VPH-DARE@IT Newsletter Issue 3

Newsletter Issue III - MARCH 2015

I N T H I S I S S U EEditorialProject Focus

Deliverable Reviews

Partner Profi les Empirica - Communication and

Technology Research ESI Group

Action Line Focus Yiannis Ventikos - UCL

People Matteo de Marco - USFD Toni Lassila - USFD

Research Highlights Advanced imaging proto-

col design and feasibility studies in volunteers

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Project coordinator: The University of Sheffi eld

Contact person: Professor Alejandro Frangi

Tel: +44 114 222 6071

Email: [email protected]

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Editorial

Welcome to the third issue to the VPH-DA-RE@IT newsletter! We are fast approaching the end of the second year of the project and we, in the PMO in Sheffi eld are busy preparing for the upcoming reporting period and review meeting. Preparations for these key milestones are already well underway in the project management offi ce, with dates already in the diary for our second review meeting in Brussels. The review will take place on Tuesday 26th and Wednesday 27th May 2015, and prepara-tions for this key milestone will be the focus of our 4th General Assembly meeting in Rotterdam in March 2015.The project has progressed well since the kick off in April 2013, and one of the strengths of the consortium is the quality of the deliverables produced and submitted to the European Commission. In this issue, project manager, Matthew Henry and reviewers Dr. Rainer Thiel and Prof. Jyrki Ltjnen tell us about the quality control procedures in place to ensure that the quality of the research output is consistent and maintained across the consortium. There has been a lot of activity since the last issue of the newsletter, and in this issue we hear from project partners on the activities taking place in the different workpackages. Prof. Yiannis Ventikos at UCL provides an update on the progress in Action Line 2, and Prof. Sebastian Kozerke at ETHZ tells us about the Advanced Imaging protocol design and feasibility studies taking place in workpackage 2.We also hear from project partners ESI and Empirica about their roles in the project, and we meet new members of the team, Dr. Toni Lassila (Research Associate) and Dr Matteo de Marco (Research Associate) at the University of Sheffi eld. We also catch up with Prof Alejandro Frangi who gave a keynote lecture about the project at the recent Alzheimers Research UK Yorkshire Network Scientifi c Meeting, hosted by Prof. Annalena Venneri at the University of Sheffi eld. We would like to thank all of our contributors for taking the time to talk to us about the work they have been involved in during the last 6 months. We have a lot coming up in the next few months, our 4th General Assembly and 2nd review meeting being two of the key challenges in the coming months. We hope you enjoy this issue of the newsletter, and as always, if you have any views, comments or suggestions for future issues, please do not hesitate to contact us: [email protected], we would love to hear from you!

Aisling CoolingVPH-DARE@IT Communications Offi cerCentre for Computational Imaging & Simulation Technologies in Biomedicine (CISTIB)Department of Electronic and Electrical Engineering - The University of Sheffi eldPam Liversidge Building Mappin Street Sheffi eld, S1 3JD T: +44 114 222 6071E: a.cooling@sheffi eld.ac.uk

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By Professor Jyrki Ltjnen (VTT), Dr. Rainer Thiel

(EMP), Dr. Matthew Henry (USFD)

A key output from VPH-DARE@IT is a number of deliverables, some

of which will be publically available. To ensure these deliverables are of the

highest quality and meet with the European Commissions requirements, we have an internal

quality-control (QC) process in place. Here, we highlight the importance of the process and how it adds value to each

deliverable and the project as a whole.

The QC process covers all aspects of producing deliverables. Each deliverable is subject to 3 levels of quality control prior to submission to the European Commission. These levels are:

1) An initial review of the deliverable by the Work Package Leader to be completed within 10 working days.

2) An internal peer review process by two of the projects researchers who have not been involved in its preparation. This review is to be completed at least 3 weeks before the deliverable due date.

3) A final check by the PMO to ensure consistency with other project deliverables.

The Project Management Office (PMO) will provide reminders to deliverable authors and their respective Work Package Leaders to identify suitable internal reviewers at least 3 months in advance of the first draft being available for review.

The initial draft of the deliverable should be completed at least 6 weeks prior to the final submission date. Deliverable authors are to use the Deliverable template, the latest version of which is available in the Documents Manager on EMDesk. Once the deliverable has been reviewed and revised accordingly, the PMO will upload a copy to EMDesk and submit a copy to the European Commission for acceptance.

The QC process is an important feature of the project and was highlighted in the Period 1 Review by the independent reviewers, who remarked that it constitutes one of the strong parts of the project.

When writing a deliverable for an EU project, authors should keep in mind the target audiences for whom the document is written. There are basically two main target groups:

1) independent reviewers set by the European Commission (EC)

2) scientists and other people interested in the topic, either from within or outside the project.

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Deliverable Reviews

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Independent reviewers

Deliverables are the main source of information for the EC to assess whether the project has progressed as planned, i.e., as promised in the description of work (DoW). Independent reviewers perform the work on behalf of the EC. In summary, they are asked to evaluate the following aspects: progress towards objectives set in the DoW, progress of each individual work package, progress towards each milestone and deliverable specified in the DoW, relevance of the plans for the next period, use of resources, management, collaboration between beneficiaries, roles of beneficiaries, impact and exploitation (especially on SMEs), dissemination, involvement of potential users and stakeholders, and finally, links with other projects.

Not all these issues are expected to be covered in each deliverable, but it is good to keep in mind that identifying links to the bigger picture is important, as well as describing the topic of the deliverable. In addition, it is important to remember that reviewers cannot be experts on all the possible topics covered in each deliverable arising from such a big project. Therefore, the text should be written in such a way that people with common knowledge of science and engineering are able to comprehend the message without the need for extensive background reading. All authors who have acted as reviewers for journal papers know that reading fluent text leads to a more positive review of a manuscript.

Scientists and other people interested in the topic

These people read deliverables in order to learn information about the topic, and this audience appreciates a well-structured and well-written document. The majority of the VPH-DARE@IT deliverables are confidential which means that they are intended to deliver information just to the project team, in addition to independent reviewers. However, some deliverables are public which means that anyone interested in the project and topic area can access them. This aspect makes it important to have supreme quality and give a good impression of our work.

