR’s research field is early identification of alcohol problems, developing models for referral of problem drinkers to right treatment, use of health care technology in treatment, strategies to improve compliance in treatment and implementation of findings into daily practice. Amongst other studies, UCAR currently performs the large research program, named the RESCueH studies. 129

GROUPGROUP NAME: NAME UCAR GROUP LEADERS UCAR Annette Søgaard Nielsen & Bent Nielsen

MAIN PROJECTS The Relay Study: A randomized controlled study, focusing on referrals to outpatient treatment for alcohol use disorder after discharge from somatic hospital. The Elderly Study: This multi-centre study is a randomized controlled trial with two arms and is conducted in three different drinking cultures. Patients, aged 60+ years, seeking treatment for alcohol use disorders at three facilities in Denmark, Germany and US are enrolled in the study, and randomized to either Brief Intervention, or Brief Intervention plus adjusted Community Reinforcement Approach (CRA-Senior). The Self-match Study: is a randomized controlled study on the importance of patient involvement. The Cue Exposure Study: compares aftercare based on cue exposure delivered either by a therapist or through a smartphone application with standard aftercare. The Healthy Lifestyle Study: tests whether the addition of moderate physical training to standard treatment for alcohol dependency will increase compliance with alcohol treatment.

KEY PUBLICATIONS 1. Sari S, Müller AE, Roessler KK. Exercising alcohol patients don’t lack motivation but struggle with structures, emotions and social context – a qualitative dropout study. B M C Family Practice, Vol. 18, 45, 2017., DOI: 10.1186/s12875-017-0606-4 2. Emiliussen J, Andersen K, Nielsen AS. Why do some older adults start drinking excessively late in life? Results from an Interpretative Phenomenological Study. Scandinavian Journal of Caring Sciences. In print. 2017 jun 4. 3. Mellentin AI, Stenager E, Nielsen B, Nielsen AS, Yu F. A smarter pathway for delivering cue exposure therapy?: The design and development of a smartphone application targeting alco-hol use disorder. J M I R mHealth and uHealth. 2017;5(1). 4. Andersen, K. & Nielsen, B. Coercion in psychiatry: the importance of extra- mural factors. Nord J Psychiatry, 2016: 1-5 5. Hellum R, Bjerregaard L, Nielsen AS. Factors influencing whether nurses talk to somatic pa-tients about their alcohol consumption. Nordic Studies on Alcohol and Drugs, 2016;33:415-436 6. Nielsen AS, Nielsen B, Andersen K, Roessler KK, Søgaard J, Bühringer G, Bogenschutz M, Ekstrøm CT. The RESCueH programme: Testing new non- pharmacologic interventions for Alcohol Use Disorders: Rationale and methods. European Addiction Research, 2016;22:306–317 130

GROUPGROUP NAME: NAME UCAR GROUP LEADERS UCAR Annette Søgaard Nielsen & Bent Nielsen

7. Mellentin AI, Brink M, Andersen L, Erlangsen A, Stenager E, Christiansen E. The Risk of Offspring Developing Substance Use Disorders when Exposed to One versus Two Parent(s) with Alcohol Use Disorder: A Nationwide, Register-based Cohort Study. Journal of Psychiat-ric Research. 2016;80(September):52-58. 8. Nielsen AS, Ellermann AE. Need to know and wish to know: What individuals find important to know about treatment for alcohol problems in order to be able to decide whether to start treatment or not. Nordic Studies on Alcohol and Drugs, 2016;33;2:123-137 9. Mellentin, AI, Nielsen B, Stenager E. Nielsen AS. The effect of co-morbid depression and anxiety on the course and outcome of alcohol outpatient treatment: a prospective cohort study. Nordic Journal of Psychiatry 2015; 69(5):1-8. (doi:10.3109/08039488.2014.981857) 10. Nielsen AS, Nielsen B. Implementation of a Clinical Pathway Improves Alcohol Treatment Outcome. Addiction Science & Clinical Practice, 2015; 10:7 (7 March 2015), DOI 10.1186/s13722-015-0031-8 11. Roessler, K.K., Bilberg, R., Jensen, K., Kjaergaard, AS., Dervisevic, A., Nielsen B., Exercise as outcome treatment of alcoholics. A pilot study assessing the effect of the short-term physical activity on adherence, fitness, depression and anxiety. Sport Science Review, vol XII, no. 3-4, 2013 12. Schiotz M, Price M, Frolich A, Søgaard J, Kristensen JK, Krasnik A, et al. Some thing is amiss in Denmark: A comparison of preventable hospitalisations and readmissions for chronic medical conditions in the Danish Healthcare system and Kaiser Permanente. BMC Health Serv Res 2011 Dec 22;11(1):347. 13. Hansen ABG, Hvidtfeldt UA, Grønbæk M, Becker U, Nielsen AS, Tolstrup JS. The number of persons with alcohol problems in the Danish population. Scand J Public Health 2011 Mar;39(2):128-36.

KEY Danish: COLLABORATIONS Professor Kirsten Kaya Roessler, Psychological Institute, SDU; Professor Anne-Marie May, Department of Culture, SDU; Professor Aleksander Kragh, Clinical Institute, SDU, Professor Tine Kold Jensen, Environmental Medicine, SDU, Professor Claus Thorn Ekstrøm, Biostatistics, Copenhagen University

International: Professor Gerhard Buehringer, (1) Chair of Addiction Research, Technische Universität Dresden, and (2) Institut für Therapieforschung, Munich; Professor 131

GROUPGROUP NAME: NAME UCAR GROUP LEADERS UCAR Annette Søgaard Nielsen & Bent Nielsen

Michael Bo-genschutz, Department of Psychiatry, NYU, Langone Medical Center, New York. Associate professor Teresa Moyers, CASAA, University of New Mexico, professor Gerard Schippers, Academic Medical Centre, Dept. of Psychiatry and Addiction Amsterdam

INFRASTRUCTURE A coding lab for assessing quality of psycho social interventions

A team of skilled interviewers to collect data from patients Posters 133

Treatment with transcranial pulsed electromagnetic fields enhances functional rate-of-force development during chair rise in persons with Parkinson's disease

A.S.B. Malling1 ([email protected]), B.M. Morberg1, L. Wermuth1, O. Gredal2, P. Bech3, B.R. Jensen1

1Odense University Hospital, University of Southern Denmark, Denmark; 2The Danish Rehabilitation Centre for Neuromuscular Diseases, Denmark; 3Psychiatric Centre North Zealand , University of Copenhagen, Denmark

Purpose Method Ninety-seven persons with PD received T-PEMF (squared bipolar pulses, 2.25 ms To investigate the effect of treatment duration, ±50 mV, 50 Hz, 5-8 mT at 1 cm from coils [3]) or placebo treatment (double- with transcranial pulsed electromagnetic blinded, randomized controlled trial) 30 min/day for 8 weeks (Figure 1). Of these, 43 fields vs. placebo treatment on functional and 41 persons receiving T-PEMF and placebo treatment respectively performed sit- rate-of-force development during chair- to-stand trials pre and post treatment. Sitting on a height-adjustable chair allowing only rise in well-medicated persons with the bare feet to exert force on a force plate, the subject performed trials of six sit-to- idiopathic Parkinson’s Disease. stand cycles as fast as possible with the arms placed across the chest. Vertical RFD during rising and completion time of five cycles were determined from the filtered vertical ground reaction force (double, 2nd order, 25 Hz Butterworth low pass filter). Background 1.6 1.6 Pulsed electromagnetic fields up- ) 1.2 ) 1.2 regulates neuronal growth factors and ( xBW 0.8 ( xBW 0.8 RFD may be a potential treatment of GRF 0.4 GRF 0.4 ൌ∆𝐺𝐺𝑅𝑅𝐹𝐹Ȁ∆𝑡𝑡 neurodegeneration. Parkinson’s disease 0 0 (PD) can result in lower rate-of-force 0 2 4 6 8 10 12 0 0.5 1 1.5 2 development during movement and this Time (s) Time (s) is associated to lower agonist muscle Figure 2: Vertical ground reaction force (GRF) during a sit-to-stand trial. LEFT: Full trial with 6 repetitions. X maximal force. - - - completion time; interval from maximal force in 1st peak of 1st repetition to maximal force in 1st peak of 6th repetition. activation during muscle contraction [1]. RIGHT: One sit-to-stand repetition. – 30 and 70 % of maximal force of 1st peak. This deteriorates the performance of fast movements of great importance for activities of daily living and mobility. Results Treatment with T-PEMF significantly increased RFD (mean±SD: from 10.0±2.3 to 10.5±2.6 bodyweight (BW)/s, P=0.003) whereas the placebo group did not change (P=0.45). The completion time was reduced significantly for both the T-PEMF and placebo group (T-PEMF: from 10.5±2.5 to 10.1±2.4 s, P=0.015; Placebo: from 10.2±1.9 to 9.7±1.6 s, P=0.002).

Completion time (s) RFD (BW/s) 14 14

13 13

12 12 * 11 11 * 10 10 * 9 9

8 8

7 7 Pre Post Pre Post T-PEMF Placebo T-PEMF Placebo Figure 3: Sit-to-stand completion time (LEFT) and functional rate of force development during chair rise (RFD) (RIGHT) of the transcranial pulsed electromagnetic fields group (T-PEMF) (solid, orange line) and placebo group (dashed, blue line) before (Pre) and after (Post) 8 weeks of treatment.

