ANNUAL REPORT JULY 2010 JUNE 2011

Transcription

1 CENTER FOR EARLY DIAGNOSIS AND THERAPY RESEARCH ON NEURODEGENERATIVE DISEASES A SWEDISH NETWORK ANNUAL REPORT JULY 2010 JUNE 2011 Approved by the Swedish Brain Power Governing Board date.

2 Index LÄGGAS TILL Page 2

3 Executive Summary The Swedish Brain Power Program (SBP) has now been running for 6 years. From July 2010, the Knut & Alice Wallenberg Foundation is the sole sponsor until June 30, The overall research goal for the program is to develop tools for early diagnostics and to find targets for treatment of neurodegenerative disorders, with a specific focus on ALS, Alzheimer and Parkinson disease. The research within SBP differs from ordinary research in the way that we use a new holistic concept for broad interdisciplinary integration and collaboration between academia, industry, healthcare and medical service. The SBP program spans from basic epidemiological clinical to caring research; ie platforms. This has lead to numerous successful collaborations between the research groups, resulting in many important findings and publications in high ranked journals. The Swedish Brain Power program has obtained a genuine understanding, collaboration and interaction between the involved research groups as well as individual researchers kept the managing and administrative costs to a minimum become the first-choice for most clinical trials in AD worldwide, including also new and innovative trials (active and passive immunotherapy, Dimebon, NGF therapy) developed joint clinical (MCI, dementia) and epidemiological (aging) databases (SATS, SveDem, MCI, Kungsholmen, SNAC-K, H70) established joint bio banks, including material from patients with AD, PD, ALS and healthy controls (CSF, fibroblasts, blood, brains, DNA) to a great extent reached research collaboration with the industry Important research results July 2010 June 2011 (NYA EXEMPEL SKA IN HÄR) 3

4 The Swedish Brain Power Program Short Background & Aims The Swedish Brain Power (SBP) program was established in July 2005, thanks to the initiative from the foundations Invest in Sweden Agency (ISA), KK Foundation, Foundation for Strategic Research, Vårdal Foundation, Knut & Alice Wallenberg Foundation and VINNOVA. From July 2010, the SBP program is sponsored by Knut & Alice Wallenberg Foundation for another 5 years ( ) with in total 100 million SEK. The network is formed by the Swedish leading research groups in the field of neurodegenerative disorders, with a main focus on ALS, Alzheimer and Parkinson disease. Through SBP, in-depth collaboration has been established between groups that rarely or not at all earlier used to collaborate. The scientific collaboration within SBP spans from basic to clinical, epidemiological and care/caring research. The prioritization of developing translational research has also created many contacts and new collaborations between academic research and industry. The overall aim for the SBP network is to improve early diagnosis, treatment and care of patients affected by neurodegenerative diseases. These often age-related diseases are a growing public health problem worldwide due to increased elderly population. There is a great need for new and more effective treatments for dementia and other neurodegenerative diseases, and for increased knowledge on how to give the best possible care. Unfortunately, lately many clinical trials have failed and therefore, it is of importance to continue the basic research and try to find out more about the mechanisms behind the diseases. It is necessary not to get caught in old ideas but have an open mind and shift focus of the research projects along the way, in accordance to new research findings. More specific objectives for the Swedish Brain Power program are to develop methods to identify neurodegenerative diseases as early as possible develop, test and evaluate new drugs or other treatments in the very early stages of the disease facilitate integrated research between the leading expertise in the neurodegenerative field in Sweden stimulate and facilitate translational research as a collaboration between basic, clinical, epidemiological and caring research maintain an international leading position for Swedish neuroscience in order to attract national and international industrial collaboration transfer gained new insights to other researchers nationally and internationally inform the public of new findings and shorten the way from bench to bedside 4