The internal review process has been set up in the project with the aim of checking that the quality of deliverables meets the needs of our main audiences. Authors of deliverables may think that their deliverable is just there to meet contractual obligations but that is only a part of the picture. To maximise motivation and other benefits, authors could consider the writing process as the first step towards a scientific publication, which will be of interest to most of team members.

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Dr. Matthew HenryVPH-DARE@IT Project Manager / WP10 LeaderCentre for Computational Imaging & Simulation Technologies in Biomedicine (CISTIB)Department of Electronic and Electrical EngineeringMappin Street Sheffi eld, S1 3JD T: +44 114 2229736E: m.henry@sheffi eld.ac.uk

What is empirica?empirica was founded in 1988 in Bonn, Germany, the birthplace of Beethoven. But unlike him, empirica did not leave for Vienna and today it is a leading European research institute in eHealth concepts, policies, strategic development, clinical and socio-economic impact, technology assessment and business development and is participating in fi ve VPH-related projects: VPH-DARE@IT, DISCIPULUS, VPH-Share, VPHOP, and NMS Physiome.

Building on its expertise in the VPH arena and through collaboration with the clinical, research and industrial communities, Empirica was a leading partner in the Discipulus project, drafting the research roadmap for the realisation of the Digital Patient Initiative that will be used to provide an integrative framework for Personalised, Predictive, and Integrative Medicine.

Empirica regularly undertakes assessment and evaluation studies of complex eHealth RTD developments and ICT-enabled systems and solutions applied to healthcare, including developing exploitation strategies and business

Empirica - Communication and Technology Research (EMP)

By Klaus Piesche

What is empirica?

iesche By Klaus Pi

gg pulus project, drafting the research roadmap for the er in the Discipucommunities, Empirica was a leading partneo provide an integrative framework for Personalised, at will be used torealisation of the Digital Patient Initiative tha

Predictive, and Integrative Medicine.

tudies of complex eHealth RTD developments andand evaluation stEmpirica regularly undertakes assessment auding developing exploitation strategies and business o healthcare, incluICT-enabled systems and solutions applied to

What is empirica?empirica e of Beethoven. But unlike him, empirica did not leave any, the birthplacewas founded in 1988 in Bonn, Germa

e in eHealth concepts, policies, strategic development, research institutefor Vienna and today it is a leading European rand business development and is participating in fi ve ogy assessment aclinical and socio-economic impact, technoloare, VPHOP, and NMS Physiome. PULUS, VPH-ShaVPH-related projects: VPH-DARE@IT, DISCI

llaboration with the clinical, research and industrialand through coBuilding on its expertise in the VPH arena

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Mr. Klaus PiescheResearcherEmpirica - Communication and Technology Research (EMP)Oxfordstr. 2D53111 BonnGermany T: +49 228 9853050 E: [email protected]

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plans, usually as international project leaders. It has also undertaken research on eHealth strategy development and implementation by EU States, on market trends, including establishing the EC database of good practice case studies, and has performed foresight exercises. An acclaimed EU impact assessment of eHealth solutions (eHealth IMPACT) was published in 2006.

The role of empirica in VPH-DARE@IT Empirica coordinates the evaluation and exploitation work package (WP9) and plays a role in dissemination and community building activities. Furthermore, empirica provides both clinical and socio-economic expertise on evaluation and impact assessment, patient safety, eHealth concepts and framework, and will liaise with external experts and the European Commission.

Key Activities Assessment Framework Approach and Indicator Development of VPH-DARE@ IT Health Technology Assessment (HTA) Clinical impact assessment and socio- economic cost-benefi t assessment Integrating and Exploiting the Environmental Dimension in VPH-DA RE@IT Market Analysis Exploitation and Business Planning

Key people Dr. Rainer Thiel: is the leader of workpackage 9 (Technology Assessment, Market Analysis and Exploitation). Rainer leads the research on clinical and socio-economic impact and technology assessment in the VPHOP, MD-Paedigree, and VPH-SHARE projects, and now fuses his experience into VPH-DARE@IT. As a member of Health Technology Assessment International, he has been publishing about validation and economic assessment frameworks for the application of innovative and disruptive health technologies and ICT infostructures.

Dr. Veli Stroetmann: With all of her experience as project coordinator and Principal Investigator in various eHealth projects, Veli greatly contributes to WP9 not only with her knowledge, but also with completely new trains of thought regarding integrating and exploiting the possible projects outcomes.

Dr. Karl Stroetmann: Being empiricas grand seigneur of economic impact assessment, Karl contributes many ideas on conceptual and policy issues to VPH-DARE@IT, especially in the socio-economic area when it comes to indicator development. For over 20years, his research has focused on the application of IT in the health sector.

Christianne Lavin: Christianne is our student assistant. If there would be a Master of Literature

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Research, Christianne would most surely graduate with highest honours. With her background in applied biology she is a vital contribution to empiricas team.

Klaus Piesche: is a junior research consultant at empirica. His responsibilities in the project are to carry out research on Business Modelling, Big Data Analysis and Health Technology Assessment.

We spoke to Klaus about his role in the project and when asked what he found most interesting about the project, he said that getting to know the different people involved in the project has been very interesting. He went on to say that on a technical level, it is highly impressive to see how the team tries to reduce the immanent friction losses in such a big project. I really do believe that this project, with all the expertise of the consortium members, will have an impact on the wellbeing of European citizens.

Working with the different people involved in the project clearly appeals to Klaus and he went on to

say that he enjoys the atmosphere of many people from all over Europe working together, discussing, wholeheartedly arguing over the big picture as well as over apparently non-relevant details (which ever so often later prove to be quite essential).

The Challenge for empiricaThe most challenging part of the project for empirica is to get a picture on how dementia is currently diagnosed in different countries and to input this into an impact assessment model whose environmental variables change steadily.

The teams involvement in VPH-DARE@IT will allow empirica to establish itself in another clinical community. As recent projects allowed for contact with key clinical experts in osteoporosis, now expert knowledge on neurodegenerative diseases further feeds and broadens the understanding of socio-economic impact assessment and user needs in clinical, research and industrial communities. With all this in hand, empirica hope to be able to deliver even better support when it comes to exploitation of the VPH-DARE@IT results.

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y graduate t surelyd in applied kgroundicas team.biollogy she is a vital contribution to empir

Klaaus Piesche nsultant at : is a junior research coect are to emppirica. His responsibilities in the projeg, Big Data carrry out research on Business Modelling

Anaalysis and Health Technology Asssessment.

