Annual Report 2013
Annual Report 2013
Table of contents
Word from the director ...................................................................................................... 3 1a) Objective(s) and research area ............................................................................... 4 1b) Research Programs.................................................................................................... 11 2a) Composition (input data) ......................................................................................... 26 2b) Participating researchers .......................................................................................... 28 3a) Research environment and infrastructure ............................................................. 29 3b) Valorization ................................................................................................................. 33 4a) Quality and scientific relevance ............................................................................. 35 4b) Quality control ............................................................................................................ 36 5) Output ............................................................................................................................ 38 6a) Earning capacity– NCA ............................................................................................ 39 6b) Earning capacity – Industry Alliance Office .......................................................... 40 7) Academic reputation .................................................................................................. 41 8) Society relevance ........................................................................................................ 42
Appendices (see website NCA).
Annual Report 2013
Word from the director On behalf of all partners of the Neuroscience Campus Amsterdam (NCA) – staff, coworkers and graduate students - we present the Annual Report of 2013. Several major initiatives and hallmarks are worth mentioning here. The solid impact of our research output remains based primarily on a qualityoriented and purpose-driven research strategy. There are numerous examples of multidisciplinary studies that made it into high impact journals. With a total of more than 500 peer reviewed papers and with more than 100 papers in the top 5% of the international journals, we sustain an excellent standard. In parallel, we have also implemented a further focus of our research organization by reducing the number of research programs to only 5 new research programs (as further outlined in this report). We have also put efforts in shifting our attention towards a more biotech and pharma-industry-oriented position, since we have launched the Industry Alliance Office (www.nca-iao.com). Progress in 2013 permits a further development of this 'front-office' of the NCA. The Industry Alliance Office operates as a one-stopshop to external partners and was able to successfully offer integrated propositions around a dozen outside stakeholders. To further facilitate the growth of this business model and in order to also be able to involve additional 3rd party capacity, we have decided to launch the Industry Alliance as a corporation in 2014. Our academic reputation, and the quality and quantity of our graduate programs are accredited by formal organizations and NCA continues to coordinate and run the research MSc Neuroscience program as well as the PhD Neuroscience program (ONWAR). In addition, the societal relevance has been formalized in recent years, amongst others via active memberships of our staff in DJA of the Royal Academy of Sciences. Last but not least, the alliance partnerships of the NCA with major stakeholders, notably the Departments of Neurology and of Psychiatry at the Amsterdam Medical Center (AMC), and the Department of Neuroscience of the Swammerdam Institute for Life Sciences of the University of Amsterdam (UvA) have been further developed and will hopefully formalize during 2014-2015. We also recently celebrated the sixth anniversary of NCA. Being the playground for many graduates, and graduates-to-be, and working towards further integration in the field of Translational Neurosciences, at present we have created an appealing workplace for many that offers great perspectives for a sustainable future. Prof.dr. Arjen B. Brussaard Scientific Director
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1a) Objective(s) and research area NCA is a research organization at the VU University Medical Center (VUmc) and VU University Amsterdam (VU) founded in 2008. We have created a modern research network organization where patients, medical professionals, scientists, students and professional visitors enter our facilities through the same front desk and assemble to create a 'hub' in the neuroscience community. At NCA professionals of all generations collaborate in the field of Translational Neuroscience to an extent that is unique in the Netherlands. All research activities are essentially interdisciplinary and incorporate the newest theoretical, methodological and application paradigms currently available. Our strongholds and international reputation build on recent work in understanding the human brain, on our clinical studies of its major diseases, on development of advanced technologies and on a long tradition of behavioral genetics. NCA has a mission to produce innovative research and technology leading to scientific discoveries in Neuroscience. However, Neuroscience is valuable not only for the advancement of science but also because it can greatly impact our society and economy. Over the last three decades Neuroscience has become a truly integrative science, from the molecule to the systems level and beyond, encompassing normal human brain function as well as the clinical expertise to diagnose – and address the biological mechanisms underlying - brain diseases. In the coming years, our efforts are expected to attract widespread interest, evolving into a new translational neuroscience, which further integrates basic and applied research, and may hold the key to solving many of society's problems. NCA aims to train domestic and international brain researchers by creating an environment of scientific excellence that will integrate various intellectual disciplines and, from that convergence, find solutions that will ultimately benefit society in the realms of medicine, engineering, business, and education. NCA is further set up to lend significant support to the in-house patient-clinics of the VU University campus. In this sense, NCA functions as a network organization where patient-centers, such as the Alzheimer Center, the MS Center, the Movement Disorder Clinic and the GGZ inGeest clinic for Anxiety and Depression are the major ‘hubs’ in our network.
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Research area and programs The mission of the NCA is to study the brain and its disease mechanisms through an integrative approach running from molecule-to-bedside. 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. The NCA currently is the largest neuroscience research community gathered on one campus in the Netherlands. We strongly focus 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. As of 2013, research at NCA is organized in five Research Programs (see Figure 1). Each Research Program is coordinated by a so-called Program Committee, with two Program Leaders and usually a dozen (or more) Program Members (Faculty). Program Leaders have the authority to organize and guide the program committee with respect to appointments, strategy of the research, and prioritization of proposition to the director and the Management Team. In addition they are the role models of the younger generations, identify and guide talent, prioritize and organize strategy with respect to grant opportunities. With respect to leadership, the Program Leaders represent their Program Committee when it comes to decision making at the level of NCA as an entity. The role of the Program Committees is to • describe and regularly update the overall research aim, objectives and research approach of the research program, • perform bench-marking of research activities in the international context, • provide cohesion and a strong collaborative platform for intracampus research activities aimed at (and routed) along the main research ambitions of the NCA, • identify young talent, promising research ideas and novel methodology, • lend professional intervision feedback of grant applications of younger colleagues, in addition to collaborative grants in the national or international context. In many cases this feedback will be given before the application deadline (so as to improve the success-rate of the grant applications), in other cases feedback will be given in parallel (so as to improve the complementary character and approach of individual projects), • perform midterm feedback on individual PhD- and postdoc- projects, • identify and collaborate with valuable affiliated bodies (patient clinics, business) and research organizations (both national and international), identify and describe individual research-project questions that need to be answered through data gathering/research support/analysis delivered by the (activities in) research support facilities.
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Figure e 1. Research h themes of the NCA.
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Organization
Figure 2. The NCA has a management team (MT), consisting of a representation of the research program leaders of the Institute. The current MT, appointed in the fall of 2012 for a period of 3 years, is shown in Figure 3. The director, Prof. Arjen Brussaard, was re-appointed for a period of 4 years at the beginning of 2012 and is currently full time appointed at the VUmc, acting as chair of the MT and as the Chief Scientific Officer (CSO) of the Industry Alliance Office (www.nca-iao.com). The MT meets six to eight times per year.
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A Annual Repo ort 2013
Dorret Boom msma
Guus Smit
B Brenda Penninx
Johannes de d Boer
F Frederik Barkho of
P Philips Schelten ns
Figure e 3. Manage ement Team m of the NCA A, with 3 me embers (Prof. Brenda Pen nninx, Prof. Frederik F Barkh hof and Prof.. Philip Schelltens) from th he VUmc, an nd 3 membe ers (Prof. Dorrret Boomsma, Prof. Augu ust Smit and Prof. P Johanne es de Boer) frrom the VU University U Amsterdam.
The NCA is a VUmc insttitute with a campuss-wide nettwork of professionals. The direc ctor reporrts to the dean of the medic cal center. They meet regula arly in Facu ulty Board meetings and a during g 1-on-1 ap ppointmen nts.