Figure 1: The T-PEMF applicator (Re5, Denmark) consisted of 7 coils; two at the frontal-parietal lobes, two at Conclusion the frontal-temporal lobes, two at the temporal lobes and one at the occipital lobe. Pictures from [2]. Treatment with T-PEMF increased RFD during chair rise. Both T-PEMF and placebo treatment improved the completion time. These results indicate that T-PEMF treatment can enhance the activation of agonist References muscles during chair rise. Decreased agonist activation has been shown to be [1] Rose et al. Motor Control 2013-17;203-16. [2] Morberg et al. Movement Disorders 2017, e-pub ahead associated to lower rate-of-force development in m. quadriceps during isometric leg of print extension in persons with PD [1]. A longer treatment period may enhance the [3] Rahbek et al. Oral Bioscience and Medicine 2005,2(1), 29-40 improvement of RFD and improve the ability to perform activities of daily living in persons with PD.

Neurologic Research Unit – Department of Neurology Odense University Hospital, Institute of Clinical Research University of Southern Denmark 134

CsA AMELIORATES CEREBRAL MITOCHONDRIAL DYSFUNCTION CsA Ameliorates Cerebral Mitochondrial Dysfunction A Forsse1, TH Nielsen1, K Nygaard1, JB Gramsbergen2, C-H Nordström1, FR Poulsen1 1Department of Neurosurgery, Odense University Hospital, University of Southern Denmark. 2Institute of Molecular Medicine, University of Southern Denmark

INTRODUCTION METHODS Mitochondrial dysfunction ensues after We have modified an earlier described transient cerebral ischemia and is an endothelin-1 rat model into a translational important factor in the vasospasm phase of model mimicking the vasospasm phase of subarachnoid haemorrhage(SAH) as well as a SAH. We induce transient cerebral ischemia in range of other cerebrovascular pathologies. freely moving rats and monitor the cellular Cyclosporine A (CsA), a compound used to metabolism through cerebral microdialysis. treat rheumatological conditions and graft vs The rats are treated with intravenous host disease has earlier shown injections of CsA/Placebo, and concentrations neuroprotective properties in neurotrauma of redox-metabolites are analysed in real- models. time.

Fig. 1 Mixed effect model statistical analysis of Lactate/pyruvate- ratio in CsA (NeuroSTAT®) group (N=9) vs Placebo (N=9). Ischemia induced at 1 hour, directly followed by treatment. The average difference in LP-ratio after 3 hours was 66,6% points.

RESULTS CONCLUSION The most important variable for the Our results suggest that CsA could be a part of interpretation of mitochondrial dysfunction in the future medical treatment of cerebral microdialysis, the Lactate/Pyruvate- cerebrovascular diseases. One possible ratio, was significantly lower in the treatment application is delayed neurological group, indicating ameliorated mitochondrial deterioration in subarachnoid haemorrhage. function. The effect (fig 1) can be seen from 2 Our translational animal model can be used for hours after induction of ischemia with evaluating other promising compounds simultaneous treatment. targeting dysfunctional cerebral metabolism.

Overlægerådets forskningsfond, Karen S. Jensens legat, A. P. Møllerfonden, 135

Defects in migration and neurite outgrowth in human PARK2 knockdown iPSC-derived neurons: Rescue by RhoA inhibition

H. BogetoLe1,2, P. Jensen3, J. Okarmus1, M. Agger1, M. Ryding1, S. Schmidt1, P. Nørregaard1, B. Ryan2, R. Wade-Mar1ns2, M. Røssel-Larsen3, Morten Meyer1 Summary Results PARK2 KD and control iPSCs differen7ated into Mitochondrial morphology is perturbed in PARK2 KD neurons Mitochondrial dysfunc1on plays a major role in the dopaminergic neurons pathogenesis of sporadic Parkinson’s disease (PD) and familial PD caused by muta1ons in the PARK2 gene. The encoded protein, parkin, is vital for mitochondrial func1on, but the lack of key PD phenotypes in PARK2 knockout rodent models has hindered inves1ga1ons into parkin’s role in PD pathogenesis. Human isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockdown (KD) enable studies of the effect of parkin dysfunc1on in dopaminergic neuronal cultures. We have combined such cells with a novel large-scale mass spectrometry approach to obtain an in-depth whole-proteome Novel proteomics approach iden7fies protein and PTM analysis of changes in protein levels and post- changes in PARK2 KD neurons transla1onal modifica1ons (PTMs), including phosphoryla1ons and cysteine-modifica1ons. Pathway analysis on proteomics data Pathway analysis of these proteomic changes and subsequent in vitro assays revealed perturba1ons in prolifera1on, cell migra1on and neurite outgrowth in PARK2 KD neurons. We confirmed neurite outgrowth defects using long-term engraLment of neurons into the striatum of immunosuppresed hemiparkinsonian adult rats. The GTP-binding protein RhoA, which has previously been implicated in PD and other neurodegenera1ve diseases, was iden1fied as a key upstream regulator, and by inhibi1ng this pathway the migra1on and neurite outgrowth phenotypes could be rescued. In conclusion, our study has revealed novel phenotypes in iPSC-derived PARK2 KD neurons that can be reversed by targe1ng iden1fied regulatory pathways.

Isogenic PARK2 KD iPSC-derived neuronal model

Neurite outgrowth defects in PARK2 KD neurons confirmed Impaired prolifera7on and increased cell death RhoA inhibi7on normalises migra7on and rescues neurite aEer transplanta7on and long-term survival in rat striatumA in PARK2 KD cells outgrowth defects in PARK2 KD neurons

1.Department of Neurobiology Research, Ins1tute of Molecular Medicine, University of Southern Denmark, DK Contact: cand. med. Helle BogetoLe Barnkob 2. Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Gene1cs, University of Oxford, UK Email: [email protected] 3. Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK Linkedin: Helle BogetoLe 136

The Elderly-study – a multi-national study R. Bilberg1, G. Bühringer2,3, M. Bogenschutz4, B. Braun3, S. Behrendt2, L. Worth4, A.S. Nielsen1,5, K. Andersen1,5

1Unit of Clinical Alcohol Research, Clinical Institute, University of Southern Denmark, 2Addiction Research Unit, Technische Universität, Dresden, Germany, 3IFT Institut für Therapieforschung, München, Germany 4Center for Alcoholism, Substance Abuse and Addiction (CASAA), Albuquerque, USA, 5Department of Psychiatry, Odense University Hospital, Denmark Sub-projects: Introduction: With the aging of western societies in the coming The Elderly-study involves 693 patients and > 6000 years combined with increasing alcohol consumption among elderly, variables, hence data for numerous papers to come. So far, the number of elderly with alcohol problems is expected to rise the following sub-studies are performed or planned: considerably. Little is known about what treatment to offer this • Why do some older adults start drinking late in life – a group of patients qualitative study. PhD-study • Validity of patients’ alcohol reports: Validation by The Elderly Study is an international multi-site randomized means of hair samples. PhD-study controlled trial, involving four research centers in three countries: • Factors influencing the effects of therapy. A study on CASAA, USA; Addiction Research Unit & IFT, Germany; and UCAR, treatment fidelity and therapist factors. PhD-study Denmark • Elderly drinkers’ use of social service and health care before and after treatment, compared to controls. A Aim: To investigate whether Community Reinforcement Approach, register based study. PhD-study adjusted to Elderly (CRA), in addition to Motivational Enhancement • Health Economic study on Elderly drinkers – a senior Therapy (MET) is more efficient than MET alone in treating alcohol study. Senior Study use disorder among elderly. Published papers and papers in preparation Design: Participants were randomized to MET+CRA or MET alone. MET included four sessions and CRA up to 8 sessions. Data was collected • Outpatient treatment of Alcohol Use Disorders among subjects 60+ years. Design of a randomized controlled trial conducted in three countries (Elderly-study). from the patients at baseline, 4, 12, 26 and 52 weeks. Data included • Training and supervision therapists involved in treatment of senior drinkers information on alcohol use and drinking pattern, goal for treatment, • Cross-Atlantic differences in elderly alcoholics seeking treatment : characteristics and physical and mental health, and quality of life. Data on primary differences in treatments (working title) outcome was collected at 26 weeks. Patients who were either • Never to old to get sober: Behavioral treatment for older adults with alcohol use disorder abstinent or performed controlled alcohol use were defined as • Psycho Pathology among elderly alcohol dependent patients who seek treatment treatment successes. • Differences across sites - Elderly alcoholics in Denmark, Germany, and USA • Personal happiness among elderly alcohol dependent patients Results: The study enrolled 693 participants (Figure 1), mean age was 65.5 (SD 4.6) and 60% were men. Follow up rate at 26 weeks • Personal happiness in relation to choices of modules was 78%. • Readiness to change Figure 1: Distribution of participants for each site • Early and late onset of dependency among elderly alcohol dependent patients • Identifying Risk Factors for Late-Onset (50+) Alcohol Use Disorder and Heavy Drinking: A Systematic Review • Clinical characteristics of alcohol use disorders (e.g. MINI, ADS), and in relation to drinking Denmark Germany (N=203) (N=349) • Clinical characteristics of alcohol use disorders (e.g. MINI, over time, and in relation to drinking • Use of Health care and social services (register based)

MET + CRA MET MET + CRA MET • Baseline drinking: When do the patients stop drinking and what is the impact on outcome (n=175) (n=166) (n=103) (n=100) studies? • Hair tests: validation of self-reported alcohol consumption USA • Hair-test: Does underreported alcohol consumption predict bad long term outcome? (N=149) • The alcohol and self-reported stress link among elderly treatment seeking alcohol dependent patients • Methodological paper on the cleaning process MET + CRA MET • Gender paper (n=77) (n=72) • Trajectories of alcohol use and related baseline characteristics • An article of how well different scientific explanations of the relationship between effect At 26 weeks, 51% of patients receiving MET were classified as success, and duration fit in The Elderly Study. as were 56% of patients receiving MET+CRA. Overall the success rate • An article of the validity of the MITI (4.2) and the threshold values for MI-behavior stated in was 53%. the MITI in The Elderly Study. • An article of the impact of research assessments in The Elderly Study.