Wee spoke to Klaus about his rolein tthe project and when askedwhaat he found most interestingaboout the project, he said thatgettting to know the differentpeoople involved in the project has

that on a beeen very interesting. He went on to say ee how thetechhnical level, it is highly impressive to seon losses in teamm tries to reduce the immanent frictiothis project, suchh a big project. I really do believe that tembers, will withh all the expertise of the consortium mean citizensan citizens .havee an impact on the wellbeing of Europeahavee an impact on the wellbeing of Europea

ved in the Woorking with the different people involvwent on toprooject clearly appeals to Klaus and he w

say that he enjoys the atmosphere of many people e from all over Europe working together, discussing, wholeheartedly arguing over the big picture as wellas over apparently non-relevant details (which ever so often later prove to be quite essential).

The Challenge for empiricahe most challenging part of the oject for empirica is to get picture on how dementia is rrently diagnosed in different untries and to input this into

impact assessment model hose environmental variablesange steadily.

The teams involvement in VPH-DARE@IT will allow empirica to establish itself in another clinical community. As recent projects allowed for contactcommunity As recent projects allowed for contactwith key clinical experts in osteoporosis, now expertknowledge on neurodegenerative diseases further feeds and broadens the understanding of socio-economic impact assessment and user needs in clinical, research and industrial communities. With allthis in hand, empirica hope to be able to deliver even better support when it comes to exploitation of theVPH-DARE@IT results.

Ressearch, Christianne would mostwithh highest honours. With her backbiollogy she is a vital contribution to

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went on to prooject clearly appeals to Klaus and he w

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I really do believe that this project, with all the expertise of the consortium members, will have an impact on the

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on a technical level, it is highly impressive to see how the team tries

to reduce the immanent friction losses in such a big project

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What is ESI

ESI Group is a pioneer and world-lea-ding provider of digital simulation soft-ware for prototyping and manufactu-ring processes that take into account the physics of materials. ESI Group has developed an entire suite of coherent, industry-oriented applications to rea-listically simulate a products behaviour during testing, to fi ne-tune the manu-facturing processes in synergy with the desired product performance, and to evaluate the environments impact on product usage.

ESI Group

By - Mustafa Megahed

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With the collaboration of nearly 1000 high-level specialists worldwide, the company and its global network of agents provide sales and technical support to customers in more than 30 countries.

Within the health care sector ESIs Multiphy-sics suite of tools CFD-ACE+ is widely used to model different pathologies and micro de-vices used in diagnostics and drug delivery.

Expertise

ESIs CFD and Multi-physics Centre of Ex-

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Dr. Mustafa MegahedResearcherESI GroupESI Group Headquarters ESI Group 100-102 Avenue de Suffren 75015Paris, FranceE: [email protected]

partnerscellence (CoE) focuses on the development of novel simulation techniques for advanced appli-cations. Typically, these cutting-edge solutions are pursued in collaboration with partners from industry and research organizations. Team mem-bers have different scientifi c and engineering backgrounds, which ensure the multi-disciplinary expertise required to solve technological cha-llenges.

The role of ESI in VPH-DARE@IT

We talked to Dr. Mustafa Megahed about the role of ESI in VPH-DARE@IT, and how they became involved in the project. Mustafa told us that several collaborations were pursued with some of the project partners. The mo-delling work required for VPH-DARE@IT analysis seemed like a good extension to the existing collaborations building on tools al-ready proven and in use towards next gene-ration multi-scale modelling tools. ESI was involved in some of the first discussions about scope and selection of possible methods to approach the challenge.

The main contribution of ESI to VPH-DARE@IT is the simulation of fl uid-structure interaction processes in the human brain. The objective is to gain a better understanding and a reliable, patient specifi c prediction of the infl uence that different factors may have on fl uid fl ow and the interac-tion between different compartments and how that might affect the development of dementia disease.

The main challenges in this endeavour stem from the multi-physics nature of the problem. These aspects in particular relate to the interaction of blood, CSF, and human tissue, which is porous in nature. Simulating this interaction necessitates the coupling of fl uid fl ow with elastic and multi-

compartmental poroelastic materials, where the latter are governed by the so-called MPE theory developed by UCL.

Key PeopleMembers of the CFD and Multiphysics Centre of Excellence are involved in this large project. The principle investigators are:

Dr. Joerg Willems, has a background in numeri-cal analysis and has previously worked on multi-scale problems e.g. related to fl ow in porous me-dia. Currently, he is collaborating with colleagues from other ESI offi ces to integrate the simulation tools relevant for VPH-DARE@IT in a coupling platform.

Dr. Mustafa Megahed, has more than 25 years of experience in the development of numerical algorithms and modelling. He is currently focus-sing on the interaction of pulsation blood fl ow with CSF in perivascular vessels. The interaction between the blood, the tissue and the freely avai-lable CSF leads to a form of CSF pumping the cause of which is being studied numerically.

Contributions to the project

The contribution of ESI to VPH-DARE@IT is in the coupling of different physical aspects relevant for simulating processes in the human brain. To achieve this ESI develops a platform that facili-tates the interaction of otherwise independent simulation tools. For this the platform adopts a plugin strategy, which is particularly suitable as it allows the coupling of different solvers without having to go through an expensive and error-pro-ne process of reengineering. The different physi-cal processes that will be coupled in this effort are fl uid fl ow, elasticity and multicompartmental poroelasticity. The overall coupled solution is targeted to be performed on computational do-

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mains resulting from MRI scans.

In parallel to the extremely ambitious platform development effort, existing tools are applied to investigate different details such as perivascular vessels.

We asked Mustafa what he found most interesting about being part of VPH-DA-RE@IT. He told us that in his opinion, the most interesting aspect about being part of VPH-DARE@IT is the collabora-tion with researchers and practitioners from various disciplines. This combined with the prospect that the outcome of this mutual effort may in fact signifi cantly improve the qua-lity of life of many

mains resulting from MRI scans.

In parallel to the extremely ambitious platform development effort, existing tools are applied to investigate different details such as perivascular vessels.

We asked Mustafa what he found mostinteresting about being part of VPH-DA-RE@IT. He told us that in his opinion, the most interesting aspect about being part of VPH-DARE@IT is the collabora-tion with researchers and practitioners from various disciplines. This combined with the prospect that the outcome of this mutual effort may in fact signifi cantly improve the qua-lity of life of many

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y Bringing together ideas from people with different backgrounds is in my opinion an essential ingredient for a successful outcome of such a broad

collaboration.

people across Europe and around the globe is extremely fascinating and moti-vating.

The Challenge

Mustafa went on to say that being part of a large interdisciplinary project is cer-tainly one of the main challenging and mo-tivating aspects. Bringing together ideas from people with different backgrounds is in my opinion an essential ingredient for a successful outcome of such a broad collaboration. Putting our contribution in the overall framework such that colla-borators gain the maximum output from

our work is proba-bly the biggest cha-

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llenge. Meeting this task necessitates the suc-cessful communication across disciplines, which can be rather complicated and rewarding at the same time.

The Future

The immediate pros-pect for ESI is a suc-cessful implementation of a flexible coupling platform. This will enable the implemen-tation of solutions required within VPH-DARE@IT and will take Fluid-Structure-Interac-tion solutions to the next generation solution, where components can be included or excluded

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The outcome of this mutual effort may in fact signifi cantly improve the quality

of life of many people across Europe and around the globe is extremely

fascinating and motivating

without extensive effort enabling the applica-tion of specialized tools for the problem at hand. In the case of VPH-DARE@IT these tools will include computational fluid dynamics (CFD), finite element analysis (FEA) multicom-partmental poroelasticity (MPET).

A broader prospect for ESI may be the fu-ture engagement in si-milar research efforts with a pronounced physiological emphasi-ze, which traditionally has not been the focus

of our company, but nonetheless fits ESIs core competences of providing cutting-edge simula-tion solutions.

Infl uence of perivascular pulsation on CSF fl ow rate

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In this issue, we get an update from Professor Yiannis Ventikos about the activities taking place in Action Line 2

Collaboration activities We have worked closely with ESI, establishing the necessary links between the UCL-based poroelastic

code and the software that will be used as the simulation platform that will represent the transport processes in the cerebral environment.

We have had important discussions with the Sheffi eld team regarding the modelling of lifestyle and circadian infl uences, and how these very important concepts embed themselves with the platform headed by our partners in ESI.

Furthermore, our discussions with the Sheffi eld team have also prompted the prospect of using the novel poroelastic methodology within a different setting. We call this aspect of the work the LifeV Project and we hope that a mature version of the methodology will be coded in an open source, modern and modular environment.

Active collaboration between UEF and VTT (both WP4) to transfer global transcriptomics from UEF for stochiometrical metabolite modeling at VTT (fi rst data submitted to the VTT in November 2014)

Interactions of WP4 with AL1 (particularly WP1) to derive clinical data (from WP1) for metabolomics analysis used as input in WP4.

Action Line Achievements We can highlight the testing of the coding of the MPET model in the fi nite element framework.

Further, we can highlight the development of an idealised fi rst-principles representation of the perivas-cular glymphatic system, where transport and clearance features are studied.

In WP4, we obtained the fi rst results of metabolite modelling based on transcriptomics data with clus-tering data on gene level and investigation into clustering according to Braak stages

In WP4, we extended the kinetic metabolic model to include the Pentose-Phosphate Pathway

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esentation of the perivas-

criptomics data with clus-stages

osphate Pathway

Prof. Yiannis VentikosResearcherUniversity College LondonDepartment of Mechanical Engineering - The University of Sheffi eldGower St London London, United KingdomT: +44 20 7679 2000

Multifactorial & Multiscale ModellingBy Yiannis Ventikos


Activities plannedThe following activities are planned for the next 6 months

1. Prototype release of 3D multiporoelastic brain model into ACE+ (WP5)2. Preliminary report on microscale water transport findings based on in silico

tools (WP5)3. Circadian and lifestyle models of physiological and physical dynamics in normal

subjects of dementia (WP5)4. Database for relevant biomarkers and their interdependencies with environ-

mental and lifestyle factors as captured by metabolic network model (WP4)5. Methods for connectivity modelling and how they can be used for generating

hypothesis to test mechanistic models (WP6)6. Methods for risk-scoring of dementias(WP6)7. Software tool implementing generative 3D+t spatiotemporal models of the

ageing brain: virtual population for biophysical modelling (WP6)

PublicationsJournal Articles

Vardakis J C, Chou D, Tully B, Hung C C, Lee T H., Tsui P-H., Ventikos Y (submitted). Investigating Cerebral Oedema using Poroelas-ticity. Medical Engineering & Physics.

Vardakis J C, Chou D, Tully B, Ventikos Y. The impact of nonlinear permeability on a Multicompartmental model of Poroelas-ticity. Annals of Biomedical Engineering, in preparation.

Vardakis J C and Ventikos Y . A Novel Model of Hydrocephalus using Multicompartmental Poroelasticity. Journal of Compu-tational Physics, in preparation.

Szokol K, Heuser K, Tang W, Jensen V, Enger R, Bedner P, Steinhuser C, Taubll E, Ottersen OP, Nagelhus EA. Augmentation of Ca2+ signaling in astrocytic endfeet in the latent phase of temporal lobe epilepsy. Frontiers in Cellular Neuroscience, in press.

Tang W, Szokol K, Jensen V, Enger R, Trivedi C, Hvalby , Helm PJ, Looger LL, Sprengel R, Nagelhus EA. Stimulation-evoked Ca2+ signals in astrocytic processes at hippocampal CA3-CA1 synapses of adult mice are modulated by glutamate and ATP. The Journal of Neuroscience, in press.

Pettersen KH, Lindn H, Tetzlaff T, Einevoll GT. Power Laws from Linear Neuronal Cable Theory: Power Spectral Densities of the Soma Potential, Soma Membrane Current and Single-Neuron Contribution to the EEG. PLoS Comput Biol. 10(11):e1003928 (2014)

Conferences and WorkshopsVardakis JC, Chou D, and Ventikos Y, Understanding Hydrocephalus using a Multicompartmental Poroelasticity Model, The 18th International Conference on Finite Elements in Flow Problems (FEF2015), 16-18 March 2015, Taipei, Taiwan

Vardakis JC, Chou D, Tully BJ & Ventikos Y, Multicompartmental Poroelasticity for the Integrative Modelling of Fluid Transport in the Brain, 9th European Solid Mechanics Conference (ESMC 2015), July 6 - 10, 2015, Legans-Madrid, Spain.

Frangi AF, Lassila T, Vardakis JC, Ventikos Y, Multiscale Modelling of Transport Phenomena in Biological Tissue, 4th International Conference on Computational and Mathematical Biomedical Engineering - CMBE2015, 29 June-1 July 2015, France.

Vardakis JC, Chou D, Tully BJ & Ventikos Y, A CFD and FEM Approach to a Multicompartmental Poroelastic Model for CSF Production and Circulation with Applications in Hydrocephalus Treatment and Cerebral Oedema, 4th Micro and Nano Flows Conference UCL, London, UK, 7-10 September 2014

Vardakis JC, Chou D, Tully BJ & Ventikos Y, Exploring a Multicompartmental Poroelastic Model for the Integrative Modelling of Fluid Transport, 7th World Congress of Biomechanics, Boston, Massachusetts, July 6-11, USA

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Background and Research

My name is Matteo De Marco and I am a Research Associate within the De-partment of Neuroscience at the Univer-sity of Sheffield. While my undergraduate background is in psychology, my postgra-duate studies have explored the field of neuroscience (with a focus on neurode-generation) more widely, incorporating elements of sport sciences, genetics and especially neuroimaging. As part of the Translational Neuropsychology team led by Professor Annalena Venneri, my research interests have focused over the last 2 years on non-pharmacological treatments for early-stage Alzheimers di-sease. Particularly, I have investigated the ample field of cogniti-ve stimulation and the mechanisms by which this form of inter-vention can trigger meaningful changes in brain structure and brain function.

What is your specific role in VPH-DARE@IT?

I will be involved in multiple stages of data collection for the prospective stu-dy, data analysis, and dissemination of fin-

dings and more broadly I will be involved in a range of studies which will use large retrospective datasets for addressing re-search questions related to the improve-ment of early detection of dementia.

What do you fi nd most interes-ting about the VPH-DARE@IT project?

The idea of IT giving a significant contri-bution to diagnostic routines is innovati-

ve, and might have a decisive impact on the clinical set-ting. However, what I find most interes-ting in this project is the exploratory nature of this in-vestigation. In fact,

the IT-dependent methods of data analy-sis will have the chance to process a very large set of variables, many of which are not normally used in clinical practice be-cause of their obscure interpretation. This is a great opportunity to shed new light on the hierarchies of brain structure and function, their interaction with individuals life style choices and what their importan-ce is in relation to disease.

Matteo De Marco USFD / University of Sheffi eld


ave focused over

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This is a great opportunity to shed new light on the hierarchies of brain structure and function, their

interaction with individuals life style choices and what their importance is

in relation to disease.

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What do you as a researcher find most challenging about working in VPH-DARE@IT?

I believe that a major challenging aspect of this project associated with my role will be adapting the specific interest of the research questions to the dynamics of the clinical setting. It will take effort to address the clinical needs of pa-tients and, at the same time, acquire data while sticking perfectly to the research methodolo-gical guidelines.

How do you find working as a part of a large collaborative project?

I think that the interna-tional dimension of the VPH-DARE@IT project is a great opportunity for my personal professional growth, as I will have the chance to expand my re-

search interests and, possibly, start new colla-borations. I am looking forward to attending my very first General Assembly meeting in Rot-terdam in March 2015.

How has working on VPH-DARE hel-ped to develop your career?

Being part of the VPH-DARE@IT has offered me a number of opportunities. I have now the possibility of being involved for the first time in a multicentre project, enrich my CV, and ex-pand my professional network on a worldwide scale. Moreover, the ambitious nature of this project will allow me to be part of a research output which has the potential to have a lar-

ge impact on the study and management of neurodege-nerative conditions, but, at the same time, might also help me identify new inter-esting research avenues for my future career.


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The ambitious nature of this project will allow me to be part of a research output which has the potential to have a large impact on the study and management of neurodegenerative conditions.

w w w . v p h - d a r e . e uw . v p h - d a r e . e uw w w

Toni Lassila USFD / University of Sheffi eld

Background and researchAt some point during my university studies in Finland I realised that research was the one profession that truly interested me. I subse-quently received my doctorate in mathematics from Aalto University in 2010. Since then I have worked more than three years as a post-doc at EPFL in Switzerland and moved to Sheffi eld in August 2014 to work as a research associate on VPH-DARE@IT.

While my training is in the fi eld of mathematics, I have always wanted to work on a topic that is connected to helping people and society on ge-neral, and healthcare-related projects like VPH-DARE@IT are a great opportunity for that. For several years now I have been working on mathematical modelling and simulation of fl uid dynamics in biomedical applications. This work has been mainly focusing on specifi c techniques that fall under the umbrella of model order reduction, which means taking a mathematical model that is very complex but describes the system being studied well, and trying to reduce it to something that is much faster to solve on a computer but still describes the system almost as well as the original model. In the past I have applied these tools to the simulation of the car-diovascular system, such as modelling the fl uid dynamics in the left ventricle of the heart or studying the effect of the fl ow uncertainty and shape of the end-to-side anastomosis have on


VPH-DARE@ IT


coronary bypass graft performance.

What is your specifi c role in VPH-DARE@IT?

I am currently working with Luigi Di Marco at the University of Sheffi eld to try to specify the requirements for a model of the systemic cir-culation and autonomous nervous system that will provide input to the poroelasticity models of the brain being developed at UCL. This is not unlike what I have worked with in the past, except that this time the model needs to in-corporate the effect of lifestyle factors and is driven by an experimental study starting early 2015 as part of VPH-DARE@IT. Trying to build personalised models that provide clinically pre-dictive results is always challenging. Afterwards we plan to move on to the problem of deve-loping a mathematical model for the synthe-sis, transport, clearance and accumulation of amyloid-, the peptide thought to be mainly responsible for Alzheimers disease, and incorporating it into the fluid dynamics models. That is quite a daunting task, I must say.

What do you fi nd most interes-ting about the VPH-DARE@IT project?

The prospect of using magnetic resonance elas-tography and functional magnetic resonance

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ary bypass graft performance.

at is your specifi c role in VPH-RE@IT?

currently working with Luigi Di Marcoo atniversity of Sheffi eld to try to specify ttherements for a model of the systemic cir-f d l f h i ion and autonomous nervous system tthatrovide input to the poroelasticity moddels brain being developed at UCL. Thiss is

nlike what I have worked with in the ppast, t that this time the model needs to in-rate the effect of lifestyle factors andd is by an experimental study starting eaarly as part of VPH-DARE@IT. Trying to buuild nalised models that provide clinically ppre-e results is always challenging. Afterwaards an to move on to the problem of deeve-

What do you as a researcher fi nd most challenging about working in VPH-DA-RE@IT?For me, it is understanding the clinical aspects of de-mentia and its causes. While I have worked on pro-jects with strong clinical research interests before, they have not looked at one specifi c clinical question in such all-encompassing way to sort of try to attack the problem from all angles at once (imaging, mo-delling, simulation, software platforms for diagnosis). VPH-DARE@IT is also the fi rst project I have wor-ked on which explicitly tries to model some of the complex mechanisms of the human brain.

How do you fi nd working as a part of a large collaborative project?

This is the third large European project I have been involved in. They are always very challenging because there are many deadlines and deliverables and equally many opinions and personalities. It is interesting to observe how things progress in a kind of self-orga-nised chaotic system of multiple independent actors - obstacles are met and then overcome, methodolo-gies are tweaked and experiments undertaken, and in the end a kind of consensus scientifi c idea emerges

Have you attended any of the VPH-DARE@IT project meetings and if so, what benefi ts did you get from atten-ding these events?

I attended the General Assembly Meeting in Man-chester last September. There I had the opportunity to see and meet a lot of brilliant people with exper-tise in different topics. It allowed me to really appre-ciate the diffi culty and importance of the problem.

How has working on VPH-DARE hel-ped to develop your career?

For anyone looking to one day run their own Eu-ropean project its enlightening to see how such a complex multi-national project is managed on a day-to-day basis. From a scientifi c point of view the diffi culty of even understanding, let alone modelling, something as complex as the causes and onset of Alzheimers disease really forces one to look at the clinical question and re-evaluate what I as an applied mathematician and modeller think is relevant. Being involved in VPH-DARE@IT certainly gives me more credibility when I try to convince people that mathe-matical modelling is not just a theoretical toy but an actual tool in future clinical studies, provided that fundamental clinical science is the driving force be-hind it.

17

Being involved in VPH-DARE@IT certainly gives me more credibility when I try to convince people that mathematical modelling is not just a theoretical toy but an actual tool in future clinical studies


nd most What do you as a researcher fi nPH DAPH-DA-challenging about working in VPchallenging about working inVP

RE@IT?ects of de-Forr me, it is understanding the clinical aspeed on pro-mentia and its causes. While I have workests before, jectts with strong clinical research interesal question theey have not looked at one specifi c clinicay to attack in ssuch all-encompassing way to sort of tryaging, mo-thee problem from all angles at once (imadiagnosis). delling, simulation, software platforms for have wor-VPHH-DARE@IT is also the fi rst project I me of the kedd on which explicitly tries to model so

commplex mechanisms of the human brain.

from the primordial soup of all the individual contributions.

Have you attended any of the VPH-DARE@IT project meetings and if so, what benefi ts did you get from atten-ding these events?

I attended the General Assembly Meeting in Man-chester last September. There I had the opportunity to see and meet a lot of brilliant people with exper-tise in different topics. It allowed me to really appre-ciate the diffi culty and importance of the problem.

gHow has working on VPH-DARE hel-ped to develop your career?

For anyone looking to one day run their own Eu-ropean project its enlightening to see how such a complex multi-national project is managed on a day-to-day basis. From a scientifi c point of view thediffi culty of even understanding, let alone modelling, something as complex as the causes and onset of Alzheimers disease really forces one to look at the clinical question and re-evaluate what I as an applied mathematician and modeller think is relevant. Being involved in VPH-DARE@IT certainly gives me more

imaging to non-invasively determine both the structure and function of the brain in vivo is fascinating and provides a very strong experimental basis on which to build mathematical models. It also seems that accumulation of amyloid- within the endothelium has a key influence on cerebral blood flow and that might be one of the key factors in the onset of Alzheimers disease. That to me is a great motivation to continue my work on the mathematical modelling techniques for blood flow in the arteries that I have pursued for the past several years.

Resear

Advanced imaging protocol design and feasibility studies in volunteers

One of the major pieces of work delivered in the last 6 months has been the development of the Advanced Imaging protocol design and feasibility studies in volunteers. In this issue, Prof. Sebastian Kozerke at ETH Zurich tells us about the work being undertaken in workpackage 2, what has been achieved to date and what work needs to be done.

What is MRSUB2?

MRSUB2 is a set of advanced MRI scan protocols to obtain hemodynamic and microstructural information of the brain. The information will help in mechanistic model development and potentially provide new tools with improved sensitivity and specifi city for disease staging and patient stratifi cation. Beyond structural information, MRSUB2 will assess the stiffness and complexity of vasculature, perfusion and viscoelastic properties of brain tissue.

Implementation

Since the functionality offered with MRSUB2 is not part of standard MRI scan software, so-called patches have been developed to replace product MRI software components. Using dedicated programming tools provided by Philips, the vendor of the clinical MRI platform used here, and the image reconstruction framework developed by GyroTools, a Master patch has been created which implements the necessary extensions. Software development has been conducted according to rules and guidelines required for ethical approval to perform scanning on volunteers and patients.

Testing

Initial testing of the Master patch has been carried out on healthy volunteers recruited locally at ETH Zurich. The Master patch is distributed to Klinik Hirslanden and the University of Sheffi eld, which will scan sub-cohorts of the prospective patient population scheduled.


VPH-DARE@ IT

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Diffusion

Perfusion Fraction

By Prof. Sebastian Kozerke

13

VPH-DARE@IT PartnersDuring the development and data acquisition stage, Ralph Sinkus (Kings College London), Iain Wilkinson (University of Sheffi eld) and Isabel Wanke, Daniel Ruefenacht (Klinik Hirslanden) have been involved. Parts of the image reconstruction software development have been carried out by GyroTools, an SME partner based in Zurich. At a later stage, data will be made available to partners concerned with mechanistic modelling including the groups of Yiannis Ventikos (University College London) and Alex Frangi (University of Sheffi eld).


PrepT1,T2

MultiBandDiffusion

MultiVencFlow MRE

DiffusionPerfusion

ODFsKurtosis

Velocity MKE/TKEPulsatilityTransfer

8:30 3:00 6:00

Advanced MR Imaging Protocol

Current statusThe Master patch including methods for assessing stiffness and complexity of vasculature and perfusion has successfully been implemented and tested. The patch is available for Philips SW releases 3.2.2, 4.1.3 and 5.1.7 which are run by Kings College, ETH Zurich and Clinic Hirslanden.

The next phaseCurrently, the hard and software components necessary for quantifying viscoelastic properties as developed by Kings College await integration. A key challenge faced relates to different MRI SW upgrade strategies at different sites. Since the University of Sheffi eld has upgraded their MRI system to SW release 5.1.8 recently, another software merging step is required during the next weeks. Once this step is completed and ethics approval is in place, patient recruitment can commence.

Prof. Sebastian KozerkeResearcherThe Swiss Federal Institute of Technology Zrich (ETHZ)ETH Zrich Prof. Dr. Sebastian Kozerke Institut f. Biomedizinische Technik ETZ F 94Zurich, SwitzerlandT: +41 44 632 35 49E: [email protected]

EventsEventsIn October 2014, a community of scientists researching Alzheimers disease across Yorkshire, UK met at the University of Sheffi eld for a day of scientifi c networking. Professor Annalena Venneris (WP1) Translational Neuropsychology Group at the University of Sheffi eld hosted the annual meeting of the Alzheimers Research UK Yorkshire Research Network. When asked of the purpose and the importan-ce of the event, Professor Venneri said: The annual ARUK Network scientifi c and public meetings not only crucially support collabora-tions and scientifi c exchange required to drive our research forward, but also increase public awareness to help people understand more about this cruel condition that affects so many people. I am delighted to be part of a team that is working hard to defeat dementia and raise awareness through events like this.

The meeting was well attended with over 40 researchers, clinicians and acade-mics from across Yorkshire, attending the meeting to network and disseminate progress and results of Alzheimers research in the region. A broad range of Alzheimers research was presented from neuropathology and basic neuroscien-ce to computational modelling, clinical and psychosocial aspects to applied inter-ventions. VPH-DARE@IT Coordinator, Professor Alejandro Frangi attended the meeting and gave a keynote lecture about VPH-DARE@IT and Computational imaging

and modelling for the understanding and diagnosis of dementias. Professor Frangi said: The event was an opportunity to disseminate the vision and progress made in VPH-DARE@IT to the community of Alzheimers researchers in Yorkshire. This community is very interdisciplinary with a mix of basic scientists, neuroscientists, social scientists, neurologists, psychiatrists, psychologists all with a broad knowledge of Alzheimers disease and other dementias who are open to learn from researchers in enginee-ring and physical sciences that share their interest in combatting Alzheimers disease. Members of the VPH-DARE@IT team also atten-ded the meeting and presented posters on their research in the project. Dr Rosa Sancho, representing Alzheimers Re-search UK (ARUK), gave an update on funding opportunities and grant schemes pointing to cu-

VPH-DARE@IT at the Alzheimers Research UK Yorkshire Network Scientifi c Meeting 2014 By Monika Feigenbutz

ed d

Professors Annalena Venneri, Paul Ince and Stephen Wharton (from left to right) hosted the ARUK York-shire Network Meeting at SITraN, University of She-ffi eld in October 2014.

Prof. Alejandro FrangiProject Coordinator


-r

-g -

The annual ARUK Network scientifi c and public meetings not only crucially support

collaborations and scientifi c exchange required to drive our research forward, but also increase public awareness to help people understand

more about this cruel condition.

rrent ARUK priorities including interdisciplinary research pro-jects, training and capacity building, resources, drug discovery and supporting the 15 Alzheimers Research Networks. Translational research is a clear focus, bridging the gap between research and drug development. Dr Sancho welcomed that the additional funding for Alzheimers Research pledged by the go-vernment enables ARUK for the fi rst time to encourage and sup-port more research into the prevention of Alzheimers disease. Alzheimers Research UK is the UKs leading dementia research charity, funding research into the causes of dementia, diagno-

sis, preventions and treatments. They currently fund more than 22m of dementia research across the UK, including over 500,000 of pioneering science in Yorkshire. This investment is being used to understand a wide range of complex problems, including the build-up of toxic proteins in dementia and how best to diagnose the condition. Dr Laura Phipps, Science Communications Manager at Alzheimers Research UK, said: Over 6,000 people in Sheffi eld are living with dementia and there is also an army of informal carers who work tirelessly to support loved ones. We are working hard to not only fi nd a cure for dementia but also reduce the stigma associated with this condition.

FRIDAY, JUNE 12Main SymposiumI New insights into neurodegeneration II Diagnosis and prediction of Alzheimers disease:

Update on biomarker studiesIII New advances in imagingIV Technology supported diagnosis and careGet-together Party and Posters

THURSDAY, JUNE 11Memory Day - Finnish session - Muistipiv)I Haasteena tyikisen muistipulmatII Muistisairauksien ehkisy ja kuntoutusOpening SymposiumKeynote LecturesWelcome Reception

SATURDAY, JUNE 13V Novel approaches towards prevention VI Population-based prevention studiesVII Novel approaches in clinical treatment studies

IMPORTANT DATES

Abstracts by April 30

Registration by May 10

Welcome to Kuopio !CONTACTUSSymposiumSecretariat,7thKuopioAlzheimerSymposiumUniversityofEasternFinland,NeurologyPOBox1627,FI70211Kuopio,FINLANDTel:+35850 3609123MaaritNrhi,SecretaryTel:+358403552695MariaPikkarainen,Exhibitor'sContactTel:+358403552768AnnakaisaHaapasalo,ScientificSecretary/AbstractsFax:[email protected]

www.uef.fi/kuopioadsymposium

FROM MECHANISMS TO PREDICTION AND INTERVENTION OF ALZHEIMERS DISEASE

JUNE 11-13, 2015, KUOPIO, FINLAND7th KUOPIO ALZHEIMER SYMPOSIUM

The CISTIB research group from the University of Sheffi elds Department of Electronic and Electrical Engineering at SITraN.

Research UK, said: people in Sheffi eld are living with dementia andy to support loved ones. We are working hard to not only fi nd a cure for dementia but also ntia but alsoigma associated with this condition.