5 Most important outcome/findings During the six years of the Swedish Brain Power program, besides the large number of publications, we have achieved both short term and long term added value such as: Swedish Brain Power has emerged as a nationally leading network in neurodegenerative research Swedish Brain Power facilitates inter- and intradisciplinary collaborations between researchers nationally Swedish Brain Power facilitates and encourages the discussion of new ideas for research. An increased understanding and knowledge of different disciplines has emerged from the meetings between researchers representing multiple disciplines; both in-person meetings, minor/larger group meetings, steering committee meetings and the very successful annual workshops for all SBP members Swedish Brain Power increases the possibilities for research through the funding and the additional matching funds due to the good reputation of Swedish Brain Power The Swedish Brain Power Clinical centers (Huddinge, Malmö, Göteborg) are now the first choice for new, innovative clinical trials Swedish Brain Power has been instrumental in the establishment of Collaboration contracts for basic research with national and international Biotech and Pharma industry The Swedish Brain Power program has become a model for similar networks in Germany, France, the Netherlands and UK now under development The success of Swedish Brain Power has also led to the establishment of collaboration in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) as well as Latvia in the Nordic network Nordforsk, headed by SBP researchers Stronger evidence-based conclusions on larger pooled sample sizes SCIENTIFIC OUTCOME A large number of articles proving the scientific high quality of the SBP network have been published in high ranked journals over the years. These are all listed on our website ( At the end of this report, all publications year 6 are listed. In addition to the Publication List, we have chosen to extract the more important findings from the scientific reports. These are listed below, related to platforms: CLINICAL RESEARCH PLATFORM Diagnostics and Therapeutics, Biomarkers Oligomeric Aβ42 impairs in human embryonic stemcells differentiation into functional neurons, whereas fibrillar Aβ42 promotes astrogliosis rather than neurogenesis. Fibrillar Aß exerts neurotoxic effects mediated partly through a blockade of a7 nachrs, whilst oligomeric Aß may act as a ligand activating a7 nachrs, thereby stimulating downstream signaling pathways. 5

6 Decline in cerebral glucose metabolism was measured in AD mutation carriers (PSEN1 mutation) before onset of symptoms. Neuritic plaque pathology, not tangle, appears to correlate with 18F-FDG measures. High levels of reactive astrocytes (11C-deprenyl binding) have been measured in brain of MCI patients and presymptomatic early-onset familial AD. Longitudinal PET studies with 11C-PIB indicate an increase in fibrillar amyloid during preclinical stages of ad, while stable levels at clinical AD. Adding Hippocampal volume to CSF data improved the prediction of progression from MCI to dementia Biochemical fingerprints representative of subcortical (NFL; MBP, TIMP-1) and cortical alterations (T-tau, P-tau) discriminated between patients with manifest small vessel disease and AD, respectively. Abeta deviations were found in both disorders. Encapsulated NGF producing cells imolanted into the basal forebrain is a safe and tolerable method in AD patients. Further analyses have shown: o low cell survival and NGF release after 12 months. o patients with clear pathological EEG at baseline did not improve during the study, while those with a less pathological or normal EEG pattern at baseline showed with NGF treatment improvement in neurophysiological parameters. o MMSE responders showed increased Chat-activity in CSF during the study Each FTLD subtype have a specific pattern of hippocampal deformation caused by atrophy Epidemiology & Neuropsychology In pooled analyses of data from Stockholm and Gothenburg, onset of accelerated cognitive decline for fluid (speed, memory) versus crystallized (verbal, clock reading) abilities occurred approximately 10 and 5 years before diagnosis. Temporal lobe atrophy and white matter lesions on CT increases risk for dementia Parkinson s patients with MCI have lowered working-memory related fmri activity Will add from the Neuropsychology core BASIC RESEARCH PLATFORM Genetics/ Preclinical research & Transgenic models / Proteomics 9 genetic variations in TARDBP detected in ALS patients: 4 missense variations (2 unreported) and 5 non-coding variations (4 unreported). None of the missense variations present in 200 control individuals. The APParc mutation carriers have typical clinical biomarkers of AD, such as cognitive decline and pathological CSF biomarker profiles but yet they do not show significant binding of the amyloid-ligand PIB as measured by PET 6

7 The CSF biomarkers Aβ42 and tau are pathological in mutation carriers 10 years prior to expected disease onset Exome sequencing data from three individuals in one of the families have been analyzed, 3 5 are interesting disease causing candidates, for example a point mutation in the gene coding for synphilin-1, which protein is known to interact with α- synuclein. Variations of the CAG trinucleotide repeat in DNA polymerase gamma (POLG1) is associated with Parkinson's disease in Sweden Altered function of the dopamine system in alcohol dehydrogenase 4 (Adh4), knockout mice compared to wild type mice Significant decrease in mrna levels of the neurotrophic factors MANF and CDNF in human postmortem brains from PD patients compared to controls. In aged MitoPark mice, which model advanced stages of PD, we also found reduced levels of MANF ALS is a pleiomorphic syndrome: Mutations in Angiogenin which we in 2005 found to be associated with ALS is also associated with juvenile Parkinson s Disease The MitoPark mice: o model Parkinson in terms of neurochemistry, neuropathology and motor behavior o can be treated with l-dopa and/or an adenosine A 2A antagonist, such chronic treatment causes improved behavior (when drugs are not given). Dysfunctional mitochondria in dopamine neurons cause neurophysiological disturbances prior to overt motor disease The mtdna mutator mice; o High brain lactate is a hallmark of the aging process in both prematurely aging mtdna mutator and normally aging mice o Age-related changes in markers of plasticity and in neurotransmitters (monoamines, amino acids) in brains of mtdna mutator mice o The onset of visible prematurely aging phenotypes, such as kyphosis, reduced body size and alopecia is also delayed o Decreased A-beta plaque formation found in the TOJAM mouse (mtdna mutator mouse x APP/PSEN-1 mouse), suggesting that mtdna mutations and mitochondrial dysfunction are not causative factors in the onset and formation of plaques seen in Alzheimer s disease The MemoFlex mice: o Display increased sensitization to amphetamine o Crossed with APPswe/PSEN-1 mice do not differ from controls in terms of plaque load and perform at control levels in memory tests 27OHC o The transporter Abcg1-/- is of importance for the flux of 27OHC from macrophages and brain. The findings suggest that side-chain oxidized oxysterols such as 27OHC may be important for the flux of cholesterol to different compartments in the cell o 27OHC may be an important regulator of the brain rennin angiotensin system o The brain of patients with familial form of AD has a 4-fold accumulation of 27OHC 7

8 Increases in CSF cortisol levels and brain mineralocorticoid receptors (MR) expression has shown to be associated to an APOE ε4 genotype in AD Decreased levels of brain insulin are detected earlier in women and the combination of insulin, Aβ1-42 and tau measurements in CSF could improve early diagnosis of AD in women The omega-3 fatty acids DHA and EPA, precursors to PRFs, stimulates Aβ 1-42 phagocytosis. EPA down-regulated the receptor for the inflammatory cytokine IL-1 Peripheral inflammation associated with allergy results in increased tauphorphorylation and increased levels of immunoglobulins in the brain Aβ oligomers are found in transgenic rat brain, CSF and plasma. Learning and memory deficits in the transgenic rat appear at about 6 months of age Both Aph-1 forms process APP and Notch in the c/s3 sites equally well Caring and Technology Platform Rehabilitation / Care Research & Housing Environment / Information & Communication Technology / Pharmacoeconomics & Primary Care Evaluation studies of DMSS-R in clinical use in four countries showed compliance with physicians assessments in 84% of 218 patient cases, but also limitations in some physicians basic knowledge about cognitive dysfunctions The person-centeredness of care units is highly associated with staff job satisfaction, and can be used as a predictor of staff satisfaction in hospital units as well as in residential aged care units The Short-form Everyday Technology Use Questionnaire (S-ETUQ), was developed and validated; a screening tool that distinguishes MCI from controls and AD, intended to complement other functional assessments Will add from PharmaEconomy The cognitive test Cognistat has moderate clinical utility in primary care for detecting cognitive impairment and diagnosing dementia 8

9 Organisation and infrastructure The Swedish Brain Power organisation is constructed in a way to facilitate and encourage efficient interdisciplinary collaboration within the network, as well as external collaboration. In a legal aspect Swedish Brain Power is a Center of Excellence within Karolinska Institutet (KI) with collaborators all over Sweden. The Coordination Center is located at the KI Alzheimer Disease Research Center (KI-ADRC), Department of NVS, Karolinska Institutet. The SBP work is structured into three research platforms; Clinic, Basic and Caring/Technology platforms (green, blue, lilac in the figure below). Each platform is formed by several cores; eg pre-clinics & transgenic models, epidemiology, care/caring & rehabilitation. Ethics is a core of its own but not placed in a specific platform, since it concerns all kinds of research. Each core consists of research groups from different university research units, and is lead by scientific core coordinators, who in turn form the Steering Committee, (see further info below). The SBP Organisation Plan Leadership and coordination SBP is led by a Governing Board with representatives from governmental authorities, founding organisations, industry, county council and academia. The Board takes a global responsibility for the SBP program, takes the final decision on research activities and allocation of the budget, and makes the policy decisions. The Board members also act as ambassadors for the program and strive to attract additional funding and industrial collaboration. The Governing Board meets at least once per term, and additional times if required. Governing Board Håkan Eriksson, Chair (Founder repr) Agneta Holmäng, Göteborg Christer Köhler, AstraZeneca Staffan Normark, Stockholm Olle Stendahl, Linköping Göran Stiernstedt, Stockholm 9

10 Co-opted members of the Governing Board Kerstin Tham, Head of NVS Dept, KI Bengt Winblad, Director SBP Maria Eriksdotter Jönhagen, Co-Director SBP Gunilla Johansson, Coordinator SBP Steering Committee The Steering Committee (SC) consists by all core coordinators (see list next page). The SC deals with more specific issues, such as scientific activities including a first evaluation of the research projects and preparing a recommendation to be presented to the Board for decision. The SC meets 1-2 times per term. Executive Group The Executive Group deals with the day-to-day decisions and consists of Director Bengt Winblad, Co-Director Maria Eriksdotter Jönhagen and Coordinator Gunilla Johansson. SBP PhD s and PhD students During the first five years, 40 SBP-connected PhD students have passed their examination. Currently, SBP-projects involves 30 Postdocs and 15 registered PhD students obtaining salary support from the program. In addition a number of Postdocs & Senior researchers are mainly/partly involved in the research projects. All collaborators are listed on the next pages. 10

11 SWEDISH BRAIN POWER Core Coordinators and Other Members Director: Bengt Winblad, Professor Co- Director: Maria Eriksdotter Jönhagen, Professor Coordinator: Gunilla Johansson Communication Manager: Annbritt Ryman Core Coordinators Other Members Diagnostics and Therapeutic research, Clinical Trial Center Karolinska Institutet, Stockholm Agneta Nordberg, Professor Skåne University Hospital, Malmö Lennart Minthon, Assoc Professor Sahlgrenska Academy, Univ of Gothenburg Anders Wallin, Professor Karolinska Institutet, Stockholm Niels Andreasen, MD, PhD Maria E Jönhagen, Professor, MD Dag Aarsland, Professor, MD Vesna Jelic, MD, PhD Anne- Rita Öksengård, MD, PhD Taher Darreh- Shori, PhD Ahmadul Kadir, PhD Michael Schöll, PhD stud Skåne University Hospital, Malmö Elisabeth Londos, Assoc Prof, MD Katarina Nägga, MD, PhD Oskar Hansson, MD, PhD Åsa Wallin, MD, PhD Erik Stomrud, PhD Malin Lavesson, other Sahlgrenska Academy, Univ of Gothenburg Arto Nordlund, PhD Anne Börjesson- Hansson, MD, PhD Maria Svensson, PhD stud Eva Bringman, research nurse Ewa Styrud, research nurse Uppsala University Lars Lannfelt, Professor Uppsala University Lars Nilsson, Assoc Prof Epidemiology Lund University Patrik Brundin, Professor Karolinska Institutet,Stockholm Laura Fratiglioni, Professor Lund University Gunnar Gouras, Professor Davide Tampellini, PhD Sonia George, PhD Géraldine Petit, PhD Karolinska Institutet, Stockholm Nancy Pedersen, Professor Miia Kivipelto, Assoc Professor Hui- Xin Wang, PhD Chengxuan Qiu, PhD Sara Angleman, PhD Lina Rosvall, PhD Barbara Caracciolo, PhD stud Sahlgrenska Academy, Univ of Gothenburg Ingmar Skoog, Professor Sahlgrenska Academy, Univ of Gothenburg Deb Gustafsson, PhD Pernille Olesen, PhD 11

12 Neuropsychology Karolinska Institutet, Stockholm Lars Bäckman, Professor University of Gothenburg Boo Johansson, Professor Umeå University Lars Nyberg, Professor Karolinska Institutet, Stockholm Stuart MacDonald, PhD Ove Almkvist, PhD University of Gothenburg Linda Hassing, Assoc Prof Valgeir Thorvaldsson, PhD Umeå University Anna Neely, PhD Daniel Sjölie, PhD stud Care Research, Rehabilitation Umeå University, Umeå Per- Olof Sandman, Professor Umeå University Birgit Rasmussen, RN, PhD David Edvardsson, RN, PhD Karolinska Institutet Louise Nygård, Professor Lund University Anna- Karin Edberg, Professor Karolinska Institutet, Stockholm Lena Borell, Professor Camilla Malinowsky, PhD stud Eva Lindqvist, PhD stud Lund University Anneli Orrung Wallin, PhD stud University of Gothenburg Helle Wijk, Assoc Professor Hanna Falk, PhD Primary Care, Health Economics, Interactive training technology Karolinska Institutet, Stockholm Anders Wimo, Professor Linköping University Hospital Jan Marcusson, Professor Umeå University Gösta Bucht, Professor Karolinska Institutet, Stockholm Linus Jönsson, MD, PhD Anders Gustavsson, PhD Anders Sköldunger, PhD stud Britt- Marie Sjölund, PhD stud Linköping Univ Hospital Anna Segernäs, PhD stud Umeå University Helena Lindgren, PhD Biomarkers (Imaging, CSF etc) Sahlgrenska Academy, Univ of Gothenburg Kaj Blennow, Professor Karolinska Institutet, Stockholm Lars- Olof Wahlund, Professor Lars Farde, Professor Sahlgrenska Academy, Univ of Gothenburg Henrik Zetterberg, MD, Assoc Prof Niklas Mattsson, PhD stud Annika Sjölander, PhD stud Karolinska Institutet, Stockholm Agneta Nordberg, Professor Christer Halldin, Professor Per Julin, MD, PhD Olof Lindberg, PhD stud Uppsala University Bengt Långström, Professor Marie Svedberg, PhD 12

13 Genetics, Brain Bank Karolinska Institutet, Stockholm Caroline Graff, MD, Assoc Professor Sahlgrenska Academy, Univ of Gothenburg Elias Eriksson, Professor Umeå University Peter M Andersen, Professor Karolinska Institutet, Stockholm Lars Olson, Professor Tatjana Nilsson, PhD Marie Westerlund, PhD Andrea Carmine Belin, PhD Dagmar Galter, PhD Lina Rosvall, PhD Anna Zettergren, PhD stud Huei- Hsin Chiang, PhD stud Anna Anvret, PhD stud Caroline Ran, PhD stud Sandra Gellhaar, PhD stud Sahlgrenska Academy, Univ of Gothenburg Hans Nissbrandt, Professor Olle Bergman, PhD Umeå University Stefan Marklund, Professor Anna Birve, PhD Lund University Patrik Brundin, Professor Pre- clinical research, Transgenic models Karolinska Institutet, Stockholm Lars Olson, Professor Angel Cedazo- Minguez, Assoc Professor Ingemar Björkhem, Professor Karolinska Institutet, Stockholm; M Schultzberg, Professor Nils- Göran Larsson, Professor Urban Lendahl, Professor Eirikur Benedikz, Assoc Prof Helena Karlström, PhD Andrea Carmine Belin, PhD Dagmar Galter, PhD Anna Mattson, PhD Jaime Ross, PhD stud Fredrik Sterky Hansson PhD stud Erik Hjorth, PhD Maria Ankarcrona, Assoc Prof Lars Tjernberg, Assoc Prof Erik Sundström, Assoc Prof Uppsala University Lars Lannfelt, Professor Martin Ingelsson, Assoc Prof Hedvig Welander, PhD Ethics Karolinska Institutet, Stockholm Erik Sundström, Assoc Professor Maria Eriksdotter Jönhagen, Professor Karolinska Institutet, Stockholm Sara Stormoen, PhD stud 13

14 Information dissemination Disseminating information, both external and internal, is one of SBP s priorities. Externally, the aim is to reach relevant target groups such as other scientists, physicians clinics, patients and decision makers within society and industry as well as the general public. Internally, the aim is to facilitate and enhance the communication within the network. The goal is to promote a positive development for neuroscience, business enterprise and care of patients with neurodegenerative disorders. To this end, SBP has, since October 2007, a half time employed communication manager who works close together with the Executive Group. External Publications in scientific journals are of course the main channel for scientific information dissemination, both nationally and internationally. The many SBP publications are presented under Scientific impact. The prominent scientists in the SBP network often give lectures and present the SBP program at scientific as well as public meetings, both nationally and internationally. Another information channel is open seminars. At a summarizing seminar in Stockholm in May 2010 research results from the first five SBP years were presented. SBP initiatives have also resulted in two computerized databases for dissemination of research results and quality development of the care of dementia patients; the SveDem quality register and the register for behavioral and psychological symptoms (BPSD). A portable roll up is currently produced to present the SPB and its urgent message for more money for research on our most dreaded brain diseases. The roll up will be distributed to members of the network for them to use in public performances. Internal Every year an SBP workshop is organized. For two days, all researchers in the network meet and exchange experiences, ideas and results. The workshops focus on giving PhD students and Postdocs an opportunity to present their projects. A quarterly newsletter has been electronically distributed to the members of the SBP Network, the Governing Board and to representatives for the founders. Both external and internal The SBP website ( plays an important role in the information dissemination, both externally and internally. The site presents the SBP and SBP related news to external target groups and to the public. The website is currently being updated to also offer an internal channel of communication to further facilitate and enhance cooperation among researchers in the network. The updated website is planned to be launched in late September SBP is, since summer 2011, also present on facebook and twitter. 14

15 Research Budget Allocation The grant for the SBP program during July 2010 June 2015 (5 yrs) is in total 100 million SEK. During year 6, approx 14 million has been allocated to research projects in form of 50% salary support. Approx X (will add here) million has been used for managerial and administrative costs, including part-time salary for the director, co-director, coordinator and communication manager, as well as costs related to the website and meetings/travels for all researchers involved in the program. A full economy report is given separate. Below is summarized the allocation of grant year 6 per university/unit and platform (fig 1) and per disorder (fig 2). No of Project Leaders per university: KI 18, Gbg 6, Malmö 1, Umeå 4, Lund 2, Nordanstig 1, Linköping 1, Uppsala 1. Fig 1 Fig 2 *Neurodeg NUD = Neurodegeneration without further definition 15

16 Swedish Brain Power In FUTURE Both nationally and internationally, Swedish Brain Power has become a well-known trademark. The many recent publications in high impact journals and the high number of excellent PhD examinations so far, is a proof of the scientific quality. The collaboration between involved researchers has become very natural. The demand on collaboration for budget allocation has been a good initial incitement to achieve interaction between the research groups. Now, collaboration has become very natural since all have very positive experience from this. Being a part of Swedish Brain Power is something all are proud of. With the positive outcome from these 6 years on our backs, we now carry on the research program and look optimistic on future results. Still, to be able to keep and further improve the success of the integration and the added value from our multidisciplinary, translational approach demands continuous efforts and economic support. Will add more specific regarding future research focus here. For the Swedish Brain Power Program: Bengt Winblad Director Maria Eriksdotter Jönhagen Co-Director Gunilla Johansson Coordinator 16

17 LIST OF RESEARCH PROJECTS 17

18 Clinical Platform (PI within brackets) 1. Multi-tracer PET studies for understanding of disease processes and development of early diagnostic biomarkers (A Nordberg) 2. Studies of neuroplasticity and functional neurogenesis in AD (A Nordberg) 3. Early diagnosis of AD a multidisciplinary approach (L Minthon) 4. A longitudinal study of 200 healthy elderly subjects with focus on early markers for dementia disorders (L Minthon) 5. Neurochemical identification of incipient subcortical VaD and AD (A Wallin) 6. Functional and structural brain imaging in normal aging, vascular and non-vascular MCI (A Wallin) 7. NGF-mediated cell therapy in AD (M Eriksdotter Jönhagen) 8. Genetic background and lifestyle-related factors in relation to risk of dementia and cognitive decline (L Fratiglioni & I Skoog) 9. Longitudinal population-based studies in Sweden: defining new clinical outcomes (L Fratiglioni) 10. Brain atrophy and cerebrovascular disease on CT in elderly population samples; risk factors, secondary changes and prognosis (I Skoog & LO Wahlund) 11. Individual differences in pre-clinical onset of dementia: What contributes to early/late onset of accelerated cognitive decline? (L Bäckman & B Johansson) 12. The role of dopamine in cognitive plasticity across the adult life span (L Bäckman) 13. Cognitive training and transfer in normal and pathological aging (L Nyberg) 14. Early diagnosis of neurodegenerative diseases; Assessment of emotional and cognitive impairment with Virtual Reality (VR) technique in combination with brain imaging (functional MRI) VRfMRI (G Bucht) 15. Biomarkers to study molecular mechanisms and disease pathogenesis in AD (K Blennow) 16. Acute effect on the Aβ isoform pattern in CSF in response to treatment in AD patients (K Blennow) 17. MRI studies of the fore brain in health and disease (LO Wahlund) Basic Platform 18. Genetic studies in FTD and ALS patients (C Graff) 19. Clinical and experimental studies of FAD: a model for identifying prognostic and early diagnostic markers of sporadic AD (C Graff) 20. Prion-like propagation of Aβ- and tau-pathology in AD: translational studies in Tg mouse models (P Brundin) 21. Disease-causing mutations in familial PD (H Nissbrandt) 22. Identification and modelling genetic in PD (A Carmine Belin) 23. Closing some of the gaps between genetic studies and pathology (D Galter) 24. Investigating the selective neuronal vulnerability in AD pathogenesis (A Sandebring) 25. Biomarker characterization (CSF and Imaging) of patients with mutations in different genes associated with ALS and ALS-dementia (P M Andersen) 26. Animal models for the formation of lasting memories and to alter plaque load (L Olson) 27. The mitochondria theory of aging, mtdna mutator mice and high brain lactate as early biomarker of AD (L Olson) 28. APOE genotype and life-style risk factors in AD; to understand the underlying mechanisms (A Cedazo Minguez) 29. Role of cholesterol metabolism and functions of oxysterols in healthy and AD brains (A Cedazo Minguez & I Björkhem) 18

19 30. Role of the oxysterol 27-OHC in neurodegeneration (I Björkhem) 31. Inflammation as target for treatment of AD with special focus on the resolution phase (M Schultzberg) 32. Biomarkers and memory in the transgenic AD rat (E Benedikz) 33. Role of the Aph-1 isoforms in the γ-secretase complex for selective processes of APP and Notch (H Karlström) 34. Neuronal cell cultures derived from induced pluripotent cells as a platform to study AD mechanisms (E Sundström) 35. Investigating the diagnostic value of soluble protein aggregates in neurodegenerative disorders (L Lannfelt) Caring / Technology Platform 36. Living dementia knowledge a web-based system for collaborative knowledge development and dissemination (G Bucht) 37. From rhetoric to research: person-centred care for people with dementia (PO Sandman) 38. Evidence-based environments, optimizing the preconditions for in-patient dementia assessment (AK Edberg & H Wijk) 39. Detection of subtle and early signs of disability in terms of difficulties in everyday technology use in MCI and AD patients (L Nygård) 40. The influence of cognitive assistive technology in supporting daily living among ADpatients in early stages (L Borell) 41. The academic nursing home a large scale intervention of the national guidelines for care of dementia (L Borell & PO Sandman) 42. Development of simulation models for neurodegenerative disorders (A Wimo) 43. Functional capacity and costs of care (A Wimo) 44. Dementia; costs for disease, drugs and diagnostics (A Wimo) 45. Cognitive testing and functional evaluation in primary care dementia investigations (J Marcusson) 46. Decision making ability in patients with cognitive impairment (E Sundström) 19

20 IMPORTANT PUBLICATIONS INCL IMPACT FACTORS YEAR 6 20