Funded by: Lundbeck Foundation, Region of Southern Denmark, and • Why do some older adults start drinking excessively late in life? Results from an Interpretative Phenomenological Study University of Southern Denmark • How do family pressure, health and ambivalence factor into entering alcohol treatment?

International collaboration : Funded by:

Randi Bilberg Klinisk Institut

J.B. Winsløws Vej 20, http://www.sdu.dk/en/om_sdu/institutter_centre/ucar 5000 Odense C

[email protected]

+4521379485 137

THE “ S E G T N A N P R O J E C T ” 2017-2024 Mentor: Poul Flemming Høilund-Carlsen 1887 1914 2017

Nansen von Monakow Segtnan

«The Neuronal Diaschisis «Prognostic Value of Doctrine» «Shocked Throughout» Diaschisis»

b 1b

Dementia Neurosurgery Glioblastoma

SEGTNAN METHOD Connectomal diaschisis test Multiple Sclerosis Apoplexia

Cerebrum Cerebellum

Est. 2017

Alcoholism Chronic depression

Dizziness- Audio Epilepsy

2017 2019

Collaborators OUH/SDU: A Gjedde (Neurobiology/pharmacology), Oltmann and Brandt (Programming), Z Iliez (MS), T Nielsen (Neuro-surgery), L Wermuth (Dementia) J Wanscher (Dizziness/Audio), AS Nielsen (Alcoholism), K Andersen (Psychiatry). International collaborators: J Ivanidze (Cornell, USA), A Alavi (Uni.PA, USA), Revheim (UIO, NOR). 138

Genetic and phenotypic heterogeneity suggest

Katrine M Johannesentherapeutic2,3*, Markus Wolff1*, Ulrike BS Hedrich4,* , Silvia Masnada5, Guido Rubboliimplications2,6, Elena Gardella2,3, Gaetan Lesca7,8,9, Dorothée Ville10, Mathieu Milh 11,12in, Laurent VillardSCN2A12, Alexandra Afenjar13, Sandra Chantot-Bastaraud-related13, Cyril Mignot14, Caroline Lardennois15, Carolinedisorders Nava16,17, Niklas Schwarz4, Marion Gérard18, Laurence Perrin19, Diane Doummar20, Stéphane Auvin21,22, Maria J Miranda23, Maja Hempel24, Eva Brilstra25, Nine Knoers25, Nienke Verbeek25, Marjan van Kempen25, Kees P Braun26, Grazia Mancini27, Saskia Biskup28, Konstanze Hörtnagel28, Miriam Döcker28, Thomas Bast29, Tobias Loddenkemper30, Lily Wong-Kisiel31, Friedrich M Baumeister32, Walid Fazeli33, Pasquale Striano34, Robertino Dilena35, Elena Fontana36, Federico Zara37, Gerhard Kurlemann38, Jörg Klepper39, Jess G Thoene40, Daniel H Arndt41, Nicolas Deconinck42, Thomas Schmitt-Mechelke43, Oliver Maier44, Hiltrud Muhle45, Beverly Wical46, Claudio Finetti47, Reinhard Brückner48, Joachim Pietz49, Günther Golla50, Dinesh Jillella51, Karen M Linnet52, Perrine Charles53, Eve Õiglane-Shlik54, 55, John F Mantovani56, Kristen Park57, Marie Deprez58, Emmanuel Scalais59, Laila Selim60, Rudy Van Coster61, Lieven Lagae62, Marina Nikanorova2, Helle Hjalgrim2,3, G. Christoph Korenke63, Marina Trivisano64, Nicola Specchio64, Damien Lederer58, Berten Ceulemans65, Thomas Dorn66, Katherine L Helbig67, Maja Hempel68 , Katia Hardies68, 69, Hannah Stamberger68, 69, 70, Peter de Jonghe68, 69, 70, Sarah Weckhuysen68, 69, 70, Johannes R Lemke71, Ingeborg Krägeloh-Mann1, Ingo Helbig45,72, Gerhard Kluger73,74$, Holger Lerche4$, Rikke S Møller2,3$

1: Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany 2: The Danish Epilepsy Centre, Dianalund, Denmark 3: Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark 4: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany 5: Department of Brain and Behavior, University of Pavia, Italy 6: University of Copenhagen, Copenhagen, Denmark 7: Department of Genetics, Lyon University Hospital, Lyon, France 8: Claude Bernard Lyon I University, Lyon, France 9: Lyon Neuroscience Research Centre, CNRS UMRS5292, INSERM U1028, Lyon, France 10: Department of pediatric Neurology, and Reference Center for Rare Children Epilepsy and Tuberous Sclerosis, Hopital Femme Mere Enfant, Centre Hospitalier Universitaire de Lyon, HCL, France 11: APHM Service de neurologie pédiatrique, Marseille, France 12: Aix Marseille Univ, Inserm, GMGF, UMR-S 910, Marseille, France 13: APHP, Unité de Gènètique Clinique, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire de l’Est Parisien, Paris, France 14: APHP, Département de Génétique; Centre de Référence Défiences Intellectuelles de Causes Rares; Groupe de Recherche Clinique UPMC “Déficiences Intellectuelles et Autisme” GH Pitié-Salpêtrère, Paris, France 15: Service de Neurologie Pédiatrique, Hôpital d’Enfants de La Timone, 13385 Marseille cedex 5, France 16: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, France 17: Department of Genetics, Pitié-Salpêtrière Hospital, APHP, F-75013 Paris, France 18: Service de Génétique Clinique, CHU de Caen 19: Department of Genetics, Robert Debré hospital, APHP, Paris, France 20: AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, Paris, France 21: Université Paris Diderot, Sorbonne Paris Cité, INSERM UMR1141, Paris, France. 22: AP-HP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, Paris, France 23: Department of Pediatrics, Herlev University Hospital, Herlev, Denmark 24: Institute of Genetics, University of Hamburg, Germany 25: Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands 26: Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, the Netherlands 27: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands 28: CeGaT - Center for Genomics and Transcriptomics, Tübingen, Germany 29: Epilepsy Center Kork, Kehl, Germany 30: Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Harvard Medical School, Boston MA, USA 31: Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester MN, USA 32: Children’s Hospital, RoMed Klinikum, Rosenheim, Germany 33: Pediatric Neurology, University Hospital Cologne, Germany 34: Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini' Institute, Genova, Italy 35: Servizio di Epilettologia e Neurofisiopatologia Pediatrica, UO Neurofisiopatologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy 36: Centro di Diagnosi e Cura delle Epilessie Infantili, Azienda Ospedaliera -Policlinico Gianbattista Rossi, Verona, Italy 37: Laboratory of Neurogenetics, Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, 4 "G. Gaslini" Institute, Genova, Italy 38: Department of Pediatric Neurology, University Children’s Hospital, Münster, Germany 39: Children’s Hospital, Klinikum Aschaffenburg, Germany 40: Division of Pediatric Genetics, Metabolism & Genomic Medicine, Ann Arbor, Michigan, United States 41: Division of Pediatric Neurology & Epilepsy – Beaumont Children's Hospital, William Beaumont Oakland University School of Medicine, Royal Oak, Michigan, United States 42: Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium 43: Children's Hospital Lucerne, Luzerner Kantonsspital, Kinderspital Luzern, CH-6000 Luzern 16, Switzerland.44: Children's Hospital, St. Gallen, Switzerland 45: Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany46: Gillette Children's Specialty Healthcare, Saint Paul, MN, USA. 47: Klinik für Kinder- und Jugendmedizin, Elisabeth-Krankenhaus, Essen, Germany 48: Medical Praxis in collaboration with Kinderklinik Ravensburg, Germany 49: University Medical Center for Children and Adolescents, Angelika Lautenschläger Children’s Hospital, Heidelberg, Germany 50: Klinik für Kinder- und Jugendmedizin, Klinikum Lippe GmbH, Detmold, Germany 51: Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA.52: Department of Pediatrics, Aarhus University hospital, Aarhus, Denmark 53: Department of Genetics and Cytogenetics, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France. 54: Children's Clinic, Tartu University Hospital, Tartu, Estonia55: Children's Clinic, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.56: Department of Pediatrics & Mercy Kids Autism Center, Mercy Children’s Hospital, St. Louis, Missouri, United States 57: Department of Pediatrics and Neurology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States 58: Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium 59: Pediatric Neurology Unit, Pediatric Department, Centre Hospitalier de Luxembourg, Luxembourg 60: Department of Pediatrics, Pediatric Neurology and Neurometabolic Unit, Cairo University Children Hospital, Cairo, Egypt 61: Department of Pediatrics. Division of Pediatric Neurology and Metabolism. Ghent University Hospital. Ghent, Belgium 62: Department of Development and Regeneration, Section Pediatric Neurology, University Hospital KU Leuven, Leuven, Belgium 63: Zentrum für Kinder- und Jugendmedizin (Elisabeth Kinderkrankenhaus), Klinik für Neuropädiatrie u. Angeborene, Stoffwechselerkrankungen, Oldenburg, Germany 64: Neurology Unit, Department of Neuroscience, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy65: Kinderneurologie UZA, Wilrijkstraat 10, B-2650 Edegem, Belgium 66: Swiss Epilepsy Center, Zurich, Switzerland67: Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, California, USA 68: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp 69: Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 70: Division of Neurology, University Hospital Antwerp (UZA), Antwerp, Belgium 71: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany 72: Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, United States 73: Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schoen Klinik Vogtareuth, Vogtareuth / Germany 74: PMU Salzburg, Austria

SCN2A mutations are associated with a spectrum of Purpose: Results: epilepsies and neurodevelopmental disorders. - 9 benign neonatal/infantile seizures - 28 encephalopathy with early infantile onset epilepsy (<3 Here, we report the phenotypic spectrum in a large cohort of months), including Ohtahara syndrome (8) and epilepsy of patients, describe the effect of sodium channel blockers (SCBs) on infancy with migrating focal seizures (5) epileptic seizures, and correlate the findings with genetic and - 29 encephalopathy with infantile/childhood onset epilepsy (≥3 functional properties. months of age), including West syndrome (9), Lennox-Gastaut syndrome (6), and focal epilepsies with an ESES-like EEG Fig.1 Distribution of phenotypes pattern (6). - 5 intellectual disability and autism without seizures.