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d there is also an army of informal carers whoal carers whl fi d f d b lb l

The event was an opportunity to disseminate the vision and progress made in VPH-DARE@IT to the community of

Alzheimers researchers in Yorkshire.

D 4.2 ASD Detailed workfl ow specifi cation and component roadmap for high-throug put image analysis of large-scale studies

D 8.3 VTT Design specifi cations and requirements for a dementia-specifi c metabolic network model

M 2.2 EMC Normal ageing brain models Initial phenomenological model and links to me-chanistic modelling framework

D 7.1 USFD Architectural framework design and interoperability

D 9.1 EMP VPH-DARE@IT Health Technology Assessment conceptual framework

D 10.3 USFD First periodic progress report, including public summary of each work for publication

MS102 USFD Appointments to Scientifi c Advisory Board Completed

Deliverables and Milestones completed

Publication Highlights1. Vardakis J C, Chou D, Tully B, Hung C C, Lee T H., Tsui P-H., Ventikos Y (submitted). Investigating Cerebral Oedema using

Poroelasticity. Medical Engineering & Physics.

2. Vardakis J C, Chou D, Tully B, Ventikos Y. The impact of nonlinear permeability on a Multicompartmental model of Poroelasti-city. Annals of Biomedical Engineering, in preparation.

3. Vardakis J C and Ventikos Y . A Novel Model of Hydrocephalus using Multicompartmental Poroelasticity. Journal of Computa-tional Physics, in preparation.

4. Szokol K, Heuser K, Tang W, Jensen V, Enger R, Bedner P, Steinhuser C, Taubll E, Ottersen OP, Nagelhus EA. Augmentation of Ca2+ signaling in astrocytic endfeet in the latent phase of temporal lobe epilepsy. Frontiers in Cellular Neuroscience, in press.

5. Tang W, Szokol K, Jensen V, Enger R, Trivedi C, Hvalby , Helm PJ, Looger LL, Sprengel R, Nagelhus EA. Stimulation-evoked Ca2+ signals in astrocytic processes at hippocampal CA3-CA1 synapses of adult mice are modulated by glutamate and ATP. The Journal of Neuroscience, in press.

6. Pettersen KH, Lindn H, Tetzlaff T, Einevoll GT. Power Laws from Linear Neuronal Cable Theory: Power Spectral Densities of the Soma Potential, Soma Membrane Current and Single-Neuron Contribution to the EEG. PLoS Comput Biol. 10(11):e1003928 (2014)

7. Di Marco LY, Venneri A, Farkas E, Evans PC, Marzo A, Frangi AF. Vascular dysfunction in the pathogenesis of Alzheimers disease A review of endothelium-mediated mechanisms and ensuing vicious circles. Journal of Alzheimers Disease (Submitted 18 Jan 2015)

8. Di Marco LY, Farkas E, Martin C, Venneri A, Frangi AF. Is vasomotion in cerebral arteries impaired in Alzheimers disease? - A review study. Neurobiology of Disease [In preparation]

9. Schmidt-Richberg A, Ledig C, Moren RG, Molina-Abril H, Frang AF, Rueckert D, (2014) Learning biomarker models for progression estimation of Alzheimers disease, Medical Image Analysis, Sumbitted)

10. Cash DM, Rohrer JD, Ryan NS, Ourselin S and Fox NC. (2014) Imaging endpoints for clinical trials in Alzheimers disease, Alzheimers Research & Therapy


VPH-DARE@ IT

EventsUpcoming events SPIE Medical Imaging Conference 2015 - Orlando, Florida, United States

21 - 26 February 2015 http://spie.org/medical-imaging.xml

ECR 2015 - Vienna, 4-8 March 2015 http://www.myesr.org/cms/website.php?id=/en/ESR_ECR_news.htm#30494

International Symposium on BIOMEDICAL IMAGING - New York - USA, 16-19 April 2015

http://biomedicalimaging.org/2015/

Dementia Challenge 2015 - London, UK, 2nd June 2015 http://www.dementia-challenge2015.co.uk/event-home

7th Kuopio Alzheimer Symposium - Kuopio, Finland, 11 - 13 June 2015 http://www.uef.fi /kuopioadsymposium

AAIC15 - Washington DC, USA, 18 - 23 July 2015 http://www.alz.org/aaic/

Action Line 1 Focus Partner Profiles:

Hirslanden Klinik Philips Medical Systems

Periodic Review 2

In the next issue...


To ensure that we capture all the important issues from across the research arena, we invite you to send us your ideas, comments and suggestions for future editions to [email protected]. Non-VPH-DARE@IT participants interested in receiving this newsletter can subscribe via the VPH-DARE@IT website at www.vph-dare.eu

AcknowledgmentThis project has received funding from the European Unions Seventh Framework Programme for research, technological development and demonstration under grant agreement no FP7-ICT-2011-9-601055

This project has received funding from the European Unions Seventh Framework Programme for research, technological development and demonstration under grant agreement no FP7-ICT-2011-9-601055

VPH-DARE@ITVirtual Physiological Human: DementiA Research Enabled by IT

Project coordinator: Alejandro Frangi - The University of Sheffi eldTimetable: April 2013 to March 2017

VPH-DARE@IT ProjectUniversity of Sheffi eld

Sir Frederick Mappin Bldg, Mappin StreetS1 3JD Sheffi eld, UK+ 44 114 222 6071

[email protected]

VPH-DARE@IT Partners

USFD The University of Sheffi eld

VTT VTT Technical Research Centre of Finland

ESI ESI Group S.A

ASD ASD Advanced Simulation & Design GmbH

EMP Empirica Gesellschaft fr Kommunikations und Technologieforschung mbH

UIO Universitetet i Oslo

EMC Erasmus Universitair Medisch Centrum Rotterdam

HIRS Hirslanden Klinik

PMS Philips Medical Systems Nederland BV

ETHZ Eidgenssische Technische Hochschule Zrich

KCL Kings College, London

PRH Philips Technologie GmbH

STH Sheffi eld Teaching Hospital NHS Foundation Trust

UCL University College London

UEF It-Suomen yliopistoUMA University of Maastricht

TO Kinematix

ICL Imperial College of Science, Technology and Medicine

EIBIR EIBIR Gemeinntzige Gmbh zur Frderung der Erforschung der Biomedizinischen Bildgebung

UOXF The Chancellor, Master and Scholars of the University of Oxford

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