Prof. Wim Stalma an
VU University U Medical Cen nter - chair
Prof. Hubertus Irtth
Faculty of Exac ct Sciences & Faculty of Earth h and Life Sc ciences
Prof. Bauke Oud dega
Faculty of Psychology and d Education
e 1. Faculty Bo oard of the NCA. N Table
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Faculty
Department
VU Medical Center Anatomy and Neurosciences Clinical Chemistry, Metabolic Unit Cllinical Genetics Clinical Genetics, Medical Genomics Clinical Genetics, Functional Genomics Clinical Neurophysiology / MEG Centre Epidemiology and Biostatistics Physics and Medical Technology Gynaecology & Reproductive Medicine Internal Medicine Molecular Cell Biology and Immunology Neurology Neurosurgery Pathology Pediatrics/Child Neurology Physiology Psychiatry VUmc Radiology and Nuclear Medicine
Division Div. II Div. V Div. V Div. V Div. V Div. II Div. VI Div. V Div. III Div. I Div. V Div. II Div. II Div. V Div. III Div. IV Div. II Div. V
GGZ inGeest Psychiatry GGZ inGeest Faculty of Science Physics and Astronomy Biophotonics & Medical Imaging Mathematics Statistics of Life Sciences Group Faculty of Psychology and Education Biological Psychology Faculty of Earth and Life Sciences Integrative Neurophysiology Functional Genomics (also VUmc) Molecular and Cellular Neurobiology
Table 2. Faculties and departments participating in the NCA.
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Scientific Advisory Board and Committee of Recommendation The Scientific Advisory Board (see Table 3) consists of five top scientists from the Netherlands. The Scientific Advisory Board members lend their expertise to advise the Neuroscience Campus on research operations, planning and progress, and make comprehensive evaluations. The Advisory Board meets to provide advice to the Director, about the research and management of the institute. The chairposition will be reconsidered during the spring of 2013 and handed over from Prof. Martinus Niermeijer, who served as an excellent chairperson from the beginning of the institute in 2008, to Prof. Gert Jan van Ommen. We look forward to their advisory role, also in preparation for the upcoming audit of NCA over the period 2009-2014.
Prof. Gert Jan van Ommen
PhD, Human Genetics - chair
Prof. Martinus F. Niermeijer
MD, PhD, Medical Genetics
Prof. Ivo van Schaik
MD, PhD, Neurology
Prof. Frank Verhulst
MD, PhD, Psychiatry
Prof. Chris de Zeeuw
MD, PhD, Neurosciences
Table 3. Scientific Advisory Board of the NCA.
The Committee of Recommendation supported the NCA with advice in view of setting up a professional network organization, the strategic agenda, valorization-strategy and branding. In addition, individual members of the committee gave the director feedback on the development of a business plan, the link to society and sponsor events. The term of this committee ended during 2013. In 2014, we may need to consider the appointment of a new committee of Key Opinion Leaders from the biotech- and/or pharma-industry. We acknowledge the contribution of each of the members at the various stages of our six year existence.
Alexander Pechtold
D66 political party leader
Raoul Oberman
McKinsey (NL)
Rik van Terwisga
former Vitens, Twijnstra Gudde, independent business consultant
Herman Leisink
former FNV-Kiem, independent communication consultant
Harry Starren
former De Baak, independent networking consultant
Table 4. Committee of Recommendation of the NCA.
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marketing
and
Annual Report 2013
1b) Research Programs Brain Imaging Technology
Research Program Committee: • • • • • • • • • • • • • • • • • •
Frederik Barkhof (program leader) Bart van Berckel Ronald Boellaard Johannes de Boer (vice program leader) Dennis van 't Ent Marloes Groot Mathisca de Gunst Davide Iannuzzi Klaus Linkenkaer-Hansen Huibert Mansvelder (program leader) Jan de Munck Petra Pouwels Kees Stam Ruud Toonen Dick Veltman (vice program leader) Hugo Vrenken Ysbrand van der Werf Bert Windhorst
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 and in particular optical 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: • • • • • • •
positron/single photon emission tomography (PET/SPECT); magnetic resonance imaging (MRI), including two 3 Tesla MR scanners for functional MRI (fMRI) and MR spectroscopy (MRS); combined PET/3T MRI scanner; magneto-encephalography (MEG) and EEG, including MRI-compatible EEG; repetitive transcranial magnetic stimulation (rTMS); optical imaging (OCT, third harmonic microscopy, multiphoton LSM etc.); two-photon laser-scanning microscopy (2PLSM).
Since state-of-the-art applied research requires similarly advanced methodological expertise, the Brain Imaging Technology program encompasses all methodological developments needed to pursue advanced research goals in applied (clinical and preclinical) projects. The objectives of the Brain Imaging Technology research program are twofold. Firstly the program committee aims to facilitate the optimal use of the in vivo imaging and photonics facilities at the VU/VUmc campus, and to integrate these techniques with each other, wherever possible. The program committee
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functions as a group of experts, providing advice and assistance to neuroscientists for all NCA participants. This includes securing access to the most suitable advanced image acquisition and analysis techniques, but also education and training. Secondly, the program instigates and performs methodological imaging research, in particular with regard to functional and structural connectivity, and molecular imaging. This includes novel dataacquisition techniques (hardware and tracers) as well as novel analysis techniques. 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 cellular and molecular substrates 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 and to evaluate new treatment strategies. Imaging techniques range from microscopic techniques such as two-photon laser scanning to macroscopic techniques like structural MRI. They also cover an array of chemical, molecular and functional imaging techniques. Areas of unique translational and complementary expertise include: • • • • •
target visualization – developing labeling techniques ranging from fluorescence, receptor ligands to contrast agents; image analysis – developing segmentation and quantification techniques ranging from microscopy to MRI; novel contrast mechanisms – using physical properties like refraction to biochemical ones like receptor engagement; network analysis – understanding in vivo structure and function based on cellular/animal models and computational models; eye-brain connection – using the retina as a window to the brain, for example to study neurodegeneration.
Key publications Wink, A.M., Munck, J.C. de, Werf, Y.D. van der, Heuvel, O.A. van den & Barkhof, F. (2012). Fast eigenvector centrality mapping of voxel-wise connectivity in functional magnetic resonance imaging: implementation, validation, and interpretation. Brain Connectivity, 2(5), 265-274. Schmaal, L., Joos, L., Koeleman, M., Veltman, D.J., Brink, W. van den & Goudriaan, A.E. (2013). Effects of Modafinil on Neural Correlates of Response Inhibition in Alcohol-Dependent Patients. Biological Psychiatry, 73(3), 211-218. Golen, L.W. van, Kuijer, J.P., Huisman, M.C., IJzerman, R.G., Barkhof, F., Diamant, M. & Lammertsma, A.A. (2013, Epub ahead of print). Quantification of cerebral blood flow in healthy volunteers and type 1 diabetic patients: Comparison of MRI arterial spin labeling and [15 O]H2 O positron emission tomography (PET). Journal of magnetic resonance imaging: JMRI 2013 Nov 8. Steenwijk, M.D., Pouwels, P.J., Daams, M., Dalen, J.W. van, Caan, M.W., Richard, E., Barkhof, F. & Vrenken, H. (2013). Accurate white matter lesion segmentation by k nearest neighbor classification with tissue type priors (kNN-TTPs). NeuroImage.Clinical, 3, 462-469.
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Bospoort, R. van de, Farina, M., Schmitz, S., Jong, A.P.H. de, Wit, H. de, Verhage, M. & Toonen, R.F.G. (2012). Munc13 controls the location and efficiency of dense-core vesicle release in neurons. Journal of Cell Biology, 199(6), 883-891.
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Brain Mechanisms in Health & Disease Research Program Committee: • • • • • • • • • • • • • • • • • • • • • • •
Truus Abbink Niels Cornelisse Sander Groffen Mathisca de Gunst Vivi Heine Ronald van Kesteren Marjo van der Knaap (program leader) Christiaan de Kock Ka Wan Li Huibert Mansvelder Rhiannon Meredith Pim van Nierop Danielle Posthuma Gajja Salomons Wiep Scheper Sophie van der Sluis Oliver Stiedl Ruud Toonen Matthijs Verhage (program leader) Mark Verheijen Jeroen Vermeulen Jan van Weering Nicole Wolf
This program brings together researchers at the NCA that focus on the elucidation of the mechanisms that underlie brain functions and dysfunctions. The researchers investigate how signal transduction networks orchestrate cellular functions, how mutations in the components of such networks lead to disease, how neuronal networks orchestrate behavior and how dysregulation of their activity leads to aberrant behavior. The program has two main themes that run in parallel: A. Systems Biology of the Synapse B. Childhood White Matter Disorders A. Systems Biology of the Synapse In this theme we aim to understand how the nervous system builds synapses between neurons, which components they contain, how these components together organize synaptic transmission and plasticity, how synapses are regulated by glia cells, how synapses together drive behavior and how synaptic dysfunction gives rise to many disorders of the brain (synaptopathies). This theme focuses on mechanistic studies, both top-down and bottom-up, to elucidate the causal relations between molecular events, how synaptic transmission and – plasticity emerges from these concerted events and how, in turn, behavior emerges from the concerted actions of many synapses.