See fig. 1 for distribution

The use of SCBs was associated with significant seizure reduction or seizure freedom in children with early infantile epilepsies, whereas SCBs were rarely effective in epilepsies with later onset.

Truncating mutations were seen exclusively in patients with late onset epilepsies and lack of response to SCB.

Missense mutations associated with early infantile epilepsy and a good response to SCBs, resulted in increased sodium channel activity with gain-of-function (GOF). See figures 2 and 3 for details.

In contrast, mutations in patients with late-onset forms and an insufficient response to SCB were associated with loss-of-function effects (LOF).

Method: 71 unpublished children with SCN2A mutations were collected across multiple centers in Europe and the US. Fig. 3 Treatment response Cases were analyzed regarding genotype, phenotype and response to SCB.

Functional studies were performed in selected missense mutations using whole cell patch-clamping.

Fig. 2 Electrophysical characterisation of 4 different mutations

Conclusion: Our study reflects the large spectrum of SCN2A-related disorders. We establish two distinct groups with seizure onset either before or after three months of age, which show phenotypic differences, GOF vs. LOF effects and a likely related differential response to treatment with SCB

www.filadelfia.dk Correspondance to: [email protected] 139 140

Combination of Imipramine and Pregabalin for the Treatment of Painful Polneuropathy Jakob V. Holbech1, Flemming W. Bach2, Nanna B. Finnerup3, Kim Brøsen4 Troels S. Jensen3, Søren H. Sindrup1 1 Department of Neurology, Odense University Hospital, Odense. 2 Department of Neurology, Aalborg University Hospital, Aalborg. 3 Danish Pain Research Center, Aarhus University Hospital, Aarhus. 1 2 Department4 Clinical Pharmacology, of Neurology, Institute of Odense Public Health, University University Hospital, of Southern Odense. Denmark, Odense,Department Denmark of Neurology, Aarhus University Hospital, Aalborg Hospital, Aalborg. 3 Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark Background and aim

Monotherapy with first line drugs for neuropathic pain often fails to provide sufficient pain relief or

has unacceptable side effects because of the need (NRS) for high doses1. The aim of this trial was to test if * the combination of imipramine (tricyclic * antidepressant) and pregabalin (anticonvulsant) in Pain moderate doses relieve pain more effectively than * monotherapy with each of the drugs. †

Methods Week Figure 1: Change in total pain scores from baseline (0) to week 5 for the 4 different treatments Design (Combination: black, Imipramine: red, Pregabalin: blue, Placebo: green,). Randomized, double-blind, placebo-controlled, 4- * Significantly different from placebo. † Significantly different from each monotherapy. way cross-over. Baseline = 1 week. Treatment periods = 5 weeks, separated by 1 week washout periods. Placebo No other pain alleviating therapy allowed. Treatments a. Imipramine 75 mg/day Pregabalin b. Pregabalin 300 mg/day c. Combination a+b d. Placebo Imipramine Patients Painful polyneuropathy with symptoms for more than 6 months. Combination Age 20-85 years. Pain intensity more than 4 on a 0-10 point numeric rating scale (0 = no pain, 10 = worst pain ≥ 50% pain relief ≥ 30% pain relief Non reponders ever) (NRS). responders responders Pain at least 4 days a week. Primary outcome Median total pain intensity on the NRS during the Figure 2: The 28 out of the 48 per protocol patients who have responded (more than 30% pain relief) to at last week of each treatment period. least one of the treatments. Pain relief is based on changes from baseline in total pain as measured by NRS Secondary outcome (pain diary). Each column represents one patient, ie. the third patient is a responder on all treatments, 30% Pain relief on a 6-point verbal scale. on placebo and pregabalin, and 50% (exact 86%) on imipramine and combination. The figures in the boxes Sleep disturbance on the NRS. are the exact pain reductions in percent. N = no response. C = complete response. Specific pain symptoms (constant burning, constant deep aching, paroxysmal, touch-evoked and pressure-evoked) on the NRS. Consumption of escape medicine in mean tablet Results Conclusion counts of paracetamol.

The effect on average total pain in comparison with Combination of moderate doses of TCA and placebo was: combination - 1.67 NRS points pregabalin is significantly superior to each of the Results (p<0.001), imipramine - 1.08 NRS points (p<0.001) drugs in monotherapy and should be considered as and pregabalin - 0,48 NRS points (p=0.03). an alternative to high-dosage monotherapy. The combination therapy was significantly superior However, the trial also emphasized that balance to each of the monotherapies: combination vs between efficacy and safety is an issue. Screened: 262 imipramine (p=0.009), combination vs pregabalin (p<0.001). Furthermore combination therapy Randomized: 73 showed significant effect on all of the secondary Reference outcome measures. Included in analysis (intention to treat): 69 During combination therapy, the dropout rate was 1 Finnerup NB, Sindrup SH, Jensen TS. The evidence higher (combination n=9, pregabalin n=5, for pharmacological treatment of neuropathic pain. imipramine n=4 and placebo n=4) and the patients Pain. 2010 Sep;150(3):573-81.

reported a higher rate and severity of SE. Supported by Pfizer and Odense University Hospital. The trial drugs were provided by Pfizer and Nycomed. Odense University Hospital 141

(—THIS SIDEBAR DOES NOT PRINT—) Familial Mul>ple Sclerosis: a clinical gene>c and QUICK START (cont.) DESIGN GUIDE epidemiological study on e>ology and courses How to change the template color theme This PowerPoint 2007 template produces an A0 1,2,3 1,2 2 3,4 1,2 You can easily change the color theme of your poster by going presentation poster. You can use it to create your M.Steenhof , K.Brusgaard , K.Kyvik , E.Stenager , J.M.Hertz to the DESIGN menu, click on COLORS, and choose the color research poster and save valuable time placing titles, theme of your choice. You can also create your own color theme. subtitles, text, and graphics. 1. Department of Clinical Gene3cs, Odense University Hospital, Denmark. 2. Department of Clinical Research, University of Southern Denmark,

3. Department of Neurology, Hospital of Southern Denmark, 4. Department of Regional Health Research, University of Southern Denmark We provide a series of online tutorials that will guide you through the poster design process and answer your poster production questions. To view our template tutorials, go online to PosterPresentations.com and Introduc>on Epidemiological study click on HELP DESK. This study is a neurogenetic Ph.D. project involving epidemiological, clinical and molecular Our hypothesis is that the distribution of courses is different in familial MS cases as compared to You can also manually change the color of your background by When you are ready to print your poster, go online to biological aspects of familial Multiple Sclerosis (MS). non-familial MS cases, reflecting differences in the pathophysiology of relapsing and going to VIEW > SLIDE MASTER. After you finish working on PosterPresentations.com The main purpose is to examine epidemiological differences between familial and non-familial progressive MS. the master be sure to go to VIEW > NORMAL to continue MS, and to investigate whether familial progressive MS can be caused by mutations related to working on your poster. hereditary spastic paraplegia. Material: Need assistance? Call us at 1.510.649.3001 We have information on 25,471 MS patients from in The Danish Multiple Sclerosis Register. How to add Text Background Course of MS was first included in The Danish MS Register in 1994, meaning that we have The template comes with a number of pre- Multiple sclerosis is a heterogenic disorder characterized by three different subtypes: primary missing information in the first years. The MS cases missing information on courses are nearly progressive MS (PPMS), relapsing-remitting MS (RRMS) and secondary progressive MS equally distributed among familial and non-familial MS (35% vs. 38%). Information on courses formatted placeholders for headers and QUICK START (SPMS). The etiology behind MS is not fully understood, and around 20 % have relatives with is missing in 4,755 MS cases. In total, we included 7,782 MS cases. text blocks. You can add more blocks by MS. copying and pasting the existing ones or by adding a text box from the HOME menu. Zoom in and out Hereditary spastic paraplegia is characterized by a slowly progressive spasticity in the lower 25,471 MS pa/ents from The Danish Mul/ple Sclerosis Register. As you work on your poster zoom in and out to limbs, the same clinical feature as seen in PPMS patients. Hereditary spastic paraplegia is related Text size the level that is more comfortable to you. Go to mutations in a number of different genes. to VIEW > ZOOM. Adjust the size of your text based on how much content you Timeperiode have to present.

Materials and methods The default template text offers a good starting point. Follow Title, Authors, and Affiliations 12,537 of them are diagnosed from 1994-­‐2014 the conference requirements. Start designing your poster by adding the title, the names of Data are obtained from The Danish Multiple Sclerosis Register, The National Patient Register and The Danish Civil Register for both the epidemiological and the clinical part of the study. the authors, and the affiliated institutions. You can type or How to add Tables paste text into the provided boxes. The template will MS courses: To add a table from scratch go to the INSERT menu automatically adjust the size of your text to fit the title box. 7,782 have informa/on on MS courses and are included in the popula/on for and click on TABLE. A drop-down box will help you You can manually override this feature and change the size of this study select rows and columns. your text. Clinical and molecular gene>c study 7,314 of them are in the non-­‐familial group and 468 are in the familial group. You can also copy and a paste a table from Word or another

PowerPoint document. A pasted table may need to be re- TIP: The font size of your title should be bigger than your The aim of the clinical part of the study is to explore whether hereditary spastic paraplegia is formatted by RIGHT-CLICK > FORMAT SHAPE, TEXT BOX, name(s) and institution name(s). underestimated among familial cases of progressive MS Margins.

Materials: Results: 70

Distribu/on of MS courses for Graphs / Charts

familial and non-­‐familial MS is 60 You can simply copy and paste charts and graphs from Excel 225 PPMS cases from the region of Southern Denmark, shown in the bar chart. A logis/c or Word. Some reformatting may be required depending on were contacted regression analysis is in process. Adding Logos / Seals 50 how the original document has been created.

Most often, logos are added on each side of the title. You can insert a logo by dragging and dropping it from your desktop, 40 Non-­‐familial MS How to change the column configuration copy and paste or by going to INSERT > PICTURES. Logos Familial MS RIGHT-CLICK on the poster background and select LAYOUT to taken from web sites are likely to be low quality when 30 see the column options available for this template. The printed. Zoom it at 100% to see what the logo will look like 119 MS cases are excluded. Respons from 144 (64%) (No rela3ves with MS or no interest in poster columns can also be customized on the Master. VIEW > 20 on the final poster and make any necessary adjustments. par3cipa3ng) MASTER.

TIP: See if your school’s logo is available on our free poster 10 templates page. How to remove the info bars 0 If you are working in PowerPoint for Windows and have RRMS PPMS SPMS Photographs / Graphics finished your poster, save as PDF and the bars will not be included. You can also delete them by going to VIEW > You can add images by dragging and dropping from your In total, 25 families / 35 familial MS cases are included Conclusion (preliminary data): Inclusion is s3ll ongoing, ends July 2017. MASTER. On the Mac adjust the Page-Setup to match the desktop, copy and paste, or by going to INSERT > PICTURES. A difference in the distribution of familial and non-familial PPMS was found (8.8 % vs. 14.3 %) Page-Setup in PowerPoint before you create a PDF. You can Resize images proportionally by holding down the SHIFT key There were no major differences among the distribution of familial and non-familial MS in also delete them from the Slide Master. and dragging one of the corner handles. For a professional- RRMS and SPMS. looking poster, do not distort your images by enlarging them Thus, the distribution of familial and non-familial MS may be different in different courses of MS. disproportionally. Save your work The familial MS cases are invited for clinical interview, pedigree drawing and Save your template as a PowerPoint document. For printing, bloodsamples for molecular gene/c testning using Next Genera/on Acknowledgements save as PowerPoint or “Print-quality” PDF. Sequencing (NGS)

Print your poster When you are ready to have your poster printed go online to

ORIGINAL DISTORTED PosterPresentations.com and click on the “Order Your Poster” Corner handles button. Choose the poster type the best suits your needs and submit your order. If you submit a PowerPoint document you will be receiving a PDF proof for your approval prior to Image Quality Check Using NGS we are sequencing printing. If your order is placed and paid for before noon, Zoom in and look at your images at 100% magnification. If 160 genes related to hereditary Pacific, Monday through Friday, your order will ship out that they look good they will print well. spas/c paraplegia and similar Funding: same day. Next day, Second day, Third day, and Free Ground disorders. The gene panel is Region of Southern Denmarks ph.d funding and research funding (Regions Syddanmarks ph.d. services are offered. Go to PosterPresentations.com for more customized for the study pulje og frie forskningsmidler), Jascha Fonden, Fonden for Lægevidenskabens Fremme information. (Maersk), Aase og Ejner Danielsens Fond

Student discounts are available on our Facebook page. Contact information: Go to PosterPresentations.com and click on the FB icon. Maria Steenhof, MD, Ph.d. Student

Bad prin/ng quality E-mail: [email protected] Good prin/ng quality Results: The molecular genetic testing will be done in the Fall 2017 © 2015 PosterPresenta/ons.com 2117 Fourth Street , Unit C Berkeley CA 94710 RESEARCH POSTER PRESENTATION DESIGN © 2015 www.PosterPresentations.com [email protected] 142

Secondary Injury Mechanisms after Spinal Cord Injury in Mice

Lambertsen group, Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark

INTRODUCTION Contusion spinal cord injury (SCI) results in: • Primary injury, which is irreversible, caused by mechanical trauma. • Secondary injury, which is a wave of toxic neuronal and glial events, leading to an inflammatory response (Figure 1).

Figure 1. SCI is divided into two phases, primary and secondary injury. Modified from (2) The pro-inflammatory cytokine tumor necrosis factor (TNF) is important for Figure 2. XPro1595 is a dominant negative inhibitor of solTNF, leaving the effect of mTNF intact. Etanercept inhibits both solTNF and mTNF. (Courtesy Jessica Ashbaugh) inflammation, demyelination and remyelination following CNS injury. It exists in

two active forms; soluble TNF (solTNF) and membrane-bound TNF (mTNF), which appear to have opposing effects (1,3,4,5). TNF derived from myeloid cells Hypothesis (macrophages and neutrophils) plays a detrimental role in neuroinflammation Our hypothesis is that blocking solTNF expression in infiltrating leukocytes and demyelination, while microglial-derived TNF is neuroprotective (6). We use can reduce lesion size and improve functional outcome after SCI. transgenic mouse models and therapeutic approaches in combination with molecular and behavioural approaches to study the importance of microglial- Aim versus myeloid-derived TNF in SCI. We have shown that epidural inhibition of The primary aim of our studies is to uncover the dichotomy of functions for solTNF is therapeutic following moderate SCI in mice (5) (Figure 2). TNF and its microglial versus myeloid mTNF and solTNF on neuroinflammatory receptors are accessible drug targets, so there is real prospect that this work responses, tissue loss and functional recovery after moderate SCI. lead to new potential neuroprotective targets after SCI.

RESULTS AND CONCLUSIONS

Epidural inhibition of solTNF significantly improves functional outcome, reduces lesion volume and alters the inflammatory response after SCI

Figure 3. BMS scores were comparable in mTNF / , Figure 4. BMS scores in mice treated with anti-TNF Figure 5. XPro1595 significantly reduce neutrophil and macrophage infiltration into mTNFwt/wt, TNF-/- and TNF+/+ mice demonstrating thatΔ Δ therapies demonstrating that epidural administration of the lesioned spinal cord, whereas the microglial population is increased 14 days after genetic ablation of solTNF or germline TNF does not affect the solTNF inhibitor XPro1595 significantly improves SCI. functional recovery after SCI. functional recovery after SCI.

Figure 6. Epidural XPro1595 treatment significantly reduce lesion volume 35 days after SCI. Figure 7. TNFR2 expression is preserved in XPro1595-treated mice.

FUTURE PERSPECTIVES To increase our knowledge of the role of TNF after SCI further we aim to:

• Determine the role of microglial versus myeloid TNF in SCI (Figure 8). • Determine the therapeutic potential of blocking microglial- versus macrophage-derived solTNF after SCI.

We believe that targeting TNF is a feasible clinical approach in SCI and hope to help provide better neuroprotective treatments for patients Figure 8: What are the roles of myeloid versus microglial TNF after SCI. Modified from (1) with SCI.

REFERENCES ACKNOWLEDGMENTS 1. Kwon BK, Tetzlaff W, et al. The Spine Journal (2004). RYK – Rygmarvsskadede i Danmark, IFP - Internationale Stiftung für 2. https://seekingalpha.com/article/307331-invivos-innovative-instigation-in-spinal-cord-injury Forschung in Paraplegie, Zürich, Switzerland, Offerfonden, Aase og Ejnar 3. Clausen BH, Degn et al. Scientific Reports (2016). 4. Madsen PM, Motti D et al. The Journal of Neuroscience (2016). Danielsens Fond, Carlsbergfondet, Fonden til Lægevidenskabens Fremme, The 5. Novrup HG, Bracchi-Ricard V et al. Journal of neuroinflammation (2014). Søren & Johanne Wiibroe Segel’s Research Fund, Overlægerådets Legatudvalg - 6. Gao H DM, Choi CS et al. Cell Reports (2016). OUH, and Lundbeckfonden.

Contact info: Kate Lambertsen ([email protected]), Ditte Ellman ([email protected]) or Minna Christiansen Lund ([email protected]) Department of Neurobiology, Institute of Molecular Medicine University of Southern Denmark

143

Neuroinflammatory Processes in Amyotrophic Lateral Sclerosis

Mads Nikolaj Olesen, M.Sc. Dept. of Clinical Immunology and Biochemistry, Vejle Hospital and Dept. of Neurology, Slagelse Hospital, Institute of Regional Health Research & Institute of Molecular Medicine, University of Southern Denmark

Main supervisor: Nasrin Asgari M.D. Ph.D. Dept. of Neurology, Slagelse Hospital, Institute of Regional Health Research & Institute of Molecular Medicine, University of Southern Denmark

Background

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder which appears mostly idiopathic, however several risk- associated gene variants are known and typically lead to distinct clinical phenotypes. A growing body of evidence suggests an important role for the immune system in disease progression. It is not known if or how the immune system reacts distinctly in patients with risk- associated gene variants.

The Idea

We propose that distinct immune changes occur in patients depending on the disease-associated gene variants, and moreover that differences in the immune response may be associated with distinct clinical phenotypes.

