NCA annual report 2014 by Vrije Universiteit Amsterdam

Annual Report 2014

Table of contents

Word from the director .................................................................................................... 3 1a) Objective(s) and research area ............................................................................. 4 1b) Research Programs ................................................................................................. 11 2a) Composition (input data) ...................................................................................... 23 2b) Participating researchers ....................................................................................... 25 3a) Research environment and infrastructure ........................................................... 26 3b) Valorization............................................................................................................... 30 4a) Quality and scientific relevance ........................................................................... 32 4b) Quality control ......................................................................................................... 34 5) Output ......................................................................................................................... 35 6a) Earning capacityâ&#x20AC;&#x201C; Neuroscience Campus Amsterdam ................................... 37 6b) Earning capacity â&#x20AC;&#x201C; Industry Alliance Office ........................................................ 39 7) Academic reputation ............................................................................................... 40 8) Societal relevance .................................................................................................... 41 Appendices (see website NCA).

Annual Report 2014

Word from the director On behalf of all partners of the Neuroscience Campus Amsterdam (NCA) â&#x20AC;&#x201C; staff, coworkers and graduate students - we present the Annual Report of 2014. 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 550 peer reviewed papers and with more than 100 papers in the top 5% of the international journals, we maintain an excellent standard. 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). The Industry Alliance Office (IAO) operates as a one-stop-shop to external partners. The IAO Business Developers in collaboration with the Scientific Director of NCA were able to contract integrated propositions with at least 15 different external 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 started to launch the Industry Alliance as a corporation (BV i.o.). 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), and the ENC-Network (www.enc-network.eu), one of our European programs for graduate education. 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. 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 the second half of 2015. Also the alliance with the Amsterdam Brain & Cognition (ABC) institute, and the VU-institutes LEARN, and EMGO are further formalized in the so-called Amsterdam Brain & Mind Project (www.abmp.eu). Finally, we recently celebrated the seventh anniversary of NCA. Being the playground for many graduates, and graduates-to-be, and working towards full integration in the field of Translational Neurosciences, we have succeeded in creating an appealing workplace for many and great perspectives on a sustainable future. Prof.dr. Arjen B. Brussaard Scientific Director of NCA and CSO of the Industry Alliance Office www.neurosciencecampus-amsterdam.nl and www.nca-iao.com 3

Annual Report 2014

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 â&#x20AC;&#x201C; 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, the Center for Childhood White Matter Disorders and the GGZ inGeest clinic for Anxiety and Depression are the major â&#x20AC;&#x2DC;hubsâ&#x20AC;&#x2122; 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. During the last 3 years, research at NCA was 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 1. Research 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 scientific director, Prof. Arjen Brussaard, is full time appointed at the VUmc, acting as chair of the MT, in addition to being the Chief Scientific Officer (CSO) of the Industry Alliance Office (www.nca-iao.com).

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Dorret Boomsma

Guus Smit

Brenda Penninx

Johannes de Boer

Frederik Barkhof

Philips Scheltens

Figure 3. Management Team of the NCA, with 3 members (Prof. Brenda Penninx, Prof. Frederik Barkhof and Prof. Philip Scheltens) from the VUmc, and 3 members (Prof. Dorret Boomsma, Prof. August Smit and Prof. Johannes de Boer) from the VU University Amsterdam.

The NCA is a VUmc/VU institute with a campus-wide network of professionals. The director reports to the dean of the medical center. They meet regularly in Faculty Board meetings and during 1-on-1 appointments. Prof. Hans Brug

VU University Medical Center - chair

Prof. Karen Maex

Faculty of Exact Sciences & Faculty of Earth and Life Sciences

Prof. Peter Beek

Faculty of Psychology and Education

Table 1. Board of Deans of NCA from VU and VUmc

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Table 2. Faculties and departments of VU and VUmc, participating in NCA.

