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1 we care about the brain Annual Report 2010

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5 Table of contents 1. Table of Contents Preface Description Research Institute Structure Research Institute SWOT Analysis News & Highlights International Collaboration Input Research Institute...19 a) Funding b) Fte per type of funding c) Number of newly started PhD projects Output Research Institute...23 a) Scientific Output b) Scientific Quality c) Indicators of Esteem d) Societal Impact 10. Per Research Program...29 a) Description b) Input (per program) c) Output (per program) 11. Scientific Research Committees Education & Training...58 Appendices

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7 2. Preface Here we present our third annual report. We have grown since 2008 both in numbers of coworkers being involved, in the total number of publications and in particularly also with regard to the high impact of our collaboration. We were able to continue our grant successes, including more acquisition in FP7, participation in a new FES consortium (www.neurobasic.nl) and being awarded with a so-called Erasmus Mundus Master Course stipend-program, under guidance of our European Neuroscience Campus Network (www.encnetwork.eu), which was previously awarded with a Erasmus Mundus Joint Doctorate program. By combining the latter two acquisitions in the ENC- Network, under our coordination, we have now formalized the European dimensions of our graduate training. The aggregate of conditional funding for the Neuroscience Campus Amsterdam in 2010 amounted to ~ 30 M, which is a major increase since 2008 and The number of shared and high impact publications has stabilized since We have a collective strategy, resulting in a major wave of over 80 collaborative projects. In 2010, this resulted in more than 450 peer reviewed research reports, of which > 60 papers had an impact factor of >10, including several Nature Genetics papers, many papers in the Lancet (Neurology), in addition to a few papers in Science, in Brain and in PNAS. With Queen Beatrix, we celebrated the 10 year jubilee - and opening of the new housing facilities - of the VUmc Alzheimer Center under guidance of Prof. Philip Scheltens. We have made new investments in infrastructural facilities for stem cell research, for cellomics, and for photonics and life cell imaging. In addition, our biobanking, genomics and electron microscopy facilities have been modified and updated. We have also witnessed the contributions of a senior role model, Prof. Dennis Selkoe from Harvard University and recipient of the 2010 Honorary Doctorate from the VU University Amsterdam in collaboration with the VU Medical Center. Dennis Selkoe - who has devoted his lifetime career to the use of molecular approaches to study neurodegenerative diseases - inspired us to start thinking about a valorization strategy, as extensively discussed during last year s Valorization Symposium on 19 October in the ING house. In short, all aspects of running a translational research institute are presented, and it is on behalf of all students and coworkers that we deliver this annual report. Arjen Brussaard director 5

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9 3. Description Research Institute Neuroscience Campus Amsterdam Neuroscience research is a high profile knowledge industry and aims at making seminal contributions to the understanding of the human brain and the fight against brain disease. Our current insight coming from recent studies of Neuroscience Campus investigations into the human genome and networks of genes, interacting proteins, neuron-glia interactions, and synaptic transmission embedded in neuronal networks has paved the way towards the understanding the molecular and cellular basis of higher brain functions and its pathology. In parallel, on our campus, numerous brain imaging, neurological studies and psychiatric research of large cohorts of patients have created valuable assets that are unique worldwide. We have transcended the boundaries of various disciplines including biomedical, biophysical, biopsychological and clinical neurosciences. The ongoing research strategy, and output of the collaborative research programs of the Neuroscience Campus Amsterdam, thereby focusing on the most important and pioneering areas of neuroscience, have been described in the annual report. The Neuroscience Campus Amsterdam houses more than 450 professionals on one campus and they all collaborate in the field of Translational Neurosciences to an extent that is unique in the Netherlands. The partners in this network organization are the investigators and graduate students, gathered in interdisciplinary research teams and executing our research programs. All our research activities are essentially interdisciplinary and incorporate the newest theoretical, methodological and application paradigms currently available. Our strongholds and international reputation builds both on previous work in molecular biology and biology and genetics of the brain, synapse function and neuronal networks, as well as on our clinical studies of the major brain diseases. We study the brain and its disease mechanisms through an integrative approach from molecule-to-bedside and back. We apply a systems biology approach of the brain where clinicians and clinical researchers are working side-by-side with neuroscientists, geneticists, psychologists, biophysicists and statisticians. Through this collaboration we aim at delivering proof-of-concept for radically new approaches in the early diagnosis of brain disease, the elucidation of its underlying mechanisms, and thus providing new perspectives on therapy. 7

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11 4. Structure Research Institute Mission The mission of the Neuroscience Campus Amsterdam is to study the brain and its disease mechanisms through an integrative approach running from molecule-tobedside. We apply a systems biology approach of the brain where clinicians and clinical researchers are working side-by-side with neuroscientists, geneticists, psychologists, biophysicists and statisticians. Aims & Objectives The Neuroscience Campus Amsterdam currently the largest neuroscience research community gathered on one campus in the Netherlands. We are strongly focusing on molecular neurobiology, going all the way from biophysics, genetics, genomics and systems biology of the synapse, to heritability and genetic basis of brain function. Research Activities The Neuroscience Campus Amsterdam teams focus on three areas of research supported by Support Facilities: Advanced technology Programs, Genes & the Brain and Brain Disease Mechanisms. Advanced Technology Programs Brain Disease Mechanisms Research Support Facilities Genes & the Brain Figure 1. Main stream research areas of the Neuroscience Campus Amsterdam 9

12 Figure 2. Research Programs. As shown in Figure 2, each research activity area is further subdivided in a focused number of research programs and facilities. These have been further described in section 10 of this annual report. 10

13 Advanced Technology Programs The Neuroscience Campus Amsterdam puts much effort in Advanced Technology Programs, thereby securing a strong translational link between those groups providing for instance tailor-made Photonics technology and laboratories where these methods can be successfully applied (i.e. human health and life sciences). In additional there is an established translational link between the Brain Imaging experts and those involved in any of our Brain Disease Programs, including our so-called imaging genetics initiatives. Statistical geneticists, biostatisticians and bioinformatics experts provide state-of-the-art Integrated Analysis and Modeling methodology; (neuro)psychologists and clinicians apply this methodology when screening patients, their genes and their endophenotypes. Further novel insight is being generated through reconstruction of synaptic gene networks in the Systems Biology of the Synapse program. Finally, there is potentially a strong link between the Drugs screening and Therapy Design program and clinical activities of the Brain Disease Mechanisms teams Genes and the Brain The words molecules, genes, synapses, connectivity and brain function are the buzzwords of all our initiatives. This interest provides a strong translational potential between genetics, molecular neurobiology, functional genomics, neurophysiology, psycho-pharmacology and behavioral neuroscience within the area 'genes and the brain' but also between the latter and the 'brain disease mechanism' programs. There is strong collaboration between labs providing research support and investigators that largely depend on such activities including the clinicians and the statistical geneticists. Brain Disease Mechanisms All research in the Brain Disease Mechanisms programs is aimed and integrated with our in-house patient clinics, notably the VUmc Alzheimer Center, the Multiple Sclerosis Center Amsterdam and the treatment of Depression in the GGZBA-clinic. In addition, given the fact that we have a growing number of Parkinson's disease patients, the research program also includes research on patient-material from these patients. Moreover, also nicotine- and alcohol-abuse data of our depressed patients is being analyzed in the Addictive Behavior Program. The link between attentive traits in human twins and those being observed in ADHD patients continues to provide a further strong translational program towards the understanding of attentive behavior, impulsivity and cognition in general. Support Facilities Support Facilities are aimed at one-way research support, thereby serving as core facilities to generate data and provide tissue- or sample-analysis, or generate models (including transgenic mice and cell lines) in relation to specific research-project questions. The research project questions are generated, prioritized and argued (in relation to the overall research program) by the program committee c.q. the program leaders. 11

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15 5. SWOT Analysis Rationale In order to be able to continue to invest in scientific excellence and the translational potential of our disease-oriented brain research and graduate training, the Neuroscience Campus Amsterdam needs to generate new funding. This SWOT analysis outlines arguments and reasons why now is the right time to orient part of our research activities towards collaboration with the industrial market. The aim of such shift towards a market oriented position would be to capitalize on our scientific expertise and academic excellence and create an open innovation climate on campus both for technology-push and market-pull and to stimulate the market-potential of our young graduates and upcoming professionals. Strength Since the start of this campus-wide collaboration we have been forming new expertise-teams and have invested in more than 80 new translational projects. In addition to the 120 PhD projects currently running on campus, the European Neuroscience Campus Network (ENC-Network) was set up, to formalize the international setting of our graduate training program, both of the Master of Neurosciences and of the Joint PhD in Neurosciences. This has brought the Neuroscience Campus Amsterdam in connection with a selection of major and opinion leading institutes in Europe. The acquisition of National Research Council and European funding is currently funding around 75% of our ongoing concern (current acquisition ~ 25 M /year). New infrastructures including an automated cellomics facility, photonics setups and a stem cell laboratory was installed. Major prizes and research grants were awarded including an ERC Advanced Grants, an Erasmus Mundus Joint Doctorate grant, a Marie Curie ITN network grant and coordinatorship of at least two large collaborative FP7 grants. When it comes to brain disease, the Neuroscience Campus Amsterdam is focused on Alzheimer's disease, Multiple Sclerosis and chronic depression. Within these research programs, our MDs bring clinical issues to the lab, and vice versa PhDs participate in identifying new biomarkers, diagnostic as well as putative targets and tools for therapy. In doing so, we aim both at technology push and at market pull valorization, using our advanced technology research programs, our in-depth knowledge of the genetics of the brain, and having access to large patient cohorts, bio-banking capacity, transgenic mouse models and state of the art genomics, proteomics, brain imaging as well as brain modeling expertise groups. Weaknesses To make the efforts of the collaborations within the Neuroscience Campus endurable initiatives we need to design alternative strategies that would give rise to new funding for innovation initiatives on campus. Thus in addition to dedicating tenured, and collaborating on conditional national and European funding, we need to invest in endurable collaborations with industry. 13

