MHeNs School for Mental Health & Neuroscience Annual Report 2014

Transcription

1 MHeNs School for Mental Health & Neuroscience Annual Report 2014 Maastricht University Faculty of Health, Medicine and Life Sciences & Health Institutes: Maastricht University Medical Centre + RIAGG Maastricht PMS Vijverdal Mondriaan Zorggroep Heerlen

2 Content Preface and future directions of MHeNs and EURON 2 1. Organizational structure 4 2. Divisions 2.1 Division I: Cognitive Neuropsychiatry and Clinical Neuroscience Division I: Research lines Division II: Mental Health Division II: Expert groups Division III: Neuroscience Division III: Research lines Facts and Figures Earning Power Research Staff Output results Aggregated results of the School Output Best publications PhD theses Master and PhD Educational Activities Master Program PhD Program 38 Annexes: I MHeNs / EURON PhD Educational Program 2014 II Current PhD theses III Publications Annual Report 2014 MHeNs 1

3 Preface Prof.dr. Harry W.M. Steinbusch Scientific Director Dear colleagues, I am pleased to provide you with our Annual Research Report It presents a full overview of the work and provides information concerning the School for Mental Health and Neuroscience (MHeNs) in the fields of research output, earning power, staff members and postdoctoral teaching activities in MHeNs has continued to grow not only regarding the number of publications as requested by the Faculty of Health, Medicine and Life Sciences (FHML) but more importantly also in the quality of the papers as indicated by an increase in the average impact factors. We were encouraged to increase the number of papers in particular in the top 10% and in general in the top 25% of the impact fields in which we are working. The increase in non-tenured staff members has resulted in a steady increase in the number of PhD theses to 32 in MHeNs currently hosts about 170 PhD students. The guidance of these students is a significant challenge that requires an enormous and coordinated effort of all our staff members, resulted optimally in two supervisors to guide one PhD student. In accordance with the performance contract with FHML we have focused on increasing more funding from NWO (Dutch Medical Research Council) and FP7- Horizon EU grants, which has resulted in depending less on grants obtained from other peerreviewed agencies. Grants obtained from industrial contract research now represent a more limited component of our funding. Research in MHeNs is guided by the insight that the brain mediates behavioural adaptation to the environment, and that higher order mental, motor and sensory processes converge to guide adaptive behaviour in complex ways. Individual differences in mentation and behaviour are related to (epi)genetic variation and early environmental influences with enduring developmental impact. Research in MHeNs attempts to trace the origin of cognitive, motor, sensory and behavioural dysfunction to interacting genetic and environmental influences, and to elucidate the biological and mental mechanisms between aetiology and symptoms. We focus on common biological pathways such as epigenetics, neuroplasticity, neuronal excitability, neurodegeneration, inflammation, and cerebrovascular regulation. Thereby, we are working toward establishing how they sub serve early imbalance in mentation and functional abilities of the central nervous system (cognition, emotion, incentive salience, movement and pain perception), finally resulting in diagnosable mental and neurological syndromes requiring treatment. 2 MHeNs Annual Report 2014

4 Neuroscience research is becoming more focused on the major topics. More intense cooperation among the different units is becoming more efficient. Restructuring has resulted in one division focused on Cognitive Neuropsychiatry and Clinical Neuroscience, one division on Environmental Psychiatry and the third one on Fundamental and Systems Neuroscience. In line with this, educational activities of the Master s programs correspond to these three divisions. The prime strength of MHeNs is a strict translational approach, e.g., Division 1 concerns and combines neuro-epidemiology and brain imaging, Division 2 focuses on gene-environmental changes/interactions related to psychiatric disturbances such as psychoses, and Division 3 uses post-mortem brain, in vivo blood samples from humans as well as animal, and cellular models related to systems-level research. These lines of research at MHeNs will continue to find much synergy within collaborative projects and research networks, in the areas of the cross-divisional task force Crossspecies Research and Translational Neuropsychiatry, and studies related to the disturbances of the Brain vasculature, leading to Vascular dementia and dysfunctioning of the Blood Brain Barrier. In addition MHeNs has also further developed in closed relationships with Brains Unlimited and the Faculty of Psychology and Neuroscience resulting into highprofile articles with authorships from the three MHeNs divisions. Future directions of the School for Mental Health and Neuroscience (MHeNs) The School will be facing some important changes in the immediate forthcoming period. However, we believe changes will also create opportunities. The first opportunity is related to the establishment of the Maastricht UMC+ and its decision to stimulate Translational Neuroscience, the clinical counterpart of MHeNs within Maastricht UMC+. The School will try to match this initiative with an amount of 0.5 million. The additional funding provided by Maastricht UMC+ will be deployed with a view to put in effect and consolidate strategic choices for expansion and strengthen the positions of postdocs and researchers at the assistant professorship level. At present, all these positions are, unfortunately, non-tenured while what are really needed are tenure-track positions to support and recruit excellent career-oriented staff members from within or beyond. Another consideration regarding Strategic Goals for the years till 2020 is the implementation of the Neuro-Intervention Centre (NIC) a Clinically-driven Research Unit, headed by i.e. Prof. J. van Os, MD PhD. NIC will start in 2015 and will deal with all aspects of mental health related issues related to research, patient care and education in the Academic Hospital Maastricht. NIC and MHeNs will jointly work together. As mentioned before this relationship has resulted in direct opportunities for translational research from bed to bench and vice-versa. Finally, we would like to provide some additional thoughts with respect to EURON. We have mentioned before that MHeNs is a fully integrated partner in EURON and moreover the coordinator. However, EURON comprises ten other universities in the Euregio as well. MHeNs has been taking the lead in all organizational aspects. Because it already provides an excellent opportunity for networking, further Euregional activities and introducing an international or European Master in Translational Neuroscience have great potential, which we will incorporate in the next period. A further specific point deserving our attention is our partnership with the Faculty of Psychology and Neuroscience (FPN). In our School within Division 1, the Department of Psychopharmacology, (FPN) headed by Prof. J. Ramaekers, PhD is already participating. In addition, there is a strong link with educational activities at the level of the Research Master Program Cognitive and Clinical Neuroscience in which the School is involved in two of the four tracks. Thus the FHML is the principal coordinator of two tracks of the Research Master. We would like to build further and even strengthen our partnership with other groups in FPN, such as the Neuroimaging group of Prof. R. Goebel, PhD and the Neuroplasticity group of Prof. P. De Weerd, PhD. These partnerships are important for research and educational exchanges and should result within the next period result into Centre for Interactive Neuroscience (CIN). In conclusion, I would like to thank all members of MHeNs for contributing their knowledge and expertise to the School and students in the past years. Importantly, these changes and improvements that have been made will create new opportunities for the upcoming years. I look forward to new directions and challenges in the coming year. Prof. Harry W.M. Steinbusch, PhD Scientific Director School for Mental Health and Neuroscience Annual Report 2014 MHeNs 3