Aims

1) To examine and identify clinical and immunological markers in blood and CSF for the clinical development and progression of ALS Clinical Gene-cs data 2) To investigate whether levels of inflammatory cytokines are associated with specific clinical features or genetic subtypes of ALS Serology CSF Scientific approach and methods

Based on a Scandinavian collaboration, we have access to a large collection of blood and cerebrospinal fluid from clinically characterized ALS patients – all have been genotyped for known disease-associated gene variants. A panel of selected cytokines will be analyzed using Clinically relevant the Simoa™ platform at Dept. of Clinical Immunology and Biochemistry, Lillebaelt Hospital, Vejle immunological markers

SIngle MOlecule Array (SIMOA) digital detection of inflammatory markers Immunohistochemistry Allows for detection with hitherto unprecedented sensitivity Preliminary data: Cross section through a cervical Analog and digital detection. (A) analog measurements give increasing intensity as enlargement of the spinal cord obtained at autopsy from an the concentration increases. (B) By contrast, digital measurements are independent of ALS patient. Increased microglia reactivity is present in the intensity and simply rely on a signal/no signal readout. From Cretich et al, Trends anterior horn of the grey matter and in the white matter Biotechnol, 2015 corresponding to the lateral corticospinal tract, and compared to control area From Wirenfeldt et al, 2016, unpublished

Setup experiment on human CSF:

100 100 IL-10 calibrator Nothing abnormal in 10 10 follow-up n 1 Significant pleocytosis 1 AEB 0.1 r2 = 0.9991 IL-10 pg/mg 0.1 0.01 Limit of quantification

Limit of detection 0.001 0.01 0.01 0.1 1 10 100 pg/ml Parameters: Human CSF 4x pre-diluted sample, neat protocol Project supported by - Grosserer L F Foght Foundation - University of Southern Denmark - Research Council at Lillebaelt Hospital - Region of Southern Denmark

AUTHOR FOR CORRESPONDANCE: Mads Nikolaj Olesen, M.Sc. biochemistry E-mail: [email protected] 144

Does the use of psychotropic medication go up - during focused efforts to bring coercion and restraint down? Mikkel Højlund1,2,4, Lene Høgh1, Povl Munk-Jørgensen2,3 and Elsebeth Stenager1,3,4 1Department of Psychiatry Aabenraa, 2Psychiatric Research Academy Odense, 3Department of Psychiatry Odense. Mental Health Service Region of Southern Denmark and 4Department of Regional Health Research, University of Southern Denmark

6 2013 2016 4

2

Total dose of antipsychotics (DDD) antipsychotics of dose Total 0 All F0x F1x F2x F3x F6x diff: -0.23, p = 0.44 diff: 0.41, p = 0.57 diff: -0.49 p = 0.35 diff: -0.02, p > 0.99 diff: 0.02, p = 0.67 N = 82 N = 99 N = 3 N = 11 N = 14 N = 49 N = 47 N = 10 N = 15 N = 12 N = 20 x = 1.75 x = 1.51 x = 2.80 x = 0.50 x = 0.91 x = 2.32 x = 1.83 x = 1.29 x = 1.27 x = 0.81 x = 0.83

Figure: Comparison af mean total dose of antipsychotic for individual admissions. Squares represent individuals, and bars represent resp. 25% percentile, median og 75% percentile. Comparisons are made by Mann-Whitney U test.

AIM METHODS This project investigates if initiatives to Cohort study which compares exposure to case records, or have been discharged reduce coercion in a ward, leads to antipsychotic medication during the project within 24 hours of admission. increased use of antipsychotic period, with similar admissions from same Data: medications. ward before the project period. Information is obtained through review of Inclusion: case records: Cause and means of BACKGROUND Patients are included in the analysis if they hospitalization, psychiatric diagnoses, Department of Psychiatry Aabenraa have been admitted to the ward during the substance abuse, violence risk, participates in a nation-wide project to first six months of 2013 or 2016, and have a prescriptions and administered doses of reduce coercion and restraint. In order to diagnosis (ICD-10) of F0x, F1x, F2x, F30-31 psychotropic medication is collected from avoid these measures the department or F60-61. day 1 to 7 of admission and at discharge. Doses of antipsychotics are converted to systematically identifies patients in risk, Exclusion: defined daily doses according to WHO, and analyses all prior episodes, have Patients are excluded from the analysis if are compared with Mann-Whitey U test. adequate staffing levels, use they have no prescription history in their deescalating principles and work with patient involvement. RESULTS In this ward the number of episodes with mechanical restraint has decreased from A total of 308 admissions was screened patients was 1.75 DDD in 2013 and 1.51 26 episodes in 2013 to 9 episodes i 2016. (174 from 2013 and 134 from 2016), of DDD in 2016, with a non-significant Analyses of episodes with coercion have which 116 where excluded due to lack of decrease of 0.23 DDD (p=0.44) (See identified that patients in risk are agitated, prescription history or single-day Figure). During the project period quetiapine often with diagnoses of psychotic admissions, leaving 192 for further analyses was the most commonly prescribed disorders, personality disorders or (89 resp. 103 admissions). Among included antipsychotic in fixed doses (38%), followed substance abuse. Episodes occur most patients psychotic disorders were the most by olanzapine (22%), risperidone (18%) and frequently within the first 4 days after frequent (57 resp. 46%) followed by clozapine (15%). As pro necessitate admission. personality disorders (15 resp. 20%), bipolar prescriptions the most common disorder (11 resp. 16%), substance abuse antipsychotic was also quetiapine (50%), As exposure to antipsychotic drugs can (17 resp. 16%) and least frequent organic followed by olanzapine (27%) and contribute to the development of mental disorders (0 resp. 3%). Median total chlorprothixene (17%). cardiovascular disease and reduced dose of antipsychotic medication for all mortality, it is important that reduced coercion does not result in increased exposure to these drugs. CONCLUSION There are no exact information available Reduction of coercion at the Department of Psychiatry Aabenraa has not led to increased of this exposure in this specific population, consumption of antipsychotic medication. but it is paramount for the overall evaluation of the efforts to reduce coercion.

Contact information: [email protected]

Presented at the 25th European Congress of Psychiatry, 1-4 April 2017, Florence, Italy EPA17-0263 145

TRANSLATIONAL MULTIOMICS OF DE- AND REMYELINATION Nellie A Mar*n, Viktor Molnar, Arkadiuz Nawrocki, Maria L Elkjær, Eva K Thygesen, Justyna Okarmus, Agnieszka Wodarczyk, Ferenc Gallyas Jr, Nicolas Alcaraz, Eudes GV. Barbosa, Kirs*ne Juul Elbæk, Helle H Nielsen, Tobias S Mathiesen, Mar*n R. Larsen, Jan Baumbach, Péter Ács, Miklós Palkovits, Zoltán Hegedús, Finn Sellebjerg, Allan Stenballe, Eirikur Benedikz, Trevor Owens, Hans Lassmann, Asa F Svenningsen, Zsolt Illes

Mouse: Cuprizone (CPZ) model of Human: Mul?ple Sclerosis experimental de- and remyelina?on

Induc*on of: Mul*ple sclerosis (MS) Transcriptome § early demyelina*on (2 weeks) - Data from open acces datasets § full demyelina*on (4 weeks) § acute remyelina*on ( 2 days) § full remyelina*on (2 weeks)

microRNA microarray dataset Transcriptome dataset 3 differen*ally expressed microRNAs 1239 differen*ally expressed genes

miR-146a miR-193 miR-181b 5

4

3

2 CSF proteomics

relative expression Iden?fica?on of de- and relative expression relative expression 1 Genes all expressed during 0 progressive MS (n=57) 2wr remyelina?on related Ctrl 4wd 2dr 2wr Ctrl 4wd 2dr 2wr Ctrl 4wd 2dr acute remyelina?on relapsing MS(n=40) Varifica*on at protein level in CPZ model genes in MS (n=98)

Targeted proteomics of 132 pep?des:

In vivo: In vitro: Cellular source: microglia miR-146a KO Iden?fica?on of poten?al MS biomakers: and WT mice

APOC2 B2MG UFO (AXL) TIMP1 CPZ ** ** * **

* **

miR-146a KO mice are protected against CPZ induced demyelina*on and axonal loss: RRMS SPMS PPMS RRMS PPMS RRMS SPMS PPMS RRMS PPMS

Demyelina*on Axonal damage miR-146a KO microglia cells are more prone to ac*va*on: Expression of TNF in response to LPS correla*on with inflamma*on (36 markers) (lep) and myelin (right): no correla*on with axonal damage (neurofilament) WT WT miR-146a KO

*** *** *** *** *** IL-6 IL-6 IL-6 IL-6 IL-2 IL-2 IL-16 IL-16 KO *** TIMP1 UFO APOC2 APOC2

Department of Neurology, Ins*tute of Clinical Research, University of Southern Denmark (SDU)/ Odense Universitry Hospital (OUH), Denmark; Department of Neurobiology, Ins*tute of Molecular Medicine, SDU Odense, Denmark; Department of Neurology, University of Pecs Medical School, Pecs, Hungary; Department of Gene*cs, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary; Department of Biochemistry and Clinical Chemistry, University of Pecs, Pecs, Hungary; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark; Department of Anatomy, Histology and Embryology, Semmelweis University,1085 Budapest, Hungary; Center for Brain Research, Medical University of Vienna, Vienna, Austria Funding: Lundbeckfonden, OTKA, Region of Southern Denmark, Jascha Fonden, Direktør Ejnar Jonasson kaldet Johnsen og hustrus mindelegat, Odense University Hospital, Fonden for Lægevidenskabensfremme 146

MIF increases regeneration in the CNS Simone Hjæresen and Åsa Fex Svenningsen Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark

MIF and HTRA1 The functions of MIF and HTRA1 in glia cells of the CNS MAP-2/MIF RIP/MIF MIF is a protein with hormone-, cytokine and enzyme-like properties. MIF regulates cell proliferation, apoptosis and migration of many Astrocytes different cell types via the receptors CXCR2, CXCR4 and CD74. Because of the dysregulation of MIF and HTRA1 in the RRMS patients, we investigated MIF and HTRA1s effect on astrocyte migration

MAP-2/HTRA1 RIP/HTRA1 the function of the MIF-HTRA1 binding. It is 2 15

MIF is widely expressed in most tissues m known that FGF-8 increases astrocyte c **** **** **** n including most cell types in the CNS (Figure 1). i migration and is a target of HTRA1, we c h

t 10 therefore tested the MIF-HTRA1 interaction on a

MIF has been implicated in the pathology of c r s n

many different diseases (Figure 2). this. i

n 5 o i

We have identified a new binding partner to c t u

MIF inhibited HTRA1’s proteolytic effect on d

GFAP/MIF Figure 1 shows the protein MIF - the serine protease HTRA1. e expression of MIF and FGF-8 and restored the FGF-8 induced R 0 HTRA1 in different cells in l ntro GF-8 RA1 MIF l MIF trA1 the CNS as well as MIF HTRA1 cleaves several known growth factors increase in astrocyte migration (Figure 4). Co ml F + HT A1 + g/m /ml H ng/ F-8 HTR 50 n 5 ng mRNA expression 25 FG -8 + 12, thereby inhibiting their growth-stimulating FGF properties. Figure 4 shows the effect of the MIF-HTRA1 binding on astrocyte migration GFAP/HTRA1 Some of its known targets are; is IGF-BP-5, MIF and HTRA1 itself did not have any FGF-8 and TGF-β. significant impact on astrocyte migration, but if Blocking of MIF receptors in astrocytes 25 the MIF receptor CXCR4 is blocked astrocyte % n i

MIF binds HTRA1 both at its PDZ and protease migration is increased too (Figure 5). h 20 **** c t a

domain and MIF can therefore inhibit HTRA1’s r

c 15 proteolytic properties. s n A i

N MIF mRNA expression in CNS cell types n R When examining the MIF receptors 10 o m 0.20 i t F I c

M expression in astrocytes we saw that the

u 5 f 0.15 d o Multiple e n astrocytes express the CXCR4 receptor at o R

i Rheumatoid

s sclerosis 0

s 0.10

e arthritis very high levels (Figure 6). r ol dy ist p ontr ibo on x C ant ntag e g a 0.05 **** ckin R4 e blo CXC v 4 µ i CXCR2 CXCR4 CD74 D7 M t l C 50 a µg/m v 0.00 5 e

l Alzheimers ) ) ) ) ) e in + n + + + Psoriasis ra 4 io a -2 B Figure 5 shows the effect of the MIF receptors CD74 and R h B (O ct lp A 11 le es le -a CS D ho yt se R A (C CXCR4 on astrocyte migration W c ll F s ( ia ro ce DG te gl nd e P y ro e iv s ( oc ic od at C tr M ig g P s ol ne O A e s ( ur n at ro m eu Sceptic MIF Im N HtrA1 shock Cerebral Figure 6 shows the protein expression of known MIF receptors in astrocytes small vessel Mild Figure 2 shows all the disease disease pathologies MIF cognitive Oligodendrocytes and HTRA1 has been impairment implicated in Parkinson Cancer disease The addition of MIF significantly increases proliferation of oligodendrocyte precursors (OPCs) MIF and HTRA1 concentrations (Figure 7). in the CSF of RRMS patients

MIF has previously been implicated in the disease pathology of Multiple sclerosis, but MIF concentrations in CSF has not been thoroughly investigated. Figure 7 shows the effect of MIF on OPC proliferation In CSF samples from patients with RRMS 250 %

n Microglia we found a significant difference in the i 200 n

levels of both MIF and HTRA1 compared to o i t

a 150 It is known that MIF inhibits a shift in microglia from the anti-inflammatory M2 phase the healthy controls. r t n

e (non-migrating) to the pro-inflammatory M1 phase (migrating). It is also known that

c 100 * The MIF concentration is reduced in the MS n * microglia secrete MIF by themselves. We blocked MIF using the MIF antagonist o c 50 ISO-1 and blocking antibodies to MIF’s most common receptor CD74.

patients compared to controls (Figure 3). F I M There was no difference in MIF between 0 We found that blocking MIF increased microglia migration and that this can be ls e e ntro has has co ing p ng p relapses and times of remission (Figure 3). althy psn mitti mediated via the MIF receptor CD74. He Rela Re HTRA1 was significantly higher in the Blokcing of MIF in microglia Blocking of the CD74 receptor in microglia patients both in the relapsning and HtrA1 concentrations in CSF 60 60 % remitting phase (Figure 3). 300 % % n n i * i * n i h h c c n t *** t a o We also found a correlation between the a i

r 40

r 40 t **** c 200 c a s s proteins in the healthy controls. When MIF r t n n n i i

is low, HTRA1 is high. e n c n o n o 20 20 i i t o 100 t c c c u u 1 d d A e e r t This is interesting because HTRA1 has not R R 0 H 0 0 previously been associated with MS and ol IF y SO O-1 ontr l M ibod ols se se DM µ IS C ng/m ant ontr pha pha ,1 % 0 M 50 king currently the data regarding MIF in MS is hy c tting ning 0 10 bloc ealt emi laps D74 H R Re /ml C conflicting. Both an increase and decrease 5 µg concerning MIF has been suggested. Figure 3 shows the concentrations of MIF and HTRA1 in CSF Figure 8 shows the effect of the MIF antagonist ISO-1 and CD74 blocking antibody on microglia migration from MS in the relapsing and remitting phase compared to healthy controls

5 At a later timepoint MIF might reduce the 4 The released MIF migration of astrocyte through the will bind HTRA1 CXCR4 receptor. A receptor known to be leading to increased associated with increased migration of availability of growth oligodendrocyte to the white matter in Conclusion factors, including mice after an injury FGF-8 that increases astrocyte 3 MIF inhibits microglia migration entering the M1 phase and reduces migration (and MIF is reduced in the CSF of RRMS patients while HTRA1 is increased in CSF of the perhaps inflammatory resopnse) same patients MIF inhibits the enzymatic activity of HTRA1 and this affects astrocyte migration 1 MIF is directly involved in proliferation of OPCs and the migration of microglia cells 2 The released MIF increases OPC proliferation The new The data suggest that MIF may be important in regeneration processes after a MIF is OPCs can replace the dead released from oligodendrocytes intracellular storage upon relapse or injury injury 147 148

Prenatal exposureto pesticides and neurodevelopmental disorders in children Bettina Fage-­Larsen, MD1, Helle Raun Andersen, PhD2, Niels Bilenberg,PhD 1 1)Department of Child and Adolescent Mental Health Odense, Research Unit, Mental Health Services in the Region of Southern Denmark,J.B. Winsløwsvej 16, indgang 230, 5000 Odense C, bettina.fage-­larsen @rsyd.dk 2) Environmental Medicine, Department of Public health, University of Southern Denmark, Odense.

Objectives Preliminary results Methods

To examine whether there is an association between Odds ratio a (95% CI) for ADHD cbcl score above the 90 percentile (pct ) in q This is a prospective, observational cohort prenatal exposure to insecticides and the prevalence of children at 2,5 years of age and maternal urinary concentrations of 3-­ PBA (metabolite ofpyrethroids ) and TCPY (metabolite chlorpyrifos of ) study, embedded in the Odense Child Cohort neurodevelopmental disorders (NDD) in preschool (OCC) study which follows approximately children. Boys (N=308) Girls (N=281) 2,500 children from pregnancy to age 18-­year. Number of 308 281 q Part of the SAFARI study which investigates We hypothesize that pregnant women's exposure to low chlidren (N) the importance of social, family and doses of neurotoxic insecticides through food can affect environmental factors for development of N with ADHD 58 35 the development of their children’s central nervous ADHD score > 90pct system and increase their risk of developing symptoms q Measures: of ADHD. 3-­PBA above 3.00 (1.59;; 5.66)* 1.26 (0.61;; q Spot urine samples from mothers on median 2.58) their 28. week of gestation analyzed Findings will be implemented in the municipalities as for metabolites of insecticides. TCPY above 0.89 (0.50;; 1.60) 0.66 (0.32;; part of a preschool ADHD risk index and thus benefit the q Child behavior Checklist (CBCL) to median 1.35) entire child population. assess symptoms of ADHD 3-­PBA+TCPY 4.25 (1.60;; 11.33)* 1.00 (0.32;; (both above 3.11) median)

* p<0.01;;a adjusted for maternal education level Background Perspectives Maternal spot urin samples ADHD symptoms assessed ADHD symptoms assessed analysed for insecticide with CBCL with CBCL. Worldwide NDD-­ including ADHD -­ affect millions of metabolites N=1796 Urin samples from the children This study may contribute important knowledge: N=957 analysed for insecticide metabolites children leading to severe mental and social impairment in (ongoing) adulthood and large costs for the society. q About the consequences of insecticide exposure on Both genetic and environmental factors influence the OCC children’s development, health and wellbeing N=2500 q development of ADHD. Neurotoxic chemicals such as families On how the chemical environment affects the pesticides are suspected to cause permanent damage to the 28.week of gestation 2,5 years of age 5 years of age development of ADHD fetal brain, increasing the risk of ADHD. Pesticides are used in large amounts in Denmark and This study may contribute: abroad and residues is known to be present in 50% of fruit, vegetables and breakfast cereals, and more than 25% q To future regulation of permissible pesticides residue contain more than one pesticide. levels. Setting of maximum residue levels (MRLs) for pesticides in q To recommendations on how to avoid harmful foodstuffs does not include data on potential developmental pesticide residue and which foods carry a particularly neurotoxicity. high risk of exposure 149