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The Scientific Advisory Board (see Table 3) consists of five (externally appointed) 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. In 2013, the chair position, previously held by professor Niermeijer, who served as an excellent chairman from the beginning of the institute in 2008, was adopted by professor Van Ommen. We benefit from the advisory role of these external members of NCA, also in preparation for the upcoming audit of NCA over the period 2009-2014 and that will take place in the fall of 2015. 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. External members of the Scientific Advisory Board of NCA.

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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) Frank Verbraak 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 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 11

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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 data-acquisition 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. Highlights 1. 2. 3.

Spinoza Imaging Center became operational in November/December 2014. NCA-cluster computer became operational. H2020 ERC Proof of Concept-grant Mansvelder: development of an ultra-fast, plug-and-play, photon counter.

Key publications 1.

3. 4.

Tewarie, P., Steenwijk, M.D., Tijms, B.M., Daams, M., Balk, L.J., Stam, C.J., Uitdehaag, B.M.J., Polman, C.H., Geurts, J.J.G., Barkhof, F., Pouwels, P.J.W., Vrenken, H. & Hillebrand, A. (2014). Disruption of Structural and Functional Networks in Long-Standing Multiple Sclerosis. Human Brain Mapping, 35(12), 5946-5961. Schmaal, L., Marquand, A.F., Rhebergen, D., Tol, M.J. van, Ruhé, H.G., Wee, N.J. van der, Veltman, D.J. & Penninx, B.W. (2014) Predicting the Naturalistic Course of Major Depressive Disorders Using Clinical and Multimodel Neuroimaging Information: A Multivariate Pattern Recognition Study. Biological Psychiatry. Nov. 2014. Cijsouw, T., Weber, J.P., Broeke, J.H.P., Broek, J.A., Schut, D., Kroon, T., Saarloos, I., Verhage, M. & Toonen, R.F.G. (2014). Muncl 8-1 redistributes in nerve terminals in an activity- and PKCdependent manner. Journal of Cell Biology, 204(5), 759-775. Bloem, B., Schoppink, L., Rotaru - Marcu, D.C., Faiz, A., Hendriks, P., Mansvelder, H.D., Berg, W.D.J. van de & Wouterlood, F.G. (2014). Topographic Mapping between Basal Forebrain Cholinergic Neurons and the Medial Prefrontal Cortex in Mice. Journal of Neuroscience, 34(49), 16234-1646.

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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 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. 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, 13

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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 (MRI) and spectroscopy (MRS), metabolic studies of body fluids (including GC-MS and LC-MS/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 and metabolic defects, 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.

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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.

Danielle Posthuma received a VICI grant. Huibert Mansvelder received a VICI grant. Marjo van der Knaap received Gold medal award from the American Society of Pediatric Neuroradiology, May 19, 2014. Montreal, Canada. Symposium Updates on Neurometabolic Disorders, 19-20th of June 2014, VUmc, Amsterdam, including inauguration lecture of Dr. Gajja S. Salomons. CNCR PhD students Anke Hammerschlag and Sabine Mous won NWO Brain & Cognition award.

Key publications 1. 2. 3. 4. 5.

Testa-Silva, G., Verhoog, M.B., Linaro, D., Kock, C.P.J. de, Baayen, J.C., Meredith, R.M., Zeeuw, C.I., Giugliano, M. & Mansvelder, H.D. (2014). High bandwidth synaptic communication and frequency tracking in human neocortex. PloS Biology, 12(11), e1002007. Wolf, N.I., Salomons, G.S., Rodenburg, R.J., Pouwels, P.J.W., Schieving, J.H., Derks, T.G.J., Fock, J.M., Rump, P., Beek, D.M. van, Knaap, M.S. van der & Waisfisz, Q. (2014). Mutations in RARS Cause Hypomyelination. Annals of Neurology, 76(1), 134-139. Lubbers, B.R., Mourik, Y. van, Schetters, D., Smit, A.B., Vries, T.J. de & Spijker, S. (2014). Prefrontal gamma-aminobutyric Acid type a receptor insertion controls cue-induced relapse to nicotine seeking. Biological Psychiatry, 76(9), 750-758. Cijsouw, T., Weber, J.P., Broeke, J.H.P., Broek, J.A., Schut, D., Kroon, T., Saarloos, I., Verhage, M. & Toonen, R.F.G. (2014). Muncl 8-1 redistributes in nerve terminals in an activity- and PKCdependent manner. Journal of Cell Biology, 204(5), 759-775. 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: • 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. Among the currently available resources, there is extensive expertise in clinic research, collection of patient cohorts (also collaborative with other centers),

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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. 2. 3. 4. 5.