5 1. Organizational structure MHeNs is managed by the Board of MHeNs. The board is the body where strategies issues are discussed and effectuated. It consists of five members: the scientific director, the managing director and the three division leaders. Dean of the Faculty Health, Medicine and Life Sciences Prof. A. Scherpbier, MD PhD Scientific Director Prof. H. Steinbusch, PhD Managing Director L. Louwies Cognitive Neuropsychiatry and Clinical Neuroscience Prof. F. Verhey, MD PhD (1) Deputies Prof. R. van Oostenbrugge, MD PhD (2) Prof. C. van Heugten, MD PhD (1) Psychiatry & Neuropsychology (section Neuropsychology) Neurology General Practice Human Movement Sciences Internal Medicine Otorhinolaryngology Radiology Mental Health Prof. I. Myin-Germeys, PhD until October 2014 (3) Prof. J. van Os, MD PhD since October 2014 (3) Deputies Prof. T. van Amelsvoort, MD MSc PhD (3) Dr. K. Schruers, MD PhD (3) Psychiatry & Neuropsychology (section Psychiatry) Neuroscience Dr. B. Rutten, MD PhD (3) Deputies Prof. Y. Temel, MD PhD (4) Dr. J. Prickaerts, PhD (5) Psychiatry & Neuropsychology (section Neuroscience) Neurosurgery Anaesthesiology Urology Ophthalmology Paediatrics Figure 2.1 Organogram of MHeNs: the contribution of the different Departments of FHML to the current three Divisions of MHeNs. Participating departments Core Departments Anaesthesiology Prof. W. Buhre; MD PhD, Prof. B. Joosten, MD PhD; Prof. M. Van Kleef, MD PhD Neurology (2) Prof. R. Van Oostenbrugge, MD PhD; Prof. A. Aldenkamp, MD PhD, Prof. R. Hupperts, MD PhD; Prof. H. Vles, MD PhD - Clinical Neurophysiology Prof. W. Mess, MD PhD Neurosurgery (4) Prof. J. Van Overbeeke, MD PhD; Prof. Y. Temel, MD PhD Ophthalmology Prof. W. Webers, MD PhD; Prof. R. Nuijts, MD PhD Psychiatry & Neuropsychology Prof. J. Van Os, MD PhD - Section Psychiatry (3) Prof. J. van Os, MD PhD, Prof. Th. Van Amelsvoort, MD PhD; Prof. Ph. Delespaul, MD PhD; Prof. P. Harten, MD PhD; Prof. F. Peeters, MD PhD; J-P. Selten, MD PhD - Section Neuropsychology (1) Prof. F. Verhey, MD PhD, Prof. C. Van Heugten, MD PhD; Prof. R. Ponds, MD PhD - Section Neuroscience (5) Prof. H. Steinbusch, PhD, Prof. K.-P. Lesch, MD PhD Urology G. Van Koeveringe, MD PhD 4 MHeNs Annual Report 2014

6 Non Core Departments General Practice Human Movement Science Internal Medicine Otorhinolaryngology Paediatrics Radiology Prof. J. Metsemakers, MD PhD Prof. M. Hesselink, MH PhD Prof. C. Stehouwer, MD PhD; Prof. H. Ten Cate, PhD Prof. B. Kremer, MD PhD, Prof. R. Stokroos; MD PhD Prof. L. Zimmerman, MD PhD, Prof. B. Kramer, MD PhD Prof. J. Wildberger, MD PhD; Prof. W. Backes, MD PhD Members of EURON MHeNs is the coordinator of the European Graduate School of Neuroscience (EURON). EURON is a research and training network of 11 universities in four countries i.e. Belgium, Germany, France and the Netherlands. Belgium Universiteit Hasselt Katholieke Universiteit Leuven Université de Liège Université catholique de Louvain EURON MHeNs Germany RWTH Aachen University University of Bonn University of Cologne France Université Lille 1 Université Paris Descartes Figure 2.2 EURON in relation to MHeNs. The Netherlands Maastricht University (MHeNs, FHML) and FPN Annual Report 2014 MHeNs 5

7 2. Divisions 2.1 Division I: Cognitive Neuropsychiatry & Clinical Neuroscience Division Leader: Prof. F. Verhey MD PhD Deputies: Prof. R. Van Oostenbrugge MD PhD Prof. C. Van Heugten MD Staff: P. Aalten MD PhD J. Adam MD PhD M. van den Akker MD PhD Prof. B. Aldenkamp MD PhD L. Anteunis MD PhD W. Backes MD PhD S. Burgmans MSc PhD J. Dijkstra MD PhD A. Duits MD PhD C. Faber MD PhD E. Gronenschild MD PhD P. Hofman MD PhD Prof. R. Hupperts MD PhD J. Jansen MD PhD H. Jacobs MD PhD Prof. H. Kingma MSc PhD S. Köhler MsC PhD V. Kranen van Mastenbroek MD PhD Prof. B. Kremer MD PhD Abraham Kroon, MD PhD Albert Leentjens MD PhD Prof. Peter de Leeuw MD PhD Prof. W. Mess MD PhD Prof. J. Metsemakers MD PhD Prof. F. Mottaghy MD PhD Prof. R. Ponds MD PhD I. Ramakers MsC PhD J. Reijnders, PhD O. Schiepers, MsC PhD P.-J. Visser MSc PhD M. Vlooswijk MSc PhD M. de Vugt MD PhD Prof. J. Wildberger MD PhD I. Winkens MD PhD C. Wolfs MD PhD Goals & Results CNP&CNS performs fundamental and applied research on brain-cognition relationships. CNP&CNS mission is to generate new insights into neurocognitive and neurobehavioural mechanisms, which help to improve the treatment and care for people with cognitive and other neurological disorders. Since 2009, clinical neuroscience researchers have been assigned to the Division 1 Cognitive Neuropsychiatry & Clinical Neuroscience (CNP&CNS), a name expressing the translational nature of the research program, and the multidisciplinary perspective. With respect to the medical core topics, the focus is upon neurodegeneration of the central nervous system, more specifically Alzheimer s disease and its prodromal phases, Vascular Cognitive Impairment / dementia, other related cognitive disorders, Parkinson s disease, peripheral nervous system disease, such as small fibre neuropathy, acquired brain damage, such as stroke, traumatic brain injuries, and epilepsy. Researchers in the division investigate the contribution of biological, neuropsychological and psychosocial factors, single and in combination, and the effects of ageing on the normal development of normal neurocognition and on mild to severe cognitive dysfunction. Research in Division 1 is typically conducted in a multi-disciplinary way, with contributions of scholars with a background in the departments of Psychiatry, Neuropsychology, Clinical neurology, Neuroradiology, Neurophysiology, and Otorhinolaryngology. In 2014, we further pursued our studies into normal, successful and pathological ageing, with a great interest in translating basic insight into practical application. Collaboration between the departments of Psychiatry, Neurology and Neuroradiology were intensified. Studies that were carried out as part of the NWO/FES program on Center of Translational Molecular Medicine and Brain and Cognition are producing the first results and products. New grants were obtained from both national and international (EU) sources (JPND, IMIF). 7 PhD students successfully defended their thesis. Below, several examples are presented of ongoing and recently started research projects that are at the core of the research in this division. 6 MHeNs Annual Report 2014

