Annual Report. Department of neuroscience. Uppsala university

Transcription

1 Annual Report 2009 Department of neuroscience Uppsala university Cover Picture: Nature - nurture interplay: genetic influences on behaviour in different environments and environmental influences on gene expression. Erica Comasco, Neuropsychopharmacology. Box 593 SE Uppsala Editor: Cecilia Yates (cecilia.yates@neuro.uu.se)

2 INTRODUCTION The Department of Neuroscience covers a broad range of basic and clinical research as well as education on the nervous system. Today, the Department has around 160 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 teaching and research responsibilities within the Department. The preclinical research groups are concentrated within the facilities of Uppsala University Biomedical Center, but the clinical research groups have been spread out in four different buildings in the main University Hospital campus, and in fifth site at Ulleråker. As part of efforts to concentrate the Department s activities, the unit for Physiotherapy and the unit for Speech Physiology and Pathology will move to the Biomedical Center in January 2010 from their current separated location at the University Hospital, and the research groups in psychiatry will be housed in the same building in the hospital grounds by early The organizational expansion of the Department has also been associated with a strong expansion 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 differences in administrative, teaching and research culture between the individual units as well as their dispersal locations. A major 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. The restructured website that was launched in 2008 has continued to support research groups and individuals to present and update relevant information for intradepartmental communication, as well as for providing external information, thereby providing a significantly better visibility of the Department to the scientific and public community. Continuous updates based on daily searches, mainly in national media websites, on the engagement and visibility of the Department s scientists and teachers in the community are continuously presented on the Department s website. This newsservice has become a popular means for increasing in-house information on the external activities of the Department. Research In order to concentrate research competencies and resources the Department has identified four major areas (themes), which are already successful, and which are promising for building bridges between basic and clinical neuroscience. Important factors in the subsequent departmental discussions were i) to build upon already existing strong and promising research areas, ii) to build workable bridges between preclinical and clinical research, and iii) to create opportunities for innovation by bringing research groups from a wide range of disciplines together. As a result the four thematic areas briefly described below have been defined as priority areas for the Department. The conceptual focus on these areas combined with proactive measures by the Department is likely to reap rewards in the future by strengthening scientific impact, increasing national and international recognition, attracting of young promising scientists, as well as in increasing success rates in the competition for major national and international funding

3 Thematic Research Areas 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. This is a very promising area with highly active and productive research along several mutually stimulating research lines, including novel approaches for repair of spinal cord injury. Neural basis of body weight control. This area encompasses basic science research on regulation of appetite, food intake, the gastrointestinal tract and muscle wasting as well as clinical research on eating disorders, physical training and behavioural medicine. Basic research in this area has been very productive and has led to several interesting discoveries during Neurotrauma. This area explores experimental models of brain injury, with the aim of identifying targets for neuroprotection and strategies for brain repair, 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 leading role in Uppsala Brain Injury Center (see which is a major center for translational research in neurotrauma. Members of the Department are also closely involved in the Center of Excellence in neurotrauma at the University Hospital. Genetics and clinical neuroscience. This area focuses on understanding the genetics of disorders with neurological and psychiatric components, as an entrance to elucidating their pathophysiological mechanisms and, from there, to therapeutic improvements. The research has its foundations in clinical neurology and psychiatry, and connects to basic science in neurogenetics, neurobiology and transgene technology. A central task for the Department in the near future will be to strengthen these areas, for exemple - by creating new interdepartmental cooperative activities, promoting high- level PhD education and the establishment of key technological and competence platforms, as well as in the consideration of new recruitments. Undergraduate and Graduate Education The Department has extensive responsibilities within the Physiotherapy program, as well as the Speech Pathology and Therapy program. The Department has played a major role in launching the Speech Pathology and Therapy program. The second group of logopedic students finished their education in the fall of The Department also has extensive commitments within the Biomedical, Medical, Nursing, Pharmacy 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 has been involved in the Master s program in Public Health since its start, and is currently engaged in developing a Master program in biomedicine in collaboration with other departments within the medical and pharmaceutical faculties. The structure and pedagogy of the Department s courses for medical students have now been adapted to the new medical curriculum which was introduced in During this process, the teaching involvements and responsibilities of the Department have increased substantially. Education in neurosciences is already introduced from the start of the new curriculum, largely - 3 -