VU/VUmc has 11 out of 20 awarded projects in ZonMW Memorabel call. Accreditation of the ‘Parelstatus’ for Parkinson’s Disease program in November 2014, presented with Koning Willem Alexander attending during the ParkinsonNet symposium. Start of 100+ study (www.100plus.nl) with lots of media attention. Number of PhD graduations: 12. Wiesje van der Flier appointed as professor at VUmc (1 December 2014).

Key publications 1.

3. 4. 5.

Duits, F.H., Teunissen, C.E., Bouwman, F.H., Visser, P.J., Mattsson, N., Zetterberg, H., Blennow, K., Hansson, O., Minthon, L., Andreasen, N., Marcusson, J., Wallin, A., Rikkert, M.O., Tsolaki, M., Parnetti, L., Herukka, S.K., Hampel, H., Leon, M.J. de, Schroder, J., Aarsland, D., Blankenstein, M.A., Scheltens, P. & Flier, W.M. van der (2014). The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean? Alzheimers & Dementia, 10(6), 713-723. Dubois, B, Feldman, H.H., Jacova, C., Hampel, H., Molinuevo, J.L., Blennow, K., Dekosky, S.T., Gauthier, S., Selkoe, D., Bateman, R., Cappa, S., Crutch, S., Engelborghs, S., Frisoni, G. B., Fox, N.C., Galasko, D., Habert, M.O., Jicha, G.A., Nordberg, A., Pasquier, F., Rabinovici, G., Robert, P., Rowe, C., Salloway, S., Sarazin, M., Epelbaum, S., Souza, L.C. de, Vellas, B., Visser, P.J., Schneider, L., Stern, Y., Scheltens, P. & Cummings, J.L. (2014). Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurology, 13(6), 614-629. Vriend, C., Pattij, T., Werf, Y.D. van der, Voorn, P., Booij, J., Rutten, S., Berendse, H.W. & Heuvel, O.A. van den (2014). Depression and impulse control disorders in Parkinson's disease: Two sides of the same coin? Neuroscience and Biobehavioral Reviews, 38, 60-71. Olde Dubbelink, K.T.E., Hillebrand, A., Stoffers, D., Deijen, J.B., Twisk, J.W.R., Stam, C.J. & Berendse, H.W. (2014). Disrupted brain network topology in Parkinson's disease: a longitudinal magnetoencephalography study. Brain, 137(1), 197-207. Vegh, M.J., Heldring, C.M., Kamphuis, W.W., Hijazi, S., Timmerman, A.J., Li, K.W., Nierop, P. van, Mansvelder, H.D., Hol, E.M., Smit, A.B. & Kesteren, R.E. van (2014). Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer's disease. Acta Neuropathologica Communinications, 2, 76.

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Neuroinflammation Research Program Committee: • • • • • • • • • • • • • •

Sandra Amor 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 Hugo Vrenken Elga de Vries (program leader) Mike Wattjes

Multiple Sclerosis (MS) The primary goal of the research program Neuro-inflammation is to perform internationally distinctive translational research that allows better understanding and treatment of neuroinflammatory disorders, predominantly MS. MS research at the VUmc is centred 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 over 100 experts of different disciplines within the VU University medical center (VUmc) cooperate. This MS Center Amsterdam 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.

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•

Perform in vivo imaging to visualize, characterize and predict neurodegeneration and -protection in patients with MS using structural and functional MRI and PET 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 experimental findings and human tissue further on to development of novel diagnostic tools and, ultimately, the clinic, we address the abovementioned research goals in our multi-disciplinary research program. Highlights 1. 2. 3.