8 2.1.1 Research lines Neurodegenerative disorders: mechanisms, early diagnosis and biomarkers Neuroepidemiology: Course and determinants of normal, successful and pathological cognitive ageing Psychosocial interventions and cognitive rehabilitation Epilepsy Neuromuscular disorders The sense of hearing and balance: advanced diagnosis and substitution Research line: PI: Research Staff: Postdocs: PhD-students: Co-investigators extern: Focus of research: Neurodegenerative disorders: mechanisms, early diagnosis and biomarkers Prof. F. Verhey MD PhD P. Aalten, MD PhD, M. Van Boxtel MD PhD, Prof. R. Van Oostenbrugge MD PhD, P. Hofman MD PhD, Prof. W. Backes MD PhD, J. Jansen MD PhD, A. Leentjens MD PhD, A. Duits MD PhD, E. Gronenschild MD PhD, S. Köhler MD PhD, P-J. Visser MD PhD, Prof. F. Verhey MD PhD S. Burgmans MSc PhD, H. Jacobs MD PhD, I. Ramakers MD PhD L. Clerx MSc, L. Elias MSc, H. van de Haar MSc, R. Handels MSc, M. Huijts MSc, A. Moonen MSc, S. Schievink MSc, T. Van der Voort MSc, S. Vos MSc, W. Janssen MSc, R Hamel MSc, B. Reijs MSc, E. Zhang MSc, A. Mertens MSc European Alzheimer s Disease Consortium Translational research into the early diagnosis of pathological ageing A large-scale national biobank, coordinated by MUMC and the VU-MC, formed the infrastructure for translational research into the early diagnosis of pathological ageing (Parelsnoer Neurodegeneratief), coordinated by Proven F. Verhey. Novel diagnostic technology for the early detection of Alzheimer s disease will be examined and evaluated in terms of Health Technology Assessment, i.e., with respect to its added value to existing diagnostic procedures (LeARN, CTMM). A project funded by VSB was started on the prediction of individual trajectories in cognitive disorders. Collaboration with the Departments of Neurology and Radiology was intensified, which has led to a new study on neurovascular mechanisms of cognitive disorders, and the interaction between vascular and neurodegenerative mechanisms. To assess brain microvascular pathology in the brain in vivo, novel imaging techniques are currently being developed. Dr S. Burgmans and W. Backes started a pilot study on blood-brain barrier leakage in dementia (funded by an ISAO pilot award). They hypothesized increased blood-brain barrier permeability in Alzheimer patients and developed a new dynamic contrast enhanced MRI scan. A new grant of was obtained by these researchers to expand this research line. On the European level, the research group has leading roles in projects on standardisation of biomarker assessment (JPND BIOMARKAPD) and the set-up of a European Medical information framework (IMI EMIF-AD), Collaboration between the departments of Psychiatry, Neurology and Radiology was intensified, which has led to a new study on neurovascular mechanisms of cognitive disorders, and the interaction between vascular and neurodegenerative mechanisms. To assess brain microvascular pathology in the brain in vivo, novel imaging techniques are currently being developed. Dr S. Burgmans and Prof. W. Backes started a pilot study on blood-brain barrier (BBB) leakage in dementia (funded by an ISAO pilot award). They hypothesized increased blood-brain barrier permeability in Alzheimer patients and developed a new dynamic contrast enhanced MRI scan. A second BBBB project started up investigating the role of BBB leakage in patients with Vascular Cognitieve Impariment (Prof. R. van Oostenbrugge, Prof. W. Backes). Annual Report 2014 MHeNs 7

9 The VSB fonds/zonmw for a research program on successful psychosocial reintegration of patients and caregivers after stroke continued in 2013; at the moment all data are collected and follow-up measurements are being completed. In this program 4 PhD students (Maastricht, Nijmegen and Utrecht) investigate the course and predictors of psychosocial functioning, costs of psychosocial care and effectiveness of two new psychosocial interventions for patients and caregivers aimed at self-management and cognitive behavioural therapy for post-stroke depression and anxiety. All projects will be finished in Research line: PI: Research Staff: Postdocs / PhD-students: Focus of research: Neuroepidemiology: Course and determinants of normal, successful and pathological cognitive ageing M. van Boxtel, MD PhD Prof. F. Verhey, MD PhD, Prof. W. Backes, MD PhD, J. Jansen, PhD, Prof. R. Van Oostenbrugge, MD PhD, S. Köhler, PhD F. van Dooren, MSc, P. Spauwen, MSc, W. van Zwam, MSc, MSc F. van Bussel, K. Deckers, MSc, M. Wong MSc, L. Berk, MSc. Insight into the prevention, etiology and treatment of cognitive dysfunction in the normal adult population Division staff members are active contributors to the Maastricht Study (MS), a study to provide more insight into the prevention, aetiology and treatment of type 2 diabetes and other chronic diseases in relation to mental health. The MS is a good example of the integrative approach that we aim for, with multidisciplinary input from the departments of Psychiatry & Neuropsychology, Neurology, Neuroradiology, and Neuro-ophthalmology and Otolaryngology. The FP7 funded 3-year s study into preventive strategies to ameliorate the individual dementia risk profile of middleaged individuals (see produced an evidence-based risk factor algorithm to estimate individual dementia risk. This product was implemented in an ongoing multicenter European intervention study aimed to reduce the dementia risk profile in middle-aged individuals. Final results and recommendations for its use in primary care are expected in early The project by J. Jansen (VENI grant) on multi-parametric imaging of cerebral biomarkers of cognitive deterioration using MRI in diabetes type-2 in the context of the Maastricht Study is now well underway. This project encompasses a multi-disciplinary approach between the departments of Radiology, Internal Medicine and Psychiatry & Neuropsychology. Furthermore, the NWO/FES program Healthy Cognitive Ageing aimed at the development of internet-based lowlevel intervention strategies to support the cognitive ageing process in middle-aged and older adults has rounded off the data-collection of a large intervention study. Results were implemented in an e-health module ( Keep your brain fit!, now available for the general public. The Maastricht Ageing Study continuous to be a major source for new studies into determinants of cognitive ageing, including studies on positive affect and hypertension. Collaborations with international partners in dementia epidemiology and prevention have been started and/or intensified (e.g. Dr Launer, NIH; Prof. Brayne, U Cambridge, UK; Prof. Yaffe, USCF, USA). New avenues are explores on the role of mindfulness in cognitive ageing and in the incidence of cognitive complaints, both in observational and in intervention studies. The Weijerhorst foundation supported further research of the blood-brain-barrier between the departments of Radiology and Neurology to develop MRI methods and apply these in patients with small vessel disease (SVD) to get more insight in the etiology of SVD and to link this with both pathological and normal ageing and cognitive decline. 8 MHeNs Annual Report 2014

10 Research line: Psychosocial interventions and cognitive rehabilitation PI: Research Staff: Postdocs / PhDstudents: Co-investigators extern: Focus of research: Prof. C. van Heugten MD PhD Prof. R. Ponds MD PhD, M. van Boxtel MD PhD, Prof. F. Verhey MD PhD, M. de Vugt MD PhD I. Winkens MD PhD, C. Wolfs MD PhD, G. Wolters MSc, I. Klinkenberg Msc, C. Bakker Msc.B. Dandachi-Fitzgerald MSc, L. Boots Msc, I. Brands MSc, J. Collet MD, M. van Eeden MSC, M. Fens MSc, R. van Knippenberg MSc, B. ter Mors MSc, V. Moulaert MSc, S. Smeets MSc, N. Tielemans MSc, M. van Eeden MSc, A. Dam Msc, L. Kerpershoek Msc, J. Millenaar Msc, E. Tan MD, B. Appelhof Msc, A. Gerritsen MD, J. van Duin Msc. International Interdem network Cognitive rehabilitation and health service evaluation research. Interventions in cognitive and acquired brain disorders In this research line a strong focus is put on evidence-based neuropsychological interventions, psychosocial interventions, caregiver interventions, cognitive rehabilitation and health service evaluation research. Interventions are investigated in cognitive and acquired brain disorders. In addition, research is focusing on the development and evaluation of new instruments to measure outcome of treatment and on investigating factors which influence outcome. Innovative treatment techniques are being evaluated in this programme, such as selfmanagement techniques and e-health interventions. The program on psychosocial aspects and interventions to support dementia patients and informal caregivers has received grants from Alzheimer Netherlands, Alzheimer Research Fund Limburg and the European Joint Program of Neurodegenerative Diseases (JPND)/ ZonMW..An important focus of the program is e-health interventions; with three PhD students (L. Boots, MsC / R. van Knippenberg, MsC/ A. Dam, MsC) that study the feasibility and effectiveness of newly developed e-health interventions. The program was expanded in 2014 with a JPND funded European study on the development of an e-learning tool specific for young onset dementia (Dr J. Millenaar, Post doc Ch. Bakker), and an Erasmus funded project on the development of an online master program on positive aspects of dementia (Post doc Inge Klinkenberg). In addition, a JPND grant was received in 2014 to study access to timely formal care in dementia (Dr L. Kerpershoek, Post doc C. Wolfs). In collaboration with Alzheimer Center Nijmegen three external PhD students study aspects and interventions in young onset dementia (B. Appelhof, MsC, A. Gerritsen, MsC, J. van Duin, MsC). In the program on neuropsychological interventions for patients with acquired brain injuries 2 PhD students successfully finalized their research. M. Fens, MsC defended her thesis on a research project evaluating a long-term care model for stroke patients and V. Moulaert, MsC finalized her research project on activity and life after surviving a cardiac arrest. Both projects led to new tools for clinical practice (i.e. screening tools and psycho-educational interventions). In the ZonMw/VSB fonds Restore4stroke program 4 PhD students study the quality of life and participation of stroke patients and their partners until 2 years after stroke. This program is a joint initiative of Maastricht, Utrecht and Nijmegen In which different methodologies are combined (i.e. prospective cohort study, record linkage study, burden of disease study, randomized clinical trials and economic evaluations). The NWO/FES Brain & Cognition program (0.9 Me) continued in 2014 studying the effectiveness of cognitive rehabilitation and factors influencing the success of cognitive rehabilitation. In 2014, new interventions for executive dysfunction in Parkinson patients (Groningen), errorless learning augmented Goal Management Training (Nijmegen), problem solving therapy for stroke patients (Rotterdam) and the ABC method for severe behavioural problems after acquired brain injury (Maastricht) have been developed, and recruitment for efficacy studies has started. In addition, factors influencing rehabilitation outcome are being studied: self-awareness (Maastricht), learning style and learning potential (Utrecht/Maastricht). Annual Report 2014 MHeNs 9