16 One way of generating more research funding would be to invest in profitable Contract Research (CR) and participate more in Clinical Trials (CTs) than is currently done. Also funding coming from consultancy services to biotechnology and pharmaceutical industry could be increased and professionalized. Also, our bio-banking efforts are thus far not used as an asset in any for-profit business model. Finally, Clinical Trials are performed with external CROs (Contract Research Organizations) and Contract Research is not sufficiently organized by - or stimulated with - the help of the faculties and the medical school. Opportunities The industrial market and putative sponsors are often oriented towards thematically organized knowledge-domains and innovation - and not towards mono-disciplinary R&D. The Neuroscience Campus Amsterdam is an ideal party to collaborate with industry since it has organized its R&D by building on the trans-disciplinary strengths of our collaborations. The international reputation of our publications is strong, and of high impact. The expertise and infrastructure is excellent. However, as indicated above, we fail to benefit from this in an economic perspective. Therefore now is the right time to start creating industrialacademic partnership on campus, and start building on collaborations that are characterized by open innovation and where creating new funding for the academic sector is an integral part of the business model. Our unique selling point is that clinical trials performed on campus can be directly coupled to laboratory based contract research aimed at generating mechanistic insights. Finally, we can combine the clinical and preclinical CRO activities with a solid support of applying for European FP7 funding aimed by IAPP and other grants. Threats In order to be able to implement this novel valorization strategy aimed at servicing and collaborating with industrial partners, a new business model needs to developed, aimed at setting up a dedicated CRO office for the Neuroscience Campus Amsterdam. In this market-oriented front office, scouting of new collaborations, advertisement of our research capacity to participate in product development, and consultancy and professional expertise will be organized. The modus operandi of the CRO office is to support both technology push (being an integral function of TTO) and organize market pull. The CRO office would function as an 'outlet' of our translation potential, our patient cohorts, the expanding research capacity and our human resources. Moreover in doing so we would open the road for young professionals to participate in spin-off as well in spin-in research collaborations. Not making choices and not taking consequences of choices both may seriously hamper the forward transition of our institute-strategy. Not making choices with respect to deciding which research-groups in fact can bring our campus in the best position to continue our achievements with respect to scientific excellence but to also combine this with modern and common sense valorization strategy. And not taking the consequences of such choices, regardless of whether it concerns the organizational and administrative setting of interfaculty research institutes, its housing conditions or budget shift within the VU University and VU medical center, from input-based to output-based budgeting. 14

17 6. News & Highlights of the year 2010 Events Neuroscience Campus Amsterdam - Second Annual Meeting - 3 April 2010 Opening of new MEG facility at VUmc 31 May 2010 Science Center NEMO research on intelligence summer 2010 Opening of new Alzheimer Center VUmc by Queen Beatrix 28 September 2010 Valorization Meeting in ING house 19 October 2010 Honorary Doctorate for Prof. Dennis Selkoe, Harvard University at the VU/VUmc 20 October 2010 Marjo van der Knaap and Vivi Heine, in collaboration with FALW perform kickoff of the Stem Cell Facility 19 December 2010 Major Publication Output Boomsma & Penninx c.s. participate in Nature Genetics paper (IF = 34.3) Science paper (IF = 29.7) by the Sander Groffen & Matthijs Verhage Science paper by the Gajja Salomons & Prof. Marjo van Knaap Heidi de Wit & Matthijs Verhage participate in study published in Science Chris Polman participates in study published in Nature Medicine (IF = 27.1) Opinion leading perspective in Neuron by Sushant Jain & Peter Heutink (IF = 13.6) Fifteen additional papers in peer reviewed journals with Impact Factor of > 10 as primary and/or last/senior author(s) Forty two additional papers in peer reviewed journals with Impact Factor of > 10 as associated author(s) 48% of 453 papers in top 10% of International Journals 22% of papers in next segment of the top quartile (11-25%) of International Journals sorted on Relative Impact Factor Grants for individuals in 2010 VICI grant for Brenda Penninx Major external funding acquired in 2010 NWO TOP subsidy for Christel Middelkoop c.s. (500 k, research program Attention & Cognition) Stichting International Parkinson awards grant to NCA team-leaders Benjamin Druckarch, Anne-Marie van Dam and Wilma van de Berg. Brain & Cognition grant for Danielle Posthuma c.s. (600 k, research Integrative Analysis & Modelling) ZonMW Middelgroot subsidy to Marloes Groot & Huibert Mansvelder, c.s. (675 k, research program Photonics & Life Cell Imaging) ZonMW Middelgroot subsidy to Ronald van Kesteren & Guus Smit (675 k, research program Drugs Screening & Therapy Design) 15

18 ZonMW TOP subsidy for Niels Cornelisse c.s. (research Systems Biology of the Synapse) ENC-Network - Erasmus Mundus Joint Doctorate grant (6.7 M ) to Neuroscience Campus Amsterdam started (www.enc-network.eu). ENC-Network Erasmus Mundus Master Course grant 1.25 M for the ENC-Network through work by Huibert Mansvelder & Arjen Brussaard (www.enc-network.eu) SynSys - FP 7 grant (12 M of which 2.5 M for NCA) to Guus Smit (coordinator), Huibert Mansvelder & Matthijs (SynSys - research program Systems Biology of the Synapse, started in 2010 NeuroBasic PharmaPhenomics - FES grant support (Bsik) (13 M of which 4.8 M for NCA) to profs Arjen Brussaard (managing director), Matthijs Verhage, Guus Smit en Huibert Mansvelder, in collaboration with Synaptologics (www.neurobasic.eu), started in 2010 BBMRI - Biobanking Infrastructure: Biobanking and Biomolecular Resources Research Infrastructure to profs Jan Smit & Dorret Boomsma as coapplicants (chair Prof. GertJan van Ommen c.s. (total grant 22 M ; participation from Neuroscience Campus Amsterdam-part pending), started in 2010 MS Research Foundation grant of 2.5 M for research under coordination of Jeroen Geurts and Elga de Vries Additional 1.1 M donation to Polman & Geurts for MS research New Facilities Heidi de Wit updates EM facility with support of Neuroscience Campus Amsterdam and with matching of CNCR. Huibert Mansvelder & Marloes Groot built additional photonics setups for life cell imaging, including dyeless imaging using third harmonics microscopy (and published recently in PNAS) Van Kesteren & Guus Smit add on to the Cellomics facilities at FALW New stem cell facility under coordinatorship of Vivi Heine in FALW building Newly appointed professors Prof. John van Swieten newly appointed as research professor at VUmc Prof. Brenda Penninx appointed as full professor at VUmc Prof. Danielle Posthuma appointed as Fenna Diemer Lindeboom Professor at the VU 16

19 7. International Collaboration Implementation of newly established collaborations Prof. Philip Scheltens, representing the Alzheimer Center VUmc and the Neuroscience Campus Amsterdam, appointed as national coordinator Joint Programming (FP7 collaboration) CNCR and Synaptologics join in major FP7 collaboration called SynSys - coordinator Prof. Guus Smit (www.synsys.eu) CNCR and Synaptologics join in setting up and acquiring new FES consortium called NeuroBasic PharmaPhenomics - managing director Prof. Arjen Brussaard (see Neuroscience Campus Amsterdam sets up and coordinates the European Neuroscience Campus Network (ENC-Network), an Erasmus Mundus Joint Master Programme and Joint Doctorate Programme, aimed at funding > 125 new MSc students, in addition to > 50 new PhD projects. The estimate is that of around thirty of the newly appointed PhD students will graduate at VU/VUmc - director Prof. Arjen Brussaard (see 17

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21 8. Input Research Institute 8a) Funding Combined financial investments since the start of collaboration Since the start of the organization, the Neuroscience Campus Amsterdam was supported with significant starting grant by the CvB, RvB and the participating faculties. This starting grant has been invested in Support Facilities and Research Program activities, according to the principle that any investment from this starting grant is (at least) equally matched by financial support from the participating labs. Thus far towards the end of 2009, this type of financial strategy amounted to a combined funding of 3.2 M in Advanced Technology Programs (including 800 keuro for Photonics) 2.5 M in Innovation of Infrastructure of the Support Facilities (including 250 keuro for Genomics/Proteomics/Cellomics and 100 keuro for EM microscopy) 3.1 M in Research Projects (Meetfonds fase 1 and Centre Medical Systems Biology - granted in 2008 and matched by Neuroscience Campus) In addition, the collective and aggregate acquisition of external funding since then amounted to a major wave of awarded grants with many highlights (also in 2010, see section 6) and a cumulative sum of more than 22 M of external grant support in 2009 and ~ 30 M in 2010 (see below). In addition, thanks to embedding in the Neuroscience Campus Amsterdam, we participate in a number of major grants with (inter)national consortia that started in 2010 (such as the ENC-Network Erasmus Mundus Joint Doctorate grant 6.7 M, a number of FP7 grants including SynSys - 12 M, a FES-subsidy of 13 M for NeuroBasic PharmaPhenomics (see and the BBMRI grant of 22 M for Biobanking as mentioned previously). External Funding - Neuroscience Campus Amsterdam gs 2 gs 3 gs 4 (mix) Total Total Total Total ,939,262 18,172,132 3,534,291 29,645,685 6,594,300 13,580,420 2,576,000 22,750,720 3,533,146 6,449, ,165 10,909,000 Table 1 Acquisition of grants by collaborative efforts of the Neuroscience Campus Amsterdam - started in 2010 and compared to 2008 and 2009 acquisition. For further information, on acquisition per research program, see section 10b. In this overview, gs 2 is NWO funded research, gs3 is project funding from non-profit, ministries, FES & EU and gs4 is based on a mix of contract-research (for profit/industry) and donations/philanthropy. 19

22 8b) Fte per type of funding (research time) Total fte research (including PhD students) Type of funding gs 1 gs 2 gs 3 gs 4 mixed Total Total n.a Total n.a Total Total fte research PhD students Type of funding gs 1 gs 2 gs 3 gs 4 mixed Total Total n.a Total n.a Total Table 2 Total of research appointments. A total of > 400 scientists even excluding support and technical - contribute to this total. The research time per research program is split in section 10b. In this overview, gs2 is NWO funded research, gs3 is project funding from non-profit, ministries, FES & EU and gs4 is based on a mix of contractresearch (for profit/industry) and donations/philanthropy. For a full list of all coworkers see appendix 1. 20

23 8c) New PhD projects started 2010 In 2010, 36 new PhD projects were started. For a full list of all newly started projects and PhD students, see appendix 2. We are confident about the future perspectives of Neuroscience Campus Amsterdam, given the acquisition of the Erasmus Mundus Joint Doctorate (with in total 50 additional PhD projects to be appointed up to 2014, of which ~ 25 projects are primarily or in collaboration with the Neuroscience Campus Amsterdam) and the International Training Network (Marie Curie) called BrainTrain (with in total 12 additional PhD projects, all in executed in Neuroscience Campus Amsterdam labs). PhD projects newly started Table 3 Newly started PhD project in recent years. The boost in 2009 is explained by the start of BrainTrain. Currently around 50% of the project is funded by European grants. 21