Awarded program grant FACING MS for the MS center Amsterdam financed by the Dutch MS Society (5 PhD students). Awarded grants from the International Progressive MS Alliance for three committee members (Charlotte Teunissen, Sandra Amor and Jack van Horssen). Within the MS center, 9 PhD students defended their thesis in 2014.

Key publications 1. 2.

3. 4. 5.

Balk, L.J., Twisk, J.W.R., Steenwijk, M.D., Daams, M., Tewarie, P., Killestein, J., Uitdehaag, B.M.J., Polman, C.H. & Petzold, A.F.S. (2014). A dam for retrograde axonal degeneration in multiple sclerosis? Journal of Neurology, Neurosurgery and Psychiatry, 85(7), 782-789. Nijland, P.G., Witte, M.E., Hof, B. van het, Pol, S.M.A. van der, Bauer, J., Lassmann, H., Valk, P. van der, Vries, H.E. de & Horssen, J. van (2014). Astroglial PGC-1alpha increases mitochondrial antioxidant capacity and suppresses inflammation: implications for multiple sclerosis. Acta Neuropathologica Communinications, 2, 170. Steenwijk, M.D., Daams, M., Pouwels, P.J.W., Balk, L.J., Tewarie, P.K., Killestein, J., Uitdehaag, B.M.J., Geurts, J.J.G., Barkhof, F. & Vrenken, H. (2014). What Explains Gray Matter Atrophy in Long-standing Multiple Sclerosis? Radiology, 272(3), 832-842. Vogel, D.Y.S., Heijnen, P.D., Breur, M., Vries, H.E. de, Tool, A.T., Amor, S. & Dijkstra, C.D. (2014). Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation. Journal of Neuroinflammation, 11, 23. Prins, M., Dutta, R., Baselmans, B., Brevé, J.J.P., Bol, J.G.J.M., Deckard, S.A., Valk, P. van der, Amor, S., Trapp, B.D., Vries, H.E. de, Drukarch, B. & Dam, A.M.W. van (2014). Discrepancy in CCL2 and CCR2 expression in white versus grey matter hippocampal lesions of Multiple Sclerosis patients. Acta Neuropathologica Communinications, 2(1), 98.

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Neurobiology of Mental Health Research Program Committee: • • • • • • • • • • • • • • • • • • • • • • • • • • •

Meike Bartels Dorret Boomsma Leontien Diergaarde Madeleine Drent Mathisca de Gunst Odile van den Heuvel Rick Jansen Christiaan de Kock Adriaan Lammertsma Klaus Linkenkaer-Hansen Huibert Mansvelder Christel Middeldorp Yuri Milaneschi 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

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 disorders both in rodent models and humans allows translational research that is embedded in mechanistic understanding of the brain.

Annual Report 2014

Common goals of this program are: • to further improve diagnostic and prognostic markers for early detection and novel therapeutic targets for mental health and disorders ; • to gain insight into risk factors (e.g., genetics) and underlying pathophysiological mechanisms for the development into mental health disorders in both laboratory animals (rodents) and humans to develop novel therapeutic approaches; 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 state-ofthe-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, brain stimulation, running or light therapy) in animal and/or human models to examine changeability of psychiatric symptoms and endophenotypes. Highlights 1.

2. 3.

4. 5.

Lianne Schmaal and Odile van den Heuvel received NIMH funding for leading the ENGIMAconsortium working groups on Major Depressive Disorder and Obsessive Compulsive Disorder, in which brain imaging research around these psychiatric disorders, involving many international research groups are coordinated. Meike Bartels has been promoted to University Research Professor of Genetics and Wellbeing. Several researchers of the Neurobiology of Mental Health program obtained prestigious personal research grants and awards: Anke Hammerschlag and Sabine Mous from the Complex Trait Genetics group received the NWO Brain & Cognition award, Lianne Schmaal obtained a fellowship from the Dutch Brain Foundation. Professor Danielle Posthuma received a VICI grant from NWO. Professor Dorret Boomsma was awarded with the KNAW Academy Professor Prize. The NeuroBasic PP consortium published with Maarten Loos, Sabine Spijker and co-authors in Biological Psychiatry about the discovery of a gene explaining impulsivity. Professor Penninx and Boomsma received BBMRI funding for their BIONIC project in which they will develop and use an online tool to measure major depressive disorder in many Dutch cohorts with existing genome-wide data. This project will yield large-scale information that will stimulate Dutch genetic research in the area of depression.