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We apply the latest methodology to purify and identify synaptic components and to construct protein interaction models (interactome) of the synapse, based on quantitative experimental data. We exploit a large variety of functional assays to elucidate causal relations between synaptic components and brain functions, from electron microscopy and gene/protein expression analyses to life cell imaging, neurophysiology in vitro and in vivo, optogenetics and behavioral studies in mice. Mathematical models support the evaluation of these experimental data. The research groups in this theme bring together the best available methodology for these studies, such as quantitative proteomics, advanced microscopy for living tissue, optogenetics, 3D electron microscopy, in vivo single unit recordings, human iPS cell derived neurons, neuron-glia cocultures and innovative behavioral phenotyping for mice. These studies together provide a quantitative description of the synapse, identifies targets for synaptic modulation and dissects disease phenotypes. This theme brings together 19 research teams from four NCA departments: VUmc Clinical Genetics, FALW Molecular & Cellular Neuroscience, FALW Integrative Neurophysiology and FALW Functional Genomics. B. White Matter and Childhood White Matter Disorders In this theme we aim at understanding normal white matter physiology and pathophysiology. Major brain white matter components are axons, myelin, astrocytes and oligodendrocytes, which together orchestrate the connectivity of the brain. Childhood white matter disorders are most often genetically determined disorders that affect these components, leading to abnormal white matter development, dysfunction of white matter components, and structural damage with loss of myelin and axons. For many of the affected children, the cause of the disease is unknown. In this program we search for novel white matter disorders by clinical criteria, metabolic profiles and MRI pattern recognition. We search for causative gene defects and subsequently study disease mechanisms to find openings for treatment. For these studies we have developed multiple mouse models that we use to study the pathophysiology of diseases and to develop treatment. Understanding of mechanisms underlying white matter disorders yields often unexpected insight into white matter physiology. Within this theme we also work the other way around and primarily study white matter physiology, looking at the process of normal myelination and studying determinants of axonal integrity. We apply a wide range of techniques, including magnetic resonance imaging and spectroscopy, metabolic studies of body fluids (including GC-MS and LCMS/MS), transfections and functional studies, exome sequencing, RNA sequencing, molecular technologies such as gene and protein expression profiling, immunohistochemistry, electron microscopy, cell culture and myelinating co-culture systems, stem cell technology including iPS cell technology, and neurophysiology of cells and brain slices. Subjects of special attention are astrocyte function and dysfunction, myelination and disturbances thereof, white matter metabolism en metabolic defects,
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determinants of preservation of axonal integrity in the context of white matter disorders, white matter ion and water homeostasis, and iPS cell-based therapy for white matter disorders. This theme comprises research teams from: VUmc Child Neurology, VUmc Metabolic Laboratory, FALW Molecular & Cellular Neuroscience, and FALW Integrative Neurophysiology, in close collaboration with VUmc Neuroradiology, VUmc Neuropathology, VUmc Physics and Medical Technology, VUmc Clinical Genetics and FALW Functional Genomics. Highlights 1. 2.
3.
4. 5.
6.
Danielle Posthuma (FALW & VUmc) and Huib Mansvelder (FALW) both received a prestigious Vici grant (NWO). They are two out of eight VU and VUmc top-scientists to receive 1,5 million euro each for conducting research for the following five years. CNCR scientists participated in Human Brain Project : Early October, the Human Brain Project – an EU Flagship initiative in which over 80 partners will work together - was launched. The initiative will realize a new "ICT-accelerated" vision for brain research and its applications. The VU-CNCR is one of the partners. Sabine Spijker, Guus Smit and Huib Mansvelder participate in this research. Christiaan Levelt was appointed professor at CNCR in the ‘Molecular and cellular mechanisms of cortical development and plasticity. He has been appointed by the “de Stichting het Vrije Universiteitsfonds”. The Chair is embedded in the Department of Molecular and Cellular Neurobiology. van der Sluis received NWO Vidi grant. With the grant, CNCR scientist Van der Sluis will build her own research line. Sabine Spijker successfully applied for an Innovative Doctorate Programme, funded by the EU Marie Curie agency to the amount of 3.3 M€. The consortium she will coordinate runs under the title "CognitionNet". A total of 14 doctorate students will be guided towards their graduation in the coming years. Sander Groffen received NWO-middelgroot grant NWO has granted funding for the purchase of research equipment and the development of data collections. The total investment amounts to 6.5 million euros. 15 grant applications were honored.
Key publications
Bugiani, M.*, Depienne, C.*, Dupuits, C., Galanaud, D., Touitou, V., Postma, N.L., Berkel, C.G.M. van, Polder, E., Tollard, E., Darios, F., Brice, A., Die-Smulders, C.E. de, Vles, J.S., Vanderver, A., Uziel, G., Yalcinkaya, C., Frints, S.G., Kalscheuer, V.M., Klooster, J., Kamermans, M., Abbink, T.E.M., Wolf, N.I., Sedel, F.** & Knaap, M.S. van der** (2013). Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurology, 12(7), 659-668. *Shared first authors, **shared senior authors. Nota, B., Struys, E.A., Pop, A., Jansen, E.E., Ojeda, M.R.F., Kanhai, W.A., Kranendijk, M., Dooren, S.J.M. van, Bevova, M.R., Sistermans, E.A., Nieuwint, A.W.M., Barth, M., Ben-Omran, T., Hoffmann, G.F., Lonlay, P. de, McDonald, M.T., Meberg, A., Muntau, A.C., Nuoffer, J.M., Parini, R., Read, M.H., Renneberg, A., Santer, R., Strahleck, T., Schaftingen, E. van, Knaap, M.S. van der, Jakobs, C.A.J.M. & Salomons, G.S. (2013). Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2-and L-2-Hydroxyglutaric Aciduria. American Journal of Human Genetics, 92(4), 627-631. Taft, R.J., Vanderver, A., Leventer, R.J., Damiani, S.A., Simons, C., Grimmond, S.M., Miller, D., Schmidt, J, Lockhart, P.J., Pope, K., Ru, K.L., Crawford, J., Rosser, T., Coo, I.F.M. de, Juneja, M., Verma, I.C., Prabhakar, P., Blaser, S., Raiman, J., Pouwels, P.J.W., Bevova, M.R., Abbink, T.E.M., Knaap, M.S. van der* & Wolf, N.I.* (2013). Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity. American Journal of Human Genetics, 92(5), 774-780. *Shared senior authors. De Rubeis, S., Pasciuto, E., Li, K.W., Fernández, E., Di Marino, D., Buzzi, A., Ostroff, L.E., Klann, E., Zwartkruis, F.J., Komiyama, N.H., Grant, S.G., Poujol, C., Choquet, D., Achsel, T., Posthuma, D.,
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Smit, A.B. & Bagni, C. (2013). CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron, 79(6), 1169-1182. Verhoog, M.B., Goriounova, N.A., Obermayer, J, Stroeder, J., Hjorth, J.J.J., Testa-Silva, G., Baaijen, J.C., Kock, C.P.J. de, Meredith, R.M. & Mansvelder, H.D. (2013). Mechanisms underlying the rules for associative plasticity at adult human neocortical synapses. Journal of Neuroscience, 33(43), 17197-17208. Aarts, E., Verhage, M., Veenvliet, J.V., Dolan, C.V. & Sluis, S. van der (2014). A solution to dependency: using multilevel analysis to accommodate nested data. Nature Neuroscience 17(4):491-496.
