CENTER FOR EARLY DIAGNOSIS AND THERAPY RESEARCH ON NEURODEGENERATIVE DISEASES A SWEDISH NETWORK

Transcription

1 CENTER FOR EARLY DIAGNOSIS AND THERAPY RESEARCH ON NEURODEGENERATIVE DISEASES A SWEDISH NETWORK ANNUAL REPORT JULY 2011 JUNE 2012

2 Table of Content Page Summary..3 Background & Objectives...4 Outcome & Major Achievements External Collaboration 9 Organisation and infrastructure List of Core Coordinators and other members Information Dissemination Research Budget Allocation Swedish Brain Power in Future..20 List of Research Projects.21 Publication List

3 Summary The Swedish Brain Power (SBP) program started in summer From July 2010 Knut & Alice Wallenberg (KAW) Foundation is the sole sponsor (until June 2015). SBP is now well established as a leading national research network focusing on early diagnosis and therapy research on neurodegenerative diseases. The program also serves as a model for research networks established in Germany, France and The Netherlands. Collaboration One of the main goals for SBP was to increase the interaction between the national experts in the area and by that increase the possibility to reach the aim of the program. This goal has definitely been reached; the Swedish Brain Power program has obtained a genuine understanding, collaboration and interaction between the involved research groups, as well as individual researchers. SBP has also led to the establishment of both a Nordic collaborative academic program, and joint experimental research projects between SBP academia and other national & international research groups. SBP researchers also has an extensive collaboration with both pharma and biotech industry, and the involved clinical centers are the first choice (worldwide) for new, innovative clinical trials. The SBP initiated quality registry (SveDem) is now established. SveDem currently comprises patients (out of which from Primary Care) and is the data source for several quality indicators in dementia care. A large number of research projects and publications are now based on this registry. Through SBP joint bio banks all over Sweden, including material from patients with Alzheimer Disease (AD), Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and healthy controls (cerebrospinal fluid (CSF), fibroblasts, blood, brains, DNA) has been established. SBP also collaborates with the StratNeuro strategic research program including Karolinska Institutet, the Royal Institute of Technology (KTH) and the SBP members from Umeå University. Scientific outcome In the scientific field, it is now harvest time. One proof of our scientific outcome is the large number of articles of high scientific value produced by the SBP researchers (see attached Publication List). A summary of the major achievements are listed on pages 7-8. Several SBP researchers have received prestigious awards for their contribution to the research field, eg the International Alzheimer Association Lifetime Achievement Award, given to Prof Kaj Blennow, the Eric K Fernström s award to Prof Henrik Zetterberg for new research that increases the possibility for early detection of Alzheimer disease and the Eric & Waijlit Forsgrens pris to Profs Bengt Winblad, Laura Fratiglioni and Kaj Blennow. 3

4 The Swedish Brain Power Program Background & Objectives 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 KAW 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 SBP research program spans from basic to clinical, epidemiological and caring research. The organisation is outlined in order to facilitate and encourage collaboration between the involved research groups. The prioritization of developing translational research has also created many contacts and new collaborations between academic research and industry. It is an incentive for the program to keep the administrative costs as low as possible, and focus our efforts on research. The overall aim for the SBP network is to improve early diagnosis, treatment and care of patients affected by neurodegenerative diseases (Alzheimer and Parkinson disease, Amyotrophic Lateral Sclerosis). 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. SPECIFIC OBJECTIVES To increase our knowledge regarding the pathogenesis of neurodegenerative diseases To validate the basic research target findings in cell and animal models To translate our basic research on biomarkers o to improve diagnostic accuracy 4

5 o to identify adequate target populations for intervention To identify new mutations and risk genes To further identify and validate preventive strategies and initiate prevention trials To validate different treatment strategies in preclinical phases To achieve efficacious treatment of neurodegenerative diseases on a personalized basis To develop o new instruments for improved measurement of intervention/treatment effects o new caring strategies, such as environmental, psychosocial, educational etc 5

6 Outcome & Major Achievements So far, the Swedish Brain Power program, besides the large number of publications, have fulfilled many of the outlined objectives and 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 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 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 Thanks to the Swedish Brain Power program and the pioneering research on biomarkers, the project BIOMARKAPD within the JPND-EU program is now headed by Sweden; Project Coordinator Bengt Winblad, PI Kaj Blennow, Co-PI Henrik Zetterberg, Financial & Administrative Manager Gunilla Johansson. The project involves 51 centers from 23 countries in Europe. The funding is national, in Sweden VR contributes with approx 2.4 MSEK over three years. SCIENTIFIC OUTCOME During current period, 50 research projects have been run, (all project titles are listed on pages 21-22). A large number of articles proving the scientific high quality of the SBP research results have been published in high ranked journals. An updated publication list for the period can be found on our website ( 6

7 During this year, 94 articles have been published (full publication list at the end of this report). Seven SBP PhD students have defended their thesis during current period. MAJOR ACHIEVEMENTS First-choice for most worldwide clinical trials in Alzheimer disease; (active and passive immunotherapy, gamma-secretase inhibitors, NGF (nerve growth factor) therapy); o Active vaccination; CAD106. The first Phase I-study has been performed within the SBP network, showing satisfactory antibody production and no side effects. o NGF; Encapsulated NGF cell therapy to the basal forebrain performed in six patients, showed improved cognition, increased nicotine binding and improved EEG-activity in 2/6 patients. Additional four patients have now got NGF-releasing implants. Development of joint databases (Clinical: SATS, SveDem, Mild Cognitive Impairment. Epidemiological: Kungsholmen, SNAC-K, H70.) Establishment of joint bio banks, includes material from patients with AD, PD, ALS and healthy controls (CSF, fibroblasts, blood, brains, DNA). Improved early diagnosis including development of new biomarkers for early diagnosis of cognitive impairment (CSF (Aß, Tau, Proteomics, 24Shydroxycholesterol), PET Imaging (amyloid load, glucose metabolism), MRI (atrophy hippocampus and temporal lobe), TRX80; potential target molecule for AD treatment), further developed Neuropsychological tests; o Combination of Hippocampal volume, neuropsychological test and CSF markers predict conversion from MCI to dementia to a very high degree. o Cognitive testing shows that accelerated decline occurs in closer proximity to diagnosis in Vascular dementia (VaD) compared to Alzheimer disease. However, once accelerated decline occurs, rate of deterioration is faster in VaD than in AD. o Striatal DA D1 receptor density is related to functional brain activation during working memory and reduced receptor density contributes to altered activation patterns and impaired cognitive performance in aging. Training of working memory leads to increased functional brain activity and to increased release of DA in striatum. Identification of risk genes and mutations and clarifications of underlying function; o In ALS; SOD1 and ITPR2. Homozygous deletion of SMN2 has shown to be a protective genetic factor for developing ALS in Sweden. o In Frontotemporal lobe dementia; GRN. o The APOE risk gene for AD, together with a high carbohydrate diet affects cognitive functions in young mice. 7