Personal experiences of recovery facilitated by participation in an individual placement and support intervention I Gammelgaard, E. Stenager, L. Eplov, KS Petersen

Background: Conclusion: The Individual Placement and Support in- tervention (IPS) supports people with se- IPS and employment; vere mental illness in achieving competi- ...impact personal recovery tive employment and is labelled a recovery oriented intervention. ...may influence negative symptoms Aim: The aim of the study was to investi- gate how IPS and employment influences personal and clinical recovery in people ...have no effect on psycotic symptoms with severe mental illness. Method: A qualitative study including in- created an equal, acknowledging and safe relationship terviews of 12 participants in an IPS inter- where participants’ needs were taking into consideration vention in the search and support for job or education. Results: IPS contributed to both personal In combination with employment the role of the IPS con- and clinical recovery: sultant contributed to normalization and stabilisation of Personal Recovery: The IPS consultants participants’ daily lives and changed their behaviours and beliefs about obtaining new achievements, personal goals and dreams. Clinical Recovery: IPS and employment may influence the work function and decrease depressive and negative symptoms, but do not seem to impact psychotic symp- toms. Mixed-Method-Study

RCT (n=716) Qualitative interviews (n=12)

Results Analysis

Merging

Discussion and Conclusion 150

Optic neuritis: Clinical, Immunological and experimental aspects. A translational research project Kerstin Soelberg M.D. Main supervisor: Nasrin Asgari M.D. Ph.D. Dept. of Neurology, Slagelse Hospital, Institute of Regional Health Research & Institute of Molecular Medicine, University of Southern Denmark

“The eye is the window to the brain” Background

Optic neuritis (ON) is a common inflammatory optic neuropathy primarily The optic nerve is an area of in young adults that is highly associated with multiple sclerosis (MS) and the CNS where the blood antibody-mediated ON. Clinically ON manifests typically as a sub-acute brain barrier is most episode with decreased vision and pain on eye movement. Some permissive. AQP4 is densely localized and expressed by patients have persistent visual problems. Differentiation of acute astrocytes that surround the episodes of MS-ON from antibody-mediated ON is important due to optic nerve. MOG is highly differences in prognosis and therapy. expressed in the optic nerve Soelberg et al unpublished Methods Clinical study: A prospective cohort study of patients with idiopathic ON in the Region of Southern Denmark from 2014-2016 with a one year follow-up was performed including acute ON evaluation. Patients were seen in a coordinated diagnostic investigation including clinical examination, analysis of blood and cerebrospinal fluid, measurement of visual field, visual evoked potentials (VEP), optical coherence tomography (OCT) and MRI of the brain including the orbit. Experimental study: An antibody-mediated ON mouse model was established in C57BL/6 mice by intrathecal injection of ON patient-derived IgG + human complement into the CSF at cisterna magna. Results Clinical studies: OCT findings in patients with optic neuritis Sixty-three patients were evaluated and 52 fulfilled the This patient were criteria for ON. All were Caucasian, with a female:male diagnosed with MS in the clinical follow up ratio of 2.2:1 and a median age at onset of 38 years A: OCT findings in the acute episode of ON. (range 16-66). B: 1 year follow up Studies in progress: which shows temporal atrophy of the retinal 1. Identification of biomarkers in blood and CSF A nerve fiber layer. B 2. Analysis of optic nerve and retinal ganglion cell status by MRI and OCT in ON patients C: OCT illustrates normal RNFL thickness Experimental study: in a control eye D: OCT shows general Pathogenic mechanisms of antibody-mediated ON in the RNFL atrophy in an mouse model. We will investigate optic nerve MOG-IgG seropositive patient astrocytopathy, demyelination and retinal cell damage D using histological and molecular biological methods C (flow cytometry and quantitative PCR analysis).

Optic nerve MRI findings Experimental antibody-mediated optic neuritis model B: Isolation of optic nerve Coronal image Axial image Parasagittal image A: Experimental design

Cisterna Magna

A B C MRI findings in acute optic neuritis in a patient with intraorbital lesion in the A: A single intrathecal injection of ON patient-derived aquporin-4-IgG is right optic nerve. 3D Fluid-attenuated inversion recovery (FLAIR) administered into the CSF. sequences coronal (A) axial (B) and parasagittal (C). MRI images reveal B: Visualization of anatomical structures of human brain and the anterior high-signal-intensity lesions in the right optic nerve (arrowheads). The visual system in the mouse brain. The anatomical structures include the optic patient presented with ocular pain and loss of visual function. nerve(red), optic tract(green) and chiasma optica(yellow). Optic nerves including optic chiasma were isolated from mice

Perspective: This translational study will provide new insight in ON disease pathogenesis and may lead to improvement in diagnosis and treatment.

Publications: PMID: 27802824: We reported a case of antibody-mediated ON in the context of thyroid cancer expressing high-level AQP4, expanding the spectrum of paraneoplastic autoimmunity, which target this antigen. PMID: 27354988: Afferent visual system damage after ON in MOG-IgG-seropositive patients observed by OCT and reported in a multicenter international collaboration.

AUTHOR FOR CORRESPONDANCE: Kerstin Soelberg, MD, PhD student E-mail: [email protected] 151

Regulatory mechanisms in neuroinflammation

Trevor Owens Lab. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark

Innate regulation of Neuroinflammation

Type I IFN Neuroinflammation IL-10 Type I IFN IL-10 Homeostatic/Repair pathways Type - Debris Clearance I IFN - Myelin Repair IL-10 Microglia Type I IFN Antibody- mediated pathology Astrocytopathy (NMOSD) Demyelination (NMOSD, MS) Blood-derived monocyte/ macrophages

Tissue damage or Type Infection I IFN IL-10 (DAMP or PAMP) Suppression of MS-like Transplantation Transplantation disease (EAE)

Microglial subsets in Microglia developing and adult CNS

Pregnancy associated remission 152

Cognition and Functioning in the Oldest-old Epidemiology and Genetics Mikael Thinggaard1,2, Marianne Nygaard1, Signe Høi Rasmussen1,3, Karen Andersen-Ranberg1,3, James W. Vaupel1,2,4, Matt McGue1,5, Axel Skytthe1, Bernard Jeune1, Lene Christiansen1, Kaare Christensen1,2,6,7

BACKGROUND AND AIM TAKE HOME MESSAGES • The improved survival among older • At a population level, cognitive and people has led to an increasing physical function is constant from age proportion of exceptionally long-lived 93 to age 100 individuals • Exceptional longevity does not appear • It is unknown whether this increase to be associated with higher levels of has resulted in today’s oldest-old being cognitive impairment more disabled or in better functional • 95-year olds born in 1915 have a better health than their latter-day overall functioning that 93-year olds counterparts born in 1905 • Aim: To assess the health and cognitive • Cognitive function is influenced by and physical functioning of the very old genetic factors, e.g. by variations in the • In addition, genetic determinants of APOE gene that is also involved in exceptional functioning at the highest Alzheimer’s disease ages have been explored.

WITHIN COHORTS: AGE TRAJECTORIES ACROSS COHORTS: A SUCCESS OF SUCCESS

The 1905 Birth Cohort Study The 1905 vs the 1915 Birth Cohorts: A Comparison Study Participation rates varied from 58-78% in each of the 4 waves. 1905: Participants aged 92-93 y (participation rate 61%)

On average: Stable level of cognitive and physical functioning from 1915: Participants aged 94-95 y (participation rate 61%) age 92-93 to age 99-100 .

Mean cognitive score 25 Cognition and functioning 22.8***

20

21.4 0.5*** 15 2.3*** 2.1 0 1905 1.9*** 10 1915 1.7

5 1905 1915 0 *** = p<0.001 MMSE Cognitive ADL: Males ADL: Females Christensen et al, PNAS 2008 composite Christensen et al, Lancet 2013 GENETICS OF COGNITION: PREVIOUS, CURRENT AND FUTURE STUDIES Previous and on-going genetic studies: • Studies of both common and rare variants in candidate genes, e.g. genes previously shown to be associated with neurodegenerative diseases or diseases affecting the cognitive function, like Alzheimer’s disease • Examples of candidate genes are APOE, CLU, PICALM, KLOTHO, and CR1 • Genome-wide studies of common genetic variants, epigenetic variation or gene expression levels

Future genetic studies: • Investigation of polygenetic risk scores and the genetic overlap between Alzheimer’s disease, education and cognitive function among the oldest-old • Studies of copy number variants

CORRESPONDING AUTHOR: MIKAEL THINGGAARD; [email protected]

1Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, Denmark References 2Max-Planck Odense Center on the Biodemography of Aging, University of Southern Denmark, Odense, Denmark Christensen, Kaare, et al. "Exceptional longevity does not result in excessive levels of disability." Proceedings of the National 3Department of Geriatrics, Odense University Hospital, Odense, Denmark Academy of Sciences 105.36 (2008): 13274-13279. 4Max-Planck Institute for Demographic Research, Rostock, Germany

5 Christensen, Kaare, et al. "Physical and cognitive functioning of people older than 90 years: a comparison of two Danish Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA 6 cohorts born 10 years apart." The Lancet 382.9903 (2013): 1507-1513. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark 7Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark

UNIVERSITY OF SOUTHERN DENMARK 153