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Neurodegeneration Research Program Committee: • • • • • • • • • • • • • • • • • • • • • • • • • •
Bart van Berckel Henk Berendse Wilma van de Berg Benjamin Drukarch Eric van Exel Wiesje van der Flier (program leader) Jeroen Geurts Odile van den Heuvel Henne Holstege Jeroen Hoozemans Conny Jimenez Ronald van Kesteren Adriaan Lammertsma Yolande Pijnenburg Niels Prins Annemieke Rozemuller Philip Scheltens Wiep Scheper Guus Smit (program leader) Kees Stam Charlotte Teunissen Rob Veerhuis Saskia van der Vies Pieter Voorn Ysbrand van der Werf Micha Wilhelmus
This is a true translational program, clinically oriented but with a strong background in preclinical neuroscience. The aim is to unravel the underlying often overlapping pathophysiologic substrates of the common neurodegenerative disorders with a main interest in how these substrates act on synaptic dysfunction in selectively vulnerable areas. To enable targeted drug therapies, an adequate characterization of the underlying pathology at protein level as well as synaptic and network level is needed. The translational ambition of this program will be achieved in a bidirectional approach by using biomarkers and clinical information from patients to guide the preclinical program and vice versa, findings from cellular and genetic research can immediately be tested and validated in clinical studies. Common goals of this program are: •
• •
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to further unravel the, possibly in part common, neuronal substrates, as well as neuropathological and pathogenetic mechanisms of the above mentioned disorders; to develop early, preferably even presymptomatic, diagnostic markers; to develop novel therapeutic approaches.
Annual Report 2013
Among the currently available resources, there is extensive expertise in clinic research, collection of patient cohorts (also collaborative with other centers), phenotyping (including imaging), and studies of 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 (AD) Parkinson’s disease and parkinsonian syndromes (PD and Dementia with Lewy Bodies, DLB) FrontoTemporal Lobar Degeneration (FTD) Normal Aging
Highlights 1.
First conference on Alzheimer’s disease and related disorders organized within the framework of the Translational Neuroscience Network (TN2): 10-11 October 2013. 2. Opening Alzheimer Research Center (www.arconderzoek.nl); 31 January 2013. 3. Alzheimer Association International Conference (AAIC); Boston, USA: unprecedented representation from VUmc. Scheltens member scientific committee. 4. Important grants: IMI: EMIF-AD (PJ Visser); CVON: Heart-Brain-Axis (van der Flier); FP7: PredictND (van der Flier); Marie-Curie Grant (Ossenkoppele). 5. Awards: ISAO postdoc award for Rik Ossenkoppele. 6. Visiting professorship: Gil Rabinovici visited VUmc Alzheimer Center for 3 months. 7. Alzheimer Award: Best article of the year 2012 Journal Alzheimer’s Disease (Ineke van Rossum). 8. Marie Curie ITN grant TRANSPATH; focusing on the pathological role and therapeutic targeting of Transglutaminase in various diseases. Together with nine other European teams, Anne-Marie van Dam (PI), Benjamin Drukarch and Micha Wilhelmus (Dept. Anatomy & Neurosciences, VUmc) have received a Marie Curie ITN grant. 9. Marie Curie ITN grant COGNITIONNET; focusing on cognitive function and dysfunction. Grant to CNCR, 14 PhD projects; coordinator Sabine Spijker. 10. Award of ZonMw subsidy for CHEVAL study of Elisabeth Foncke
Key publications
Jokinen, H., Schmidt, R., Ropele, S., Fazekas, F., Gouw, A.A., Barkhof, F., Scheltens, P., Madureira, S., Verdelho, A., Ferro, J.M., Wallin, A., Poggesi, A., Inzitari, D., Pantoni, L. & Erkinjuntti, T. (2013). Diffusion changes predict cognitive and functional outcome: The LADIS study. Annals of Neurology, 73(5), 576-583. Dijk, K.D. van, Persichetti, E., Chiasserini, D., Eusebi, P., Beccari, T., Calabresi, P., Berendse, H.W., Parnetti, L. & Berg, W.D.J. van de (2013). Changes in endolysosomal enzyme activities in cerebrospinal fluid of patients with Parkinson's disease. Movement Disorders, 28(6), 747-754. Ossenkoppele, R., Prins, N.D., Pijnenburg, Y.A.L., Lemstra, A.W., Flier, W.M. van der, Adriaanse, S.F., Windhorst, A.D., Handels, R.L.H., Wolfs, C.A.G., Aalten, P., Verhey, F. R. J., Verbeek, M.M., Buchem, M.A. van, Hoekstra, O.S., Lammertsma, A.A., Scheltens, P. & Berckel, B.N.M. van (2013). Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers & Dementia, 9(4), 414-421. Harten, A.C. van, Smits, L.L., Teunissen, C.E., Visser, P.J., Koene, T., Blankenstein, M.A., Scheltens, P. & Flier, W.M. van der (2013). Preclinical AD predicts decline in memory and executive functions in subjective complaints. Neurology, 81(16), 1409-1416.
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Jager, A.M. de, Wildt, B. van der, Schul, E., Bol, J.G.J.M., Duinen, S.G. van, Drukarch, B. & Wilhelmus, M.M.M. (2013). Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy. Neurobiology of Aging, 34(4), 1159-1169. Doorn, K.D., Goudriaan, A., Blits-Huizinga, C., Bol, J.G.M., Rozemuller, A.J.M., Hoogland, P.V.J.M., Lucassen, P.J., Drukarch, B., Berg,W.D.J van de & Dam A.M.W. van (Epub ahead of print). Increased amoeboid microglial density in the olfactory bulb of Parkinson’s and Alzheimer’s patients. Brain Pathology 2013 Aug 23 Olde Dubbelink KTE, Stoffers D, Deijen JB, Twisk JW, Stam CJ, Berendse HW. Cognitive decline in Parkinson’s disease is associated with slowing of resting-state brain activity: a longitudinal study. Neurobiol Aging 2013; 34:408-418.
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Annual Report 2013
Neuroinflammation Research Program Committee: • • • • • • • • • • • • • •
Frederik Barkhof Annemarie van Dam Christien Dijkstra Jeroen Geurts Vincent de Groot Jack van Horssen Joep Killestein (program leader) Axel Petzold Charlotte Teunissen Bernard Uitdehaag Paul van der Valk Hugo Vrenken Elga de Vries (program leader) Mike Wattjes
Multiple Sclerosis (MS) The primary goal of the research program is to perform internationally distinctive translational research that allows better understanding and treatment of neuroinflammatory disorders, predominantly MS. The MS research at the VUmc is centered within the MS center Amsterdam, which has an excellent international reputation and is among the top five MS research centers 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. This MS Center is unique because it unites a comprehensive array of disciplines ranging from experimental laboratory research to clinical research. In recent years, increasing evidence has suggested that, besides neuroinflammation, neurodegeneration plays a critical role in the pathogenesis of MS. The researchers of the VUmc MS Center Amsterdam have therefore decided to focus not only on neuroinflammatory events that underlie MS, but also on the neurodegenerative aspects of MS and to work towards identifying novel targets for future neuroprotective treatment. The goals of this research program are: •
•
Unravel the underlying mechanisms of neurodegeneration in MS and define the relation with ongoing neuroinflammatory events in experimental models to identify new targets for neuroprotective treatments. Translate findings from preclinical experimental studies to the human disease and perform fundamental and association studies on neurodegeneration in human disease. 21
Annual Report 2013
•
•
In vivo imaging to visualize, characterize and predict neurodegeneration and -protection in patients with MS in the in vivo setting, using structural and functional MR imaging measures. Establish new outcome measures for neurodegeneration in MS patients and work towards rehabilitation in a long standing MS cohort (> 20 years of disease) using OCT and MRI markers as predictor of physical and cognitive decline, to explore cognitive rehabilitation and validate the predictive value of specific body fluid biomarkers.