11 Finally, in 2014 the first steps towards the development of a brain injury center Limburg were taken. In this center patient care, research, education and societal activities are linked together In order to improve the quality of life of patients with acquired brain injury and their informal caregivers. In this center the departments of psychology of the Limburg hospitals will work together (i.e. Maastricht, Sittard, Heerlen, Roermond, Weert and Venlo). Research line: PI: Research Staff: Post doc: / PhD students: Epilepsy Prof. A. Aldenkamp, MD PhD Prof. H. Vles, MD PhD, M. Majoie, MD, PhD, G. Hoogland, MSc PhD, R. Rouhl, MD PhD, M. Vlooswijk, MD PhD, Prof. W. Backes, MD, PhD, P. Hofman MD PhD, J. Jansen, MSc PhD. E. Barendse MSc, K. Beerhorst MSc, R. Besseling MSc, R. Binie MSc, W. van Blarikom MSc, Z. Bouwman MSc, M. Buskermolen, PhD, S. Ebus MSc, N. Gosens MSc, D. IJff MSc, R. van der Kinderen MSc, S. van der Kruijs MSc, S. Klinkenberg MSc, J. Peijnenborgh MSc, J. van Tuyl MSc, T. van Veenendaal MSc, S. Schipper MSc, M. Teunissen MSc, L. Wagner MSc, C. van den Bosch MSc. In 2014, a central theme within the research topic of epilepsy was Chronic Epilepsy, funded by a substantial grant from the National Epilepsy Fund (NEF) for this program (led by Prof. A. Aldenkamp). One of the most severe consequences of chronic epilepsy is the impairment of cognitive functioning, including the general thinking, memory, language and problem-solving capabilities. The novel insight today is that epilepsy is more a network disease rather than a single focal abnormality or malfunction. Traditionally, epilepsy research utilizes different techniques and methods: measurement of brain waves (electro-encephalogaphy, EEG), imaging (acquisition of anatomic and functional brain images with scanning devices) and neuropsychological assessment. Recent technological developments of MRI methods, in particular functional and diffusion MRI, provide possibilities to obtain new insights on the organization and integrity of cerebral networks which may lead to strategies that prevent chronic epilepsy and cognitive co-morbidity. Also, further efforts are taken to unravel the neuronal en physical substrates for Psychogenic Non-Epileptic Seizures. In 2014, as a consequence of a further integration of and novel opportunities within the Academic Centre for Epileptology (ACE) new focus points for research were explored: special diagnostical methods (immunology, autoantibodies) and genetics (whole exome sequencing)) as well as special therapeutical methods (deep brain stimulation). Cognition in relation to (interictal) epileptic discharges, especially in children, is another resaerch focus point within ACE. To continue the translational and clinical epilepsy research, these new research lines have started or will be started in Next to this clinical line there is an established pre-clinical research program, which a.o. now aims at determining factors which are involved epileptogenesis and chronicity in epilepsy animal models, like epigenetics, extra-synaptic receptors and mitochondrial function. Cognition in relation to epilepsy and interictal epileptic discharges is addressed aswell in pre-clinical setting. Research line: Neuromuscular disorders PI: Prof. C. G. Faber MD PhD Reserarch Staff: I.S. J. Merkies MD PhD PhD-students: M. Bakkers MD, E. Vanhoutte MSc, B. de Greef MD, M. Sopacua MSc, T. Draak MD, B.A. Brouwer MSc Focus of research: Outcome measures, myotonic dystrophy and (painful) neuropathy/small fiber neuropathy Research into neuromuscular disorders (led by Prof. C. Faber) targets myotonic dystrophy, (painful) neuropathy/small fibre neuropathy and outcome measures/clinimetrics. A longstanding collaboration between the Maastricht UMC and Prof. S. Waxman (Yale University) and G. Lauria, MD PhD (Carlo Besta, Milan) has led to new developments in understanding the pathogenetic basis of neuropathic pain. This resulted in several papers in high-impact journals. Furthermore, grants from the European Union 7th Framework Program (grant n ) and from the Prinses Beatrix Spierfonds (W.OR12-01) were obtained. The PeriNomS study resulted in an international consensus meeting on outcome measures in peripheral neuropathies. 10 MHeNs Annual Report 2014

12 Research line: PI: Research Staff: PhD-students: Co-investigators extern: Focus of research: The sense of hearing and balance: advanced diagnosis and substitution Prof. R.J. Stokroos, MD, PhD L. J. C Anteunis, AUD, PhD, J. Brokx, AUD, PhD, E. George, MSc, PhD, Prof. H. Kingma, MSc, PhD D. Smit, MD, G. Dees, MD, MSc, D. Henatsch, MD. MSc, J. Debruyne, AUD, R. Arts, MSc, J. Smit, MD, MSc, M. van Hoof, MD, S. Wagemakers, MD, J. Hof, MD, E. Devocht, AUD, S. Schaefer, MD, T. Calon, MD, R. v.d. Berg, MD, N. Guinand, MD, R. Jansen, MSc, L. Felipe, MSc, L. van Nierop, MSc, M. van Tilburg, MD E. Formisano, PhD, Prof. Y. Temel, MD, PhD, K. Meijer, MSc, PhD, R. Peeters, MSc, PhD D. Jiang, PhD (UK), Prof. B. Kramer, MD, PhD (MUMC), D. Kunst, MD (KU Nijmegen), K. van Overbeeke, MD, PhD (MUMC), V. Demkin, MSc, PhD (Russia), J-P. Guyot, MD, PhD (Switzerland), D. Zee, MSc, PhD, (US, Johns Hopkins), S. Rauch, MSc, PhD (US, MIT) Translational research into the etiology of disorders of the senses of hearing and balance and the effect of neuromodulation with neuroprosthetic devices. Hearing and balance problems are among the most prevalent health problems in our population. Our research efforts are divided in three subcategories: Tinnitus Basic research aims to unravel central nervous mechanisms causing tinnitus by using FMRI and animal models and the potential of neuromodulation using deep brain stimulation. This translates into clinical application wherein a specific neuromodulatory device, a tinnitus suppression implant has been applied. This has attracted a great number of patients for which a care system was put in place which is systematically evaluated and improved further. Valorisation of this tinnitus care system is important since the new Dutch care standards are currently based on it. Hearing Optimizing the diagnostics of hearing loss at a very young age has been systematically studied, aimed at improving both measuring instruments and at early detection and intervention. Special attention has been addressed to basic mechanisms causing hearing damage in premature infants. Bilateral deafness treatment by cochlear implantation has been institutionalized at MUMC+. Research efforts are focused on optimizing coding strategies, on improving electrode placement using advanced fusion imaging, and on optimizing electrical and acoustic (bimodal) hearing. Single sided deafness is treated using bone conductive hearing. Research efforts are focused on optimizing abutmentskin interaction and at clinical evaluation of the Soundbite device (hearing via the teeth). Sensorineural hearing loss is treated with hearing aids. Hearing aid provision has been studied from a cost effectiveness point of view. Balance Advanced diagnosis and treatment possibilities of vestibular disorders have attracted many patients to our MUMC+. New medical and surgical treatment strategies became available for balance disorders, for example using the round window membrane as a pathway to the inner ear. However, for an important proportion of these patients, neuromodulatory devices remain the sole treatment option. A special balance belt has been developed with IDEE, supported by the Dutch Health Insurance Companies that increase the proprioceptive substitution for patients with severe balance disorders. In collaboration with Geneva and industrial partners a vestibular implant has been developed which substitutes a defect vestibular system and is currently evaluated and developed further. Annual Report 2014 MHeNs 11

13 2.2 Division II: Mental Health Division Leader: Prof. J. Van Os MD PhD MRCPsych Deputies: Prof. Th. van Amelsfoort MD MSc PhD K. Schuers MD PhD Staff: M. Bak MD PhD Prof. Ph. Delespaul SC PhD R. van Diest PhD P. Domen MD M. Drukker PhD L. Goossens PhD E. Gronenschild PhD P. Groot PhD Prof. P. van Harten MD PhD G. Kenis MSc PhD G. Konings PhD T. Lataster PhD Ch. van der Leeuw MD PhD C. Leue MD PhD R. Lieverse MD PhD R. Lousberg PhD M. Marcelis MD PhD Prof. I. Myin-Germeys, Msc, PhD N. Nicolson PhD Prof. F. Peeters MD PhD U.Reininghaus PhD B. Rutten (cross-divisional) MD PhD J. Schieveld MD PhD Prof J.-P. Selten MD PhD R. Severijns PhD C. Simons PhD J. Strik MD PhD M. Tijssen MD PhD W. Viechtbauer PhD M. Wichers PhD R. van Winkel MD MSc PhD C. van Zelst PhD 12 MHeNs Annual Report 2014

14 Goals & Results As outlined in the SEP protocol, division II Mental Health is focusing on gene-environment research in mental health and illness, within a translational context, bringing together human and animal components of gene-environment interaction research as well as translating these findings to the clinic, not only in these sense of individual patient care, but also including a public health and health services organisation component. The ultimate goal is to identify interactive determinants of reactive phenotypes at the level of lived experience relevant to mental health and resilience and implement knowledge derived from this in patient care and mental health service organisation. In 2014, we worked on the following goals: 1) The MUMC Neurointervention Centre (NIC) Division 2 is actively involved in setting up and developing the novel Neuro-Intervention Centre (NIC) at MUMC+. To this end, Division is rapidly expanding collaboration with the various clinical groups in NIC. Amongst others we are developing novel mhealth tools to facilitate outcome research in the area of neuromodulation 2) NWO Graduate School Division 2 and 3 successfully applied for an NWO Graduate School. Four 4 translational PHD projects were established in the context of this grant. 3) In order to improve G*E studies searching for the causes of complex diseases such as severe mental disorders, increasingly large sample sizes are urgently required. The EU-GEI study with 28 European partners, funded by a large FP7 grant, is almost reaching the end. The last consortium meeting in 2014 demonstrated that the study is going well, with all centres being actively involved in data collection. Secondly, a large general-population study has been set up together with the Trimbos Institute. The NEMESIS II study has been finishing its genetic data collection and completing its third follow-up on mental health in 7000 participants from the general population. Division II was specifically involved in collecting data on psychosis. The third wave of this study was initiated in Third, the third wave of data-collection in the national (Amsterdam, Utrecht, Groningen, Maastricht) GROUP study was completed. This study is following up 1000 patients with psychosis, 1000 relatives and 1000 parents and 500 controls over a period of 10 years. The third wave data cleaning was undertaken in Finally, the large dataset of real-life ESM data combined with genetic information was analysed in ) Division 2 has set up the infrastructure for implementation of its psychosis and health services research, setting up a series of collaborations with insurers, ehealth experts and experts by experience to obtain funding for a large scale disruptive innovation pilot introducing a completely new mental health service in an area of , based on three pillars of (i) ehealth/mhealth, (ii) nonprofessional sources of help and (iii) scaling back the size of mental health services to the level of integration in a neighbourhood of population (10 GP practices). Research will focus on process outcomes and population health outcomes based on the new definition of health (the ability to adapt and self-manage given physical and mental challenges). 5) Combining imaging data with real-time and real-world person-environment interaction patterns is a powerful way of conducting experimental medicine research, since it provides ecological validity for the neuroimaging data, correlating real life behaviour with alterations in specific brain regions, and vice-versa, improves the understanding the neural mechanisms associated with real-life behaviour. Division II has been conducting a large cross-diagnosis study focusing on underlying mechanisms of reward, stress and aberrant salience, studied with experimental fmri paradigms as well as real-life ESM assessment. The data collection of this large SMARTSCAN project (funded by the Weijerhorst Stichting) has been progressing well throughout In a second study, funded by an ERC consolidator grant, the neural effects of a psychological real-life intervention will be assessed in a combined ESM PET approach. This INTERACT study has been progressing well in A multimodal imaging study (SMURF) looking at the neurobiological basis of cognition in psychosis, funded by a VIDI, is now underway as well. 6) In 2014, the PsyMate app was further developed and is now consumer grade and downloadable from itunes and Android Store. It includes a web-based feedback module; the PsyMate Annual Report 2014 MHeNs 13

15 server now records 10,000 interactions per day. Currently around 29 different studies are being conducted using PsyMate technology, including studies to develop mrom, a number of n=1 single case experiments, novel psychopharmacological personalised dose-finding studies, novel studies of networked psychopathology models, PsyMate intervention studies based on, for example, ACT modules in PsyMate, positive health feedback modules, salience exposure modules and others. We also are conducting a clinical trial investigating a new PsyMate Acceptance and Commitment therapy, which will be applied both in the SMARTSCAN and INTERACT studies. 7) Translational studies bringing together basic animal research and patient studies remain a core research line within division II. The translational expert group has initiated a number of studies, translating human findings to animal models and vice versa, with a particular focus on epigenetic mediation of environmental exposure effects, epigenetic mediation of ECT therapy, and epigenetic mediation of interferon alpha therapy. with external funding in the URC is on the first randomised controlled trial of peer support in the Netherlands with exciting results that have now been submitted for peer review. A very successful initiative of the URC was the website www. psychosen.nl, which now attracts around a 1000 visitors per day and has proven to be a good way to conduct health promotion, empowerment and self-management for patients with severe mental illness. It has also generated a long overdue debate in the Netherlands, amongst others at the Royal Netherlands Academy of Arts and Sciences on 20th May 2015, about meta-epidemiological issues in schizophrenia research and mental health practice. The methodological expert groups within the division focus on 1) genetics, 2) Experience Sampling, 3) Neuroimaging, 4) Clinical epidemiology and Mental Health Services Research, 6) Translational approaches and 7) Lived experience. 8) Division II is actively involved in forming international networks to accelerate psychiatry research. The EURON Psychiatry Institute has been formed to formalize the intensive collaboration between the University of Leuven (UPC Kortenberg) and Division II of Maastricht University. This formal collaboration will also strengthen the clinical neuroscience within EURON. Second, members of division II are active partners in the European FP7 ROAMER project, which has set up a European Roadmap to Mental Health Research which was completed in Division II is also a partner in PSYSCAN (FP7). 9) Division 2 is proud to host the first User Research Centre (URC) in the Netherlands. The User Research Centre is a facility where academics with lived experience in psychiatry complete PhD projects and post-doc trajectories, investigating issues that are within the remit of Division 2 but developed entirely from the user perspective. The first PhD completion was in 2014, based on user-led interventions to reduce self-stigma. A successful postdoc in the User Research Centre is conducted by Dr Peter Groot, based developing methods for n=1 single case experiments for optimal dosing of psychotropic medication. This project has attracted funding from multiple sources. Another PhD project 14 MHeNs Annual Report 2014

16 Expert groups Genetics Experience Sampling Neuro-imaging Clinical epidemiology and mental health services research Expert-group: Coordinator: Staff: Postdoc: PhD students: Focus of research: Genetics R. van Winkel MD MSc PhD Prof. J. Van Os MD PhD MRCPsych, B. Rutten MD PhD, G. Kenis MSc PhD, W. Viechtbauer PhD, M. Drukker PhD, M. Wichers PhD C. Simons PhD, M. van Nierop PhD C. Hamels MSc, J. Decoster MSc, C. Lothmann PhD The design of genetic studies in the field of psychiatry as well as investigating the role of genetic variances and gene-environment interactions in the etiology, severity and course of psychopathology The genetics expert group coordinates the design of genetic studies in the field of psychiatry as well as the choice of various genetic methodologies, choice of polygenic scores, pathway scores, epigenetic scores and genes of interest for the different research lines. Furthermore, it offers a platform for bringing together several disciplines in order to conduct adequately designed, multi-disciplinary and translational research to establish the role of genetic variances and gene-environment interactions in the etiology, severity and course of psychopathology and dimensions of psychological and psychiatric traits. Expert-group: Coordinator: Staff: Post doc: PhD students: Focus of research: Experience Sampling J. Bakker MSc M. Wichers PhD, Prof. Myin-Germeys PhD, T. Lataster PhD, N. Nicolson PhD, W.Viechtbauer PhD, N. Jacobs PhD, Prof. Ph. Delespaul SC PhD, Prof. J. van Os MD PhD MRCPsych C. Simons PhD, D. Collip PhD, J. Lataster PhD C. Lothmann MSc, J. Decoster MSc, C. van Zelst MSc, F. Smeets MSc, I. Kramer MD, J. Hartmann MSc, M. Janssens MSc, M. Gevonden MSc, M. van Winkel MSc, T. Batink MSc, Z. Kasanova MSc, T. Vaessen MSc, Y. Van der Steen MSc, A. Klippel MSc, H. Steinhart MSc To guard and increase the quality of ESM data collections and analyses, as well as to increase statistical expertise and analytic possibilities. The aim of the EXM expert group is to guard and increase the quality of ESM data collections and analyses, to examine the validity of the method and the items used in ESM and report on this in international peer-reviewed journals, as well as to increase statistical expertise and analytic possibilities, such as time-series analysis in ESM. Expert-group: Coordinator: Staff: Post doc: Neuro-imaging M. Marcelis MD PhD K. SchruersMD PhD, E. Gronenschild PhD, Prof. van Os MD PhD MRCPsych, L. Ritsaert MD PhD, Prof. T van Amelsvoort MD MSc PhD L. Goossens PhD, S. Peeters PhD PhD students: P. Domen MD, Z. Kasanova MSc, S. Michielse MSc, I. Lange MSc(res), C. Vingerhoets MSc, G. Bakker MSc, C. van der Leeuw MD, Focus of research: To combine expertise on various neuroimaging modalities (eg. smri, DTI, fmri, PET, SPECT, MRS) and analysing techniques to examine brain structure and function in psychiatric disorders Annual Report 2014 MHeNs 15

17 The expert group Neuro-imaging is a group of researchers that are using various neuroimaging modalities (e.g. smri, DTI, fmri, SPECT, PET, MRS) and analysing techniques to examine brain structure and function in psychiatric disorders, such as psychotic and anxiety disorder. Our main goals are to examine i) neurobiological pathways influencing psychopathology, ii) genetic and environmental determinants of brain phenotypes, and iii) neural mechanisms underlying therapeutic interventions. Expert-group: Coordinator: Staff: PhD students: Focus of research: Clinical epidemiology and mental health services research M. Drukker PhD W. Viechtbauer PhD, Prof. J. van Os MD PhD MRCPsych, R. Lousberg PhD, M. Drukker PhD, M. Bak MD PhD, Prof. Ph. Delespaul SC PhD, G. Driessen MSc, F. van Dael MD, F Smeets MSc, C Lothman MSc, T. Mentzel MSc, S. Michielse MSc, I. Lange MSc, Z. Kasanova MSc A. Frissen MD, S. Guloksuz MSc, W. Boevink MSc To discuss the correct use of research methods (epidemiology) and meta-analyses as well as to work on data of patient registers and monitors. In addition, this expert group is in charge of the Psychiatric Case Register South Limburg and the medication monitor (in Dutch AP monitor). Finally, the expert groups coordinates health services research. Over the last years, MHeNS has strategically developed the Translational Neuropsychiatry (TNP) task force. The TNP scientists (Rutten, MD PhD, D. van den Hove, PhD, G. Kenis MSc PhD, Prof. H. Steinbusch, PhD, Lesch, Prof. J. van Os, MD PhD, P-J. Visser, PhD and Prof. F. Verhey, MD PhD) have initiated successful cross-species research with parallel designs in addressing research questions on stress-related neurodevelopmental and neurodegenerative disorders in a translational setting using human, animal, and cell culture methods, yielding high-impact publications with contributions from all scientists affiliated with three MHeNs divisions. 16 MHeNs Annual Report 2014

18 2.3 Division III: Neuroscience Division Leader: Bart Rutten, MD, PhD Deputies: Prof. Y. Temel, MD, PhD J. Prickaerts, PhD Staff: Prof. M.de Baets, MD, PhD T. Berendschot, PhD Prof. W. Buhre, MD, PhD M. van Duinen, PhD L. Eijssen, MSc, PhD D. Gavilanes, MD, PhD Th. Gorgels, PhD G. Hoogland, PhD D. van den Hove, PhD A. Jahanshahianvar, PhD Prof. Bert Joosten, PhD Prof. A. Kijlstra, PhD Prof. M. van Kleef, MD, PhD G. van Koeveringe, MD, PhD I. Koneczny, MSc, PhD Prof. B. Kramer, MD, PhD M. Lagiere, MSc, PhD F. van Leeuwen, PhD Prof. K.-P. Lesch, MD, PhD M. Losen, PhD Prof. M. Marcus, MD, PhD P. Martinez, PhD C. Meriaux, MSc, PhD J. Mey, PhD L. Nijs, MSc, PhD Prof. K. van Overbeeke, MD, PhD J. Prickaerts, PhD A. Saxena, PhD Prof. H. Steinbusch, PhD Prof. R. Stokroos, MD, PhD T. Strekalova, PhD J. Vangeneugden, MSc, PhD Prof. H. Vles, MD, PhD J. de Vry, PhD Prof. C. Webers, MD, PhD Prof. L. Zimmermann, MD, PhD Goals & Results The Division Neuroscience performs fundamental and translational neuroscience research on the biological mechanisms involved in experiencedependent neuroplasticity, neurodegeneration and regeneration across the life span. It should be noted that the division is currently developing and converging the activities of the different research lines as described below into the thematic research lines: 1. Neurobiology and Neuropsychopathology 2. Neuropsychopharmacology 3. Neuroinflammation 4. Neuromodulation Thus, we aim to gain knowledge of physiological and pathophysiological mechanisms underlying affective, cognitive and motor functions and disorders thereof and to develop strategies for improving healthy living, as well as preventing and treating neurological and psychiatric disorders. Our main research lines converge on cell signalling, regulation of neurotransmitter functioning, brain plasticity and biological mechanisms mediating gene-environment interactions (such as epigenetic control of gene expression and neuroinflammation) in a lifetime perspective. Thus, our neuroscience studies combine fundamental and clinical expertise and interests on developmental programming (including prenatal and perinatal life), experiencedependent plasticity during sensitive time-windows and age-related changes of the nervous system. Technological expertise in our division is centralised in our expertise groups that are coordinated by senior staff members and supported by experienced technicians. In addition to investigations on overt dysfunctions involving mainly the central nervous system such as in depression, dementia and psychosis, we also investigate mechanisms mediating central control of peripheral bodily function such as pain, vision and neuro-urogenital functioning. Our researchers conduct several study paradigms to answer clinically relevant research questions, typically by combining a range of techniques and approaches such as detailed cellular work, experimental animal studies as well as observational human studies and preclinical trials. The multidisciplinary staff consists of professionals from relevant disciplines within research and clinic. There are collaborations within world-wide Annual Report 2014 MHeNs 17

19 international networks of research offering a strong academic environment. By doing so, we attempt to improve scientific knowledge on healthy functioning of the brain, on the aetiology of disorders while translating relevant scientific findings swiftly into new neurotherapies including life-style interventional, pharmacotherapeutical, antibody-based or deep brain stimulation based strategies. The results of the research efforts in division 3 are described by the different Principal investigators and expertise groups. 18 MHeNs Annual Report 2014

20 2.3.1 Research lines Neurobiology and Neuropsychopathology Neuropsychopharmacology Neuroinflammation Neuromodulation Research Line: PI: Staff: PhD-students: Associated researchers: Focus of research: Neurobiology and Neuropsychopathology Alzheimer disease; neurodegeneration and posttranslational modifications of proteins F. Van Leeuwen, PhD Prof. H. Steinbusch, PhD R. Gentier Msc. Prof. D. Hopkins, PhD Protein quality control in Alzheimer s disease Efficient neuronal function depends on cellular homeostasis. In view of the modest number of human genes, other mechanisms such as posttranslational modifications (e.g., ubiquitination and phosphorylation) must contribute too many functions such as control of short-lived proteins, transcription factors and degradation of aberrant proteins. These homeostatic control mechanisms are often flawed during aging and disease. Our research focuses on quality control mechanisms such as exerted by the ubiquitin-proteasome system (UPS). We have discovered that mutant ubiquitin (UBB +1 ) accumulates in the hallmarks of Alzheimer s disease (AD), suggesting that it has a function in this multifactorial disease. Indeed, UBB+1 inhibits the UPS dose dependently and results in neuronal dysfunction. We developed tools (e.g., transgenic animals) to study the effects of UBB +1 in vivo. We have addressed anatomical, neurochemical and behavioural aspects (e.g., nest building, Morris water maze and fear conditioning) in these UBB +1 mice (line#3413) as well as genetic crossbreeds with the Alzheimer mouse model line (APP-Swe/PSEN1, exon9). Significantly, interactions between UBB +1 and Aβ plaque formation have already been shown, e.g., plaque load changes. Aβ plaque formation is a prominent cellular hallmark of AD. To date, immunization trials in AD patients turned out not to be effective in terms of curing or ameliorating dementia. However, in studies on transgenic animals (line 85; APP Swe PSEN1 exon 9) it was shown that there is limited clearance of pre-existing amyloid plaques. Most likely, immunization trials in humans were initiated too late, suggesting treatment of AD needs to start earlier which is not yet a realistic option. Therefore, more knowledge on the mechanism of Aβplaque formation is required before reconsidering trials. Our new data implicate that there is strong cross talk between a failing protein quality control by the UPS and Aβplaque formation mediated via specifically by γ secretase. For more than a decade a relation between a dysfunctional UPS and Aβ plaque formation has been surmised. Recently, it was shown that pooled GWAS studies, pathway analysis and proteomics also identified protein ubiquitination as one of the key modulators of AD and pointed to a dysfunctional UPS as a causative factor of AD. It is now possible to address this issue by using our transgenic lines (e.g., lines #3413 with postnatal UBB +1 overexpression and proteasomal inhibition, line#85 with Aβ plaque formation starting at 4 months of age and their crossbreed (i.e., lines #3413 x #85. What we know: In the crossbreed Aβ plaque generation is attenuated during the critical period by a dysfunctional UPS while γ secretase activity (not those of α and β) is enhanced resulting in impaired contextual memory. Apparently there is strong interaction between a failing protein quality control and Aβ plaque formation. What is not known: The mechanism of the link between the UPS and Aβ plaque formation is unknown. We surmise that the expression of E3 ligase synoviolin is upregulated and RER1 (retention in endoplasmic reticulum) is down regulated in the crossbreed. These results show a striking inverse correlation between γ secretase activities and Aβ plaque load and will contribute to a better understanding of strategies to ameliorate or cure AD, via γ secretase modulation. Interestingly, via stimulation of γ secretase. Annual Report 2014 MHeNs 19