Annual Report 2014

Key publications 1.

3. 4. 5.

Wit, S.J. de, Alonso, P., Schweren, L., Mataix-Cols, D., Lochner, C., Menchon, J.M., Stein, D.J., Fouche, J.P., Soriano-Mas, C., Sato, J.R., Hoexter, M.Q., Denys, D., Nakamae, T., Nishida, S., Kwon, J.S., Jang, J.H., Busatto, G.F., Cardoner, N., Cath, D.C., Fukui, K., Jung, W.H., Kim, S.N., Miguel, E.C., Narumoto, J., Phillips, M.L., Pujol, J., Remijnse, P.L., Sakai, Y., Shin, N.Y., Yamada, K., Veltman, D.J. & Heuvel, O.A. van den (2014). Multicenter Voxel-Based Morphometry MegaAnalysis of Structural Brain Scans in Obsessive-Compulsive Disorder. American Journal of Psychiatry, 171(3), 340-349. Wright, F.A., Sullivan, P.F., Brooks, A.I., Zou, F., Sun, W., Xia, K., Madar, V., Jansen, R., Chung, W., Zhou, Y.H., Abdellaoui, A., Batista, S., Butler, C., Chen, G., Chen, T.H., Dâ&#x20AC;&#x2122;Ambrosio, D., Gallins, P., Ha, M.J., Hottenga, J.J., Huang, S., Kattenberg, V.M., Kochar, J., Middeldorp, C.M., Qu, A., Shabalin, A., Tischfield, J., Todd, L., Tzeng, J.Y., Grootheest, G., Vink, J.M., Wang, Q., Wang, W., Wang, W., Willemsen, G., Smit, J.H., Geus, E.J.C. de, Yin, Z., Penninx, B.W.J.H. & Boomsma, D.I. (2014). Heritability and genomics of gene expression in peripheral blood. Nature Genetics, 46(5), 430-437. Verhoeven, J.E., Revesz, D., Epel, E.S., Lin, J., Wolkowitz, O.M. & Penninx, B.W.J.H. (2014). Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study. Molecular Psychiatry, 19(8), 895-901. Lubbers, B.R., Mourik, Y. van, Schetters, D., Smit, A.B., Vries, T.J. de & Spijker, S. (2014). Prefrontal gamma-aminobutyric Acid type a receptor insertion controls cue-induced relapse to nicotine seeking. Biological Psychiatry, 76(9), 750-758. Loos, M., Mueller, T., Gouwenberg, Y., Wijnands, R., Loo, R.J., Birchmeier, C., Smit, A.B. & Spijker, S. (2014). Neuregulin-3 in the mouse medial prefrontal cortex regulates impulsive action. Biological Psychiatry, 76(8), 648-655.

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2a) Composition (input data)

Tables 4. Total of appointed research time. Numbers are excluding support- and technical staff and only give FTE quota spent on research. The research time per research program is split in Table 6. 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 a major part on the basis of for-profit/industrial funding and minor part on the basis of donations/ philanthropy; gs5: funds that do not fit the other categories).

Annual Report 2014

Table 5. Newly started PhD projects in recent years. See appendix 2 at the website for a full list.

Table(s) 6. 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 a major part on the basis of for-profit/industrial funding) and donations/philanthropy.

Annual Report 2014

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 participates 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.

Annual Report 2014

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, laser technology, 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 provided the industry with 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 Neuroscience Campus Amsterdam both has the expertise and experience to develop biomarker assays and, in cooperation with the patient cohorts, to validate such assays.

Biobanks The Neuroscience Campus Amsterdam 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 cerebrospinal fluid (liquor), blood, brain tissue samples and iPS 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 related to several neurological diseases and a control subpopulation. 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 26

Annual Report 2014

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 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 and PET/SPECT tomography combined with extensive neuroimaging analysis expertise.

Omics Through the combination of cellomics, genomics and proteomics, changes in the human genome and proteome underlying clinical phenotypes can be identified which may serve as candidate biomarkers or drug targets. 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. Using the latest proteomics technology, proteins can characterized based in body fluids (e.g. serum, cerebrospinal fluid) from cellular fractions. By genomics sequencing and phenotyping are provided. For these aspects the Genomics facility is used, equipped with state-of-the-art instruments. These aspects have limited capability to be commercial exploited by itself. However, these aspects do play a vital role within the integration of the other elements and the broad service-offering proposition of the Office.

Clinical Expertise Various clinical departments and related clinics of VUmc and VU are affiliated with Neuroscience Campus Amsterdam. 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, Movement Disorder Clinic, MS Center Amsterdam, the Center for Children with White Matter Disorders, the 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.

Annual Report 2014

Patient Cohorts Neuroscience Campus Amsterdam has access to large and extensive patient cohorts of VUmc and VU. The patient cohorts are a strong asset due to the location in a metropolitan area with a high population density, several surrounding hospitals and clinics, and existing infrastructure which secures a rapid follow-up. This facilitates the broad range of disease topics covered in the patient cohorts and a control subpopulation, vital for optimization of research results

Neuropathology The infrastructure of Neuroscience Campus Amsterdam includes a Neuropathology section with unique expertise in the field of pathology. Due to pathology, new proteins can be found 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 for 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 During various research activities substantial amounts of data are generated. With mathematical and computer models and analytical tools, research data can be integrated and translated into, among other, statistics, biology-based mathematics and computational models. In addition, model-based statistical tools can be designed.

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 other commercial activities and services in, mostly, preclinical settings. Additionally, new mouse models can be developed on industry request.

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 behavior screens without human intervention. Automation also enables longitudinal analyses, high content 28

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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.

iPS center Neuroscience Campus Amsterdam 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 model these at cellular level to test the genetic variation of various brain diseases.

Complex Trait Genetics Research in CTGlab explores the genetic and environmental causes of individual differences in behavior, cognition and mental and physical health. Knowledge from different fields (biology, genetics, neuroimaging, bioinformatics) is integrated and statistical tools are being developed to analyze and understand genomic data for complex traits.

Annual Report 2014

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 in 2015. 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 illustrated by the so-called NCA Matrix. Commercial validation indicated that the business propositions of NCA are welcomed and interest was generated by the several assets of the institute.

Annual Report 2014

Figure 4. 'Overview of the business portfolio offered by the Industry Alliance Office'.

The service-offering propositions of the NCA consist of the bundling and integration of several commercial research services, based on three brain disease areas, i.e. Neurodegenerative Diseases (Alzheimerâ&#x20AC;&#x2122;s and Parkinsonâ&#x20AC;&#x2122;s Disease), White Matter Diseases (in particular Multiple Sclerosis) and Anxiety and (Unipolar) Depression.

Annual Report 2014

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 7). 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 recent years the total number of reports has settled to > 600. Of this total, 560 were peer reviewed reports (see Table 9), with 77% being published in a top 25% journal and 45% being in the top-10% journals (see Table 7). Another way of benchmarking the output of NCA is to score the absolute impact factors: in 2014, we had > 20 % of these papers (i.e. 110 papers out of 560 peer reviewed) in the highest impact journals (i.e. IF ~ 9 or higher). In Table 8, the relative impact and the number of high impact papers is further subcategorized per research program.

Table 7. Percentage of papers categorized according to the relative impact factors scores for 2014.

Annual Report 2014

Table 8. Quality of the different Research Programs in 2014. 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.

Annual Report 2014

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 lead by 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 Checklist needs to be used for execution of project run by PhD students, post docs and other affiliated coworkers. The VUmc Research Guide provides a 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.

Annual Report 2014

5) Output

Table 9. 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.

Abbreviations table 9 and table 10: 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

Annual Report 2014

Table 10. Output per Research Program of the NCA. A full list of publications is outlined in appendix 3 at the website. See footnote on previous page for abbreviations. WpREF statistics contains 68 reports that were categorized in more than one NCA research program. In Table 9 only unique (i.e. individual) items were scored.

Annual Report 2014

6a) Earning capacity – NCA The collective and aggregate acquisition of external funding in 2014 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 > 34 M€ of external grant support (see Table 11). This is substantially more than in previous years: two major factors contributing to the vast increase is our success in the so-called Memorabel ZONMW call 2014 (~ 6.6 M€ for NCA) and the major research funding coming from alliances with industry (~ 8.5 M€ for NCA), i.e. the earning power of the Industry Alliance Office (www.nca-iao.com) is becoming apparent and further outlined in section 6b. The breakup grant acquisitions per research program are given in Table 12. In 2014, Prof. Huibert Mansvelder was awarded with an ERC grant and Prof. Dorret Boomsma was appointed as KNAW professor. Not implemented in the 2014 acquisition is the Human Brain Project (Flagship grant of the EU) with Prof. Huibert Mansvelder c.s. because the exact total grant support for NCA still needs to be negotiated and will not start until after 2014.

Table 11. Acquisition of grants by collaborative efforts of the NCA - started in 2014 – and compared to 2008-2013 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 contract-research (for profit/industry) and donations/philanthropy.

Annual Report 2014

Table 12. Grant acquisition per Research Program of 2014. Acquisition in 2014 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.

Annual Report 2014

6b) Earning capacity – Industry Alliance Office The Industry Alliance Office, headed by the director of the NCA, has a cumulative deal flow of over 10 M€ in 2013-2015.

Table 13. Impression of deal flow generated by Industry Alliance Office in 2013-2015. The projects acquired in 2014 were included in the ‘gs4’ statistics of Table 11-12.

Annual Report 2014

7) Academic reputation As already outlined in previous sections: • The number of peer reviewed reports has stabilized (Table 9 and 10), with 77% being published in a top 25% journal and 44% being in the top-10 (see Table 7). • More than 20 % of these papers (i.e. 110 papers out of 560 peer reviewed) were published in highest impact journals (i.e. IF ~ 9 or higher). • In Table 8, 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 Neuro-degenerative Diseases (www.neurodegenerationresearch.eu).

Annual Report 2014

8) Societal impact “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, the Childhood Center for White Matter Disorders 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 ‘outreach’ activities. In addition the outreach activities have been further formalized in recent years via active memberships of our staff in “De Jong Akademie” (DJA) of the Royal Academy of Sciences, including Prof. Huibert Mansvelder, Prof. Danielle Posthuma, and Dr. Ysbrand van der Werf. Prof. Jeroen Geurts was the chair of the 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). In Table 14 we have created an overview of the different aspects of Societal Impact of the NCA.

Annual Report 2014

Demonstrable output/products

Research Quality 1. Research output and instruments: -

Demonstrable use of products

Demonstrable marks of recognition

Research articles Novel infrastructure Disserations Research assays Access to patients Patient sample collections Mouse & cell models Industry Alliances Opportunities

2. Use of research products by peers: - Citations - Reviews for peers - Use of databases and sample collections - Use of mouse & cell models - Novel interventions 3. Marks of recognition from peers: -

ERC, VIDI & VICI awards Invited lectures Advisory board memberships Editorial boards Organizer of major scientific (training) events

Relevance to society 4. Research products for societal target groups: - Deep insight in brain function & cognition - Job opportunities - Public appearance in layman stakeholder events - Understanding of major disease pathology - Giving guidance in health care 5. Use of research products by societal groups: - Translation of new disease pathways and targets in drugs - Guided access to primary material and expertise - New trial endpoint measures 6. Marks of recognition by societal groups: - Valorization opportunities - Industrial funding - Public appearance on television & symposia - Interviews in newspapers - Consultancy opportunities

Table 14. Qualitative impression of different aspects of societal impact by NCA in the period up to 2015. See Appendices 1-6 of this Annual Report for quantification.

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