In addition to focus on neurodegeneration, clinical evaluation will also comprise further tailoring of treatment with both currently and soon available disease modifying drugs; i.e. predicting response to treatment and risks, through studying clinical response to treatment, MRI and biomarkers, to timely select the best medication for individual patients. Through a close scientific interaction between various disciplines and experts, and via a strong translation of results from in vitro and animal models to pathology, and from histopathological research and human tissue further on to in vivo imaging and, ultimately, the clinic, we address the abovementioned research goals in this multi-disciplinary research program. Key publications Balk LJ, Twisk JW, Steenwijk MD, Daams M, Tewarie P, Killestein J, Uitdehaag BM, Polman CH, Petzold A. A dam for retrograde axonal degeneration in multiple sclerosis? (Epub ahead of print). Journal of Neurology, Neurosurgery, and Psychiatry 2014 Jan 28. Hulst, H.E., Steenwijk, M.D., Versteeg, A., Pouwels, P.J.W., Vrenken, H., Uitdehaag, B.M.J., Polman, C.H., Geurts, J.J.G. & Barkhof, F. (2013). Cognitive impairment in MS Impact of white matter integrity, gray matter volume, and lesions. Neurology, 80(11), 1025-1032. Vogel, D.Y.S., Heijnen, D.A.M., Vries, H.E. de, Tool, A.T.J., Amor, S. & Dijkstra, C.D. (2014). Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation. Journal of Neuroinflammation, 11, 23. Doorn, R.P. van, Nijland, P.G., Dekker, N., Witte, M.E., Lopes Pinheiro, M.A., Hof, B. van het, Kooij, G., Reijerkerk, A., Dijkstra, C.D., Valk, P. van der, Horssen, J. van & Vries, H.E. de (2012). Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. Acta Neuropathologica, 124(3), 397-410. Strijbis, E.M.M., Inkster, B., Vounou, M., Naegelin, Y., Kappos, L., Radue, E.W., Matthews, P.M., Uitdehaag, B.M.J., Barkhof, F., Polman, C.H., Montana, G. & Geurts, J.J.G. (2013). Glutamate gene polymorphisms predict brain volumes in multiple sclerosis. Multiple Sclerosis, 19(3), 281288.
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Annual Report 2013
Neurobiology of Mental Health Research Program Committee: • • • • • • • • • • • • • • • • • • • • • • • • • •
Meike Bartels Dorret Boomsma Leontien Diergaarde Madeleine Drent Mathisca de Gunst Odile van den Heuvel Christiaan de Kock Adriaan Lammertsma Klaus Linkenkaer-Hansen Huibert Mansvelder Christel Middeldorp Michel van den Oever Tommy Pattij Brenda Penninx (program leader) Tinca Polderman Danielle Posthuma Lianne Schmaal Ton Schoffelmeer Guus Smit Jan Smit Sabine Spijker (program leader) Oliver Stiedl Dick Veltman Jacqueline Vink Taco de Vries Ysbrand van der Werf
The overall aim of this program is to identify neurobiological mechanisms (e.g. pathophysiological mechanisms and genomic regions and gene variants) that mediate vulnerability to the most common psychiatric disorders; to understand this vulnerability at the synaptic and brain systems level; to determine the interaction with age, sex and environmental challenges; and to test innovative interventions that can help normalize psychiatric symptoms and endophenotypes. 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 and inflammation, (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 the program aims to uncover part of the actual pathways from ‘molecule to mind’ for these afflictions. Furthermore, preclinical models for common psychiatric disorders such as depression and anxiety, attention deficits and impulsivity, and addictive/compulsive disorder have been developed and are used to find novel targets for treatment. The joined effort of dissecting mental health and its related
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Annual Report 2013
disorders both in rodent models and humans allows translational research that is embedded in mechanistic understanding of the brain. Common goals of this program are: • to further improve diagnostic and prognostic markers for early detection and novel therapeutic targets for depression and anxiety disorders; • to gain insight into risk factors (e.g., genetics) and underlying mechanisms for the development into drug and alcohol addiction in both laboratory animals (rodents) and humans to develop novel therapeutic approaches; • to examine how individual differences in cognition (e.g. attention and impulsivity) and emotion (e.g. anxiety, depression) determine the individual susceptibility to develop addiction with the aim to identify distinct behavioral traits as treatable risk factors for comorbid diseases. To achieve these goals we use: • brain imaging techniques to examine the functional anatomy, the motivational and cognitive aspects and pharmacotherapy of e.g. relapse behavior in humans; • animal models with high face, construct and etiological validity to study cognitive and affective aspects of psychiatric diseases, like addiction, attention-disorder, anxiety, depression, and impulsivity, for which we have shown the comorbid nature of disease phenotypes in these models; • advanced in vitro and in vivo neurophysiological techniques, and stateof-the-art genomics/proteomics expertise to identify novel targets (e.g. synaptic proteins) for pharmaco-therapeutical intervention; • genome-wide genomics data as well as detailed proteomics/metabolomics data in the Netherlands Study of Depression and Anxiety (NESDA) as well as the Netherlands Twin Register (NTR) to identify genetic risk factors, of which the functional role can be further studied in animal and human models. • novel experimental intervention studies (e.g. using medication, running or light therapy) in animal and/or human models to examine changeability of psychiatric symptoms and endophenotypes. Highlights 1.
2. 3. 4.
5.
24
Various personal career grants were obtained: a VENI grant for Lotte Gerritsen (department of Psychiatry) to study the (interacting) roles of stress, genes and the brain in depression and a NWO-talent award for the group of Danielle Posthuma and Arne Popma to conduct a neuroimaging genetics study on functional gene sets involved in endophenotypes of antisocial behavior. Receipt of a NIMH funded R01 grant to examine the role of epigenetics in major depressive disorder, within the Netherlands Study of Depression and Anxiety. A large ‘zwaartekracht’ project into ‘Individual development: why some children thrive’ in which Dorret Boomsma’s research group participates. Marie Curie Innovative Doctoral Program ‘CognitionNet’ coordinated by Sabine Spijker for a total of 14 doctorate students within the Center for Neurogenomics and Cognitive Research (CNCR). The project investigates brain mechanisms of cognition at the molecular, cellular, neural network and behavioral level, both from a basic and a clinical perspective, with the aim to integrate these results in development of novel treatment options for various forms of cognitive impairment Various smaller grants were obtained from the Brain Foundation and the Parkinson Society to further boost our neuroscience work into mental health.
Annual Report 2013
Key publications Lamers, F., Vogelzangs, N., Merikangas, K.R., Jonge, P. de, Beekman, A.T.F. & Penninx, B.W.J.H. (2013). Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Molecular Psychiatry, 18(6), 692-699. Oever, M.C. van den, Rotaru, D.C., Heinsbroek, J.A., Gouwenberg, Y., Deisseroth, K., Stuber, G.D., Mansvelder, H.D. & Smit, A.B. (2013). Ventromedial Prefrontal Cortex Pyramidal Cells Have a Temporal Dynamic Role in Recall and Extinction of Cocaine-Associated Memory. Journal of Neuroscience, 33(46), 18225-18233. Heuvel, O.A. van den, Gorsel, H.C. Van, Veltman, D.J. & Werf, Y.D. van der (2013). Impairment of executive performance after transcranial magnetic modulation of the left dorsal frontalstriatal circuit. Human Brain Mapping, 34(2), 347-355. Smoller, J.W., Ripke, S., Lee, P.H., et al (including Boomsma DI, de Geus EJ, Penninx B, Posthuma D, Smit JH) (2013). Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet, 381(9875), 1371-1379. Loos, M., Staal, J.I., Smit, A.B., Vries, T.J. de & Spijker, S. (2013). Enhanced alcohol self-administration and reinstatement in a highly impulsive, inattentive recombinant inbred mouse strain. Frontiers in Behavioral Neuroscience, 7, Article 151, p. 1-10
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Annual Report 2013
2a) Composition (input data)
Total fte research (including PhD students) Type of funding gs 1
gs 2
gs 3
gs 4
gs 5
Total
Total - 2013
63.5
41.3
69.2
7.7
N.A.
181.8
Total - 2012
63.8
48.4
70.2
7
0.1
190.4
Total - 2011
72.6
46.7
81.1
8.6
N.A.
208.9
Total - 2010
69
41
68
11.4
N.A.
189.4
Total - 2009
62.5
39
63
14.7
N.A.
179.2
Total - 2008
56.8
23.2
47
2.1
13.5
142.6
Total fte research PhD students Type of funding gs 1
gs 2
gs 3
gs 4
gs 5
Total
Total - 2013
13.3
26.8
46
6
N.A.
92.1
Total - 2012
13.7
29.3
42.4
5.9
0.1
91.4
Total - 2011
18.6
32.8
44.3
3
N.A.
98.7
Total - 2010
14.6
25.9
32.2
5.6
N.A.
78.2
Total - 2009
13.6
24.5
45.9
11
N.A.
95
Total - 2008
12.2
17.7
33.4
2
9.7
74.9
Tables 5. Total of appointed research time. Numbers are excluding support- and technical staff and only give FTE quota spend on research. The research time per research program is split in Table 7. In this overview, gs 2 is NWO funded research, gs 3 is project funding from non-profit organizations, ministries, FES & EU and gs 4 is based on a mix of contract-research (for profit/industry) and donations/ philanthropy; gs5: funds that do not fit the other categories.