8 o APOE4 induces impairment of the Thioredoxin 1 (Trx1) systems in neurons. APOE4 affects both synthesis and degradation of Trx1, which is a vital defense against Aβ. Establishment of new transgenic animals of great value for the translation of basic findings into humans (MitoPark, MemoFlex, Swe mutation Tg2576, Swe APP rat); o In the MemoFlex mice it has been shown that the Nogo receptor 1 (NGR1) is important for spatial memory and for drug-induced memories. Inability to down-regulate NGR1 alters sensitization to amphetamine and long term memory of amphetamine. This is important for understanding addiction and general memory mechanisms, not the least the role of emotional weight for strength of memories formed. Development of technological assessments/training methods (using Virtual reality, Functional MRI, PET); o Long periods of cognitive training in patients with Parkinson disease, that foster strong performance on the criterion task can induce robust transfer even in elderly participants. Establishment of new instrument to measure function in normal elderly, MCI patients and demented individuals and resource utilization in dementia (ETUQ, SITA, Personcentered care, assessment scale for nursing strain, RUD); o The ETUQ rating scale displayed sound psychometric properties when used on adult persons with intellectual disabilities and could separate these subjects into three distinct groups based on their cognitive function. This further supports the potential of the ability to use technology being a sensitive marker of disability when cognitive impairment is present. 8

9 External Collaboration NATIONAL & INTERNATIONAL EXTERNAL COLLABORATION (ie outside SBP) Except for the internal collaboration between involved SBP research groups, the individual SBP researchers have an extensive national and international collaboration, eg; - EU projects o EU Dimi, INMIND o EURODEP o BIOMARKAPD o FTD consortium (GWAS), Early onset dementia consortium & the GENFI group o CLINIGENE (the NGF study was included) - National Academic collaboration o Malmö Diet and Cancer study o FAS Epi Life Center, Gothenburg ( o StratNeuro program at Karolinska Institutet o Dept of Clinical Neuroscience, Dept of Mol Medicine and Surgery, Karolinska Institutet o KTH (Royal Institute of Technology) o Luleå University - International Academic collaboration o NIA & NIH, Bethesda o MedCoast (Gothenburg-Oslo MCI study) o Vas-Cog; LADIS o ICINET o McGill Univ Canada, South Carolina Univ US (Prof A-C Granholm), John Hopkins Univ Baltimore o Ageing Research Unit, Australian National Univ (collaboration to validate an evidence-based dementia risk assessment tool) o Prof Ullman Lindenberger, Berlin, Germany o The IALSA Consortium ( o Dept of Biomedical Engineering, Univ of Alberta, Edmonton, Canada o Genetic Epidemiology of Parkinson Disease (GEO-PD) o Prof Nils-Göran Larsson, Max Planck Institute for Biology of Ageing o Univ of Bologna, Prof Roberto Rimondini o Tübingen Univ, Dept of Neurology o La Trobe Univ, Australia o Oslo Univ, Norway o Kobe Univ, Japan - Industrial o GE Healthcare o Bayer Pharma o DiaGenic 9

10 o NsGene A/S o Context vision AB o Depona AB o Hoffmann-La Roche o AstraZeneca o Hoehringer-Ingelheim o Amorfix Life Sciences o Gyros AB, Uppsala o BioArctic, Stockholm o Daniel Medical Center & Bucheon Medical Center, South Korea o Ibaraki Medical Association, Osaka, Japan o Janssen-Cilag In addition, a large number of clinical trials, sponsored by the pharma industry, are performed at the three involved clinics on the SBP prioritized diseases: ALS, Alzheimer and Parkinson diseases. 10

11 Organisation and infrastructure The Swedish Brain Power is organised 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 NVS, Karolinska Institutet. SBP is directed by Prof Bengt Winblad, together with Maria Eriksdotter as co-director and Gunilla Johansson as Coordinator. The SBP work is structured into three research platforms; Clinic-Epidemiology, 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 research areas. 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, (further info next page). The SBP Organisation Plan Leadership and coordination SBP is led by a Governing Board with representatives from governmental authorities, the founder, 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. 11

12 Governing Board Håkan Eriksson, Chair Agneta Holmäng, Göteborg Christer Köhler, Stockholm Staffan Normark, Stockholm Olle Stendahl, Linköping Göran Stiernstedt, Stockholm Co-opted members of the Governing Board Kerstin Tham, Head of NVS Dept, KI Bengt Winblad, Director SBP Maria Eriksdotter, Co-Director SBP Gunilla Johansson, Coordinator SBP Steering Committee The Steering Committee (SC) consists of 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 to be presented to the Board for decision. The SC meets 1-2 times per term. Executive Group The Executive Group deals with the daily decisions and consists of Director Bengt Winblad, Co-Director Maria Eriksdotter 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 involve 36 post docs and 30 registered PhD students obtaining salary support from the program. In addition a large number of post docs & senior researchers are mainly/partly involved in the research projects. All collaborators are listed on page During year 7, seven PhD students have defended their thesis; - Barbara Caracciolo - Huei-Hsin Chiang - Michael Jonsson - Tobias Karlsson - Olof Lindberg - Camilla Malinowsky - Michael Schöll 12

13 SWEDISH BRAIN POWER Core Coordinators and Other Members Director: Bengt Winblad, Professor Co-Director: Maria Eriksdotter, 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, Professor Sahlgrenska Academy, Univ of Gothenburg Anders Wallin, Professor Uppsala University Lars Lannfelt, Professor Lund University Gunnar Gouras, Professor Karolinska Institutet, Stockholm Niels Andreasen, MD, PhD Maria Eriksdotter, Professor, MD Dag Aarsland, Professor, MD Vesna Jelic, MD, PhD Taher Darreh-Shori, PhD Ahmadul Kadir, PhD Stephen Carter, PhD Michael Schöll, PhD Anna Lilja, PhD stud Ruiqing Ni, 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 Gustav Torisson, PhD stud Malin Lavesson, RN Sahlgrenska Academy, Univ of Gothenburg Arto Nordlund, PhD Anne Börjesson-Hansson, MD, PhD Carl Eckerström, PhD Michael Jonsson, PhD Maria Svensson, PhD stud Eva Bringman, research nurse Ewa Styrud, research nurse Uppsala University Martin Ingelsson, Assoc Prof Joakim Bergström, PhD Hedvig Welander, PhD Lund University Patrik Brundin, Professor Davide Tampellini, PhD Sonia George, PhD Géraldine Petit, PhD Epidemiology Karolinska Institutet,Stockholm Laura Fratiglioni, Professor Karolinska Institutet, Stockholm Miia Kivipelto, Professor Hui-Xin Wang, PhD Chengxuan Qiu, PhD Sara Angleman, PhD Lina Rosvall, PhD Barbara Caracciolo, PhD 13

14 Sahlgrenska Academy, Univ of Gothenburg Ingmar Skoog, Professor Sahlgrenska Academy, Univ of Gothenburg Pernille Olesen, PhD Svante Östling, PhD 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 Erika Jonsson Laukka, PhD Yvonne Brehmer, PhD University of Gothenburg Linda Hassing, Assoc Prof Valgeir Thorvaldsson, PhD Anne Ingeborg Berg, PhD Umeå University Anna Neely Stigsdotter, PhD Daniel Sjölie, PhD stud Urban Ekman, PhD stud Care Research, Rehabilitation Umeå University, Umeå Per-Olof Sandman, Professor Umeå University Birgit Rasmussen, RN, PhD David Edvardsson, RN, PhD Karin Sjögren, RN, PhD stud Karolinska Institutet Louise Nygård, Professor Lund University Anna-Karin Edberg, Professor Karolinska Institutet, Stockholm Lena Borell, Professor Camilla Malinowsky, PhD Eva Lindqvist, PhD 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 Helena Lindgren, PhD Karolinska Institutet, Stockholm Linus Jönsson, MD, PhD Anders Sköldunger, PhD stud Britt-Marie Sjölund, PhD stud Linköping Univ Hospital Anna Segernäs, PhD stud Biomarkers (Imaging, CSF etc) Sahlgrenska Academy, Univ of Gothenburg Kaj Blennow, Professor Sahlgrenska Academy, Univ of Gothenburg Henrik Zetterberg, MD, Professor Niklas Mattsson, PhD Maria Bjerke, PhD 14

15 Karolinska Institutet, Stockholm Lars-Olof Wahlund, Professor Lars Farde, Professor Karolinska Institutet, Stockholm Agneta Nordberg, Professor Christer Halldin, Professor Olof Lindberg, PhD Genetics, Brain Bank Karolinska Institutet, Stockholm Caroline Graff, MD, Professor Sahlgrenska Academy, Univ of Gothenburg Hans Nissbrandt, Professor Umeå University Peter M Andersen, Professor Karolinska Institutet, Stockholm Lars Olson, Professor Mimmi Westerlund, PhD Andrea Carmine Belin, PhD Dagmar Galter, PhD Lina Rosvall, PhD Anna Anvret, PhD Huei-Hsin Chiang, PhD Caroline Ran, PhD Sandra Gellhaar, PhD Sahlgrenska Academy, Univ of Gothenburg Elias Eriksson, Professor Olle Bergman, PhD Umeå University 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 Eirikur Benedikz, Assoc Prof Helena Karlström, PhD Andrea Carmine Belin, PhD Dagmar Galter, PhD Jaime Ross, 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, Professor Karolinska Institutet, Stockholm Sara Stormoen, PhD stud Kevin Grimes, PhD Mette Bergman, PhD stud 15

16 Information dissemination Knowledge dissemination and communication, both internal and external, is one of SBP s priorities. To this end SBP has, since October 2007, engaged a Communication Manager at halftime to work close together with the Executive Group. Externally the aim is to reach relevant target groups such as other scientists, physicians, clinics, patients, decision makers in society and industry as well as the general public. Internally the aim is to facilitate and enhance the communication and collaboration within the network. Both External and Internal The SBP website plays an important role in knowledge dissemination, both externally and internally. The site presents the SBP and SBPrelated news to external target groups and to the public. This year, the news about a successful study on a vaccine against Alzheimer disease, conducted by several researchers in the network, became one of the top 5 news on the Internet and reached hundreds of thousands around the world. SBP s presence on Facebook and Twitter twitter.com/swedbrainpower has also contributed to a growing interest from the public and media. The update of the website included the launch of an internal channel of communication to further facilitate and enhance communication and cooperation between the members of the network. Efforts to further increase the website s accessibility and usability is made continuously by search optimizing and updating both content and technical functions. External Publication in scientific journals is the main channel for scientific knowledge dissemination, both nationally and internationally. News about important publications in major scientific journals is reported on the website in a popular form along with links to the articles. The prominent scientists in the SBP network often give lectures and present the SBP program at scientific conferences as well as public meetings and seminars, both nationally and internationally. This year, among other things, SBP participated at the Almedalsveckan in July (a traditional and popular meeting place for the public and politicians to discuss social and political issues). Ten of SBP's top scientists appeared and spoke about the latest research findings in a well-attended seminar, for which we were happy. However, as we did not manage to attract politicians or journalists, the evaluation after the event resulted in that our presence during Almedalsveckan will not be repeated. In September SBP co-hosted a seminar on the annual Alzheimer Day Sep 21, which was broadcasted by Swedish national television (SVT) on the Knowledge Channel and has been watched by a large number of people. 16

17 Portable roll ups in both Swedish and English for use at public performances have been produced together with a folder and a flyer to give a short presentation of the program. In April, Swedish Brain Power got a debate article published in the Swedish newspaper Dagens Medicin about the future research policy in Sweden. In the article 30 of SBPs top scientists made a joint statement arguing for collaboration and urgent necessary societal investments in research to combat the big challenge of dementia. Internal Every year, a very appreciated 2-day workshop is organized where all researchers in the network meet and exchange experiences, ideas and results. This year s workshop focussed on giving PhD students and post docs an opportunity to present new cutting edge projects. Two international well-reputed researchers also presented their work. During these workshops, many new collaborations are born. 17

18 Research Budget Allocation The grant for the SBP program during July 2010 June 2015 (5 yrs) is in total 100 MSEK. During year 7 ( ), approx 18 MSEK has been allocated to research projects in form of 50% salary support. Approx 3.2 MSEK 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. See table below. KOORDINATIONSCENTRUM Lönekostnader ÅR 6 ÅR 7 Löner (Director, Co-Director, Adm coord) Informatör/kommunikatör Styrelsearvoden Biostatistiker 0 0 SUM LÖNER ÖVRIGA KOSTNADER Lokalhyra Möten (styrelse, ledningsgrupp, arbetsgrupper) Resor Workshop SBP Rekryteringsannonsering Dator, datorprogram, webhotell Kontorsmaterial Övriga driftskostn SUM ÖVRIGA KOSTN SUM LÖNE- och ÖVRIGA KOSTNADER INDI 19%, 19.07% resp 15,38% SUBTOTAL; kostn tagna vid koord-centrum FÖRDELADE MEDEL TILL DELTAGANDE SBP-GRUPPER Fördelade medel inkl 19% INDI Fördelade medel inkl 19,07% INDI Fördelade medel inkl 15,38% INDI SUBTOTAL; FÖRDELADE MEDEL TOTALA KOSTNADER

19 Below is summarized the allocation (%) of grants (year 6-7) per university and per project leader. No of Project Leaders per university: KI 18, Gbg 6, Malmö 1, Umeå 4, Lund 2, Nordanstig 1, Linköping 1, Uppsala 1. Budget allocation research projects SBP Nordanstig Uppsala 3% 3% Linköping 2% Umeå 9% Nordanstig 16% Malmö/ Lund 16% Malmö/Lund 9% Karolinska Institutet 56% Uppsala 16% Göteborg 16% Göteborg 18% Linköping 8% Umeå 13% Karolinska Institutet 15% Per university (%) Per project leader (%) 19

20 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 demand on collaboration for budget allocation has been a good initial incitement to achieve interaction between the research groups and collaboration between involved researchers is now has well established. Being a part of Swedish Brain Power is something all are proud of. Lately many clinical trials on neurodegenerative disorders have failed. This makes it of utmost importance to be able to continue the basic research and try to find out more about the mechanisms behind these 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 with new research findings. Some of our new research projects are focussed on these new ideas, eg finding CSF/blood biomarkers for synaptic dysfunction which could lead to a number of neurodegenerative disorders. Recently, new criteria for diagnosis of Alzheimer disease including preclinical stages, have been published. In addition to current assessment, biomarkers (such as CSF Aβ and tau measurement and imaging methods) are added as support for the diagnosis. Using biomarkers, it is assumed that it will be possible to diagnose AD even before the clinical symptoms are present. The new criteria will be validated by the clinics in SBP. As we are now entering into our third year (out of currently supported five), we have started our efforts to try to attract continuous funding. Unfortunately, most efforts and announcements are being directed towards project grants and the specific universities. Finding support for networks and interuniversity research so far seems hard. Still, we are believers and are convinced we will manage to persuade funding organisations and governmental authorities that it would be a real waste if we were not able to continue the successful research program of Swedish Brain Power. For the Swedish Brain Power Program Bengt Winblad Director Maria Eriksdotter Co-Director Gunilla Johansson Coordinator 20

21 LIST OF RESEARCH PROJECTS 21

22 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. Imaging of astrocytes, fibrillar amyloid load and cerebral glucose metabolism in Tg mice with APPswe mutation with µpet technique (A Nordberg) 4. The Normal Material Study 2 (NoMaS 2) (L Minthon) 5. Cognitive impairment in elderly medical inpatients (L Minthon) 6. Neurochemical identification of incipient subcortical VaD and AD (A Wallin) 7. Functional and structural brain imaging (MRI) in normal aging, vascular and non-vascular MCI (A Wallin) 8. Encapsulated cell bio-delivery of nerve growth factor (NGF) to Alzheimer disease patients (M Eriksdotter) 9. Genetic background and lifestyle-related factors in relation to risk of dementia and cognitive decline (L Fratiglioni & I Skoog) 10. Pre-mild cognitive impairment, MCI and pre-dementia: identifying different forms of cognitive decline in large population-based studies in Sweden (L Fratiglioni) 11. Brain atrophy and cerebrovascular disease on CT in elderly population samples; risk factors, secondary changes and prognosis (I Skoog & LO Wahlund) 12. Individual differences in pre-clinical onset of dementia: What contributes to early/late onset of accelerated cognitive decline? (L Bäckman & B Johansson) 13. The role of dopamine in cognitive plasticity across the adult life span (L Bäckman) 14. Cognitive training and transfer in normal and pathological aging (L Nyberg) 15. Virtual reality and rehabilitation (L Nyberg) 16. Biomarkers to study molecular mechanisms and disease pathogenesis in AD (K Blennow) 17. Acute effect on the Aβ isoform pattern in CSF in response to treatment in AD patients (K Blennow) 18. The aging frontal lobe in health and disease (LO Wahlund) BASIC PLATFORM 19. Genetic, neuropathological and clinical studies in FTLD (C Graff) 20. Clinical and experimental studies of FAD: a model for identifying prognostic and early diagnostic markers of sporadic AD (C Graff) 21. Coordinator for a common neuropathological strategy in SBP projects (C Graff) 22. Prion-like propagation of Aβ- and tau-pathology in AD: translational studies in Tg mouse models (P Brundin) 23. Disease-causing mutations in familial PD (H Nissbrandt) 24. Identification and modelling genetic in PD (A Carmine Belin) 25. Closing some of the gaps between genetic studies and pathology (D Galter) 26. Investigating the selective neuronal vulnerability in AD pathogenesis (A Sandebring) 27. Biomarker characterization (CSF and Imaging) of patients with mutations in different genes associated with ALS and ALS-dementia (P Andersen) 28. Animal models for the formation of lasting memories and to alter plaque load (L Olson) 29. The mitochondria theory of aging, mtdna mutator mice and high brain lactate as early biomarker of AD (L Olson) 22

23 30. Translating ageing findings in mice to human brains. Expression patterns of LDH-A and B and other genes found to underlie increased lactate levels in ageing mice (L Olson) 31. APOE genotype and life-style risk factors in AD; to understand the underlying mechanisms (A Cedazo Minguez) 32. Modulation of gamma-secretase by APOE, a mechanistic explanation leading to sporadic AD (A Cedazo Minguez) 33. Role of cholesterol metabolism and functions of oxysterols in healthy and AD brains (A Cedazo Minguez & I Björkhem) 34. Oxysterols in plasma and CSF and possible risk factors for neurodegeneration (I Björkhem) 35. Role of the oxysterol 27-hydroxycholesterol in neurodegeneration (I Björkhem) 36. Inflammation as target for treatment of AD with special focus on the resolution phase (M Schultzberg) 37. Biomarkers and memory in the transgenic AD rat (E Benedikz) 38. Role of the Aph-1 isoforms in the γ-secretase complex for selective processes of APP and Notch (H Karlström) 39. Neuronal cell cultures derived from induced pluripotent cells as a platform to study AD mechanisms (E Sundström) 40. Evaluation of Aß oligomers/protofibrils as biomarkers for Alzheimer disease (L Lannfelt) CARING / TECHNOLOGY PLATFORM 41. Providing tailored ICT-support to individuals with suspected or early dementia in their home and to their health professionals (Helena Lindgren) 42. Exploring person-centred care and associated resident and staff outcomes in Swedish residential aged care units (PO Sandman) 43. Detection of subtle and early signs of disability in terms of difficulties in everyday technology use in MCI and AD patients (L Nygård) 44. The academic nursing home a large scale intervention of the national guidelines for care of dementia (L Borell) 45. Evidence-based environments, optimizing the preconditions for in-patient dementia assessment (AK Edberg) 46. Functional capacity and costs of care (A Wimo) 47. Dementia; costs for disease, drugs and diagnostics (A Wimo) 48. Cognitive testing and functional evaluation in primary care dementia investigations (J Marcusson) 49. To live with risk for Alzheimer disease (Maria Eriksdotter) 50. Medical decision making capacity in patients with compromised cognitive functions (E Sundström) 23

24 PUBLICATIONS YEAR 7 24

25 CLINICAL PLATFORM; (DIAGNOSTICS, THERAPEUTICS, CLINICAL TRIALS, EPIDEMIOLOGY, NEUROPSYCHOLOGY) 2012 Andersson M, Guo X, Börjesson-Hanson A, Liebetrau M, Östling S, Skoog I. A population based study on dementia and stroke in 97-year-olds. Age Ageing Jul;41(4): Andel R, Crowe M, Hahn EA, Mortimer JA, Pedersen NL, Fratiglioni L, Johansson B, Gatz M. Work-related stress may increase the risk of vascular dementia. J Am Geriatr Soc. 2112;60(1): Bao et al. Different amyloid oligomer assemblies in Alzheimer brains correlate with age of diease onset and impaired cholinergic activity. Neurobiol Aging 2012;33. Brehmer Y, Westerberg H & Bäckman L. Working-memory training in younger and older adults: Training gains, transfer, and maintenance. Frontiers in Human Neuroscience, 2012;(6):63. Caracciolo B, Gatz M, Xu W, Pedersen N, Fratiglioni L. Differential Distribution of Subjective and Objective Cognitive Impairment in the Population: A Nation-Wide Twin-Study. J Alzheimers Dis. 2012;29(2): Carter S et al. Evidence for astrocytosis in prodromal Alzheimer s disease provided by 11 C- Deuterium-L-Deprenyl - A multi-tracer PET paradigm combining 11 C-PIB and 18 F-FDG. J Nucl Med, 2012;53: Ekman, U, Eriksson J, Forsgren L, Mo S J, Riklund K, & Nyberg L. Functional brain activity and presynaptic dopamine uptake in patients with Parkinson s disease and mild cognitive impairment: a cross-sectional study. Lancet Neurology, 2012;11(8): Eriksdotter-Jönhagen M, Linderoth B, Lindb G, Aladellie L, Almkvist O, Andreasen N, Blennow K, Bogdanovic N, Jelic V, Kadir A, Nordberg A, Sundström E, Wahlund LO, Wall A, Wiberg M, Winblad B, Seiger Å, Almqvist P, Wahlberg. Encapsulated cell biodelivery of NGF to the basal forebrain in patients with Alzheimer s disease. Dem Ger Cogn Disord. 2012;33: Eriksdotter-Jönhagen M, Linderoth B, Lind G, Eyjolfsdottir H, Seiger Å, Almqvist P, Wahlberg L. Intracerebral tillförsel av tillväxtfaktorn NGF med inkapslade celler hos patienter med Alzheimers sjukdom. Neurologi 1: 25-30, Gustafson DR, Bäckman K, Joas E, Waern M, Östling S, Guo X, Skoog I. A 37-years of body mass index and dementia. Observations from the Prospective Population Study of Women in Gothenburg, Sweden. J Alzheimers Dis 2012 Jan;28(1): Gustafson D, Bäckman K, Lissner L, Carlsson L, Waern M, Östling S, Guo X, Bengtsson C, Skoog I. Leptin and dementia over 32 years - the Prospective Population Study of Women. Alzheimer s & Dement Jul;8(4):

26 Hansson O, Stomrud E, Vanmechelen E, Östling S, Gustafson D, Zetterberg H, Blennow K, Skoog I. Evaluation of plasma Aβ as predictor of Alzheimer s disease in older individuals without dementia: a population-based study. J Alzheimers Dis Jan;28(1): Hjelm C, Dahl A, Broström A, Mårtensson J, Johansson B, Strömberg A. The influence of heart failure on longitudinal changes in cognition among individuals 80 years of age and older. J Clin Nurs. 2012;21(7-8): Joas E, Bäckman K, Gustafson D, Östling S, Waern M, Guo X, Skoog I. Trajectories of blood pressure from mid- to late-life in relation to dementia in women followed for 37 years. Hypertension 2012 Apr;59(4): Johansson L Skoog I, Gustafson D, Olesen PJ, Waern Bengtsson C, Björkelund C, Pantoni L, Simoni M, Lissner L, Guo X, Midlife psychological distress associated with late-life brain atrophy and white matter lesions: a 32-year population study of women. Psychosom Med Feb-Mar;74(2): Jokinen H, Lipsanen J, Schmidt R, Fazekas F, Gouw AA, van der Flier WM, Barkhof F, Madureira S, Verdelho A, Ferro JM, Wallin A, Pantoni L, Inzitari D, Erkinjuntti T; LADIS Study Group. Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study. Neurology 2012 May 29;78(22): Landgren S, von Otter M, Seibt Palmér M, Zetterström C, Nilsson S, Skoog I, Gustafson DR, Minthon L, Wallin A, Andreasen N, Bogdanovic N, Marcusson J, Blennow K, Zetterberg H, Kettunen P. A novel ARC gene polymorphism is associated with reduced risk of Alzheimer's disease. J Neural Transm Jul;119(7): Laukka EJ, MacDonald SWS, Fratiglioni L, Bäckman L Preclinical cognitive trajectories differ for Alzheimer's disease and vascular dementia. JINS 2012;18:1-9. Lindberg O, Walterfang M, Looi JCL, Malykhin N, Ostberg P, Zandbelt BB, Oberg J, Zhang Y, Wahlund L-O. Hippocampal shape analysis in Alzheimer s disease and frontotemporal lobar degeneration subtypes. J Alzheimers Dis Jan 1;30(2): MacDonald S W S, Karlsson S, Rieckmann A & Bäckman L. Age-related increases in behavioral variability: Relations to losses of dopamine D1 receptors. Journal of Neuroscience, 2012;32: Nordberg A et al. European multi-center PET study of fibrillar amyloid in Alzheimer s disease. Eur J Nucl Med Mol Imaging DOI /s Nyberg L, Lövdén M, Riklund K, Lindenberger U & Bäckman L. Memory aging and brain maintenance. Trends in Cognitive Sciences, 2012;16: Qiu C, Zhang Y, Bronge L, Herlitz A, Aspelin P, Bäckman L, Fratiglioni L, Wahlund LO. Medial temporal lobe is vulnerable to vascular risk factors in men: a population-based study. Eur J Neurol 2012 Jan

27 Religa D, Spångberg K, Wimo A, Edlund A-K, Winblad B, Eriksdotter-Jönhagen M. Dementia diagnosis differs in men and women and depends on age and dementia severity. Data from SveDem, the Swedish Dementia Quality Registry. Ger Cogn Disord 2012;33: Schöll M et al. Low PIB PET retention in presence of pathological CSF biomarkers in Arctic APP mutation carriers. Neurology 2012;79: Skoog I, Olesen PJ, Blennow K, Palmertz B, Johnson SC, Bigler ED. Head size may modify the impact of white matter lesions on dementia. Neurobiol Aging Jul;33(7): Thorvaldsson V, Skoog I, Hofer SM, Börjesson-Hansson A, Östling S, Sacuiu S, Johansson B. Non-linear blood pressure effects on cognition in old age: Separating between-person and within-person associations. Psychol Aging Jun;27(2): Wang H-X, Gustafson DR, Kivipelto M, Pedersen NL, Skoog I, Windblad B, Fratiglioni L. Education halves the risk of dementia due to apolipoprotein epsilon 4 allele: A collaborative study from the Swedish Brain Power initiative. Neurobiol Aging May;33(5):1007.e Andel R, Crowe M, Hahn EA, Mortimer JA, Pedersen NL, Fratiglioni L, Johansson B, Gatz M. Work-related stress may increase the risk of vascular dementia. J Am Geriatr Soc 2012 Jan;60(1):60-7. Bellander M, Brehmer Y, Westerberg H, Karlsson S, Fürth D, Bergman O, Eriksson E & Bäckman L. Preliminary evidence that allelic variation in the LMX1A gene influences trainingrelated working memory improvement. Neuropsychologia, 2012;49: Brehmer Y, Rieckmann A, Bellander M, Westerberg H, Fischer H & Bäckman L. Neural correlates of training-related working-memory gains in old age. Neuroimage, 2012;58: Brodaty H, Breteler, DeKosky ST, Dorenlot P, Fratiglioni L, Hock C, Kenigsberg PA, Scheltens P, De Strooper B. The World of Dementia Beyond J Am Ger Soc 2011; 59(5): Bäckman L, Karlsson S, Fischer H, Karlsson P, Brehmer Y, Rieckmann A, MacDonald S W S, Farde L & Nyberg L. Dopamine D 1 receptors and age differences in brain activation during working memory. Neurobiology of Aging, 2011;32: Bäckman L, Nyberg L, Soveri A, Johansson J, Andersson M, Dahlin E, Neely A S, Virta J, Laine M & Rinne J O. Effects of working-memory training on striatal dopamine release. Science, 20111;333:718. Edman A, Edenbrandt L, Fredén-Lindqvist J, Nilsson M, Wallin A. Asymmetric cerebral blood flow in patients with mild cognitive impairment: possible relationship to further cognitive deterioration. Dement Geriatr Cogn Dis Extra Jan;1(1):

28 Fratiglioni L, Qiu C. Prevention of cognitive decline in ageing: dementia as the target, delayed onset as the goal. Lancet Neurol. 2011; 10(9): Gustavsson A, Svensson M, Jacobi F, Allgulander C, Alonso J, Beghi E, Dodel R, Ekman M, Faravelli C, Fratiglioni L, Gannon B, Jones DH, Jennum P, Jordanova A, Jönsson L, Karampampa K, Knapp M, Kobelt G, Kurth T, Lieb R, Linde M, Ljungcrantz C, Maercker A, Melin B, Moscarelli M, Musayev A, Norwood F, Preisig M, Pugliatti M, Rehm J, Salvador- Carulla L, Schlehofer B, Simon R, Steinhausen HC, Stovner LJ, Vallat JM, den Bergh PV, van Os J, Vos P, Xu W, Wittchen HU, Jönsson B, Olesen J; CDBE2010Study Group. Cost of disorders of the brain in Europe Eur Neuropsychopharmacol Oct;21(10): Haasum Y, Fastbom J, Fratiglioni L, Kåreholt I, Johnell K. Pain treatment in elderly persons with and without dementia: a population-based study of institutionalized and home-dwelling elderly. Drugs Aging 2011 Apr 1;28(4): Karlsson S, Rieckmann A, Karlsson P, Farde L, Nyberg L & Bäckman L. Relationship of dopamine D 1 receptor binding in striatal and extrastriatal regions to cognitive functioning in healthy humans. Neuroimage, 2011:57: Lilja A et al. Functional interaction of fibrillar and oligomeric amyloid-ß with alpha7 nicotinic receptors in Alzheimer s disease. J Alzheimer Disease 2011; 23: Lindwall M, Larsman P & Hagger M S. The Reciprocal Relationship Between Physical Activity and Depression in Older European Adults: A Prospective Cross-Lagged Panel Design Using SHARE Data. Health Psychology, 2011;30: MacDonald S W S, Karlsson S, Fratiglioni L & Bäckman L. Trajectories of cognitive decline following dementia onset: What accounts for variation in progression? Dementia and Geriatric Cognitive Disorders, 2011;31: Mustafiz T et al. Characterization of the brain ß-amyloid isoform pattern at different ages of Tg 2576 mice. Neurodegener Dis 2011;8: Piccinin AM, Muniz G, Matthews FE, Johansson B. Terminal decline from within- and between-person perspectives, accounting for incident dementia. J Gerontol B Psychol Sci Soc Sci. 2011;66(4): Rieckmann A, Karlsson S, Fischer H & Bäckman L. Caudate dopamine D1 receptor density is associated with individual differences in fronto-parietal connectivity during working memory. Journal of Neuroscience, 2011;31: Rieckmann A, Karlsson S, Karlsson P, Brehmer Y, Fischer H, Farde L, Nyberg L & Bäckman L. Dopamine D 1 receptor associations within and between dopaminergic parhways in younger and elderly adults: Links to cognitive performance. Cerebral Cortex, 2011;21: Rolstad S, Berg AI, Bjerke M, Blennow K, Johansson B, Zetterberg H, Wallin A. Amyloid-β₄₂ is associated with cognitive impairment in healthy elderly and subjective cognitive impairment. J Alzheimer s Dis. 2011;26(1):

29 Schöll M et al. Time course of glucose metabolism in relation to cognitive performance and postmortem neuropathology in Met146ValPSEN1 mutation carriers. J Alzheimer s Dis 2011;24: The LADIS Study Group, Poggesi A, Pantoni L, Inzitari D, Fazekas F, Ferro J, O'Brien J, Hennerici M, Scheltens P, Erkinjuntti T, Visser M, Langhorne P, Chabriat H, Waldemar G, Wallin A, Wahlund A : A Decade of the LADIS (Leukoaraiosis And DISability) Study: What Have We Learned about White Matter Changes and Small-Vessel Disease? Cerebrovasc Dis. 2011;32(6):

30 BASIC RESEARCH PLATFORM (EXPERIMENTAL RESEARCH, GENETICS, ANIMAL MODELS) 2012 Anvret A, Ran C, Westerlund M, Gellhaar S, Lindqvist E, Pernold K, Lundströmer K, Duester G, Felder MR, Olson L, Galter D and Belin AC. Adh1 and Adh1/4 knockout mice as possible rodent models for presymptomatic Parkinson's disease. Behavioral Brain Research Feb 1;227(1): Anvret A, Ran C, Westerlund M, Galter D, Sydow O, Willows T, Olson L, Belin AC. Genetic Screening of Mitochondrial Rho GTPases, MIRO1 and MIRO2, in Parkinson s disease. Open Neurol J. 2012;6:1-5. Belin AC, Ran C, Anvret A, Paddock S, Westerlund M, Håkansson A, Nissbrandt H, Söderkvist P, Dizdar N, Ahmadi A, Anvret M, Willows T, Sydow O, Galter D. Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease. Neurosci Lett Jul 26;522(1):30-5. Corcia P, Ingre C, Blasco H, Press R, Praline J, Antar C, Veyrat C, Guettard YO, Camu W, Andersen PM, Andres C, Vourc h P. Homozygous SMN2 deletion is a protective factor in the Swedish ALS population. Eur J Hum Genet 2012;20: Daher JP, Pletnikova O, Biskup S, Musso A, Gellhaar S, Galter D, Troncoso JC, Lee MK, Dawson TM, Dawson VL, Moore DJ. Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2. Hum Mol Genet Jun 1;21(11): Diekstra FP, van Vught PWJ, van Rheenen W, Koppers M, Pasterkamp RJ, van Es MA, Schelhaas HJ, de Visser M, Robberecht W, Andersen PM, van den Berg LH, Veldink JH. UNC13A is a modifier of survival in amyotrophic lateral sclerosis. Neurobiol Aging 2012;33. Diekstra FP, Saris CGJ, van Rheenen W, Franke L, Jansen RC, van Es MA, van Vught PWJ, Blauw HM, Groen EJN, Horvath S, Karol Estrada K, Rivadeneira F, Hofman A, Uitterlinden AG, Robberecht W, Andersen PM, Melki J, Meininger V, Hardiman O, Landers JE, Brown, Jr. RH, Shatunov A, Shaw CE, Leigh PN, Al-Chalabi A, Ophoff RA, van den Berg LH, Veldink JH. Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS. PloS ONE 2012;7:e Gil-Bea F, Akterin S, Persson T, Mateos L, Sandebring A, Avila-Cariño J, Gutierrez-Rodriguez A, Sundström E, Holmgren A, Winblad B, Cedazo-Minguez A.Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer's disease brain. EMBO Mol Med Oct;4(10): Gispert S, Kurz A, Waibel S, Bauer P, Liepelt I; Geisen C, Gitler AD, Becker T, Weber M, Berg D, Andersen PM, Krüger R, Riess O, Ludolph AC, Auburger G. The modulation of Amyotrophic 30

31 Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol Dis 2012;45: Hedskog L, Brohede J, Wiehager B, Pinho CM, Revathikumar P, Lilius L, Glaser E, Graff C, Karlström H, Ankarcrona M. Biochemical Studies of Poly-T Variants in the Alzheimer's Disease Associated TOMM40 Gene. J Alzheimers Dis May 16. Hjorth E, Freund-Levi Y. Immunomodulation of microglia by docosahexaenoic acid and eicosapentaenoic acid. Curr Opin Clin Nutr Metab Care 2012;15: Ibáñez C, Simó C, Martín-Álvarez PJ, Kivipelto M, Winblad B, Cedazo-Mínguez A, Cifuentes A. Toward a predictive model of Alzheimer's disease progression using capillary electrophoresis-mass spectrometry metabolomics. Anal Chem Oct 16;84(20): Kacem I, Funalot B, Torny F, Lautrette G, Andersen PM, Couratier P. Early-onset parkinsonism associated with an intronic SOD1 mutation. ALS 2012;13: Katz JS, Katzberg HD, Woolley SC, Marklund SL, Andersen PM. Fronto-temporal dementia with Aphasia and later Amyotrophic Lateral Sclerosis in a Patient with the I113T SOD1 Gene Mutation. ALS 2012;13: Maioli S, Puerta E, Merino-Serrais P, Fusari L, Gil-Bea F, Rimondini R, Cedazo-Minguez A. Combination of apolipoprotein e4 and high carbohydrate diet reduces hippocampal BDNF and arc levels and impairs memory in young mice. J Alzheimers Dis Jan 1;32(2): Miralbell J, Spulber G, Hooshmand B, Besga A, Mataró M, Cedazo-Minguez A, Kivipelto M, Wahlund LO. Grey matter and cognitive patterns in cognitive impaired subjects using CSF biomarker cut-offs. J Alzheimers Dis. 2012;29(4): Ran C, Westerlund M, Anvret A, Willows T, Sydow O, Galter D, Belin AC. Genetic studies of the protein kinase AKT1 in Parkinson's disease. Neurosci Lett Aug 21;501(1):41-4. Sarlus H, Olgart Höglund C, Karshikoff B, Wang X, Lekander M, Schultzberg M, Oprica M. Allergy influences the inflammatory status of the brain and enhances tau phosphorylation. J Cell Mol Med 2012 Feb 22. Smith BN, Newhouse S, Vance C, Lee Y, Weale ME, Topp S, Millar J, Johnson L, Troakes C, Hortobagyi T, Al-Sarraj S, Rogelj B, Powell J, Lupton M, Lovestone S, Sapp P, Nestor PS, Schelhaas, Silani V, Gelera C, Van den Berg L, Veldink J, van Damme P, Robberecht W, de Jong V, Shaw PJ, Kirby J, Paul H, Morrison KE, Bass, Andersen PM, Landers J, Brown RH, Al- Chalabi A, Shaw CE. The C9ORF72 expansion mutation is derived from a single founder in European ALS/FTD patients and is highly unstable. Eur J Hum Genet, Epub June 13, Synofzik M, Rochi D, Keskin I, Basak AN, Wilhelm C, Gobbi C, Birve A, Biskup S, Zecca C, Fernandez-Santiago R, Kaugesaar T, Schöls L, Marklund SL, Andersen PM. Mutant Superoxide Dismutase-1 Indistinguishable from Wild Type Causes ALS. Hum Mol Genet 2012;21: