DEPARTMENT OF NEUROSCIENCE ANNUAL REPORT

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1 DEPARTMENT OF NEUROSCIENCE ANNUAL REPORT 2007 Med tillstånd från Dr. Nicolas Rougier

2 INTRODUCTION History and Organization The Department of Neuroscience covers a broad range of basic and clinical research and education on the nervous system. The Department was formed in 1998 by the fusion of ten previous basic science and clinical departments, with the addition of the Neuroanatomy group from the former Department of Anatomy. In 2002, parts of the former Department of Physiology and in 2003 the unit of Comparative Medicine were incorporated into the Department of Neuroscience. A further expansion took place in 2005 when a unit in Speech Physiology and Pathology and a research group in Molecular Genetics Developmental Neuroscience were added to the Department. Today, the Department has about 130 employees, 80 PhD students, and a large number of postdoctoral fellows. In addition, the clinical research groups include numerous clinicians employed by the University Hospital, but with part-time obligations within the teaching and research responsibilities of the Department. The preclinical research groups are reasonable well concentrated in the facilities of Uppsala University Biomedical Center, but the clinical research groups are currently spread out in four different buildings in the main University Hospital campus, and a fifth site, the Ulleråker grounds. The Department is striving towards concentrating its operations. As part of these efforts, the units for Physiotherapy and Speech Physiology and Pathology are anticipated to move from their current separated location in the university hospital site to the Biomedical Center within the next one-two years. The organizational expansion of the Department has been associated with a strong expansion also in educational commitments, and research activities. Although administrative reasons were important for the faculty reorganization in 1998, the long-term intentions of forming a joint Department from a large number of preclinical and clinical neuroscience oriented Departments is to strengthen neuroscience research in Uppsala. This is a challenging task, given the joining units differences in administrative, teaching and research culture, and geographically dispersed. A major has task until recently has therefore been to consolidate the Department s basic organization as well as to find synergies in teaching and areas for cooperative research. Research Directions and Strategies The recent years have witnessed more focused efforts to concentrate the Department s research competencies and resources towards a limited number of research themes. These emerged from the external evaluation Quality and Renewal 07 which took place in June and from subsequent bottom-up internal discussions. The external evaluation pointed out several strong research programs within the Department, including the research in clinical neurophysiology, functional neuronal networks, neurotrauma and related experimental areas, as well as in pharmacology. Important factors in the subsequent Departmental discussions were i) to build upon already existing strong and promising research areas, ii) to make workable bridges between preclinical and clinical research, and iii) to create opportunities for novelty by bringing research groups from a wide range of disciplines together. As a result four thematic areas briefly described below have been defined as priority areas for the Department. A central task for the Department in the near future will be to strengthen these areas, e.g. by creating new interdepartmental cooperative activities, promote high- level PhD - 2 -