4 as case-oriented and student-activating teaching in groups of 8-10 students and with emphasis on integrating basic and clinical sciences. In general, the new education system has been beneficial by capturing the student s interest for neurosciences early in their studies but it has also challenged the Department s teaching capacity. The Department has been involved in national collaborations to guarantee the quality as well as quantity of undergraduate education in neuroscience at the different teaching hospitals in Sweden. Yearly meetings with representatives from these hospitals, responsible for courses in clinical neuroscience, ophthalmology and psychiatry, have taken place to discuss and update national strategies and guidelines that are now incorporated in our clinical courses. 13 students received their doctoral degrees at the Department during A course on Development and Plasticity in the series Frontiers and Techniques in Neuroscience for graduate students was successfully organized by the Department. Recruitment Activities and Strategies During the previous three years the Department has experienced a period during which a large number of highly qualified teachers/scientists have retired, many of whom have now been replaced. The Department has also been fortunate in the way that many retired professors continue to be active in undergraduate and graduate education as well as active and productive in research. 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 for clinical researchers is, however, a serious obstacle. During the year Anja Smits, Robert Fredriksson and Gerd Holmström received positions as senior lecturer in Clinical Neurology, in Pharmacology and in Clinical Ophtalmology, respectively. Lena Zetterberg (Physiotherapy) and Per Östberg (Speech Pathology and Therapy) were promoted to senior lecturers. Karin Nordström (Physiology) and Julien Ochala (Clinical Neurophysiology) received Research Council supported junior researcher position placed at the Department. The advertised positions in Physiotherapy and in Clinical Neurology were closed during 2009 without being filled. However, strong and promising research activities as well as competence building in these areas are currently ongoing within the Department. Positions as senior lecturer in Physiotherapy and in Psychiatry were on their way to be finalized by the end of Negotiations were still ongoing at the end of 2009 with a highly qualified candidate for the advertised position as professor in Psychiatry. Preparations were finalized in 2009 for advertising a position as senior lecturer in Rehabilitation Medicine. Conclusion Given the qualified and dedicated staff of the Department 2010 promises to be another year that can be met with confidence and excitement, and a year that the Department will move even closer to its scientific and educational goals. Uppsala, 31 th of March 2010 Håkan Aldskogius, MD, PhD Professor, Head of Department - 4 -

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6 List of Contents ORGANIZATION 8 ADRESS LIST 10 DISSERTATIONS 16 SCENTIFIC REPORTS 18 Clinical Neurology & Psychiatri 19 Clinical Neurology 19 Neurodegeneration/Movement disorders 19 Focal epilepsy and Low grade glioma 22 Clinical Neurogenetics 27 Stroke, Headache, Multiple Sclerosis 30 Clinical Neurophysiology 33 Neuromuscular 33 Peripheral Nervous System 40 Central Nervous System 41 Psychiatry 44 Psychiatry 44 Psychiatry and Individual Differences 52 Schizophrenia 60 Neurobiology & Neuropsychology 66 Child & Adolescent Psychiatry 68 Fetal and childhood developmental abberations 70 Developmental vulnerability 73 National Center for Disaster Psychiatry 76 Psychiatric genetics 82 Experimental neuroscience 85 Developmental Genetics 85 Neuronal Circuits of Higher Brain Function 88 Neuron Glia Communication 89 Neuronal Cell Biology 92 Ophtalmology & retina biology 96 Ophtalmology 96 Ophthalmic Biophysics 96 Paediatric Ophtalmology 100 Glaucoma 104 Retinal stem and progenitor cell development 109 Physiology and Pharmacology 116 Physiology 116 Feeding dependency of small intestinal sensitivity to appetite related hormones _

7 Duodenal responses to luminal constituents 117 Neurophysiology of motion vision 119 Molecular Physiology and Neuroscience 121 Behavioural Neuroendocrinology 123 Comparative Medicine 126 Pharmacology 128 Pharmacology 128 Neuropsychopharmacology 132 Functional Pharmacology 138 Neurotrauma & Restorative Neuroscience 145 Neurosurgery 145 Clinical brain injury program 145 Experimental brain injury program 145 Molecular and genetic analysis of experimental traumatic brain injury 154 Regenerative Neurobiology 157 Physiotherapy 160 Rehabilitation and physical activity in patients with chronic diseases 160 Rehabilitation of patients with neurological or geriatric impairments 163 Behavioural medicine and physiotherapy 166 Speech and Language Pathology 169 Rehabilitation Medicine 175 UNDERGRADUATE STUDIES 178 The Physiotherapy program 179 The Speech and Language Pathology program 180 The Neuroscience Department s participation in the Biomedical Programme 181 Teaching at and by the unit for Pharmacology 182 Teaching at and by the unit for Physiology 182 Teaching at and by the unit for Developmental Neuroscience 183 Teaching at the Clinical Neuroscience units 184 Teaching at and by the unit for Psychiatry 185 Teaching at and by the unit for Ophthalmology

8 ORGANIZATION Department board Chairman Deputy chairman Research groups Research committeee Undergraduate studies committee Chief administrator Director of graduate students Section Directors Personnel administration Director of undergraduate studies Financial administration Course leader of undergraduate studies Course administration Chairman Håkan Aldskogius Deputy Chairman Lisa Ekselius Department board Anja Smits, teacher representative Per Enblad, teacher representative Lars Hillered, teacher representative Gerd Holmström, teacher representative Finn Hallböök, teacher representative Gun Schönnings, representative for technical/administrative personnel Maria Larsson, representative for technical/administrative personnel Hanna Olsén, graduate student representative Hanna-Linn Wargelius, graduate student representative Filip Olsson, student representative Jessica Risholm, student representative Klas Kullander, teacher representative, deputy Dan Larhammar, teacher representative, deputy Cajsa Öster, teacher representative, deputy Margareta Emtner, teacher representative, deputy Olof Nylander; teacher representative, deputy Anders Fredriksson, representative for technical/administrative personnel, deputy - 8 -