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25 9. Output Research Institute 9a) Scientific Output Theses Scientific papers Rest DissA DissB DissC DissD Wp WpREF WpNR VP Total Books Chptrs Total Total Total Table 5 Aggregate of the output of Neuroscience Campus Amsterdam. The numbers of refereed papers (WpRef) has increased compared to 2008 and 2009, the number of books and bookchapters and non-sci contributions was deliberately lowered since then. A full list of publications published is outlined in appendix 3. Abbreviations: Theses A: Promotion VU/VUmc PhD-student at VU Theses B: Promotion external PhD-student at VU Theses C: Promotion VU/VUmc PhD-student at other university Theses D: Promotion external PhD-student at other university (promotor, co-promotor) Wp: Books/monographs/book chapters/proceedings WpRef: Scientific Papers refereed WpNR: Scientific Papers non-refereed WB: Books/monographs WBC: - Book chapters/proceedings VP: Professional publication 23

26 9b) Scientific Output Program leaders and Support Coordinators An historical overview of the published number of articles per year and the total number of citations each year to the aggregate of these papers published by the current program leaders of the Neuroscience Campus Amsterdam shows a solid growth in output and relevance of their output (see Fig 3 and 4). At the onset of the new era in which the Neuroscience Campus Amsterdam became operational (i.e. during 2008) all program leaders of the Neuroscience Campus together had a yearly output of research papers per year. In 2008 > 9600 citations were collected to the accumulation of these research papers. Currently, this aggregate output of program leaders has increased to 320 research papers, with over citations in The sum of all citations to publications published by our program leaders accumulates to > to a total of papers, being published as corresponding author and an average of ~ 30 citations per published article. If also 'coauthor' papers are included, the program leaders together have published 4293 peer reviewed publications and have collected > citations thus far. The average total number of papers published thus far, is > 195 papers per group leader. Shown below are two graphs indicating the historical progress - prior to and - during the last three years of Neuroscience Campus Amsterdam. Total number of citations per year Figure 3. Shown is an historical perspective on the cumulative production of SCI articles (i.e. excluding reviews) per year, authored by program leaders and support coordinators (and those alike) of the Neuroscience Campus Amsterdam workforce and produced at the VU/VUmc Campus. If all program committee members are analyzed this way, currently the cumulative yearly output is 453 papers per year (see section 9a). 24

27 Figure 4. Historical perspective on the number of citations to scientific articles (SCI journals excluding reviews) authored by program leaders and support coordinators (and those alike) and produced at the VU/VUmc Campus. If all program committee members are analyzed, this way currently the yearly total number of citations is > per year. Citation analysis of program committee members To further analyze the scientific output, we have also collected the aggregate data of our 50 tenured program committee members currently collaborating in - or contributing to - the main stream activities of the Neuroscience Campus Amsterdam. Citation analysis reveals that of all of the Neuroscience Campus Amsterdam, on average a total number of > 115 research articles has been produced per author, with on average a cumulative number of ~ 3200 citations per author, an average h-value of 25 and a CPP of > 25. If we analyze program leaders only, these numbers increase to ~ 195 research articles per author, with ~ 5800 citations per author, an h-value of 36 and a CPP of 29. Figure 5: Number of published papers (research papers only) per author. Analysis of tenured (i.e. program committee members, and those alike, including affiliated research but only) primarily affiliated with the Neuroscience Campus Amsterdam on the basis of ISI Web of knowledge cross-checked with Publish or Perish (Google Scholar). On average a member in our institute had published > 115 papers towards the end of

28 Figure 6: Total number of citations per author. Analysis of tenured in the same databases as in figure 5. On average each member currently has collected > 3200 citations in total. Figure 7: The 'h-value' analysis of tenured. Similar database search as for figures 5 and 6. Figure 8: Average number of citations per published paper for all tenured. Same type of database search as for figures

29 Figure 9: Relative distribution of 2010 SCI publications (453 in total) categorized according to Relative Impact Factor. Almost half (i.e. 48 %) of the current output belongs to the category of highest impact papers (i.e. top 10%). And 7 out 10 papers belong to the top quarter of SCI journal publications and thus have a journal Impact Factor of 4 or higher. See also Table 5 for comparison with the 2008 and 2009 scores. To be able to make a comparison to the research output of previous years we have also included data and percentile scores from 2009 and 2008 respectively (see Table 5). Percentage (%) of papers distributed to the quality of the research field Relative Impact Factor Quartile Category % of 2010 papers 2010 upper quartile % score in 2010 % of 2009 papers upper quartile % score in top 10 % % % % % % of 2008 papers 52 upper quartile % score in 2008 Table 5 Comparison of Relative Impact Factors scores in 2010 compared to 2009 and

30 9c) Indicators of esteem A shortlist of awards, more details on grants awarded, and listing of other indicators of esteem are outlined in appendix 4. 9d) Societal Impact As outlined in section 6, we have proposed the candidate for the Honorary Doctorate in 2010, Dennis Selkoe from Harvard University. In the prelude to this award celebration on 20 October 2010, we also organized a Valorization Symposium in the ING House, where the basis for our current valorization strategy was laid out. In general we focus on the biological mechanisms underlying common mental health and neurological brain diseases, applying the latest technology and thereby providing new perspectives on therapy. Finding the 'cause' of brain diseases, design its 'cure' and implement this to the level of 'patient care' are all at the core of our research ambition. Many of our research projects and plans are directly (or indirectly) related to 'brain diseases' programs. This includes the activities of the VUmc Alzheimer Center, the MS Center Amsterdam, the Center for Children with White Matter Disorders and the GGZBA-clinic affiliated patient research-programs for Anxiety and Depression disorders (NESDA) of the GGZBAclinic. In doing so, we also provide community services in relation to patient care (advise and information to care takers). Notably are two initiatives, one being the so-called planned MS-supportal (a virtual reception and internet-portal for MS patients) and one the planned Memory Clinic of the Alzheimer Center to be launched coming fall. Moreover many of our senior investigators publish in national professional journals, give layman-lectures by invitation and/or participate in education projects (see appendix 5). 28

31 10. Per Research Program 10a) Description Advanced Technology Programs Research Programs in short: Figure 10 Advanced Technology Research Programs. Innovation and development of the latest techniques are embedded in independent research programs that provide 'translational potential' (as indicated by the arrows) for newly developed project in 'adjacent' research programs where this new technology is being applied in a (pre)clinical settling. 29

32 ADVANCED TECHNOLOGY PROGRAMS Brain Imaging Research Program Committee: Adriaan Lammertsma (program leader) Dick Veltman (program leader) Frederik Barkhof Eco de Geus Kees Stam Ruud Verdaasdonk Modern neuroscience increasingly depends on advanced, state-of-the-art brain imaging techniques to characterize brain function and morphology in healthy subjects and in patients with neurological and psychiatric disorders. In addition, brain imaging is increasingly being used in animal models of disease. The VU/VUmc is unique in that it is the only academic center in the Netherlands that houses all major imaging technologies: o positron/single photon emission tomography (PET/SPECT) o magnetic resonance imaging (MRI), including a 3 Tesla functional MRI (fmri) and MR spectroscopy (MRS) o magneto-encephalography (MEG) and EEG, including MRI-compatible EEG o repetitive transcranial magnetic stimulation (rtms) o optical imaging Since state of the art applied research requires similarly advanced methodological expertise, the Brain Imaging program encompasses all methodological developments needed for pursuing advanced research goals in applied (clinical and preclinical) projects. The aims of the Brain Imaging research program in recent year were twofold. The first aim was to make optimal use of the extensive imaging facilities at the VU/VUmc campus, and to integrate these techniques with each other, wherever possible. The program instigates and performs methodological imaging research, in particular with regard to functional and structural connectivity, and molecular imaging. Second, the program aimed to function as a center of expertise, providing advice and if necessary assistance to scientists from other programs. Expertise in the field of imaging and imaging-analysis are two strongholds of the VUmc, and as such provide clinicians and neuroscientists in other research programs with a unique set of tools for non-invasive, in vivo investigations of the brain, both in humans and in animal models of disease. Neuroimaging is likely to be used not only for characterizing neural substrate of various neuropsychiatric disorders, but also for assessment of psychopathological traits cutting across diagnostic categories and for identification of endophenotypes, which may aid in understanding the genetic basis of these disorders. 30

33 Key Publications - Brain Imaging Braber, A. den, Ent, D. van t, Cath, D.C., Wagner, J., Boomsma, D.I. & Geus, E.J.C. de (2010). Brain activation during cognitive planning in twins discordant or concordant for obsessive compulsive symptoms. Brain, 133(10), (IF = 9.49) Hindriks R, Bijma F, van Dijk BW, Stam CJ, van der Werf YY, van Someren EJ, de Munck JC, van der Vaart AW. (2011) Data-driven modeling of phase interactions between spontaneous MEG oscillations. Hum Brain Mapp. Jan 10. [IF 6.2] Moraal, B., Elskamp, I.J. van den, Knol, D.L., Uitdehaag, B.M.J., Geurts, J.J.G., Vrenken, H., Pouwels, P.J.W., Schijndel, R.A. van, Meier, D.S., Guttmann, C.R.G. & Barkhof, F. (2010). Long- Interval T2-Weighted Subtraction Magnetic Resonance Imaging A Powerful New Outcome Measure in Multiple Sclerosis Trials. Annals of Neurology, 67(5), (IF = 9.31) Roosendaal, S.D., Schoonheim, M.M., Hulst, H.E., Sanz-Arigita, E.J., Smith, S.M., Geurts, J.J.G. & Barkhof, F. (2010). Resting state networks change in clinically isolated syndrome. Brain, 133, (IF = 9.49) Schuitemaker A, van der Doef TF, Boellaard R, van der Flier WM, Yaqub M, Windhorst AD, Barkhof F, Jonker C, Kloet RW, Lammertsma AA, Scheltens P, van Berckel BN. Microglial activation in healthy aging. Neurobiol Aging Nov 2 (IF 6.4) Steenweg ME, Vanderver A, Blaser S, Bizzi A, de Koning TJ, Mancini GM, van Wieringen WN, Barkhof F, Wolf NI, van der Knaap MS. Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain 2010 Oct; 133(10) (IF 9.6) Tol, M.J. van, Wee, N.J.A. van der, Heuvel, O.A. van den, Nielen, M.M.A., Demenescu, L.R., Aleman, A., Renken, R., Buchem, M.A. van, Zitman, F.G. & Veltman, D.J. (2010) Regional Brain Volume in Depression and Anxiety Disorders. Archives of General Psychiatry, 67(10), (IF = 12.25) 31

34 ADVANCED TECHNOLOGY PROGRAMS Drugs Screening and Therapy Design Research Program Committee: Peter Heutink (program leader) Guus Smit (program leader) Marjo van der Knaap Adriaan Lammertsma Huibert Mansvelder Matthijs Verhage The aims of this advanced technology program are twofold: The first aim is to make optimal use of our growing potential in cellomics facilities, which currently include cell culture robots and automated fluorescence time lapse microscopy tools that allow for medium throughput screening of genetically modified celllines. The unique asset of this technology is that the Neuroscience Campus can offer new bioassays by taking gene polymorphisms or haplotypes selected in for instance Genome Wide Analyses (GWA) and model these directly at the cellular level to test the effect of genetic variation or mutations on for instance neuronal outgrowth or cell survival. Since this technology is automated and executed in multiwell plates, it allows for the focused testing of (small molecule) shrna librairies or compound libraries (in collaboration with for instance partners from TI- Pharma. The second aim is to set up a so-called stem-cell facility, and to implement and further investigate to potential of stem-cell therapy (first in mutant mouse models of Childhood White Matter Disorders and in the long run in human patients). The program s collaborative research projects concern screening of potential therapeutic compounds in view of neurodegenerative disease (grey matter) as well as while matter disorders. In particular through bundling of the newest insights into the genetic vulnerability toward grey or white matter disorders in cellular assays and combining these with drug (design) screening, will help us to achieve a number of truly translated objectives. Second, in particular for the devastating (and Mendelian genetic) child neurology disorders (but potentially in the long run also for more common diseases including MS) stem-cell therapy may be a serious option when it comes to curing the diseases. Highlights - Drugs Screening & Therapy Design The group of Prof. Marjo van der Knaap decided to set up a Stem Cell Lab, to a large extent being supported with the funding from her 2008 Spinoza Price. In the fall of 2010 this facility was finally realized in the FALW building and under coordination of dr. Vivi Heine. Facilitated by the Prinses Beatrix price for Prof. Peter Heutink, his group has started to use a multidisciplinary approach to confirm and characterize the biological relevance of risk factors and to identify all functionally interacting genes in the affected pathway by using a high throughput cellomics approach. The characterization of gene networks instead of single genes will help to identify those genes in the affected gene network that can best serve as lead targets for development of new therapeutic approaches. Key Publication - Drugs Screening & Therapy Design Jain, S. & Heutink, P. (2010). From Single Genes to Gene Networks: High-Throughput-High- Content Screening for Neurological Disease. Neuron, 68(2), (IF = 13.26) 32

35 ADVANCED TECHNOLOGY PROGRAMS Integrative Analysis & Modeling Research Program Committee: Danielle Posthuma (program leader) Mathisca de Gunst (program leader) Niels Cornelisse Jaap Heringa Klaus Linkenkaer-Hansen Pim van Nierop Arjen van Ooyen Sophie van der Sluis Aad van der Vaart The Integrative Analysis and Modeling program provides the essential expertise on modeling and data analysis for the Neuroscience Campus systems biology approach of the brain. It develops and assesses statistical methods and computational tools for the analysis of large, complex data sets. It also builds biology-based mathematical and computational models and designs modelbased statistical tools for model systems with a limited number of components that are used to unravel generic principles of the involved biological networks. The program has three aims: to develop novel research methodology for integrative research concerning large and complex data sets (Methods for Large Data Sets); to perform research aimed at developing innovative tools for dedicated mathematical and computational modeling and statistical analysis (Biologybased Modeling and Methods); to perform integrative analysis of data obtained from different disciplines and levels of data (Integrative Data Analysis) The program s collaborative research projects concern modeling and analysis of data in the areas of genetic epidemiology, gene expression analysis and gene network modeling, phenomics, and neuronal networks. The research will result in mathematical and computational models, statistical methods and data analysis tools for biological networks, as well as high-level bioinformatics algorithms, including the integration and collaborative annotation of -omic data, and optimization of statistical analyses in a cluster environment. It will also be instrumental in the transfer of technology and skills into -omic bioinformatics, and in design of experiments and predictive biology. Highlights - Integrative Analysis & Modeling In 2010, a so-called NWO Complexity-grant was awarded to Arjen van Ooyen & Jeroen Geurts. The project is entitled "Stability and rewiring in adaptive neuronal networks". The main research questions addressed include how specific functioning and connectivity emerges in developing neuronal networks and how it is maintained in the face of ongoing plasticity? The findings will be applied to shed light onto the poorly understood network degeneration in Multiple Sclerosis. In the same year, a second NWO Complexity-grant was awarded to Niels Cornelisse, Danielle Posthuma and Matthijs Verhage for a project entitled "Identification of synaptic gene networks in complex brain disorders using a Bayesian framework". Despite the fact that most brain 33

36 disorders are highly heritable it has been difficult to identify gene defects causing the disease. Most likely the expected complexity of these diseases, involving interactions between very many genes, hampered the identification of disease genes so far. In this project the investigators want to improve standard methods for identification of disease genes using Bayesian statistics. Bayesian approaches have been successfully applied to other complex problems like weather forecasting, stock market analysis and traffic prediction. Here the investigators will use a similar approach to characterize the gene networks that influence synaptic functioning. This project is expected to pave the way for new rational therapeutic strategies, exploiting the predictive power of a probabilistic network description. A third project awarded by NWO was awarded to Aart van der Vaart c.s. for a project entitled "Should Credibility Sets Instill Confidence?" From the project: 'The two main paradigms to express uncertainty in a statistical data analysis are confidence sets and credibility sets. These are both data-determined regions that are meant to contain the unknown quantity of interest with prescribed probability, say 95 %. The difference is in the interpretation of the probability. Confidence sets would contain the parameter of interest 19 out of 20 times if data were collected and analyzed under equal conditions. Credibility sets arise in a Bayesian statistical analysis and contain the parameter with probability 95% if this were generated according to a given prior distribution. In practice credibility sets are typically constructed from the 95% central elements in a simulation of the posterior distribution. Notwithstanding the increased popularity of Bayesian methods in the last decades, confidence sets are more widely accepted, as they do not depend on a prior distribution. Confidence and credibility sets differ little when the unknown parameter is a Euclidean vector and the signal to noise ratio is small, but can be very different in the other case. This proposal concerns the properties of credibility sets in the other case, semi- or nonparametric statistics, where the parameter is an unknown function.' Key Publication - Integrative Analysis & Modeling Binsl TW, Alders DJ, Heringa J, Groeneveld AB, van Beek JH. Computational quantification of metabolic fluxes from a single isotope snapshot: application to an animal biopsy. Bioinformatics Mar 1;26(5): (IF = 4.92 ) Furberg, H., Kim, Y.J., Dackor, J., Boerwinkle, E., Franceschini, N., Ardissino, D., Bernardinelli, L., Mannucci, P.M., Mauri, F., Merlini, P.A., Penninx, B.W.J.H., Smit, J.H., Vogelzangs, N., Boomsma, D.I., Geus, E.J.C. de, Vink, J.M., Willemsen, G., Tiemeier, H., Uitterlinden, A.G., Duijn, C.M. van, Maes, H.H., Audrain-McGovern, J., Posthuma, D., Thornton, L.M., Lerman, C., Kaprio, J., Rose, J.E., Ioannidis, J.P.A., Kraft, P., Lin, D.-Y. & Sullivan, P.F. (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nature Genetics, 42(5), (IF = 34.3) Roelfsema, P.R., Ooyen, A. van & Watanabe, T. (2010) Perceptual learning rules based on reinforcers and attention. Trends in Cognitive Sciences, 14(2), (IF = 11.7) Ruano D, Abecasis GR, Glaser B, Lips ES, Cornelisse LN, de Jong AP, Evans DM, Davey Smith G, Timpson NJ, Smit AB, Heutink P, Verhage M, Posthuma D. Functional gene group analysis reveals a role of synaptic heterotrimeric G proteins in cognitive ability. Am J Hum Genet Feb 12;86(2): (IF = 12.3) Van der Sluis S, Verhage M, Posthuma D, Dolan CV. Phenotypic complexity, measurement bias, and poor phenotypic resolution contribute to the missing heritability problem in genetic association studies. PLoS One Nov 10;5(11):e13929 (IF = 4.35) Van der Sluis, S, Kan, K.J. & Dolan, C.V. (2010). Consequences of a network view for genetic association studies. Behavioral and Brain Sciences, 33(2-3), (IF = 19.04) 34

37 ADVANCED TECHNOLOGY PROGRAMS Photonics and Life Cell Imaging Research Program Committee: Marloes Groot (program leader) Huibert Mansvelder (program leader) Johannes de Boer George Kraal Erwin Peterman Ruud Toonen In this research, the investigators develop integrated non-linear optical imaging systems consisting of an in vitro imaging platform and in vivo, whole animal, imaging platforms that make optimal use of shared versatile laser systems. Advancement in neuroscience research requires the development of techniques that enable in vivo visualization of individual neurons, neuronal networks, and synaptic contacts, with high spatial and temporal resolution and penetration depth, while these circuits are processing information. The development of new optical in vivo imaging modalities that have sub-cellular resolution will allow identification of novel biomarkers for early detection of brain disease. New optical tools can, in addition to identification of new biomarkers, also be developed to perturb and interfere with the progression of disease at very early (pre-clinical) stages. The ability to visualize neurons inside living brain tissue is a fundamental requirement in neuroscience and neurosurgery. Especially the development of a noninvasive probe of brain morphology with micrometer-scale resolution is highly desirable, as it would provide a noninvasive approach to optical biopsies in diagnostic medicine. Two-photon laser-scanning microscopy (2PLSM) is a powerful tool in this regard, and has become the standard for minimally invasive high-resolution imaging of living biological samples. However, while 2PLSM-based optical methods provide sufficient resolution, they have been hampered by the requirement for fluorescent dyes to provide image contrast. Here we demonstrate high-contrast imaging of live brain tissue at cellular resolution, without the need for fluorescent probes, using optical third-harmonic generation (THG). We exploit the specific geometry and lipid content of brain tissue at the cellular level to achieve partial phase matching of THG, providing an alternative contrast mechanism to fluorescence. We find that THG brain imaging allows rapid, noninvasive label-free imaging of neurons, white-matter structures, and blood vessels simultaneously. Furthermore, we exploit THG-based imaging to guide micropipettes towards designated neurons inside live tissue. This work is a major step towards label-free microscopic live brain imaging, and opens up possibilities for the development of laserguided microsurgery techniques in the living brain. In the coming years, this research program aims to bring this technique into the clinic. Based on the state of the art microscope technology described above, a prototype system will be developed that will be tested on laboratory animals at first and ultimately in the operating theatre during brain surgery. 35

38 Highlights - Photonics & Life Cell Imaging The groups of Marloes Groot, Ruud Toonen & Huibert Mansvelder have setup two major high end Laser Scanning Microscopy setups with funding in part provided by the Neuroscience Campus Amsterdam. Huibert Mansvelder and Marloes Groot were awarded in 2010 with NWO middelgroot-grant for their new technology of "Simultaneous photo-manipulation and non-linear optical imaging of single synapses and neuronal networks in intact brain." Key Publications - Photonics & Life Cell Imaging Witte S, Negrean A, Lodder JC, de Kock CPJ, Testa Silva G, Mansvelder HD*, Groot ML* (2011) Label-free live brain imaging and targeted patching with third-harmonic generation microscopy. PNAS U S A. 108(15): (*Shared senior authors) (IF = 9.43) Witte S, Salumbides M, Peterman EJG, Brakenhoff R, van Dongen G, Toonen R, Mansvelder HD, Groot ML (2009) Development of laser-based imaging systems for medical diagnostics. In: Ultrafast Phenomena XVI Springer Series in Chemical Physics, 2009, Volume 92, Part 12, Witte, S.M., Baclayon, M., Peterman, E.J.G., Toonen, R.F.G., Mansvelder, H.D. & Groot, M.L. (2009). Single-shot two-dimensional full-range optical coherence tomography achieved by dispersion control. Optics Express, 17(14), (IF = 3.3) 36

39 Genes & the Brain Research Programs in short: Figure 11 Genes & the Brain Research Programs. We have three main stream research programs in this area where mechanistic models based on the genetic makeup of the brain is the common denominator theme. The arrows indicate that the three research programs have strong translational links and in part shared expertise. 37

40 GENES & THE BRAIN Attention & Cognition Research Program Committee: Dorret Boomsma (program leader) Matthijs Verhage (program leader) Meike Bartels Niels Cornelisse Peter Heutink Jelle Jolles Huibert Mansvelder Hanne Meijers Rhiannon Meredith Pim van Nierop Tommy Pattij Brenda Penninx Danielle Posthuma Guus Smit Attention and cognition research is probably one of the most intensively studied topics in Neuroscience Research. A total of eight departments of three faculties have joined in the Attention & Cognition program. Researchers with different backgrounds, ranging from molecular genetics and biology to genetic epidemiology, psychology and clinical applications, contribute to this multidisciplinary program. This intense collaboration and the availability of unique resources, such as a large collection of twin families, well phenotyped longitudinal cohorts recruited from clinics throughout the Netherlands, novel animal models for attention and mental retardation and state of the art research facilities concentrated at one city campus, generates unique potential. Highlights - Attention & Cognition The resting-state questionnaire (RSQ): A paradigm shift in resting-state neuroimaging, under coordination of Klaus Linkenkaer-Hansen. The human brain generates complex patterns of activity and cognition during wakeful rest, but their relationship has remained largely unexplored. The team of Linkenkaer-Hansen has developed a self-report Resting-State Questionnaire (RSQ) of 50 five-point Likert items for rating feelings and thoughts during the classical eyes-closed rest condition. In the past year ( ) the RSQ was used in functional magnetic resonance imaging (fmri) to investigate links between cognition and brain activity during the resting state (RS). The RSQ data revealed large inter-individual differences in thoughts and feelings experienced by the participants during RS-fMRI imaging. As our instructions were 'typical' such differences are likely to occur in most RS measurements. PCA identified factors that were related to emotions ("I felt happy") or cognitive control ("I had difficulty holding on to my thoughts"). Independent component analysis identified distinct group-averaged networks of brain regions with temporally correlated BOLD signals, including RS networks such as the default mode and the executive networks. Importantly, the investigators observed that individual variation in resting-state cognition meaningfully explains individual variation within the fmri-derived functional brain networks. Thus, the RSQ could prove useful for shedding light on functional implications of genetic or disease-related variation in RS brain activity. Mouse model for Fragile X mental retardation: Over the last 12 months, the team of Rhiannon Meredith has continued to work on a research line using the transgenic mouse model for Fragile X mental retardation. This mouse has been shown to have mild spatial learning and 38

41 memory impairments. Two PhD students in this team, Julia Dawitz and Ioannis Kramvis have been investigating synaptic activity in the hippocampal and entorhinal cortex regions necessary for spatial learning. Using multiphoton calcium imaging and electrophysiology, their work focuses on early developmental stages of postnatal brain development. Their projects are integrated within the EC FP7 BrainTrain consortium, co-ordinated by the CNCR and the VU University Amsterdam. In a related study, Meredith c.s. published their results testing the effects of glutamatergic antagonists upon synaptic function in developing hippocampus of Fragile X model mice. They found these drugs could correct small changes in excitatory synaptic function but were restricted to a specific developmental time window. Presynaptic gene networks for ADHD and other common disorders: In 2010 the teams of Danielle Posthuma, Niels Cornelisse, Guus Smit, Peter Heutink and Matthijs Verhage have developed an integrated approach to identifying genetic networks underlying brain disorders. This has led to a publication in The American Journal of Human Genetics early 2010, two manuscripts submitted in October 2010 and several national and international invited lectures and keynote addresses. One of our major highlights was the finding that the network of genes that encode G-proteins is involved in human intelligence. In follow-up analysis from PhD student Chavarria-Siles we confirmed that G-proteins are specifically associated with grey matter volume changes in the medial frontal cortex, an area known to be involved in cognitive processing (manuscript currently under review). In addition, a successful grant (An integrated genomic approach to ADHD) was written for the NWO-NIHC initiative and currently two PhD students will continue the work on linking variation in genetic networks important to ADHD to variation in brain structure and function. The gene network approach is also carried out as part of the EU funded SynSys project. Genetics of ADHD in adults: In 2010, the Netherlands Twin Register under guidance of Dorret Boomsma c.s. was first to publish on the genetics of ADHD symptoms in adults, reporting significant heritability, that is however substantially lower in adults than in children. A follow-up study provided significant evidence for linkage for inattention and ADHD on chromosomes 18q q21.32 and 2p25.1. Currently NTR leads a consortium of 3 Dutch groups for metaanalysis of GWA of adult ADHD. Key Publications - Attention & Cognition Boomsma DI, Saviouk V, Hottenga JJ, Distel MA, de Moor MH, Vink JM, Geels LM, van Beek JH, Bartels M, de Geus EJ, Willemsen G. Genetic epidemiology of attention deficit hyperactivity disorder (ADHD index) in adults. PLoS One May 12;5(5):e10621 (IF = 4.35) Haworth, C.M.A., Wright, M.J., Luciano, M, Martin, N.G., Geus, E.J.C. de, Beijsterveldt, C.E.M. van, Bartels, M., Posthuma, D., Boomsma, D.I., Davis, O.S.P., Kovas, Y., Corley, R.P., DeFries, J.C., Hewitt, J.K., Olson, R.K., Rhea, S.-A., Wadsworth, S.J., Iacono, W.G., McGue, M., Thompson, L.A., Hart, S.A., Petrill, S.A., Lubinski, D. & Plomin, R. (2010). The heritability of general cognitive ability increases linearly from childhood to young adulthood. Molecular Psychiatry, 15(11), (IF = 15.04) Kello, C.T., Brown, G.D.A., Ferrer-i-Cancho, R., Holden, J.G., Linkenkaer-Hansen, K., Rhodes, T. & Orden, G.C. van (2010). Scaling laws in cognitive sciences. Trends in Cognitive Sciences, 14(5), (IF = 11.66) Meredith RM, de Jong R, Mansvelder HD (2011) Functional rescue of excitatory synaptic transmission in the developing hippocampus in Fmr1-KO mouse. Neurobiol Disease 41(1): (IF=4.625) Ruano D, Abecasis GR, Glaser B, Lips ES, de Jong APH, Evans DM, Davey Smith G, Timpson NJ, Smit AB, Heutink P, Verhage M, Posthuma D. Functional gene-group analysis reveals a role of synaptic heterotrimeric G-proteins in cognitive ability. Am J Hum Genet, 2010;86(2): (IF = 12.3) Ruano, D., Abecasis, G.R., Glaser, B., Lips, E.S., Cornelisse, L.N., Jong, A.P.H. de, Evans, D.M., Smith, D.G., Thimpson, N.J., Smit, A.B., Heutink, P., Verhage, M. & Posthuma, D. (2010). Functional Gene Group Analysis Reveals a Role of Synaptic Heterotrimeric G Proteins in Cognitive Ability. American Journal of Human Genetics, 86(2), (IF = 12.3) Saviouk V, Hottenga JJ, Slagboom EP, Distel MA, de Geus EJ, Willemsen G, Boomsma DI. ADHD in Dutch adults: Heritability and linkage study. Am J Med Genet B Neuropsychiatr Genet. 2011; 156(3): (IF = 3.48) Sluis, S. van der, Kan, K.J. & Dolan, C.V. (2010). Consequences of a network view for genetic association studies. Behavioral and Brain Sciences, 33(2-3), (IF = 19.04) 39

42 GENES & THE BRAIN Addictive Behavior Research Program Committee: Guus Smit (program leader) Ton Schoffelmeer (program leader) Huibert Mansvelder Brenda Penninx Sabine Spijker Dick Veltman Jacqueline Vink Taco De Vries This program addresses the development of drug and alcohol addiction as well as relapse to compulsive drug- and alcohol-seeking behavior during abstinence in both laboratory animals (rodents) and humans. The availability of operant animal models to study the motivational and cognitive aspects of addiction, the availability of advanced in vitro and in vivo neurophysiological techniques and that of state-of-the-art genomics/proteomics expertise in this program is unique. Moreover, the availability of genome-wide data in NESDA as well as the Dutch Twin Register allows us to identify genetic risk factors, whereas the application of brain imaging enables us to examine the motivational and cognitive aspects and pharmacotherapy of relapse behavior in humans. The investigators examine how individual differences in cognition (such as attention and impulsivity) and emotion (anxiety), primarily addressed in other research programs of the institute, determine the individual susceptibility to develop addictive behavior and the individual s risk to relapse to drug- and alcohol-seeking behavior during abstinence. In this respect, animal and human studies aimed to identify the genetic basis of addiction proneness (identification of vulnerability genes, including studies in twins), will be initiated. Animal studies address the psychopharmacology and neurobiology of cue-induced relapse to drug- and food-seeking behavior as well as that of extinction of drug/foodrelated memories during abstinence. Clinical studies are being performed in drug addicts, employing brain imaging (fmri) and pharmacotherapy, in order to examine the functional anatomy and pharmacotherapy of relapse behavior (predicted by animal studies). Major deliverables of this research are: Identification of genetic risk factors (polymorphisms) for the acquisition of nicotine, heroin and alcohol addiction. Identification of novel targets (e.g. synaptic proteins) for pharmacotherapeutical intervention of relapse to drug and/or alcohol consumption during abstinence. Identification of distinct impulsivity traits as treatable risk factors for the development of compulsive nicotine- and alcohol-seeking behavior. Synthesis and in vivo application of compounds targeting nicotine and glutamate receptors as putative future medicines. 40

43 Recent milestones reached include: Identification of extracellular matrix proteins involved in relapse behavior in rats. Identification of distinct SNPs exceeding genome-wide significance and associated with smoking initiation and cessation in humans. Identification of inhibitory control and impulsive choice as distinct vulnerability traits for the acquisition, extinction and relapse of nicotine, cocaine, heroin, alcohol and food-seeking behavior in rats. Identification of adolescence as a particularly vulnerable period for nicotineinduced neurocognitive alterations in the adult forebrain that mediate addictive behavior. Key Publications - Addictive Behavior Counotte D, Goriounova N, Li KW, Loos M, van der Schors R, Schetters D, Schoffelmeer ANM, Smit AB, Mansvelder HD, Pattij T (2011) Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence. Nature Neuroscience, in press. (IF = 14.3) Tobacco and Genetics Consortium (including Vink J, Geus E, Boomsma D, Hottenga JJ, Posthuma, D and Penninx BW). Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 2010;42: (IF=34.5) Thorgeirsson et al. Consortium including Penninx, B.W., Boomsma, D.I. (2010). Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nature Genetics, 42(5), (IF = 34.3) Van den Oever MC, Lubbers BR, Goriounova NA, Li KW, Van der Schors RC, Loos M, Riga D, Wiskerke J, Stegeman M, Schoffelmeer ANM, Mansvelder HD, Smit AB, De Vries TJ, Spijker S (2010) Extracellular matrix plasticity and GABAergic inhibition of prefrontal cortex pyramidal cells facilitates relapse to heroin-seeking behavior. Neuropsychopharmacology 35, (IF = 7.0) Wiskerke J, Schetters D, van Es IE, van Mourik Y, den Hollander BR, Schoffelmeer ANM, Pattij T (2011) Opioid receptors in the nucleus accumbens Shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice. Journal of Neuroscience 31, (IF = 7.2) 41

44 GENES & THE BRAIN Systems Biology of the Synapse Research Program Committee: Matthijs Verhage (program leader) Guus Smit (program leader) Niels Cornelisse Sander Groffen Marloes Groot Ronald van Kesteren Kawan Li Huibert Mansvelder Rhiannon Meredith Pim van Nierop Danielle Posthuma Sabine Spijker Oliver Stiedl Ruud Toonen Heidi de Wit The overall aim of this program is to understand molecular function and plasticity of the synapse in health and disease. In order to do so, the collaborating investigators aim at constructing protein interaction models (interactome) of the synapse that will be based on different conditions of synaptic function and on mouse knockouts of synaptic proteins. The synaptic interactome models are based on quantitative experimental data, which ultimately explain how a complex protein network drives synaptic functions in the brain and predicts its adaptive capacities in response to environmental cues, such as behavioral challenges and pharmacological interventions. Finally, knowledge about synaptic function is being integrated to study synaptic networks in vitro and in vivo. Specific objectives are to provide targets for synaptic modulation and to dissect disease phenotypes by identifying crucial nodes and connectivity of the network. In order to generate quantitative experimental data on proteins and protein states and to reveal crucial nodes of the complete synaptic system, the research apply genetic, behavioral and pharmacological intervention and analyze the perturbation outcome using synapse-wide proteomics, synapse physiology, life cell imaging techniques and electron microscopy. Between over twenty new projects were realized in which various technical approaches have been applied, ranging from whole synapse screens (itraq (quantitative) high-throughput MALDI-TOF) and subsynaptic protein complex analysis (immunoprecipitations and pull-down of tagged proteins) to biocore interaction analysis to derive kinetic parameters for proteins of interest, synaptic localization of proteins using confocal and electron microscopy. The loop between computational science and experimental neuroscience is being 'closed' by using several perturbation approaches, involving gene knockdown, over-expression, pharmacological agents, and the use of peptide 42

45 mimetics to test model robustness and refine parameters. Modeling the synapse will allow us to predict and test synapse function and the physiology of neuronal circuitry. This information is crucially needed to design future therapeutic strategies addressing the many brain disorders for which synaptic dysfunction is a central aspect. Hence a truly integrated experimental and theoretical systems approach is applied to reach the objectives. Highlight - Systems Biology of the Synapse In 2010 the team of Ronald van Kesteren and Prof. Guus Smit received a NWO-Middelgroot grant to invest in automated confocal cellular imaging and screening instrumentation. Highresolution confocal imaging, together with automated image acquisition and advanced online image analysis algorithms will be used for the systematic functional analysis genes and proteins that mediate synapse formation and synaptic plasticity in vitro. Impression of the new life cell imaging facility in this Systems Biology of the Synapse Program Key Publications - Systems Biology of the Synapse Engelhardt, J., Mack, V., Sprengel, R., Kavenstock, N., Li, K.W., Stern-Bach, Y., Smit, A.B., Seeburg, P.H. & Monyer, H. (2010). CKAMP44: A Brain-Specific Protein Attenuating Short-Term Synaptic Plasticity in the Dentate Gyrus. Science, 327(5972), (IF = 29.74) Groffen, A.J., Martens, S., Diez Arazola, R., Cornelisse, L.N., Lozovaya, N., Jong, A.P.H. de, Goriounova, N.A., Habets, R.L., Takai, Y., Borst, J.G., Brose, N., McMahon, H.T. & Verhage, M. (2010). Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release. Science, 327(5973), (IF = 29.74) Mohrman, R., Wit, H. de, Verhage, M., Neher, E. & Sørensen, J.B. (2010). Fast Vesicle Fusion in Living Cells Requires at Least Three SNARE Complexes. Science, 330(6003), (IF = 29.74) 43

46 Brain Disease Mechanisms Research Programs in short: Figure 12 Brain Disease Mechanisms Research Programs. Three main type of brain disorders are currently being investigated. Each of these research programs is based upon large groups of patient cohort and patient clinical activities. Transdisciplinary dialogue is guaranteed because most programs are being supervised by both clinical and preclinical research leaders. The aim of the Neuroscience Campus is further to provide strong translational links between the Genes & the Brain programs and expertise being developed and the patient diagnosis and therapy oriented programs. 44

47 BRAIN DISEASE MECHANISMS Anxiety & Depression Research Program Committee: Brenda Penninx (program leader) Eco de Geus (program leader) Zoltan Bochdanovits Dorret Boomsma Peter Heutink Odile van den Heuvel Adriaan Lammertsma Christel Middeldorp Guus Smit Jan Smit Oliver Stiedl Dick Veltman Matthijs Verhage The overall aim of the anxiety and depression program is to identify genomic regions and gene variants that mediate vulnerability to these affective disorders; to understand this vulnerability at the synaptic and brain systems level; to determine their interaction with age, sex and environmental challenges; and to use this understanding to explain the observed patterns of brain activity of behaving humans. Ongoing research has already linked clinical outcomes to neuroanatomy of postmortem tissue, autonomic nervous system and Hypothalamus-Pituitary-Axis function, serum markers such as vitamin D, inflammation, and (f)mri traits, as well as receptor characteristics obtained from GABA-ergic (flumazenil), dopaminergic (raclopride), and serotonergic PET ligands. By cross-linking these, and other novel endophenotypes to newly detected genetic variants for anxiety and depression the program will uncover part of the actual pathways from molecule to mind for these afflictions. Translational targets are improved diagnostics and prognostics, and stronger evidence-based and personalized therapeutic intervention. The program will provide new insights into pathophysiology of depression and suggest previously unsuspected etiologic pathways for these diseases. This will translate into better care for patients by improving early detection of individuals at risk, which is a critical concern for clinicians identifying new therapeutic targets developing targeted interventions based on genetically defined risk. Key Publications - Anxiety & Depression De Moor MH, Costa PT, Terracciano A, Krueger R, de Geus EJ, Toshiko T, Hartman C, Esko T, Madden PAF, Derringer J, Amin N, Willemsen G, Hottenga JJ, Distel MA, Uda M, Sanna S, Ferrucci L, Schlessinger D, McCrae RR, Spinhoven P, Penninx BW, Realo A, Metspalu A, Heath AC, Pergadia ML, Peng Lin AA, Grucza R, Räikkönen K, Widen E, Luciano M, Tenesa A, Houlihan LM, Davies G, Hansell NK, Medland SE, Wray NR, Wright MR, Aulchenko Y, Janssens ACJW, Oostra BA, Allik J, Abecasis GR, Deary IJ, Bierut L, Martin NG, Boomsma DI, van Duijn CM. Metaanalytic genome-wide association study in > individuals reveals new loci for the Five- 45

48 Factor Model (NEO-FFI) personality domains. Mol Psychiatry 2010; in press. (IF=12.5) Perlis, R.H., Huang, J., Purcell, S., Fava, M., Rush, A.J., Sullivan, P.F., Hamilton, S.P., McMahon, S., Schulze, T., Potash, J.B., Zandi, P.P., Willour, V.L., Penninx, B.W.J.H., Boomsma, D.I., Vogelzangs, N., Middeldorp, C.M., Rietschel, M., Nöthen, M.M., Cichon, S., Gurling, H., Bass, N., McQuillin, A., Hamshere, M.L., Craddock, N., Sklar, P. & Smoller, J.W. (2010). Genome-wide association study of suicide attempts in mood disorder patients. American Journal of Psychiatry, 167(12), (IF = 12.52) Spijker S, Van Zanten JS, De Jong S, Penninx BW, van Dyck R, Smit JH, Ylstra, B, Smit AB, Hoogendijk WJG. (2010) Molecular markers of Major Depressive Disorder based on stimulated gene expression in drug-naive blood samples. Biol Psychiatry 68: (IF=8.7) Tobacco and Genetics Consortium (including Vink J, Geus E, Boomsma D, Hottenga JJ, Penninx BW and Posthuma, D (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet 42:441-7 (IF=34.5) Tol, M.J. van, Wee, N.J.A. van der, Heuvel, O.A. van den, Nielen, M.M.A., Demenescu, L.R., Aleman, A., Renken, R., Buchem, M.A. van, Zitman, F.G. & Veltman, D.J. (2010). Regional Brain Volume in Depression and Anxiety Disorders. Archives of General Psychiatry, 67(10), (IF = 12.25) Van Tol ML, van der Wee NJA, van den Heuvel OA, Nielen MMA, Demenescu LR, Aleman A, Renken R, van Buchem MA, Zitman FG, Veltman DJ. Regional brain volume in depression and anxiety disorders. Arch Gen Psychiatry 2010; 67: (IF=14.3) Wray NR, Pergadia ML, Blackwood DH, Penninx BW, Gordon SD, Nyholt DR, Ripke S, Smit JH, Hottenga JJ, Willemsen G, Middeldorp C, de Geus EJ, Lewis CM, McGuffin P, Hickie IB, van den Oord EJ, Liu J, Macgregor S, McEvoy BP, Byrne EM, Medland SE, Henders AK, Heath AC, Montgomery GW, Martin NG, Boomsma DI, Madden PAF, Sullivan PF. Genome-wide association study of major depressive disorder: New results, meta-analysis, and lessons learned. Mol Psychiatry 2011; in press. (IF=12.5) 46

49 BRAIN DISEASE MECHANISMS Research Program Committee Philip Scheltens (program leader) Peter Heutink (program leader) Common clinical cohorts: Henk Berendse Wiesje van der Flier Research theme 1: Neuropathology and biomarker studies Wilma van de Berg Annemieke Rozemuller Research theme 2: Neurogenetics and pathogenetic mechanisms Guus Smit Pieter Voorn Research theme 3: NeuroImaging Adriaan Lammertsma Cees Stam Research theme 4: New therapeutic approaches Eric van Exel Erik Scherder This is a clinically oriented translational program. The main focus is to unravel the underlying often overlapping pathophysiologic substrates of the common neurodegenerative disorders with AD and PD as their most well known representatives. The classical forms of AD and PD are considered distinct diseases, but many patients show a large overlap in symptoms, pathology and genetic findings. To enable targeted drug therapies, an adequate characterization of the underlying pathology at protein level is needed. It has become clear that at a molecular level there are common denominators and that an integrated joint approach on neurodegenerative disease holds the best promise for unraveling the pathogenesis of these disorders. The translational component will be evidenced in a bidirectional approach by using biomarkers and clinical information from patients to guide the preclinical program and findings from cellular and genetic research can immediately be tested and validated in clinical samples. Common goals of this program are: o to further unravel the, possibly in part common, neuronal substrates, as well as neuropathological and pathogenetic mechanisms of the above mentioned disorders; o to develop early, preferably even presymptomatic, diagnostic markers; o to develop novel therapeutic approaches. 47

50 Among the current available resources, there is extensive expertise from clinic, patient cohorts (also collaborative with other centers), phenotyping (including imaging), biomarkers, (early)diagnostic markers, neuroanatomy, neuropathology, transcriptomics, proteomics, gene finding, functional characterization, cellular, animal models and therapeutic approaches. A translational research plan has been constructed according to four major disease lines in this program: Alzheimer (and related forms of dementia) Parkinson FrontoTemporal Lobar Degeneration Normal Aging Key Publications - Deerlin et al. Consortium including Heutink, P. (2010) Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions. Nature Genetics, 42(3), 234-U34 (IF = 34.28) Goos JDC, Henneman WJP, Sluimer JD, Vrenken H, Sluimer IC, Barkhof F, Blankenstein MA, Scheltens PH, Van der Flier WM. (2010) Incidence of cerebral microbleeds: A longitudinal study in a memory clinic population. Neurology 2010;74: (IF = 8.17) Jain, S. & Heutink, P. (2010). From Single Genes to Gene Networks: High-Throughput-High- Content Screening for Neurological Disease. Neuron, 68(2), (IF = 13.26) Dubois, B, Feldman, H.H., Jacova, C., Cummings, J.L., Dekosky, S.T., Barberger-Gateau, P., Delacourte, A., Frisoni, G., Fox, N.C., Galasko, D., Gauthier, S., Hampel, H., Jicha, G.A., Meguro, K., O'Brien, J., Pasquier, F., Robert, P., Rossor, M., Salloway, S., Sarazin, M., Souza, L.C. de, Stern, Y., Visser, P.J. & Scheltens, P. (2010). Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurology, 9(11), (IF = 18.12) Frisoni, G.B., Fox, N.C., Jack, C.R., Scheltens, P. & Thompson, P.M. (2010). The clinical use of structural MRI in Alzheimer disease. Nature Reviews Neurology, 6(2), (IF = 6.36) Munneke, M., Nijkrake, M.J., Keus, S.H., Kwakkel, G., Berendse, H.W., Roos, R.A., Borm, G.F., Adang, E.M., Overeem, S. & Bloem, B.R. (2010). Efficacy of community-based physiotherapy networks for patients with Parkinson's disease: a cluster-randomised trial. Lancet Neurology, 9(1), (IF = 18.12) 48

51 BRAIN DISEASE MECHANISMS White Matter Diseases Research Program Committee: Theme 1: Multiple sclerosis and other neuroinflammatory diseases Chris Polman (program leader and theme leader) Christien Dijkstra (theme leader) Frederik Barkhof (theme leader) Bernard Uitdehaag (vice theme leader) Elga de Vries Paul van der Valk Annette van der Goes (program coordinator) Theme 2: Childhood white matter diseases Marjo van der Knaap (program leader and theme leader) Gert Scheper (vice program leader) Cornelis Jakobs (theme leader) Gajja Salomons Jeroen Vermeulen (theme leader) Theme 1: Multiple Sclerosis (MS) The primary goal of the VUmc MS Center Amsterdam is to perform internationally distinctive MS research that allows better understanding and treatment of MS. The center has an excellent international reputation and is one of the top five MS research groups in the world. The MS Center Amsterdam is a multidisciplinary research center in which more than 100 experts of different disciplines within the VU university medical center (VUmc) cooperate to work on questions regarding the cause, cure and care of MS. The combination of fundamental and clinical research allows us to quickly apply new research developments in diagnosis and treatment of MS. Likewise, questions concerning the pathogenesis of the disease that arise in the clinic can be answered vice versa in collaboration with basic scientists. This MS Center is unique because it unites a comprehensive array of disciplines ranging from experimental laboratory research to clinical research. The researchers of the VUmc MS Center Amsterdam have more recently decided to join forces to devote their expertise and focus to understanding neurodegeneration in MS and to work towards identifying novel targets for future neuroprotective treatment. The leading hypothesis is that neurodegeneration is causal to clinical progression and cognitive decline in MS, and we propose that the development of neuroprotective strategies is a crucial next step in the treatment of the disease. Theme 2: Childhood white matter diseases The primary goal of the Center for Childhood White Matter Disorders (CWMDs) is to improve the diagnosis and understanding of CWMDs in order to develop better treatment. CWMDs comprise a group of disorders that can be divided 49

52 into acquired damage and genetic disorders. The genetic CWMDs can be divided in metabolic and non-metabolic. The Center for CWMDs combines diagnosis, treatment, research on disease mechanisms and development of novel therapies, both specific and symptomatic. The center is multidisciplinary with clinicians, clinical researchers and basic researchers with a broad range of expertises. This set-up facilitates easy interaction of specialists in different fields. The work of the center is greatly facilitated by a large database of information on patients from all over the world, their MRIs, DNA, body fluids, tissues and cell lines. This database is conditional for research on the etiology and pathophysiology of rare to extremely rare disorders. Optimization of symptomatic treatment is an important target, especially treatment of spasticity and loss of communication. Highlights - White Matter Disease, theme 1 Messages from the media about a possible breakthrough in the treatment of MS by intervening with presumed cervical venous insufficiency caused a lot of commotion under MS patients. Because of societal impact, and because scientific evidence supporting the venous insufficiency hypothesis was very thin, we decided to rapidly perform a pilot study on this topic. In May we completed this study and found that neck vein abnormalities were as common in people with MS as in healthy people. Moreover, the study showed that these variations did not impact the outflow of blood from the brain. This research was published in J Neurol Neurosurg Psychiatry in Oct 2010 (Epub). In June we organized an information day for MS patients of the VUmc. About 300 participants enrolled and we received very enthusiastic comments about this event. In October the VU medical center organized the sixth VUmc building walk which was a great success. The 870 participants have collected over 8000 for research by the MS Center Amsterdam. Stefan Roosendaal received both the Lucien Appel Prize of the European Society for Neuroradiology (ESNR) and the Lourens Penning Prize of the Dutch Society for Radiology for his article in the scientific journal Brain ( : ) on the use of functional magnetic resonance imaging (fmri) for measuring resting state brain activity in people with clinical isolated syndrome (CIS). Chris Polman received the Winkler medal of the Dutch Society of Neurology for his work on MS. In 2010 MS researchers of VUmc have together obtained more than 7 M for MS research. Several large projects are: o The MS center has received a program grant for 2.4 M. The grant (written by Elga de Vries and Jeroen Geurts) to further understand neurodegeneration in MS and to move towards neuroprotection in MS was awarded by the Netherlands MS Research Foundation o Jack van Horssen has received a prestigious Fellowship of 240 K from the Netherlands MS Research Foundation for his research on oxygen damage in the brains of people with MS. o Vincent de Groot from the department of rehabilitation received a grant of ZonMw of 1 M for research into the treatment of fatigue in MS o Chris Polman has received 1.1 M from a private foundation for research on neurodegeneration in MS, applying imaging and optical coherence tomography (OCT). Our excellent international position is also expressed in the large number of selected presentations and posters on the yearly MS congress ECTRIMS in Gothenburg (Sweden) in October of MS researchers of VUmc were selected for 3 invited reviews, 7 oral presentations and 13 posters. In October 2011 the international world congress of MS (ECTRIMS&ACTRIMS) will take place in the RAI in Amsterdam. Highlights - White Matter Disease, theme 2 In January 2010, Vivi Heine, a stem cell biologist, arrived to set up a stem cell laboratory in the Faculty of Earth and Life Sciences. In this laboratory research will be performed to develop glia progenitor transplantation for Vanishing White Matter (VWM). The finances for the laboratory 50

53 come from the Spinoza Award, VUmc, VU Faculty of Earth and Life Sciences, and private money. The official opening of the laboratory was December 17. In 2010 we completed the development of three mutant mouse models: two for VWM and one for megalencephalic leukoencephalopathy with subcortical cysts (MLC). We have bred the mice to homozygously mutant. These mice will be extremely important for our studies on disease mechanisms and for developing neural stem cell therapy for VWM. For VWM we have found that the genotype correlates with the phenotype and that both mutations have an influence (Neurology 2010). In collaboration with Prof. Chris Proud (Southampton) we have demonstrated that the remaining activity of the deficient enzyme, eif2b does not show any correlation with the phenotype, suggesting that eif2b may have other functions than guanine exchange activity in translation initiation. By studying autopsy brain tissue of VWM patients and controls we have obtained new insights into the mechanism of VWM at cellular level: a defect in the maturation of glia progenitor cells. Glia progenitors are increased in numbers in VWM white matter, but do not give rise to sufficient numbers of mature, functionally competent oligodendrocytes and astrocytes. We found an abnormal composition of the astrocytic cytoskeleton, which probably explains the morphological abnormalities and contributes to the dysfunction. These findings explain the lack of myelin deposition and diminished reactive gliosis in the presence of increased numbers of maturation deficient glia (J Neuropathol Exp Neurol 2010 and 2011). The defect in glia maturation appears to be a central problem in VWM. With glia progenitor transplantation we may be able to cure this problem. In 2010 we published a paper (in Human Mutation) concerning evidence for the existence of at least two types of the neurometabolic disorder D-2-hydroxyglutaric aciduria (D-2-HGA), a disorder characterized by supraphysiological levels of D-2-hydroxyglutarate (D-2-HG) in body fluids: D-2-HGA Type I, an autosomal recessive form caused by mutations in D2HGDH, and an idiopathic form. A few months after this publication, we identified the underlying genetic defect for the idiopathic form and denoted it D-2-HGA type II. It is caused by heterozygous mutations in isocitrate dehydrogenase 2 (IDH2). Mutations in the latter gene were recently reported by others to occur as somatic mutations in several types of cancer. These mutations not only disable the enzyme's normal ability to convert isocitrate to 2-ketoglutarate (2-KG), but also result in a gain of function concerning the ability to convert 2-KG to D-2-HG. We have reported our finding of de novo heterozygous germline mutations in IDH2 in 15 unrelated D-2- HGA Type II patients in Science. In 2001, we identified MLC1 as the first gene for MLC. In 2010 we published that MLC patients without MLC1 mutations present with two distinct phenotypes (Ann Neurol 2010). One is the classical phenotype with slow neurological deterioration. The other is an improving phenotype in which the white matter disease improves or normalizes and in which neurological deterioration is lacking. The patients have macrocephaly, but are otherwise normal or have a mental retardation with or without autism. In collaboration with Prof. Raúl Estévez (Barcelona) we found the second gene for MLC, HEPACAM, which codes for hepatic and glial cell adhesion molecule, GlialCAM. The different phenotypes are related to different mutations with different modes of inheritance: autosomal recessive and autosomal dominant. With this, we have also found a gene for benign familial macrocephaly and for macrocephaly with mental retardation +/- autism. A paper on the subject has been accepted by the American Journal of Human Genetics (2011). Key Publications - White Matter Diseases, theme 1 Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, Naves R, Han M, Zhong F, Castellanos JG, Mair R, Christakos A, Kolkowitz I, Katz L, Killestein J, Polman CH, de Waal Malefyt R, Steinman L, Raman C. T helper type 1 and 17 cells determine efficacy of interferonbeta in multiple sclerosis and experimental encephalomyelitis Nat Med Apr;16(4): (IF = 27.13) Geurts, J.J.G., Kooi, E.J., Witte, M.E. & Valk, P. van der (2010). Multiple Sclerosis as an "Inside-Out" Disease. Annals of Neurology, 68(5), (IF = 9.31) Killestein, J., Vennegoor, A., Strijbis, E.M.M., Seewann, A.M., Oosten, B.W. van, Uitdehaag, B.M.J. & Polman, C.H. (2010). Natalizumab Drug Holiday in Multiple Sclerosis: Poorly Tolerated. Annals of Neurology, 68(3), (IF = 9.31) Moraal B, van den Elskamp IJ, Knol DL, Uitdehaag BM, Geurts JJ, Vrenken H, Pouwels PJ, van Schijndel RA, Meier DS, Guttmann CR, Barkhof F. Long-interval T2-weighted subtraction 51

54 magnetic resonance imaging: a powerful new outcome measure in multiple sclerosis trials. Ann Neurol May;67(5): (IF = 9.31) Moraal, B., Elskamp, I.J. van den, Knol, D.L., Uitdehaag, B.M.J., Geurts, J.J.G., Vrenken, H., Pouwels, P.J.W., Schijndel, R.A. van, Meier, D.S., Guttmann, C.R.G. & Barkhof, F. (2010). Long- Interval T2-Weighted Subtraction Magnetic Resonance Imaging A Powerful New Outcome Measure in Multiple Sclerosis Trials. Annals of Neurology, 67(5), (IF = 9.31) Petzold, A.F.S., Boer, J.F. de, Schippling, S., Vermersch, P., Kardon, R., Green, A., Calabresi, P.A. & Polman, C.H. (2010). Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurology, 9(9), (IF = 18.12) Polman, C.H., Bertolotto, A., Deisenhammer, F., Giovannoni, G., Hartung, H.P., Hemmer, B., Killestein, J., McFarland, H.F., Oger, J., Pachner, A.R., Petkau, J., Reder, A.T., Reingold, S.C., Schellekens, H. & Sorensen, P.S. (2010). Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurology, 9(7), (IF = 18.12) Key Publications - White Matter Diseases, theme 2 Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS, Amiel J, Buist NR, Das AM, de Klerk JB, Feigenbaum AS, Grange DK, Hofstede FC, Holme E, Kirk EP, Korman SH, Morava E, Morris A, Smeitink J, Sukhai RN, Vallance H, Jakobs C, Salomons GS. (2010) IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330: 336 (IF 29.7) van der Knaap MS, Lai V, Köhler W, Salih MA, Fonseca MJ, Benke TA, Wilson C, Jayakar P, Aine MR, Dom L, Lynch B, Kálmánchey R, Pietsch P, Errami A, Scheper GC. (2010) Megalencephalic leukoencephalopathy with cysts without MLC1 defect. Ann Neurol 67: (IF 9.3) 52

55 10b) Input per program fte per type of funding (incl PhD students) gs 1 gs 2 gs 3 gs 4 Total Total Total Advanced Technology Brain Imaging Drugs Screening & Therapy Design Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synaps Brain Disease Mechanisms Anxiety and Depression White Matter Disease Affliated research n.a. Total fte PhD students per type of funding gs 1 gs 2 gs 3 gs 4 Total Total Total Advanced Technology Brain Imaging Drugs Screening & Therapy Design Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synaps Brain Disease Mechanisms Anxiety and Depression White Matter Disease Affliated research n.a. Total Table 6 - Input in fte per Research Program. A full list of coworkers is outlined in appendix 1. 53

56 10b) Input per program (continued) External Funding gs 2 gs 3 gs 4 Total Total Erasmus Mundus & Dissemination 5,000 3,450, ,455,000 0 Advanced Technology Brain Imaging Drugs Screening & Therapy Design Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synapse Brain Disease Mechanisms Anxiety & Depression White Matter Disease Affiliated Research 0 219, ,508 1,069, ,675,000 1,010, ,010, , , , ,513 2,551, ,063,513 1,153, , ,000 2,783, ,000 3,697, ,547,000 4,972,369 2,498,000 1,950, ,000 4,895,960 5,435,000 1,033,000 1,231, ,215 2,479,026 1,538,342 1,000,000 5,036,853 2,825,076 8,861,929 3,000, ,000 35,000 48, , ,000 Table 7 Grant acquisition per Research Program of 2010 compared to Acquisition is split in types of funding. The funding coming from Erasmus Mundus for PhD s at NCA in the ENC-Network, is estimated to be half to the total EU-acquisition for the coming five years. A full list of acquired external funding is outlined in appendix 6. In this overview, gs2 is N.W.O. funded research, gs3 is project funding from non-profit, ministries, FES & EU and gs4 is based on a mix of contract-research (for profit/industry) and donations/philanthropy. 54

57 10c) Output per program Scientific Output Theses Scientific papers Rest DissA DissC DissB DissD Wp WpREF WpNR VP Total Total Books Chapters Advanced Technology Brain Imaging Drugs Screening & Therapy Design Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synaps Brain Disease Mechanisms Anxiety and Depression White Matter Disease Affliated research Table 8 - Output in 2010 per Research Program of the Neuroscience Campus Amsterdam. A full list of publications is outlined in appendix 3. Also listed are the total output numbers (primarily determined by the WpREF) of previous year. Abbreviations: Theses A: Promotion VU/VUmc PhD-student at VU Theses B: Promotion external PhD-student at VU Theses C: Promotion VU/VUmc PhD-student at other university Theses D: Promotion external PhD-student at other university (promotor, co-promotor) WP: Books/monographs/book chapters/proceedings WP Ref: Scientific Papers refereed WP NR: Scientific Papers non-refereed VP: Professional publication 55

58 10c) Output per program (continued) % of papers in 2010 with RIF* of 5 % of papers in 2010 with RIF of 4 % of papers in 2010 with RIF of 3 % of papers in 2010 with RIF of 2 % of papers in 2010 with RIF of 1 total number of papers up to en of 2010 total number of citations up to end of 2010 average CPP towards the end of 2010 mean h - index of tenured end of 2010 Advanced Technology Brain Imaging 44% 24% 20% 12% 0% Drugs Screening & Therapy Design n.a Integrative Analysis & Modeling 38% 38% 17% 8% 0% Photonics & Life Cell Imaging n.a Genes & the Brain Attention & Cognition 59% 25% 14% 2% 2% Addictive Behavior 68% 5% 21% 5% 0% Systems Biology of the Synapse 46% 35% 19% 0% 0% Brain Disease Mechanisms Anxiety & Depression 74% 17% 6% 3% 0% % 14% 30% 5% 0% White Matter Disease 45% 19% 31% 5% 3% Affliated Research 44% 24% 20% 12% 0% * RIF = Relative Impact Factor Quartile Category: 5: top 10% 4: 11-25% 3: 26-50% 2: 51-75% 1: % Table 9 - Quality of the Program Committee per Research Program. Shown are total number of papers by Program Committee Members per Program, the Cumulative Number of Citations per group of authors, the average CPP and mean h-index. In addition, in the first five columns, per research program the % of 2010 papers categorized according to the RIF, Relative Impact Factor is shown. 56

59 11. Scientific Research Committees Quality control at the Neuroscience Campus Amsterdam is done by three internal committees, one for Biomedical Research (CWO-FALW), one for Psychology Research (CWO-FPP), and one for Medical Research (CWO-VUmc) and an external Scientific Advisory Board (chaired by Prof. Martinus Niermeijer - for more information, see our website). The chairs of the different committees meet twice a year with Management Team and moreover are involved in screening internal projects. We follow the VSNU accredited academic evaluation cycle with a Self-evaluation (Midterm) Review in 2011 and External Audit in

60 Exchange Honours students of Master of Neurosciences Amsterdam-Rotterdam (director Gerard Borst & Huibert Mansvelder) Graduate School Neurosciences Amsterdam Rotterdam (director August Smit) PhD training in Europe - ITN (coordinator Heidi de Wit) MSc & PhD training in Europe - Erasmus Mundus funded programs (director - Arjen Brussaard) 58

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