3 education and the establishment of key technological and competence platforms, as well as in the consideration of new recruitments. Body weight control. This area encompasses basic science research on regulation of appetite, food intake, the gastrointestinal tract, and muscle wasting, and clinical research on eating disorders, physical training and behavioural medicine. Neuronal networks and plasticity. This area encompasses basic science on the development and function of specific neuronal networks and their modifications following injury or disease. Model systems range from spinal locomotion and nociceptive processing to forebrain, and the basic research connects to clinical research on e.g. amyotrophic lateral sclerosis (ALS), chronic pain and neurologopedics. Neuropsychiatric genetics. This area focuses on understanding the genetics of disorders with neurological and psychiatric components, as an entrance to elucidating their pathophysiological mechanisms. The research has it foundations in clinical neurology and psychiatry, and connects to basic science in neurogenetics, neurobiology, and transgene technology. Neurotrauma. This area explores experimental models of brain and spinal cord injury, with the aim of identifying targets for neuroprotection and strategies for neuroregeneration, which are candidates for translation to clinical intervention. Within this theme clinical research aimed at optimizing early intensive care treatment, as well as post-injury rehabilitative programs are prime topics. The Department has a major role in Uppsala Brain Injury Center (see It is anticipated that the conceptual focus on these areas in combination with pro-active measures by the Department will gradually pay off, e.g. in scientific impact, national and international recognition, attraction of young promising scientist, as well as in increased success rates in the competition for major national and international funding. Recruitment Strategies The Department is in the middle of a period during which a large number of highly qualified teachers/scientists will retire or have already done so. To replace this loss of competence is a challenging and difficult task. It is, however, rewarding that there is a great interest for basic as well as clinical neuroscience among undergraduate students/clinicians. The limited time for research is, however, a serious obstacle for clinicians. It is also rewarding for the Department to have three junior and four senior research positions, two of them for part-time clinical research, funded by the Swedish Science Council. One of the holders of a senior Science Council research position was awarded a prestigous five-year research postion funded by the Royal Academy of Science. These individuals are important for the ongoing and future renewal of the Department s research. Active recruitment processes have also started concerning professor or senior lectureship positions in Neurosurgery, Ophtalmology, Pharmacology, Physiology, Physiotherapy and Psychiatry. The Department anticipates that these positions will be filled during A critical position to be filled is the Chair in Neurology, which has now been vacant since This situation, as has also been noted with other recently advertised positions, appears to reflect a decreasing mobility among Swedish medical researchers

4 Undergraduate/Advanced Education The Department s educational responsibilities have expanded during recent years. The most extensive involvements are within the Physiotherapy program, the Speech pathology and therapy program, and the Psychiatry program for nurses specializing in psychiatry. The Department has played a major role in launching the Speech pathology and therapy program and the establishment of an educational unit for this program within a neuroscience department is unique at the national leve. The Department also has extensive commitments also exist within the Biomedical, Medical and Receptarie programs. The Department has played and continues to play an active role in the efforts of the faculty to modernize the contents and improve the teaching methods of these programs. In addition, the Department is heavily involved in the pioneering Master program Public Health, and further Master programs are at the planning stage. Conclusion Given the qualified and dedicated staff of the Department, I look forward to meeting the challenges of 2008 with confidence and excitement, and anticipate that we will move closer to the joint scientific and educational goals we have set out. Uppsala, 28 th of April 2008 Håkan Aldskogius, MD, PhD Professor, Chairman - 4 -

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6 List of Contents ORGANIZATION 8 ADDRESS LIST 11 SCIENTIFIC REPORTS 17 Clinical Neurology & Psychiatry 18 Neurology 18 Neurodegenerative Disorders (Håkan Askmark) 18 Epilepsy and Low-grade Glioma (Anja Smits) 20 Clinical Neurogenetics (Atle Melberg) 23 Stroke and Stroke-related symtoms (Hans Naver) 24 Clinical Neurophysiology 27 Neuromuscular (Lars Larsson & Erik Stålberg) 27 Peripheral Nervous System (Erik Torebjörk) 29 Central Nervous System (Roland Flink) 30 Psychiatry 34 Psychiatry (Lars von Knorring) 34 Cognitive Psychiatry (Lisa Ekselius) 38 Schizophrenia (Tommy Lewander) 42 Neurobiology (Anders Fredriksson) 49 Child and Adolescent Psychiatry (Anne-Liis von Knorring) 50 National Center for Disaster Psychiatry (Tom Lundin) 52 Experimental Neuroscience 55 Genetic Developmental Biology (Klas Kullander) 55 Neuron-Glia Communication (Åsa Fex-Svenningsen) 68 Neurobiology (Dan Lindholm)

7 Ophtalmology & Retina Biology 73 Ophtalmology 73 Glaucoma (Albert Alm) 73 Paedriatric Ophtalmology (Gerd Holmström) 79 Retina Biology (Finn Hallböök) 82 Physiology & Pharmacology 86 Physiology 86 Gastrointestinal Physiology (Gunnar Flemström & Olle Nylander) 86 Cell Physiology (Jyrki Kukkonen) 88 Comparative Medicine (Hans-Erik Carlsson & Klas Abelson 90 Pharmacology 95 Pharmacology (Dan Larhammar) 95 Functional Pharmacology (Helgi Schiöth) 99 Neuropsychopharmacology (Lars Oreland) 104 Neurotrauma & Restorative Neuroscience 108 Neurosurgery 108 Clinical Brain Injury Program (Per Enblad) 114 Experimental Brain Injury Program (Lars Hillered) 116 Molecular & Genetic Analysis of Traumatic Brain Injury (T. Ebendal)117 Regenerative Neurobiology (Håkan Aldskogius & Elena Kozlova) 119 Physiotherapy (Birgitta Lindmark) 123 Rehabilitation Medicine (Jörgen Borg)

8 ORGANIZATION Department board Chairman Deputy chairman Research groups Research committeee Director of undergraduate studies Chief administrator Director of graduate students Course leader of undergraduate studies Personnel administration Course administration Financial administration Chairman Håkan Aldskogius Deputy Chairman Lisa Ekselius Department board Lisa Ekselius, teacher representative Per Enblad, teacher representative Lars Hillered, teacher representative Dan Larhammar, teacher representative Finn Hallböök, teacher representative Gun Schönnings, representative for technical/administrative personnel Birgitta Klang, representative for technical/administrative personnel Torsten Danfors, graduate student representative ) Mikael Corell,, graduate student representative ( ) Mats Ryttlefors, graduate student representative (from ) deputy ( ) Josefine Sveen, graduate student representative (from ) Anne-Li Lind, student ( ) Dan Jacobson, student ( ) Theodora Kallak, student (from ) Carl Johan Drott, student (from ) Andrea Sandberg, student (from ) - 8 -

9 Frits-Axel Wiesel, teacher representative, deputy (deceased November 2007) Birgitta Lindmark, teacher representative, deputy Anja Smits, teacher representative, deputy Anders Fredriksson, representative for technical/administrative personnel, deputy Maude Karlsdotter, representative for technical/administrative personnel, deputy Johan Alsiö, graduate student representative, deputy ( ) Anders Hånell, graduate student representative, deputy (from ) Gunilla Elmgren-Frykberg, graduant student representative, deputy (from ) Hannah Karlsson. student, deputy (from ) Chief administrator Lena Karlsson Director of graduate students Birgitta Lindmark Finn Hallböök Director of undergraduate studies Lisa Ekselius Gunnar Flemström Finn Hallböök Jarmila Hallman Karin Hellström Dan Larhammar Ingrid Lundell Peter Mattson Administration Birgit Andersson Else-Marie Andersson Marita Berg Lena Bohlin Pia Fredlund Theodora Fredriksson Marianne Jonsson (retired May 2007) Ulla Jonson Anki Gustafsson Berit Hård-Wallenqvist Inger Hedlund (started June 2007) Maude Karlsdotter Birgitta Klang Maria Larsson (started June 2007) Gun Schönnings Lotta Sjölander Lottie Söder Cecilia Yates - 9 -

10 Research committee Birgitta Lindmark Finn Hallböök Klas Kullander Helgi Schiöth Mimmie Willebrand Mikael Corell Magnus Bengtsson Work environment and equality committee Lena Karlsson Lotta Sjölander Robert Fredriksson Gunilla Jedstedt Fredrik Clausen Lena Zetterberg ( ) Ingela Nygren ( ) Prizes and awards Robert Bodén - Munken - Medical students price for excellent teaching Klas Kullander - Associate professor Klas Kullander was awarded a 5-year research position from the Royal Academy of Sciences (Kungliga Vetenskapsakademin)

11 ADRESS LIST DEPARTMENT OF NEUROSCIENCE Department of Neuroscience Address: Uppsala University, Department of Neuroscience, Box 593, Uppsala, Sweden. Fax , Phone Aare, Sudhakar Abelson, Klas Ahlqvist, Kerstin Aldskogius, Håkan Ahmad, Abdulbaghi Alasaly, Ablah Alm, Albert Alsiö, Johan Andersson, Else-Marie Andersson, Birgit Arinell, Hans Arnberg, Filip Askmark, Håkan Austeng, Dordi Banduseela, Varuna Bengtsson, Harriet Bengtsson, Henrik Bengtsson, Magnus Berg, Marita Berg Johannesson, Kerstin Bergqvist, Christina Bill, Anders Bjärnhall, Gunilla Bodén, Robert Bohlin, Lena Bohman, Hannes Boije, Henrik Borg, Jörgen Bring, Annika Broman, Jan-Erik Bäckström, Josefin Carlsson, Hans-Erik Clausen, Fredrik Comasco, Erika Corell, Mikael Cristea, Alexander Dreborg, Susanne Dyster-Aas, Johan Ebendal, Ted Edqvist, Per-Henrik Edvinsson, Dan Ekbrink, Helena

12 Ekholm, Marie Ekselius, Lisa Ekström, Curt Elmgren Frykberg, Gunilla Emilsson, Lina Emtner, Margareta Enblad, Per Engström, Ingemar Enjin, Anders Fagius, Jan Fernandez,Manuel Fex Svenningsen, Åsa Flemström, Gunnar Fredlund, Pia Fredriksson, Anders Fredriksson, Robert Fredriksson, Theodora Färdig, Rickard Gabilan Nelson Gezelius, Henrik Gillberg, Per-Göran Gloriam, David Granstam, Elisabet Gustafson, Ann-Marie Gustafsson, Ann-Catrine Grönblad, Leif Göktürk, Camilla Haglund, Kristina Haitina, Tatjana Hallböök, Finn Hallman, Jarmila Hansson, Inga Hartman, Anna Hartzell, Monica Hau, Jann Hedenius, Martina Hedlund, Inger Hedlund, Mathilde Hedström Yvette Hellström, Karin Henrohn, Dan Hesselager, Göran Hillered, Lars Holmbäck, Johanna Holmström, Gerd Hultman, Christina Hånell, Anders Hård-Wallenqvist, Berit Hägerbaum, Birgitta Höglund, Anna-Stina

13 Höglund, Per Igelström, Helena Israelsson, Charlotte Jacobsson, Josefin Janols, Lars-Olof Jansson, Lennart Jedstedt, Gunilla Jemtå, Lena Johansson, Andreas Johansson, Ewa Johansson, Henrik Johansson, Lisa Johansson Niemelä, Birgitta Jonsson, Per Jonsson, Ulf Jonson, Ulla Jordell-Kylberg, Annika Junemar Silvemark, Annika Jennische, Margareta Jägare, Annika Ka, Sojeong Kajandi, Madis Kanaykina, Nadezda Karlsdotter, Maude Karlsson, Lena Khalifa, Najah Kindlundh Högbeg, Anna Klang, Birgitta Klovins, Janis von Knorring, Anne-Liis von Knorring, Lars Korhonen, Laura Kouros, Ioannis Kozlova, Elena Krakau, Karolina Kruger-Vahlquist, Maria Kruse, Birgit Kumlien, Eva Kullander, Klas Kukkonen, Jyrki Källström, Lillemor Lagerström, Malin Lannsjö, Marianne Larhammar, Dan Larsson, Eva Larsson, Lars Larsson, Maria Larsson, Tomas Laurell, Katarina Leao, Katarina

14 Le Greves, Madeleine Le Greves, Pierre Lek, Madelene Lewander, Tommy Lewén, Anders Lewén, Sara Li, Meishan Liljegren, Ulrika Lind, Signe Lindam, Anna Lindberg, Påvel Lindblom, Jonas Lindholm, Dan Lindmark, Birgitta Lindström, Eva Lindström, Leif Ling, Maria Lundblad, Anna Lundell, Ingrid Lundin, Lars Gustav Lundin, Tom Lundström, Erik Lönngren, Ulrika Mackenzie, Åsa Mallon, Lena Marklund, Niklas Marteinsdottir, Ina Martin, Cathrin Mattsson, Peter Mattsson, Ulla-Britt Melberg, Atle Meyerson, Bengt Michel, Per-Olof Michelgård, Åsa Milesson Fors, Björn Mohell, Nina Molander, Carl Muhr, Cariin Mäepea, Olav Naver, Hans Nilsson, Anders Nilsson, Pelle Nilsson, Björn Nordh, Börje Nordquist, Niklas Nordström, Karl Nuija, Eva Nyberg, Gunnar Nygren, Karin Nylander, Olof

15 Ocampo Daza, Daniel Ochala, Julien Olinski, Robert Olsson, Gunilla Olsson, Gunilla M Olszewski, Pawel Oreland, Lars Oskooei, Safar Penayo, Ulises Pickering, Chris Pihl, Liselotte Portala, Kamilla Rabe,Nadine Ramklint, Mia Ronne, Elisabeth Rosling, Agneta Ryttlefors, Mats Röstlinger Goldkuhl, Reneè Salci, Konstantin Samuelsson, Carolina Sandborgh, Maria Sandelin, Martin Schiöth, Helgi Schönnings, Gun Sjöberg, Eva Sjöberg, Inger Sjöblom, Markus Sjölander, Lotta Smedje, Hans Sperber, Göran Sreedharan, Smitha Steen, Håkan Stjernschantz, Johan Stålenheim, Gunilla Suleman, Mbaruk Sundbom, Ann Sundelin Wahlsten, Viveca Sundström, Görel Svahn, Helena Svedbergh, Björn Swartling, Malin Söder, Lottie Söderlund, Anne Takahashi, Kayo Thorell, Eva Thurfjell, Barbro Thörnqvist, Per-Ove Tillander, Lena Tomic Lidija Urell, Charlotte

16 Waldemarson, Anne Vallstedt, Anna Wargelius, Hanna-Linn Wennström, Erik Wicher, Grzegorz Widerlöv, Birgitta Widerlöv, Erik Wikberg-Matsson, Anna Willebrand. Mimmie Wistrand, Per Wootz, Hanna Yates, Cecilia Zetterberg, Lena Zetterling, Maria Åkerberg, Helena Åkerblad, Ann-Charlotte Åkerman, Karl Åsenlöf, Pernilla Ögefeldt, Sofia Öster, Caisa Östlin, Anna-Karin

17 SCENTIFIC REPORTS

18 CLINICAL NEUROLOGY & PSYCHIATRY NEUROLOGY Neurodegenerative disorders Members of the group during 2007 Håkan Askmark, adj prof Kristin Elf, MD PhD Ingela Nygren, MD PhD Dag Nyholm, MD, PhD, postdoc Katarina Laurell, MD PhD Anders Johansson MD, PhD student Birgitta Larsson Jakobsson, nurse, PhD student Background The underlying cause of amyotrophic lateral sclerosis (ALS) and Parkinson s disease (PD) is largely unknown. The accumulation of protein aggregates in neurons is thought to play a role in the pathogenesis of both ALS and PD, and therefore studies of protein expression in the CSF from patients suffering from ALS and PD, in comparison with CSF from healthy controls, may results in the identification of biomarkers for these neurodegenerative diseases. Also, biomarkers may be used for early diagnosis, when symptomatic treatment is of clinical value for the patients. The differential diagnosis between PD and Parkinson-plus-syndrome is often difficult to make. We have used PET as a diagnostic tool with the tracers 11C-L-DOPA and 18Fdeoxyfluoro-D-glucose (FDG), but a systematic evaluation of this diagnostic method for differential diagnosis between PD and Parkinson-plus-syndrome has never been made. Motor fluctuations are a large problem for patients with advanced PD, for which the pathogenetic mechanisms are not known. Also, the quality of life and coping strategies for patients with ALS have not been studied previously. Normal pressure hydrocephalus (NPH) is a form of gait disorder and dementia that is curable when treated with ventriculoperitonela shunting in time. The diagnosis of NPH is difficult in the early phase of disease. We have recently increased the number of patients admitted to the neurological ward for diagnostic investigations of NPH, and the diagnostic procedures have been strictly standardized, by using dynamic tests of CSF circulation. Aims of the studies Identification of biomarkers for ALS and PD for early diagnosis, prognosis and response to therapy. To clarify the role of 11C-L-DOPA and 18F- FDG for differential diagnosis between PD and Parkinson-plus-syndrome. To analyze the correlation of motor fluctuations, and in particular dyskinesia, and the pharmacokinetics of L-DOPA in patients with advanced PD. To study the correlation between quality of life and progression of disease for ALS patients, and identification of coping strategies. Development of evidence-based diagnostic tests for patients with suspected NPH

19 Preliminary results PET with 11C-L-deprenyl showed binding in the pons and white matter, consistent with astrogliosis in these areas. The protein spectrum in the CSF of ALS patients is largely different from the control material, and a large number of differentially expressed proteins have been identified. Collection of clinical data is ongoing from a large number of patients with the suspected diagnosis of NPH, and today the neurology clinic at the Uppsala University Hospital is the largest NPH center in Sweden. Publications I Nygren, K Antonova, P Mattsson, H Askmark (2005). The ALS/MND prevalence in Sweden estimated by riluzole sales statistics. Acta Neurol Scand 111: Nyholm D, Nilsson AIM, Remahl I, Dizdar N, Constantinescu R, Holmberg B, Jansson R, Aquilonius S-M, Askmark H (2005) Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 64: Zetterberg L, Halvorsen K, Färnstrand C, Lundström E, Lindmark B, Aquilonius S-M (2005) Objective assessment of cervical dystonia: a pilot study. Acta Neurol Scand 112: Nyholm D, Jansson R, Willows T, Nilsson Remahl, I (2005) Long-term 24-hour duodenal infusion of levodopa: Outcome and dose requirements. Neurology 65: Ekegren T, Gomes-Trolin C (2005) Determination of polyamines in human tissues by precolumn derivatization with 9-fluorenylmethyl chloroformate and high-performance liquid chromatography. Analytical Biochemistry 338: Westin J, Nyholm D, Groth T, Dougherty MS, Yerramsetty PK, Pålhagen, SE (2006) Outcome prediction of enteral levodopa/carbidopa infusion in advanced Parkinson's disease. Parkinsonism& Relat Disord12: Nygren I, Askmark H (2006) Self-reported quality of life in amyotrophic lateral sclerosis. J Palliative Medicine 9: Johansson A, Savitcheva I, Forsberg A, Engler H, Långstrom B, Nordberg A, Askmark H (2007) [11C]-PIB imaging in patients with Parkinson's disease: Preliminary results. Parkinsonism & Relat Disord. In press, available online 14 September Johansson A, Engler H, Blomquist G, Scott B, Wall A, Aquilonius S-M, Långstrom B, Askmark H (2007) Evidence for astrocytosis in ALS demonstrated by [HC](L)-deprenyl-D2 PET. J Neurol Sci 255: Sikk K, Taba P, Haldre S, Bergquist J, Nyholm D, Zjablov G, Asser T, Aquilonius S-M (2007)Irreversible motor impairment in young addicts - ephedrone, manganism or both? Acta Neurol Scand 115: Nyholm D (2007) The rationale for continuous dopaminergic stimulation in advanced Parkinson's disease. Parkinsonism & Relat Disord 13:S13-S

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