9 Ann-Marie Gustafsson, representative for technical/administrative personnel, deputy Gunilla Elmgren-Frykberg, graduate student representative, deputy Greta Hultqvist, graduate student representative, deputy Chief administrator Lena Karlsson Director of graduate studies Lars Larsson Section Directors Margareta Emtner Bryndis Birnir Margareta Jennische Director of undergraduate studies Lisa Ekselius Peter Mattson (to ) Finn Hallböök Anja Smits (from ) Dan Larhammar Olof Nylander Lena Zetterberg Ingrid Lundell Jarmila Hallman Administration Birgit Andersson Else-Marie Andersson Marita Berg Lena Bohlin Pia Fredlund Theodora Fredriksson Ulla Jonson Anki Gustafsson Berit Hård- Wallenqvist Undergraduate studies committee Olof Nylander Ingrid Lundell Gabriella Persdotter-Hedlund Lena Zetterberg Research committee Lars Larsson Bryndis Birnir Åsa Mackenzie Helgi Schiöth Work environment committee Lena Karlsson Robert Fredriksson Equality committee Lena Karlsson Filip Olsson Inger Hedlund Maud Karlsdotter Birgitta Klang Maria Larsson Karin Nygren Gun Schönnings Lotta Sjölander Lottie Söder Cecilia Yates Finn Hallböök Dan Larhammar Jarmila Hallman Cecilia Yates Annika Bring Karin Edebol Eeg Olofsson Berit Hård Wallenqvist Siv Strömberg Karin Nygren Ellen Grut Gabriella Persdotter-Hedlund - 9 -

10 ADRESS LIST DEPARTMENT OF NEUROSCIENCE Abdulbaghi Ahmad Abelson, Klas Ablah, Alasaly Ahlqvist, Kerstin Aldskogius, Håkan Alm, Albert Alm, Per Alsiö, Johan Amandusson, Åsa Andersson, Birgit Andersson, Else-Marie Andersson, Mikael Anens, Elisabeth Aquilonius, Sten-Magnus Arinell, Hans Arnberg, Filip Askmark, Håkan Austeng, Dordi Axelson, Hans Banduseela, Varuna Bengtsson, Johan Berg, Marita Bergh Johannesson, Kerstin Bergqvist, Christina Berntsson, Shala Birgner, Carolina Birnir, Bryndis Bodén, Robert Bohlin, Lena Bohman, Hanne Boije, Henrik Botling Taube, Amelie Bring, Annika Burman, Joachim Bylund, Ann Bäckström Josefin Cedernaes, Jonathan Cesarini, Kristina Clausen, Fredrik Comasco, Erica Corell, Mikael Dahlbom, Josefin Danfors, Torsten Dyster Aas, Johan Ebendal, Ted Edebol Eeg-Olofsson, Karin Edman, Jon Edvinsson, Dan Hans

11 Ekbrink, Helena Ekholm, Marie Ekmark-Lewèn, Sara Ekselius, Lisa Ekström, Curt Elf, Kristin Elmgren-Frykberg, Gunilla Emilson, Christina Emilsson, Lina (Karolina) Emtner, Margareta Enblad, Per Enjin, Anders Eriksson, Urban Erlandsson, Anna Fagius, Jan Falck, Björn Fard, Shahrzad Fex Svenningsen, Åsa Flink, Roland Fredlund, Pia Fredriksson, Anders Fredriksson, Robert Fredriksson, Theodora Fällmar, Helena Färdig, Richard Galichanin, Konstantin Gezelius, Henrik Goldkuhl, Reneé Granstam, Elisabet Grill, Magnus Gustafson, Ann-Marie Gustafsson, Anki Haglund, Kristina Haitina, Tatjana Hallböök, Finn Hallman, Jarmila Hartzell, Monica Hedborg, Kerstin Hedenius, Martina Hedin, Anders Hedlund, Inger Hedström, Yvette Hellström, Karin Hesselager, Göran Hillered, Lars Hogmark, Åsa Holm, Sara Holmbäck, Johanna Holmström, Gerd Holtz, Anders

12 Howells, Tim Hulter-Åsberg, Kerstin Hultqvist,Greta Hynninen, Pirkko Hånell, Anders Hård-Wallenqvist, Berit Hägerbaum, Birgitta Hägglund, Maria Igelström, Helena Isaksson, Johan Israelsson, Charlotte Jacobsson, Josefin Jacobsson, Karl-Gustav Jakobsson-Larsson, Birgitta Jedstedt, Gunilla Jeneby, Maamun, M, S Jennische, Margareta Jin, Zhe Johansson, Anders Johansson, Andreas Johansson, Ewa Johansson, Henrik Johansson, Tobias Johansson-Niemelä, Birgitta Johnson, Ulf Jonson, Ulla Jonsson, Ulf Jordell Kylberg, Annika Jüris, Linda Jägare, Annika Karlsson, Lena Karlsdotter, Maude Khalifa, Najah Kilimann, Manfred Kindlundh-Högberg, Anna Klang, Birgitta Klovins, klovins Kournetas, Dimitrios Kozlova, Elena Krakau, Karolina Kronschläger, Martin Kruger-Vahlquist, Maria Kullander, Klas Kumlien, Eva Lagerström, Malin Landgren, Eva Langoi, David Lannsjö, Marianne Larhammar, Dan Larhammar, Martin tim.howells@neuro.uu.se Kerstin.Hulter.Asberg@lul.se Greta.Hultqvist@neuro.uu.se pirkko.hynninen@akademiska.se anders.hanell@neuro.uu.se berit.hard-wallenqvist@neuro.uu.se Birgitta.Hagerbaum@neuro.uu.se Maria.Hagglund@neuro.uu.se helena.igelstrom@neuro.uu.se johan.isaksson@neuro.uu.se Charlotte.Israelsson@neuro.uu.se Josefin.Jacobsson@neuro.uu.se Karl-Gustav.Jacobsson@neuro.uu.se birgitta.jakobsson.larsson@neuro.uu.se Gunilla.Jedstedt@neuro.uu.se Margareta.Jennische@neuro.uu.se Zhe.Jin@neuro.uu.se anders.johansson@neuro.uu.se Andreas.Johansson@neuro.uu.se ewa.johansson@akademiska.se henrik.johansson@neuro.uu.se Tobias.Johansson@neuro.uu.se birgitta.johansson.niemela@akademiska.se ulf.johnson@neuro.uu.se Ulla.Jonson@neuro.uu.se ulf.jonsson@neuro.uu.se Annika.Kylberg@neuro.uu.se linda.juris@akademiska.se Annika.Jagare@neuro.uu.se Lena.Karlsson@neuro.uu.se najah.khalifa@neuro.uu.se Manfred.Kilimann@neuro.uu.se Anna.Kindlundh@neuro.uu.se Birgitta.Klang@neuro.uu.se Janis.Klovins@neuro.uu.se Dimitrios.Kournetas@neuro.uu.se Elena.Kozlova@neuro.uu.se karolina.krakau@ds.se Martin.Kronschlager@neuro.uu.se Maria.Kruger.Vahlquist@neuro.uu.se Klas.Kullander@neuro.uu.se eva.kumlien@neuro.uu.se Malin.Lagerstrom@neuro.uu.se Eva.Landgren@akademiska.se David.Langoi@neuro.uu.se marianne.lannsjo@neuro.uu.se Dan.Larhammar@neuro.uu.se Martin.Larhammar@neuro.uu.se

13 Larson, Lars Larsson, Eva Larsson, Lill-Inger Larsson, Maria Laurell, Katarina Le Grevès, Madeleine Leao, Katarina Lek, Madelen Lewander, Tommy Lewén, Anders Li, Meishan Lind, Signe Lindblad, Frank Lindblom, Jonas Lindmark, Birgitta Lindström, Leif Ling, Maria Llano Diez, Monica Lundberg, Per Olov Lundblad, Anna Lundblad, Martin Lundell, Ingrid Lundin, Tom Lundström, Erik Lööv, Camilla Mackenzie, Åsa Marklund, Niklas Martin, Cathrin Mattsson, Peter Melberg, Atle Memic, Fatima Mendu, Suresh Merkoudis, Nikolaos Meyerson, Bengt Mayo, Susan Michel, Per-Olo Michelgård Åsa Milesson Fors, Björn Molander, Carl Månsson, Ann Mäepea, Olav Nehlin Gordh, Christina Neumann, Nicole Nilsson, Anders Nilsson, Pelle Nohlert, Eva Nordenankar, Karin Nordh, Börje Nordquist, Niklas Nordström, Karin

14 Nordström, Karl Noren, Niklas Norrbrink, Cecilia Nuija, Eva Nyberg, Christoffer Nygren, Ingela Nygren, Karin Nyholm, Dag Nylander, Olof Nylund, Anders Ocampo Daza, Daniel Ochala, Julien Olander, Hedvig Olerud, Johan Olsén, Hanna Olszewski, Pawel Oreland, Lars Persdotter-Hedlund, Gabriella Peuckert, Christiane Purins, Karlis Päären, Aivar Qaisar, Rizwan Rabe, Nadine Radojevic, Ivana Raine, Amanda Ramklint, Mia Rask-Andersen, Mathias Renaud, Guillaume Ring, Henrik Rogoz, Katarzyna Ronne-Engström, Elisabeth Rosling, Agneta Rystedt, Alma Ryttlefors, Mats Salci, Konstantin Sandberg Melin, Camilla Sandberg, Arne Sandberg, Tomas Sandborgh, Maria Sandelin, Martin Schepke, Bengt Schiöth, Helgi Schmidt, Roland Schulz-Key, Steffen Schönnings, Gun Sedin, John Fard, Shahrzad Fard Silvermark, Annika Sjöberg, Eva Sjöblom, Markus

15 Skoglund, Andreas Skoglund, Karin Sköld, Mattias Smith, Casey Smits, Anja Sommansson, Anna Sperber, Göran Sreedharan, Smitha Strömbeck, Anne-Sophie Strömberg, Siv Ståhl-Myllyaho, Inger Stålberg, Erik Sudhakar, Aare Sundberg, Björn Sundblom, Jimmy Sundbom, Ann Sundelin-Wahlsten, Viveka Sundström, Görel Svedbergh, Björn Sveen, Josefin Szmidt, Malgorzata Sällman-Almén, Markus Söderberg, Per Talebizadeh, Nooshin Thurfjell, Barbro Tillander Lena Tomic, Lidija Tomic, Zoran Torebjörk, Erik Törnquist, Per Urell, Charlotte Vahlberg, Birgit Waldermarsson, Anne Wang, Jing Wargelius, Hanna-Linn Vasylovska, Svitlana Wenngren, Ewa Wicher, Grzegorz Wikberg Matsson, Anna Willebrand, Mimmie Winberg, Svante Winkler, Tomas von Knorring, Anne-Liis von Knorring, Lars Wootz, Hanna Wästermark, Åke Yates, Cecilia Yu, Zhaohua Zelano, Johan Zetterberg, Lena

16 Zetterling, Maria Zoéga, Gunnar Åkerblom, Hanna Åsenlöf, Pernilla Ögefeldt, Sofia Östberg, Per Öster, Caisa end DISSERTATIONS 2009 Corell, Mikael: Genetic Developmental Biology, Two Aspects of Cell Communication: Neural Stem/Progenitor Cell Differentiation and N-cadherin Mediated Adhesion. (Licentiate Thesis) Fällmar, Helena: Pharmacology, Mutagenesis and pharmacological characterization of the human neuropeptide Y/peptide YY receptor Y2. (Licentiate Thesis) Gezelius, Henrik: Genetic Developmental Biology, Studies of Spinal Motor Control Networks in Genetically Modified Mouse Models. Goldkuhl Reneé: Comparative medicine, Surgical Stress in Rats. (Licentiate Thesis) Haitina, Tatjana: Functional Pharmacology, Function, Pharmacology, Evolution and Anatomical Localization of G Protein-Coupled Receptors and Solute carriers. Hedlund, Mathilde: Psychiatry, Coping, psychiatric morbidity and perceived care in patients with aneurysmal subarachniod haemorrhage. Johansson, Anders: Clinical Neurology, Search for biomarkers in ALS and Parkinson s disease. Positron emission tomography and cerebrospinal fluid studies. Johansson-Niemelä: Birgitta: Psychiatry, Mental health in children undergoing reconstructive surgery: studies on self-esteem and social interaction. Lundström Erik: Clinical Neurology, Spasticity after first-ever stroke. Mayo, Susan: Comparative medicine, Non-invasive antibody production in the chicken. Nilsson, Björn: Psychiatry, Physiological aberrations in patients with schizophrenia. Sojeong Ka: Retinal Cell Biology, Gene expresion in the brain of two lines of chicken divergently selected for high and low body weight. Ryttlefors Mats: Neurosurgery, Subarachnoid Hemorrhage in the Elderly. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN ;

17 Wallenquist, Ulrika: Neurosurgery. Neural Stem and Progenitor Cells as a Tool for Tissue Regeneration. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN ; 500 Åkerberg, Helena: Pharmacology, Functional studies of the neuropeptide Y system: Receptor-ligand interaction and regulation of food intake. Åslund, Cecilia: Psychiatry, Depression and Antisocial Behaviour in Adolescents. Influence from social status, shaming and genre-environment interaction

18 SCENTIFIC REPORTS Martin Larhammar, PhD student, Developmental Genetics

19 Clinical Neurology & Psychiatri Group leader: Håkan Askmark Members of the group during 2009 Clinical Neurology Neurodegeneration/Movement disorders Håkan Askmark, adj prof Kristin Elf, MD PhD Ingela Nygren, MD PhD Dag Nyholm, MD, assoc prof, postdoc Katarina Laurell, MD PhD Anders Johansson MD, PhD Birgitta Jakobsson Larsson, nurse, PhD student Alma Rystedt, pharmacist, PhD student Background The underlying causes of sporadic amyotrophic lateral sclerosis (ALS), Parkinson s disease (PD) and atypical parkinsonism such as multiple system atrophy (MSA) are largely unknown. The accumulation of protein aggregates in neurons is thought to play a role in the pathogenesis, and therefore studies of protein expression in nervous tissue samples from patients suffering from these disorders, in comparison with nervous tissue samples 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, and for following of the disease progression. The differential diagnosis between PD and atypical parkinsonism 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 atypical parkinsonism 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 well elucidated previously. The neurological clinic in Uppsala, as the first Swedish centre to use Botulinum toxin in clinical practice, has a longstanding experience of this treatment for a broad range of clinical disorders, such as focal dystonia, spasticity after stroke and hyperhidrosis. Our research is focused on defining the optimal use and dosage of Botulinum toxin for various clinical indications, as well as on analysis of the effects on symptomatic relief. An increasing number of patients are admitted to the neurological ward because of normal pressure hydrocephalus (NPH). NPH is a disorder of cerebrospinal fluid (CSF) circulation resulting in gait difficulties, cognitive impairment and incontinence. Although the knowledge of the pathophysiology of NPH is limited there is good scientific support for the treatment with ventriculoperitoneal shunting. Since the diagnosis of NPH may be difficult, multidisciplinary assessment and different diagnostic tests are used e.g. radiological parameters and dynamic tests of CSF circulation. To increase the knowledge of the

20 pathophysiology and improve the diagnostic procedure we co-operate with neuroradiology-, neuropathology-, neurosurgery and geriatric departments as well as other centres in Sweden. We conduct studies about new infusion-techniques and the predictive value of CSF dynamic tests and have recently started a study of the prognostic value of different MRI parameters. Since 2004, information about patients operated for hydrocephalus is collected in a national register and scientific reports based on these data are underway. Aims of the studies Identification of biomarkers for ALS, PD and MSA for early diagnosis, prognosis and response to therapy. To clarify the role of PET with 11C-L-DOPA and 18F- FDG for differential diagnosis between PD and atypical parkinsonism. 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. Defining the optimal use and dosage of Botulinum toxin for various clinical indications, as well as on analysis of the effects on symptomatic relief. Development of evidence-based diagnostic tests for patients with suspected NPH. Describe the outcome of a shunt operation with objective measurements of gait, balance and cognition as well as subjective rating of quality of life by the patient and relatives. Preliminary results The protein spectrum in CSF from ALS patients is largely different from the control material, and a large number of differentially expressed proteins have been identified. Disease specific increases of proteins in CSF have been found in both ALS and MSA. Levodopa requirement in PD ranges considerably between individuals and men use higher levodopa dose than women. Levodopa requirement is fairly constant during the progression of the disease in lowdose patients but increases in high-dose patients. Video recordings, as a complement to patients' self-scoring on electronic diaries, are useful in the assessment of motor performance in PD. Out of 282 patients operated for NPH in Uppsala between 2004 and 2009, the proportion of patients in wheelchair decreased from 24% to 14% and the number with normal gait increased from 4% to 20% at evaluation 3 months after a shunt-operation. Improvement after the CSFtaptest, considered as a reduction in number of steps and time on 10 meters walk, was significantly lower between 4 and 8 hours afterwords. High interrater reliability means good reliability and reproducibility of the test chosen regardless of the evaluator. At the moment, the number of patients operated in Uppsala is the highest in Sweden and the outcome is in level with international reports. Publications 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:

21 2. 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, Lewander T, Johansson A, LeWitt PA, Lundqvist C, Aquilonius SM (2008) Enteral levodopa/carbidopa infusion in advanced Parkinson disease: long-term exposure. Clin Neuropharmacol 31: Johansson A, Savitcheva I, Forsberg A, Engler H, Långstrom B, Nordberg A, Askmark H (2008) [11C]-PIB imaging in patients with Parkinson's disease: Preliminary results. Parkinsonism & Relat Disord 14: Axelson H, Öberg G, Askmark H. No benefit of treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in multifocal motor neuropathy (2008) Acta Neurol Scand 117(6); Axelson H, Öberg G, Askmark H. Successful repeated treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP (2008) J Neurol Neurosurg Psychiatry 79(5); Punga AR, Nygren I, Askmark H, Stålberg EV (2009) Monozygous twins with neuromuscular transmission defects at opposite sides of the motor endplate. Acta Neurol Scand 119: Isacson D, Bingefors K, Kristiansen IS, Nyholm D (2008) Fluctuating functions related to quality of life in advanced Parkinson disease: Effects of duodenal levodopa infusion. Acta Neurol Scand 118: Rystedt A, Swartling C, Färnstrand C, Naver H (2008) Equipotent concentrations of Botox and Dysport in the treatment of palmar hyperhidrosis Acta Derm Venereol. 88(5): Rystedt A, Swartling C, Naver H (2008) Anhidrotic effect of intradermal injections of botulinum toxin: a comparison of different products and concentrations Acta Derm Venereol. 88(3): Kristiansen IS, Bingefors K, Nyholm D, Isacson D. (2009) Short-Term Cost and Health Consequences of Duodenal Levodopa Infusion in Advanced Parkinson's Disease in Sweden: An Exploratory Study. Appl Health Econ Health Policy. 7(3): Nyholm D, Constantinescu R, Holmberg B, Dizdar N, Askmark H (2009) Comparison of apomorphine and levodopa infusions in four patients with Parkinson s disease with symptom fluctuations. Acta Neurol Scand 119, Nyholm D, Karlsson E, Lundberg M, Askmark H (2010) Large differences in levodopa dose requirement in Parkinson's disease: men use higher doses than women. Eur J Neurol. Eur J Neurol. 17(2):

22 14. Nyman R, Lundgren D, Nyholm D (2009) Soft tissue-anchored transcutaneous port attached to an intestinal tubefor long-term gastroduodenal infusion of levodopa/carbidopa in Parkinson disease. J Vasc Interv Radiol 20, Westin J, Dougherty M, Nyholm D, Groth T (2009) A home environment test battery for status assessment in patients with advanced Parkinson's disease. Comput Methods Programs Biomed Sep 7. [Epub ahead of print] 16. Sikk K, Taba P, Haldre S, Bergquist J, Nyholm D, Askmark H, Danfors T, Sörensen J, Thurfjell L, Raininko R, Eriksson R, Flink R, Färnstrand C, Aquilonius SM. Clinical, neuroimaging and neurophysiological features in addicts with manganese-ephedrone exposure. Acta Neurol Scand Dec 17. [Epub ahead of print] Reviews Nyholm D (2007) The rationale for continuous dopaminergic stimulation in advanced Parkinson's disease. Parkinsonism & Relat Disord 13:S13-S17 Nyholm D, Lennernäs H (2008) Irregular gastrointestinal drug absorption in Parkinson's disease. Expert Opinion Metab Tox 4: Smits A, Andsberg G, Andersen PM, Andersson M, Fredrikson S, Gunnarsson M, Kumlien E, Lycke J, Jensen SM, Nilsson Remahl I, Nyholm D (2008) Neurologi i förvandling - från diagnostisk till terapeutisk disciplin. Läkartidningen 105(36): Agencies that support the work ALF Selanders stiftelse Ulla-Carin Lindquist stipendium Lion s hjälpfond Swedish Society for Medical Research Parkinsonfonden Group leader: Anja Smits Members of the group during 2009 Anja Smits, MD, PhD, senior clinical lecturer Eva Kumlien, MD, PhD, assoc prof Peter Mattsson, MD, PhD, assoc prof Torsten Danfors, MD PhD student Shala Berntsson, MD, PhD student David Fällmar, junior physician Mingqi Qu, MD PhD, postdoc Focal epilepsy and Low-grade glioma

23 Projects 1) Clinical and translational studies of patients with low-grade gloma Adults with low-grade gliomas have a relatively long survival of 5-10 years but show a large variety in clinical symptoms and prognosis. Epileptic seizures are the most frequent initial symptoms of disease, and patients presenting with seizures have a more favourable prognosis compared to patients with cognitive dysfunction or neurological deficits at disease onset. The difference in survival between these two groups is strongly correlated with tumour location. For individual patients with specific tumour locations, the correlation between epileptic symptoms and tumour behaviour is not clear. Recent data from advanced neuroimaging techniques have shown that low-grade gliomas grow slowly but continuously during the non-progressive phase of disease, with a growth rate affected by the intrinsic properties of the tumour rather than by treatment-related factors. Interestingly, the molecular profiles of tumour subtypes with similar histopathology may vary between different brain locations, indicating a correlation between tumour behaviour and specific locations in the brain. Our clinical studies focus on the identification of parameters affecting specific symptoms and course of disease in this patient group. In a prospective study of newly diagnosed patients with low-grade gliomas, we have shown that global neurocognitive deficits were found already at disease onset in a subset of younger mainly male patients, characterised by relatively large frontal lobe tumours. We have further used 11 C-methionine PET as a prognostic factor for survival and as a predictive tool for evaluation of therapy. Translational studies are performed in collaboration with the Clinical Cancer Center, Karolinska Institute, with the aim to explore the molecular background of the clinical heterogeneity in this patient group. 2) Development and evaluation of a cognitive behaviour treatment program in focal epilepsy About a third of persons with epilepsy will continue to have seizures despite adequate treatment with antiepileptic drugs. In many of these cases, more and multiple medications are tried without success and more side effects. Surgical treatment of epilepsy is very rare and not applicable or available to most persons with epilepsy. There is a great need to develop a psychological treatment model of epilepsy, which focuses on empowerment of own resources for seizure management as well as support for taking steps in valued directions towards improving quality of life in the face of stigmatisation and other difficulties. The aim of the study is to develop and evaluate a cognitive behaviour treatment program in patients with epilepsy. The study is performed in collaboration with the Department of Psychology, Uppsala University. 3) Cortical activity thresholds measured by transcranial magnet stimulation (TMS) in relation to cognitive behavioural therapy in patients with epilepsy All organisms have a tendency to seize as the brain fluctuates in cortical activity. Epileptogenesis consists of neurophysiological processes in the balance between the excitatory and inhibitory systems of the brain. Excess activation of excitatory pathways may lead to hypersynchronization of cortical activity and epileptic seizures. Transcranial magnet stimulation (TMS) is a noninvasive neurophysiological method allowing evaluation of the balance between cortical inhibition and excitation