Â
26
Annual Report 2013
PhD projects newly started
2008
2009
2010
2011
2012
2013
31
48
36
32
28
37
Table 6. Newly started PhD project in recent years. See appendix 2 at the website for a full list.
FTE per type of funding (incl PhD students) gs 1
gs 2
gs 3
gs 4
Total
8.5 20.8 12.8 9.6 11.8 63.5
4.0 20.6 5.1 1.9 9.8 41.3
3.0 15.6 21.8 23.3 5.5 69.2
1.9 0.7 0.0 1.8 3.4 7.7
17.4 57.7 39.7 36.6 30.4 181.8
gs 1
gs 2
gs 3
gs 4
Total
1.5 6.3 2.5 0.8 2.2 13.3
2.4 14.5 4.8 0.9 4.3 26.8
1.9 13.9 12.9 13.5 3.8 46.0
1.8 0.7 0.0 0.2 3.4 6.0
7.5 35.4 20.1 15.4 13.7 92.1
Resea rch progra m Brain Imaging Technology Brain Mechanisms in Health & Disease Neurodegeneration Neuroinflammation Neurobiology of Mental Health Tota l
FTE PhD students per type of funding
Resea rch progra m Brain Imaging Technology Brain Mechanisms in Health & Disease Neurodegeneration Neuroinflammation Neurobiology of Mental Health Tota l
Table(s) 7. Input in fte (research time, not total number of appointments) per Research Program. A full list of coworkers is outlined in appendix 1 at the website. In this overview, gs2 is NWO funded research, gs3 is project funding from non-profit organizations, ministries, FES & EU and gs4 is based on a mix of contract-research (for profit/industry) and donations/philanthropy; gs5: funds that do not fit the other categories.
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Annual Report 2013
2b) Participating researchers The VU/VUmc continues to attract new generations of promising scientists both domestically and internationally and continues to integrate diverse research and human resources. We enjoy a distinguished international reputation as an innovative center for the field of neuroscience, biophysics, biostatistics and genetics research. All faculty staff participate as Program Committee Member in one (or sometimes two) Research Programs. A complete list of investigators, categorized by research program, is shown in the appendix. Participation in the NCA is according to rules set by the campus authorities. PhD students, team leaders and group leaders (with a few exceptions, being Prof. Brenda Penninx and Prof. Dorret Boomsma (also appointed in EMGO) and Prof. Johannes de Boer (also being director of LaserLab) can participate only in one research institute. See also appendix 1 at the website.
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Annual Report 2013
3a) Research environment and infrastructure Since the early years of this century, the VU/VUmc continues to attract new generations of promising scientists both domestically and internationally and continues to integrate diverse research and human resources. We enjoy a distinguished international reputation as an innovative center for the field of neuroscience, biophysics, biostatistics and genetics research. At the NCA we engage in interdisciplinary and synergetic workflow. We integrate various disciplines such as neurology, psychiatry, neuropsychology, neurobiology, biophysics, lasertechnology, bioinformatics, biostatics and mathematical science. We study individuals and patient cohorts, human twins, behavior, microscopic molecular structures of the brain, neurons, neurocircuits, synapses, proteins, RNA and genes. Group leaders and coworkers of NCA participate in many different research consortia and publish many collaborative reports. For indicators of the research environment and embedding in (inter)national research consortia and reflected in the table with indicators of esteem, please see our appendices. See also our appendices for an overview of the research environment, the embedding of our research in (international research consortia, and the indicators of esteem. See also appendices 2-5 at the website for more detail. NCA has all the scientific knowledge, infrastructure and state-of-the-art facilities to perform preclinical and clinical studies, often working toward end-to-end research solutions and always in a multidisciplinary setting.
Bioassays The combined in-depth knowledge of, among others, proteomics, pathology and clinical expertise can provide new pathological pathways and related biomarkers. New discoveries can facilitate the identification of novel therapy targets and/or companion diagnostics of novel therapeutic approaches. The NCA both has the expertise and experience to develop biomarker assays and, in cooperation with the patient cohorts, to validate such assays.
Biobanks The NCA has access to several in-house biobanks holding a variety of samples of the human brain, including the Twin register database, NESDO/NESDA, and the Netherlands Brain Bank. The samples include liquor, blood and cells. Most of the biobanks include longitudinal data of more than thousands patients combined with phenotyping and other biological data. In addition, these biobanks contain samples of both patients and age-matched control subjects.
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Annual Report 2013
The services related to biobanking can be twofold. Firstly, the samples and related information can be used for diagnosis on molecular and cellular level, and testing of therapy effectiveness. Secondly, the expertise and infrastructure is present to build certain biobanks on request of industrial partners.
Brain Imaging Brain Imaging techniques are a vital component for characterization of brain functions and brain morphology. These techniques are applicable in preclinical settings for fundamental research as well as in clinical settings. Imaging techniques provide a non-invasive manner of investigation and research. The current imaging facilities of VUmc and VU consist of state-of-the-art equipment, including major imaging technologies: 1,5T, 3T and 7T functional MRIs, MEG/EEG, TMS and PET/SPECT tomography combined with extensive neuroimaging analysis expertise.
Omics Through the combination of cellomics, genomics and proteomics, connections can be provided between the human genome and related phenotypes. Genomic information can be collected and may include sequencing, genotype information, gene/protein expression levels and cell biological parameters. The cellomics technology enables the screening of effects of industry compounds on cellular or genetic level. With proteomics protein pathways can characterized. In addition, genomics sequencing can be provided. For these aspects the Genomics facility is used, equipped with state-of-the-art instruments.
Clinical Expertise Various clinical departments and related clinics of VUmc and VU are affiliated with NCA. This equips the institute with a broad range of clinical expertises regarding brain diseases, which can be connected with fundamental research and, therefore, stimulate translational crosslinks. The departments include strong expertise on, among other, clinical genetics, psychiatry, (neuro)physiology and neurology. Among the clinical facilities are Alzheimer Center VUmc, MS Center Amsterdam, Movement Disorder Clinic, EMGO Institute and GGZ inGeest. Clinical validation of drug concepts and clinical compounds can be offered during both early clinical and advanced clinical phases. For these services the complete portfolio can be offered, from cellomics, brain imaging to the information stored in the in-house biobanks depending on the relative clinical stage. The biological samples and related information stored in the biobanks can be used for development and testing of potential biomarkers for the industry.
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Annual Report 2013
Patient Cohorts NCA has access to large and extensive patient cohorts of VUmc and VU. These cohorts allow extensive disease-related research, while the location of VU/Vumc in a metropolitan area (high population density) and the presence of several surrounding hospitals and clinics with excellent infrastructure, secures a rapid follow-up for the patients.
Neuropathology The infrastructure of NCA includes a Neuropathology section with unique expertise in the field of pathology, where proteins can be identified and proteins can be made visible in the brain in order to study their interaction. Furthermore, this department contributes to several in-house biobanks and can be allocated for the creation of new biobanks.
Exploratory Biology Based on the knowledge regarding cellomics, proteomics and genomics, and supported by the present mutant mouse models, services regarding signaling pathway discovery and feasibility of industrial compounds can be offered. These services are aimed at stimulation of drug discovery and development in early phase studies. In this perspective, additional value can be offered through the combination of signaling pathways knowledge and the clinical implications.
Integrative Analysis Neuroscience research activities often generate substantial amounts of data (e.g. large genome-wide data sets, extensive longitudinal mouse-behavior data sets). Part of the research at NCA focuses specifically on the development and testing of mathematical computer models and analytical tools to integrate, visualize and statistically analyze these data.
Mutant Mouse Models A large number of in-house developed mutant mouse models, for example transgenic mouse models, are available at the institute in combination with the scientific expertise and related facilities. These models can support the academic as well as contract research services. Additionally, new mouse models can be developed.
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Annual Report 2013
Mouse Phenomics We can offer high-throughput behavior assays in mice thereby strongly benefiting from the automated monitoring systems set up by the NeuroBasic PharmaPhenomics consortium using on-line video tracking 24/7. The so-called MouseHouse facility offers a wide range of behavioral screens without human intervention. Automation also enables longitudinal analyses, high content compound screening and functional analysis of genes from mutagenesis projects. Through collaboration within NeuroBasic, we can also offer pharmacologic screening in mice.
Photonics & Life Cell Imaging Photonics is an advanced technology using optical imaging systems, including an in vitro imaging platform and an in vivo animal model. The imaging technique uses laser systems aimed at photo-detection of neurotransmitters involved in various neurological disorders. The implication of this technology is the mapping of cortical networks and life imaging of neurons. The technique has therapeutic and diagnostic potentials with respect to neuronal prosthetic systems, human degenerative diseases and related neuropathology. Although this area is relatively in an early stage, it is believed that the technology holds the potential for supporting a wide range of commercial services in the future.
Stem Cell Research NCA has recently set up a modern stem cell facility in combination with research expertise that can be used for investigations on stem cell development and therapies in for example mutant mouse models and, eventually, in man. Stem cell research has a crucial role in finding cures for brain diseases. In combination with cellomics, an additional tool is provided on throughput screening of genetically modified cell lines. NCA can offer bioassays by selecting genotypes for genome analysis and use these induced Pluripotent Stem (iPS) cell models to test the genetic variation of various brain diseases.
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Annual Report 2013
3b) Valorization Working with Industry The NCA conducts research regarding brain function and brain-disease mechanisms through an integrative approach where clinical expertise and scientific knowledge are bundled. In order to secure this innovative approach, new modes of funding are required. One way of generating additional funding is to commercialize the scientific expertise and research capabilities. In order to facilitate such a valorization strategy aimed at serving and collaborating with the industry, a business model with related commercial services has been developed.
Industry Alliance Office A dedicated front-office, the Industry Alliance Office, represents the NCA and offers the internal scientific expertise and facilities to the industry. The main focus of the Industry Alliance Office is to become the preferred partner for the development of treatments and diagnostic tools for neurologic and neuropsychiatric diseases by investing in endurable strategic alliances. Hereby, a translational link between scientists and industrials will be created. The aim is to deliver value for the industry by offering tailor-made services in neurosciences, to build sustainable relationships with clients and to generate external revenues. The latter is an integral part of the business model, since new funding can be allocated to invest and further expand in the scientific excellence of the NCA regarding disease-orientated brain research. The Industry Alliance Office manages, coordinates and initiates commercial activities of the NCA, and stimulates valorization and commercialization within the institute. The organization has a lean structure consisting of a management team supported by NCA and under direction of the CEO of the institute, in addition to project management and business consultancy dedicated on a project-basis. This organizational structure will be upscaled when success and efficiency of the Industry Alliance Office is validated in the period 2012-2014. The internal value of the Alliance Office is to structure collective approaches for attracting means of funding to further support scientific research. Due to this approach it is believed that a shift can be established from single-based projects to long-term collaborations, whereby funding on a systematic basis and with higher gain can be achieved, and scientific objectives and challenges can still be met. Furthermore, the coordination of collaborative projects with Industry will be managed by the Industry Alliance Office. The NCA has the scientific expertise, infrastructure and commercial potential to offer and serve the industry. We do this through an integrated approach as
33
A Annual Repo ort 2013
illustrrated by the t so-called NCA Matrix. M Co ommercial validation n indicated d that the business propositionss of NCA are a welcom med and interest wa as generated by the several s asssets of the institute.
Figure e 4. 'Overview w of the business portfolio o offered by the Industry Alliance A Offic ce'.
The service-offfering pro opositions of the NCA N consist of the e bundling g and integ gration of several commercia c al researc ch services, based on three brain disea ase areass, i.e. Neu urodegene erative Dise eases (Alzzheimer’s a and Parkin nson’s Disease), White e Matter Diseases D (in n particular Multiple Sclerosis) S a and Anxietty and (Unip polar) Dep pression.
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Annual Report 2013
4a) Quality and scientific relevance In section 1b, per research program, an overview of the research strategy, the recent developments and a selection of key publications per research program, are outlined. A check on scientific relevance is executed by the various research program committees listed. Here we further outline a short statistical analysis of the scientific relevance of the NCA program as an Institute (Table 8). The number of articles published per year and the total number of citations each year to these papers published shows the solid growth in output and relevance of their output in recent years. At the onset of the new era in which the NCA became operational (i.e. during 2008-2009) the yearly output amounted to ~ 400 research papers per year. In 2013 the total number of reports has settled to > 600. Of this total, 510 were peer reviewed reports (see Table 10), with 80% being published in a top 25% journal and 46% being in the top-10% journals (see Table 8). Another way of benchmarking the output of NCA is to score the absolute impact factors: in 2013, we have > 20 % of these papers (i.e. 108 papers out of 510 peer reviewed) in the highest impact journals (i.e. IF ~ 9 or higher). In Table 9, the relative impact and the number of high impact papers is further subcategorized per research program.
5 4 3 2 1
top 10% 11‐25% 26‐50% 51‐75% 76‐100%
sc o up
pe r
qu
ar
til e
ap er s al lp of %
Qu
Re l
at
ar ti
iv e
le
Im
Ca t
eg
pa ct
or y
Fa ct
re
or
(%
)
Quality of total research output
46 34 14 5 1
80
Table 8. Percentage of papers categorized according to the relative impact factors scores for 2013.
35
Annual Report 2013
%
%
of p
ap er sw of ith pa RI pe Fo rs % f5 w of i th pa RI pe Fo rs % f4 w of i th pa RI pe Fo rs % f3 wi of th pa RI pe Fo rs to ta f2 w ith ln um RI Fo be nu f1 ro m be fp ro ap fh er s igh im pa ct pa p
er s
Quality of research output per research program
Brain Imaging Technology
55%
27%
12%
6%
0%
66
11
Brain Mechanisms in Health & Disease
53%
25%
15%
5%
2%
153
37
Neurodegeneration
53%
32%
13%
2%
0%
123
21
Neuroinflammation
37%
46%
13%
3%
1%
70
10
Neurobiology of Mental Health
48%
32%
11%
7%
1%
157
29
Table 9. Quality of the different Research Programs in 2013. Shown are the percentiles of papers categorized according Relative Impact Factor (RIF), the total number of papers and the number of papers published in the highest impact journals.
4b) Quality control NCA has three Research Committees (the Clinical, the Biomedical and the Psychology Research Committee) that provide an independent review of the scientific quality of research protocols brought forward by investigators. The purpose of the review is to ensure the highest quality of research and to support researchers affiliated to NCA. In addition, the Clinical Research Committee under supervision of Prof. Henk Berendse, provides the Director and Management Team with (solicited and unsolicited) advice on matters directly related to the Institute's science policy. A primary task of each Research Committee is to lend approval to any project within NCA before evaluation of a project by either the Medical Ethical Committee of the VU University Medical Center or the Animal Ethical Committee of the VU University. Since projects are executed in distinct faculties on campus, each faculty has an independent Research Committee dedicated to NCA. A secondary task of the Clinical Research Committee (VUmc) is to advise the director on the eligibility and methodological quality of all new research proposals (after grant award) brought forward by researchers for inclusion in the NCA research programs. Only after approval of the director of NCA, advised by the Research Committee, a project will be NCA-labeled. Only NCA-labeled projects are accountable for output-administrative and financial administration. NCA adheres to the Research Guide of the VU Medical Center. Specific other regulations (or adjustments) may apply for different NCA departments (in particular for those residing in other faculties). For NCA investigators, the Quality
36
Annual Report 2013
Checklist needs to be used for execution of project run by PhD students, post docs and other affiliated coworkers. The VUmc Research Guide provides an valuable overview of the available support for conducting research at VUmc. Examples: Law and regulations i.e. the medical ethical review committee, grants desk, juridical support, obtaining of (special) research materials or equipment, and documenting research projects. In addition, human resource issues such as reimbursements and obtaining permits for non-EU scientist are indexed in the Research Guide.
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Annual Report 2013
5) Output Theses DissA DissB DissC
Scientific papers Wp WpREF
DissD Books
Chptrs
WpNR
Rest VP
Total
Total - 2013
33
10
1
3
4
28
510
7
13
609
Total - 2012
18
3
0
1
5
28
606
1
21
683
Total - 2011
18
5
1
0
5
22
508
0
13
572
Total - 2010
19
2
0
0
2
19
453
5
8
508
Total - 2009
19
0
3
0
5
10
424
11
18
490
Total - 2008
28
2
2
3
35
21
413
5
17
533
Table 10. Aggregate of the output of NCA as an 'Institute'. A full list of publications is outlined in appendix 3 at the website. *See footnote for abbreviations
Theses
Scientific Output DissA
Brain Imaging Technology Brain Mechanisms in Health & Disease
DissC
DissB
Scientific papers DissD
Wp
WpREF WpNR
Books
Chapters
Rest
2013
VP
Total
2
0
0
0
0
0
76
2
2
82
11
1
6
3
0
3
158
1
0
183
Neurodegeneration
6
0
4
0
0
3
129
0
8
150
Neuroinflammation
5
0
0
0
2
8
77
1
0
93
Neurobiology of Mental Health
9
0
0
0
2
14
164
5
4
198
Table 11. Output per Research Program of the NCA. A full list of publications is outlined in appendix 3 at the website. See Footnotes for abbreviations.
Abbreviations table 10 and table 11: 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
*
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Annual Report 2013
6a) Earning capacity – NCA The collective and aggregate acquisition of external funding in 2013 amounted to a consolidation of the number and amount of awarded grants, including the number of personalized grants (see appendix 6 at the website) and a cumulative of > 23.5 M€ of external grant support (see Table 12). This is substantially more than in 2012, but comparable to earlier years, despite the fact that the number of published FP7 calls in 2012 was limited, whereas Horizon 2020 has just started in the beginning of 2014. The breakup of these acquisitions per research program is given in Table 13. In 2013, NCA investigators were awarded with the Innovative Doctorate Program (IDP) from Marie Curie by Prof. Sabine Spijker c.s. (3.3 M€). We also were awarded with two Vici grants, to Prof. Danielle Posthuma and to Prof. Huibert Mansvelder, a VIDI grant to Dr. Sophie van der Sluis and with major grant support to Dr. Wiesje van der Flier. What is not yet implemented in the 2013 acquisition is the Human Brain Project (Flagship grant of the EU) with Prof. Guus Smit c.s. of around 8 M€, because the exact total grant support for NCA still needs to be negotiated and will not start until 2014 or later. Also the earning power of the novel Industry Alliance Office (www.nca-iao.com) is becoming apparent and outlined in section 6b.
External Funding - Neuroscience Campus Amsterdam gs 2
gs 3
gs 4 (mix)
Total
Total - 2013
€ 10,896,213
€ 10,343,102
€ 2,321,406
€ 23,560,721
Total - 2012
€ 11,092,777
€ 5,741,757
€ 416,324
€ 17,250,858
Total - 2011
€ 13,182,708
€ 11,819,720
€ 3,376,520
€ 28,378,948
Total - 2010
€ 7,939,262
€ 18,172,132
€ 3,534,291
€ 29,645,685
Total - 2009
€ 6,594,300
€ 13,580,420
€ 2,576,000
€ 22,750,720
Total - 2008
€ 3,533,146
€ 6,449,689
€ 926,165
€ 10,909,000
Table 12. Acquisition of grants by collaborative efforts of the NCA - started in 2013 – and compared to 2008-2012 acquisitions. For further information, on acquisition per research program, see appendix 6 at the website. In this overview, gs 2 is NWO funded research (plus ERC funding), gs 3 is project funding from non-profit, ministries, FES & EU and gs 4 is based on a mix of contractresearch (for profit/industry) and donations/philanthropy.
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Annual Report 2013
External Funding per Research Program in 2013 gs 2
gs 3
gs 4 (mix)
Total
Brain Imaging Technology
€ 3,985,000
€ 150,000
€0
€ 4,135,000
Brain Mechanisms in Health & Disease
€ 3,004,746
€ 2,877,016
€ 1,470,000
€ 7,351,762
Neurodegeneration
€ 1,915,659
€ 3,393,406
€ 615,000
€ 5,924,065
Neuroinflammation
€ 20,000
€ 1,551,936
€0
€ 1,571,936
€ 1,970,808
€ 2,370,744
€ 236,406
€ 4,577,958
Neurobiology of Mental Health
Table 13. Grant acquisition per Research Program of 2013. Acquisition in 2013 is split in types of funding. A full list of acquired external funding is outlined in appendix 6 at the website. In this overview, gs2 is NWO-funded research (plus ERC funding from EU), gs3 is project funding from nonprofit, ministries, FES & EU and gs4 is based on a mix of contract-research (for profit/industry) and donations or philanthropy.
6b) Earning capacity – Industry Alliance Office The Industry Alliance Office, headed by the director of the NCA acquired a total of 1.78 M€ in closed contracts in 2013, with another 5.41 M€ of contract value in the pipeline for the first half of 2014. Closed deals in 2013 include collaborative research projects sponsored by Ono Pharmaceuticals Ltd., Immunovo, EuroImmun, Probiodrug and IBL. The pipeline of contracts in negotiation phase includes major contracts with Boehringer Ingelheim, Probiodrug and others.
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Annual Report 2013
7) Academic reputation As already outlined in previous sections: • The number of peer reviewed reports has stabilized (Table11 and 12), with 80% being published in a top 25% journal and 46% being in the top-10 (see Table 8). • More than 20 % of these papers (i.e. 108 papers out of 510 peer reviewed) were published in highest impact journals (i.e. IF ~ 9 or higher). • In Table 10, the relative impact is further subcategorized per research program. Program leaders of NCA and in particular the MT members of NCA have many (coordinating) active roles in national and international consortia, such as QuantiVision (www.quantivision.info), ENGAGE (European Network for Genetic and Genomic Epidemiology), ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis), the PGC (Psychiatric Genomics Consortium), in the NeuroBasic PharmaPhenomics consortium (www.neurobasic.nl) and in Parelsnoer (www.parelsnoer.org). Further we continue to coordinate European Neuroscience Campus Network (www.enc-network.eu), and will participate in the EU FET Flagship entitled the Human Brain Project (www.humanbrainproject.eu) and in the Joint Programming of Neurodegenerative Diseases (www.neurodegenerationresearch.eu).
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Annual Report 2013
8) Society relevance “We care about the brains of our patients. 'Care' in the context of being curious and being worried. Diseased individuals, both young and old, suffer from sometimes devastating and chronic brain disorders which reduce the quality of their lives and the ones that surround them.“ NCA has a mission to produce innovative research and technology leading to scientific discoveries in Neuroscience. However, Neuroscience is valuable not only for the advancement of science but also because it can greatly impact our society and economy. Over the last three decades Neuroscience has become a truly integrative science, from the molecule to the systems level and beyond, encompassing normal human brain function as well as the clinical expertise to diagnose – and address the biological mechanisms underlying - brain diseases. In the coming years, our efforts are expected to gather widespread interest, evolving into a new translational neuroscience, which further integrates basic and applied research, and may hold the key to solving many of society's problems. NCA aims to train domestic and international brain researchers by creating an environment of scientific excellence that will integrate various intellectual disciplines and, from that convergence, find solutions that will ultimately benefit society in the realms of medicine, engineering, business, and education. NCA is further set up to lend significant support to the in-house patient-clinics of the VU University campus. In this sense, NCA functions as a network organization where patient-centers, such as the Alzheimer Center, the MS Center and the GGZ inGeest clinic for Anxiety and Depression are the major ‘hubs’ in our network. Both the Alzheimer Center and the MS Center have extensive reach out activities including the 18 April 2013 ‘Samen sterk’ conference organized together with the Amsterdam Center for Aging (ACA) and the 15 Nov 2013 ’15 Year Jubilee conference in honor the MS Centrum. In addition the reach out activities have been further formalized in recent years via active memberships of our staff in DJA of the Royal Academy of Sciences, including Prof. Huibert Mansvelder, Prof. Danielle Posthuma, and Dr. Ysbrand van der Werf. Currently Prof. Jeroen Geurts holds the chair of the “De Jong Akademie” (DJA). In this and other - roles Geurts’ contribution in outreach activities are numerous and include weekly radio programs, and lectures for the Universiteit van Nederland (www.universiteitvannederland.nl). In addition, he is leading Stichting Brein in Beeld (www.breininbeeld.org).
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Neuroscience Campus Amsterdam VU University Medical Center Amsterdam / VU University Amsterdam De Boelelaan 1085 1081 HV Amsterdam The Netherlands Phone: + 31 (0) 20 598 7003 Website: www.neurosciencecampus-amsterdam.nl