24 The aim of this study is to assess cortical excitability in relation to behavior analyses in patients with focal epilepsy using transcranial magnetic stimulation. The study is performed in collaboration with the department of Neuroscience, Neurophysiology and Department of Psychology, Uppsala University. 4) Nationwide study on sociodemographic differences in anti-epileptic drug prescriptions to epilepsy patients Information on socio-demographic differences in access to neurologists and sources of AED prescriptions in epilepsy is very limited and direct measures have not been obtained. In July 2005 the Swedish Prescribed Drug Register (SPDR) was established. It contains patient identities for all dispensed prescriptions to the entire Swedish population of 9 million inhabitants. We linked data between the SPDR and other registers to examine whether prescriptions of anti-epileptic drugs by neurologists are determined by sociodemographic variables. Epilepsy patients on AED treatment were much more likely to have their prescriptions of AEDs from a neurologist than other physicians if they were women, young, well educated, had a high income, and lived in large cities. Sociodemographic disparities were also found in relation to prescriptions of individual AEDs. These findings are important because they indicate that some patients may receive health care of lower standards. Collaboration: Dept of Neurology, KI, and Centre for Epidemiology, Swedish National Board of Health and Welfare. 5) Localisation of epileptic lesions with MRI and PET Surgical removal of structural brain abnormalities offers a potential long-term cure for focal epilepsy, but it can only be performed in patients whose specific abnormality is visible through an imaging study. Magnetic resonance imaging (MRI) is the most sensitive method to detect cortical abnormalities, which may underlie an epileptic condition. However, there are many patients with epilepsy where MR-findings are negative. In these cases other methods have to be used in porder to delineate cortical abnormalities. Positron emission tomography (PET) can be used to study neurotransmission in humans. Substance-P is a signal substance that is involved in the release of the neuroexcitatory transmitter glutamate. Substance-P is primarily bound to NK1-receptors that can be blocked by GR We explored the possibility of using PET with 11-C-labelled -GR to delineate abnormalities of neurotransmission in focal epilepsy. We have investigated 30 healthy controls and nine patients with Temporal Lobe Epilepsy. Preliminary findings indicate that there is an increased uptake of the tracer in regions involved in the generation of focal seizures. The studies are performed in collaboration with Uppsala PET Centre and Department of Radiology, Uppsala University. 6) PET-studies in drug resistant epilepsy Resistance to drug treatment is an important problem in the therapy of many brain disorders, including cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. In particular, drug efflux transporters that are expressed at the blood brain barrier limit the ability of many drugs to reach the brain. Most patients with refractory epilepsy are resistant to several anti-epileptic drugs, despite the fact that these drugs act by different mechanisms. This multidrug type of resistance argues against epilepsy induced alterations in specific drug targets as the main cause of pharmacoresistant epilepsy, pointing instead to non-specific and possibly adaptive mechanisms. One reason to this might be an overexpression of drug

25 transporters that reduce the amount of drug reaching the epileptic neurons. The aim of this study is to explore the mechanisms of multi-drug resistance by use of PET with 11-C-labelled antiepileptic drugs, phenytoin and carbamazepine, in patients that respond well to medication as well as in pharmaco-resitant patients. Publications Qu M, Olofsson T, Sigurdardottir S, Kalimo H, Nistér M, Smits A, Ren Z-P (2007) Genetically distinct astrocytic and oligodendroglial components in oligoastrocytoma. Acta Neuropathol 113: Ren Z-P, Olofsson T, Qu M, Hesselager G, Soussi T, Kalimo H, Smits A, Nistér M (2007) Molecular genetic analysis of p53 intratumoral heterogeneity in human astrocytic tumors. J Neuropathol Exp Neurol 66: Persson H, Kumlien E, Ericsson M, Tomson T (2007) Circadian variation in heart rate variability in localization related epilepsy. Epilepsia 5: Samuelsson C, Kumlien E, Enblad P, Nilsson P, Hillered L, Ronne-Engström E (2007) Brain interstitial glutamine/glutamate ration and glucose metabolism in patients with subarachnoidal hemorrhage. J Cereb Blood Flow Metab 27: A Smits, E Westerberg, D Ribom D (2008) Adding 11 C-methionine PET to EORTCs prognostic factors in grade 2 gliomas. Eur J Nucl Med 1, D Hagerstrand, A Smits, A Eriksson, S Sigurdardottir, T Olofsson, M Nistér, H Kalimo, A Östman (2008) Gene expression analyses of grade II gliomas and identification of rptp beta/zeta as a candidate oligodendroglioma marker. Neuro- Oncology 1, Bajic D, Wang C, Wang C, Kumlien E, Mattsson P, Raininko R (2008) Hippocampal malrotation in subject without severe developmental anomalies higher frequency in patients having epilepsy. Eur Radiol 18: Bajic D, Kumlien E, Mattsson P, Lundberg S, Wang C, Raininko R (2009) Incomplete hippocampal inversion-is there a relation to epilepsy? Eur Radiol 19; Danfors T, Ribom D, Berntsson SG, Smits A (2009) Epileptic seizures and survival in early disease of grade 2 gliomas. Eur J Neurol 16; Lindberg N, Kastemar M, Olofsson T, Smits A, Uhrbom L (2009) Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene 28: Qu M, Aronica E, Boer K, Fällmar D, Kumlien E, Nistér M, Wester K, Pontén F, Smits A (2009) DLG3/SAP102 protein expression in malformations of cortical development: A study of human epileptic cortex by tissue microarray. Epilepsy Res 84: