2015 - Fundación CIEN

Annualreport20152015

2015

2015

2015

CIEN FOUNDATIONResearch Center for

Neurological Diseases Foundation

Centro Alzheimer Fundación Reina SofíaC/ Valderrebollo, 5. 28031 Madrid

Tel.: (+34) 91 385 22 00 Fax: (+34) 91 385 21 18www.fundacioncien.es [email protected]

Annual report

2015

Centro Alzheimer Fundación Reina SofíaC/ Valderrebollo, 5. 28031 Madrid

Tel.: (+34) 91 385 22 00 Fax: (+34) 91 385 21 18www.fundacioncien.es

“Brain frills” (“Florituras cerebrales”)Artistic rendering that combines the idea of the existence of multiple neurotransmitters (coloured barins

brain) with the action of these neurotransmitters through the brain cells. Javier de Felipe

1. Profile and presentation1.1 Who we are1.2 The CIEN Foundation in 20151.3 Letter from the Manager1.4 Letter from the Scientific Director1.5 Organizational chart1.6 Vision

2. Management report2.1 General management2.2 Management of financial and economic resources2.3 Management of Human Resources2.4 Research projects and grants2.5 Quality policy2.6 Data Protection Law

3. Scientific activity3.1 Overview3.2 Departmental structure

4. The Vallecas Project4.1 Overview4.2 Background: Pilot project4.3 The Vallecas Project

5. International relations 5.1 Overview5.2 EU Joint Programme on Neurodegenerative Diseases Research

(JPND)5.3 Network of Centers of Excellence in Neurodegeneration (COEN)5.4 International Conference on Research and Innovation in

Neurodegenerative Diseases (CIIIEN) 5.5 Other international cooperation activities

6. Scientific productivity6.1 Bibliometric analysis6.2 Publications6.3 Funded projects6.4 Patents

7. Social dissemination7.1 Outreach activities 7.2 Awards and honours7.3 Presence in media7.4 Presence in social networks

INDEX

78

1012141718

21232325313233

353737

69717172

858788

9092

94

9799

100105106

109111 115117119

The mission of CIEN Foundation, attached to the Ministry of Economy and Competitiveness through the Carlos III Institute of Health,is to promote and coordinate research in neurological diseases,mainly Alzheimer's and other dementias. The work carried out since its establishment has positioned itself asa reference entity in this field. And thanks to the continued support of the Queen Sofia Foundation, CIEN Foundation has emerged as an example of "public-private" partnership in the research field,applying a translational model for the benefit of society.

CIEN Foundation is one of the best examples of public-privatecollaboration in scientific research in Spain. Since its establishment,manages and coordinates the Alzheimer Project Research Unit (UIPA,from its acronym in Spanish), created by the Queen Sofia Foundationand located in the Alzheimer Center that bears its name.

Since April 2007, CIEN Foundation headquarters are set at theQueen Sofia Foundation Alzheimer Center. This site located in theMadrid district of Vallecas, was conceived as a pioneer Center inSpain in which comprehensively address the impact that Alzheimer'sdisease causes on both patients and their family environment. Itcame to address the social health proposed by the Alzheimer Projectof the Queen Sofia Foundation.

UIPA and CIBERNED are the only two institutions in Spain participating in theÈuropean Union Joint Programming for Disease Neudegenerative

Diseases (JPND). Its excellent infrastructures, modern methodologiesand cutting edge technologies at their disposal as well as theavailable critical mass of researchers were the criteria most valued byrepresentatives of this organization after being proposed by theCarlos III Institute of Health.

In addition, both CIEN Foundation as CIBERNED are integrated intothe international Network of Centers of Excellence in Research on

Neurodegeneration (COEN).

The Research Center for Neurological Diseases (CIEN, for its acronym inSpanish) Foundation was established by resolution of the Council ofMinisters on December 27, 2002. It is a non-profit public sectorFoundation by definition, with state-wide scope and competence.Currently under the Ministry of Economy and Competitiveness throughthe Carlos III Institute of Health.

Support, promote and coordinate research in neurological diseases,but especially in neurodegenerative diseases, are among its founding

objectives. Among its aims are also highlighted its unifying andcoordinating role of leading research groups in this field.

Collaboration with the Queen Sofia Foundation

A Foundation from the public sector

1.1. Who we are

A Center of reference in Spain on Alzheimer’s disease research

Among the tasks assigned to the CIEN Foundation include: implement a modelof translational research for conveying effectively and efficiently scientific

advances in basic research into clinical practice; promote continuoustraining of professionals involved with neurological diseases research by

conducting seminars, lectures and doctoral theses; disseminate thecalls made by funding agencies, both nationally and internationally,promoting participation; and foster the implementation ofcoordinated research projects in neurological diseases.

In addition, CIEN Foundation manages other centers related toneurodegenerative diseases research: the UIPA and Center forNetworked Biomedical Research in Neurodegenerative Diseases

(CIBERNED), and has collaboration agreements with the Carlos IIIInstitute of Health for the implementation of the strategic agenda of

the European Union Joint Programming in Neurodegenerative Diseases(JPND), particularly Alzheimer's disease, and the Madri+D Knowledge

Foundation to regulate the participation of the Foundation in the M + VISIONprogram.

The CIEN Foundation and the Queen Sofia Foundation share a commonperspective on action in relation to Alzheimer's disease: This disease requiresa comprehensive approach model where research should be one ofthe fundamental pillars. The leading exponent of this integrativemodel is the Queen Sofia Foundation Alzheimer Center, where themain backbones of Alzheimer Project converge.

1. A live-in residence for 156 Alzheimer’s patients.2. A day-care outpatient center for 40 Alzheimer’s patients.3. An Alzheimer’s research center: the so-called Alzheimer's

Project Research Unit (UIPA), managed by the CIENFoundation.

4. A training center for healthcare staff, relatives andvolunteers.

The management model implemented by the Queen SofiaFoundation Alzheimer Center has sought to summon the will andinterests of all parties involved: Administration (Central, Regional andLocal) and civil society. For this reason, management of UIPA, devoted toresearch, was assigned to CIEN Foundation, while the Ministry of Family andSocial Affairs of the Community of Madrid is responsible for healthcare and training activities.

1. PROFILE AND PRESENTATION

Focused on research in neurodegenerative diseases

An innovative, integrated vision of the fight against Alzheimer’s disease

► Overall scientific production:46 impacts.Similar level to that of 2014.

► Publications in scientificjournals: 45Similar level to that of 2014.

► The average impact factor ofpublications within the first andsecond quartile is 4.718. Increases 8% versus 2014.

► Clinical neurology and Neurosciences remain the main subjectcategories for publication according to the distribution of publications.

► The CIEN Foundation overall budget for 2015 was reduced 18.6%compared with the previous year, up to a little over 2.5 million €.

► Almost 34% of the CIEN Foundation budget comes fromthe General State Administration budget through theISCIII.

► It is noteworthy the continued financialcommitment of the Queen SofiaFoundation which in 2015 contributedmore than 400,000 €, in addition tothe assignment of the facilities thathouse CIEN Foundation and theavailable equipment.

1.2. The CIEN Foundation in 2015

Scientific activity

Key figures

► During 2015 the second, third, fourth and fifth visits of the 1,213 volunteers involved in

Vallecas project have progressed concurrently, surpassing the halfway point of this five

years study.

► CIEN Foundation researchers have produced 46 scientific publications in

2015. Among them, an article in the journal "Frontiers in Aging Neuros-

cience" describing the objectives and the methodology used in the

Vallecas project.'

► In 2015 the process of recruitment of participants in the project:

“Detection of proteins in tears as biomarkers of Alzheimer's di-

sease” has ended. In the study we participated together with

the Association of Alzheimer's and other dementias patients

relatives from Soria, the Leon Alzheimer's Association, and

the Center for Molecular Biology Severo Ochoa. In total

100 samples have been collected to be analyzed at the

Center for Molecular Biology Severo Ochoa throughout

2016.

► The international activity of CIEN Foundation has con-

tinued to strengthen during 2015. Thus, to the the mana-

gement of the development of the Research Strategic

Agenda of the European Union Joint Programme in Neu-

rodegenerative diseases, particularly Alzheimer's disease

(JPND) in collaboration with ISCIII, and its participation in the

Network of Centers of Excellence in Neurodegeneration

(COEN), we must add the involvement of our scientists in

the projects DEMTEST, on dementia, and REGISTRY, on

Huntington's disease.

► In September 2015, Malaga hosted the third edition of

the International Conference on Research and Innovation in

Neurodegenerative Diseases (CIIIEN). Among the speakers at the

Congress include some international researchers who are world

leaders in its field of research.

► At December 31, 2015, the CIEN Foundation Tissue Bank (BT-CIEN, for its

acronym in Spanish) had more than 600 registered donors. Meanwhile, the Neuro-

pathology lab processed 125 cases in 2015, of which 83 were cases of donation ex-

tracted and processed in the UIPA and 42 were consultation cases.

► In 2015, the Neuroimaging Department has carried out 5,547 MRI studies on

963 subjects. Over 43,864 sequences have been performed since the inception of

the department.


Highlighted events

One more year is a pleasure for me to address you toreview the activities undertaken by the Center forResearch in Neurological Diseases (CIEN, for itsacronym in Spanish) Foundation during the year justended.

2015 could be defined as a consolidation period ofactions initiated in prior years and of future projec-tion, always aligned with the principal axes thathave marked our progress in recent years: commit-ment to a model of translational research and inter-nationalization of our project. Without the constantsupport provided by the Queen Sofia Foundation fora decade now and without the commitment of pe-

ople within CIEN Foundation, this would not be pos-sible.

At CIEN Foundation we conceive research as a ap-plied model that allows us to translate progress in abenefit to society. Research should be a shaft ge-nerating innovation. In this regard, this year CIENFoundation has collaborated as co-owner in threepatent applications, both national and international.

Among the activities launched in previous yearshighlights the Vallecas project, one of the most am-bitious studies being developed in Spain to advancethe early diagnosis of Alzheimer's disease. In 2015,some of the 1,213 volunteers who selflessly partici-pate in the project underwent the fifth follow-up visit.Currently, the third, fourth and fifth follow-up visits arebeing carried out simultaneously.

The Vallecas Project has also begun to bear fruit. Ourresearchers have published in the journal Frontiers inAging Neuroscience an article describing the ob-jectives and the methodology used in the study. Thisarticle is included among the 46 scientific publica-tions produced in 2015, among which also highlightsthe publication in the journal Alzheimers & Demen-tia, which has led to the first high impact publicationbased on data from clinical-pathological correlationfrom Vallecas Alzheimer Center Research Program(PICAV, from its acronym in Spanish). During 2016 it isplanned to publish new work in which the first fin-dings of the project will be presented Vallecas.

At the end of the year has concluded the recruit-ment of participants in the new multicenter researchproject led by CIEN Foundation, in collaboration withAlzheimer Leon and Alzheimer Soria associations: de-tection of TAU protein in tears as a possible biomar-ker of Alzheimer’s disease. During 2016, professionalsfrom the Center for Molecular Biology Severo Ochoawill analyze the 100 samples that have been collec-ted.

1.3. Letter from the Manager of the CIEN Foundation

María Ángeles Pérez MuñozManager of the CIEN Foundation

CIEN Foundation Annual Report 2015 / 13

Meanwhile, the CIEN Foundation Tissue Bank (BT-CIEN, for its acronym in Spanish) has reached a re-cord high in the number of yearly donations (76) andat year-end has registered 600 brain donations sinceits inception in 2010. In addition, an area of samplemanagement has been set up to manage, processand track tissue samples requested by the differentresearch groups, both nationally and internationally.

At the institutional level, this has also been a fruitfulyear. In September, the third edition of the Interna-tional Conference on Research and Innovation inNeurodegenerative Diseases (CIIIEN), a scientificmeeting that brings together the efforts of theQueen Sofia Foundation, CIEN Foundation and CI-BERNED, was held and it has established itself as aninternational scientific congress of reference in thisfield.

The work developed at CIEN Foundation has onceagain been recognized by different institutions out-side the research field. More specifically, INESE hasgranted the Vallecas project one of its Insurance So-lidarity Awards and the Fuerteventura Association ofHotel and Tourism choose CIEN Foundation as thebeneficiary of the Fuerteventura Grant. In particular,it allocated 24,000 euros to fund research in Alzhei-mer's disease.

From a social perspective, activity has also been in-tense. In February we celebrate the third edition of'Vallecas Projec Volunteer’s Day' and coincidingwith the Christmas holiday season, we set up for thefifth consecutive year the 'Tree of Memories' in theMunicipal Market of Villa de Vallecas, with the sup-port of the Villa de Vallecas District Board, the Di-rectorate General of the Elderly of the MadridRegion, and traders from the market itself.

I cannot conclude without making special mentionof the actions in the area of Human Resources. Theongoing training of our professionals and the recruit-

ment and retention of talent are crucial factors forthe future development of the CIEN Foundation. Inthis regard, in 2015 we have adhered to the programof "Grants to promote young employment and im-plementation of the Youth Guarantee in R+D+i" wi-thin the framewok of the State Plan for Scientific andTechnical Research and Innovation 2013-2016 ,which has resulted in the execution of four contracts.We have also renewed the agreement with the Ma-drid M + VISION project, with the collaboration of theMassachusetts Institute of Technology (MIT) .The goalis to attract international renowned researchers wi-thin the COFUND program from the EU Seventh Fra-mework Programme.

The invaluable collaboration of our trustees and be-nefactors and the work of our professionals are twosolid pillars that support the future of CIEN Founda-tion. Our ultimate goal, to keep fighting what manypeople describe as the new epidemic of the XXIcentury: Alzheimer's disease.


1 Zea-Sevilla et al. Alzheimers Dement. 2015 Nov;11(11):1358-66

During 2015, the Alzheimer Project Research Unit lo-cated in the Queen Sofia Alzheimer Center hasbeen developing the prosed aims. This developmentis leading to the consolidation of CIEN Foundation,whose existence is due to the financial support ofthe Carlos III Institute of Health and the Queen SofiaFoundation, and in 2017 will let us reach our first 10years of existence. Thus, I would like to begin this let-ter by thanking both institutions. This year 2015 wehave had the honor to receive several visits of H.M.Queen Sofia to the CIEN Foundation. We have alsobeen visited by the ISCIII Director General and Iwould like to echo the kind words of the Director Ge-neral of the Institute, who said during his visit that if

the CIEN Foundation did not exist, it would have tobe created in order to have a national reference inthe area of neurodegeneration that is comparableto what exists in neighboring countries.

Our main objective is the development of VallecasProject, a study that has advanced to publish thisyear not only what the project is about but also thefirst results that indicate several risk factors that canaccelerate the transition from a cognitively healthystate to a mild cognitive impairment, a decline thatmay be at the beginning of disease progression.These data will be essential to carry out in the future,on a consolidated CIEN Foundation, clinical trialswith the at-risk population, which can be classifiedby the presence of the risk factors identified.

During 2015 we published 46 scientific articles, seve-ral of them in collaboration with CIBERNED groups,institution with which we share several joint interestsin the common goal of preventing and treating neu-rodegenerative diseases; and with which we carryout scientific meetings and our Annual Congress, de-veloped this year 2015 in Malaga with the support ofthe Queen Sofia Foundation and during which, inaddition to its high scientific level, we had the plea-sant news to know that HM Queen Sofia was one ofthe nominees to Peace Nobel Prize this year.

I would not like to conclude without thanking all themembers of the CIEN Foundation, including thescientific and technical, administrative, managerialstaff as well as the Scientific Advisory Committee.Their hard work and efforts, which is what allows theimprovement and gradual development of theFoundation, of which we hope to meet many moreyears.

Thank you all.

1.4. Letter from the Scientific Director of CIEN Foundation

Jesús Ávila de GradoScientific Director of CIEN Foundation

1.5. Organizational chart

CIEN FOUNTATION BOARD OF TRUSTEES

Position

Invited guests

Invited guests

Invited guests

Invited guests

Invited guests

Name

Mr. Luis de Guindos Jurado

Ms. Carmen Vela Olmo

Mr. Jesús Fernández Crespo

Mr. José Javier Castrodeza Sanz

Ms. Marina Pilar Villegas Gracia

Ms. Cristina Ysasi-Ysasmendi

Ms. Belén Bornstein Sánchez

Ms. Elena Andradas Aragonés

Mr. Emilio Lora Tamayo

Ms. Margarita Blázquez Herraiz

Mr. Manuel García León

Mr. Óscar Zurriaga Lloréns

Mr. Bernardo E. Macías Gutiérrez

Mr. Fernando Sanz García

Mr. José Luis Beotas López

Mr. Jesús Ávila de Grado

Ms. María Ángeles Pérez Muñoz

Mr. Jose Luis Nogueira Guastavino

Mr. Agustín Larrañaga Elorriaga

Ms. Mª Dolores Donoso Mencía

Title

Minister of Economy and Competitiveness

State Secretary of Research, Development and Innovation

Director of the Carlos III Institute of Health

President of the Higher Council for Scientific Research

General Director of Research, Technology and Business

Director General of Welfare Programs, Canary Islands Health Service

Secretary General of the Health Service of Castilla-La Mancha (SESCAM)

State Attorney

Scientific Director, CIEN Foundation

Managing Director, CIEN Foundation

Queen Sofia Foundation

Assistant to the Secretary

Director of the Technical Secretary, Executive Committee for Economic Affairs, President of the Government's Economics Office Deputy Director General of Evaluation and Promotion of Research, Carlos III Institute of HealthDirector General of Public Health, Quality and innovation, Ministry of Health, Social Services and Equality

Deputy General Director of Cooperative Research Networks and centers, Carlos III Institute of Health

General Secretary of Health and Consumer Affairs, Ministry of Health, Social Services and Equality

Director General for Research, Innovation, Technology and Quality, Public Health Department

Queen Sofia FoundatioAdvisor to the Office of the Secretary of State for Research

General Director de Scientific and Technical Research, Ministry of Economy and Competitiveness

Honorary Chair

Chair

Vice-Chair

Ex-officio Members

Ex-officio Members

Ex-officio Members

Ex-officio Members

Ex-officio Members

Ex-officio Members

Member And Secretary

Elected Members Andalusia

Elected Members Valencia

Elected Members Canary Islands

Elected Members Castilla La Mancha

Legal Advisor

CIEN Foundation Board of Trustees : The CIEN Foundation Board of Trustees is responsible for the government and representation of the CIENFoundation as well as for the fulfillment of the Foundation objectives, administration and management ofits capital assets. Board members represent all sectors involved in neurological diseases research: publicinstitutions related to the field of health, research, social and industrial policy, technology, business andeducation.

Board members at the end of 2015 are:




Registration of resignations and new appointments in the composition of the CIEN Foundation Board ofTrustees.

• On April 6, 2015 the termination of Mr. Antonio Luis Andreu Périz is registered and Mr Jesús FernándezCrespo is appointed as Vice President and Trustee of the Foundation by virtue of his position asDirector of the Carlos III Institute of Health.

• On January 20, 2015 are registered the termination of Ms. Maria Mercedes Vinuesa Sebastian andthe appointment of Mr. José Javier Castrodeza Sanz as Trustee of the Foundation pursuant to hisposition as Director General of Public Quality and Innovation of the Ministry of Health, Social Servicesand Equality.

• On October 9, 2015 are registered the termination of Ms. Maria Antonia Pérez Pérez and theappointment of Mr. Bernardo Emilio Macias Gutierrez as Trustee of the Foundation in accordancewith his position as Director General of Welfare Programs of the Canary Islands Health Service .

• On October 30, 2015 the termination of Ms Pilar Viedma Gil de Vergara is registered and Mr. OscarErnesto Zurriaga Lloréns is appointed as Trustee of the Foundation pursuant to his position as DirectorGeneral for Research, Innovation, Technology and Quality Public Health Department of Valencia.

• On 30 November 2015 are registered the termination of Mr. José Javier Castrodeza Sanz and theappointment of Ms. Elena Andradas Aragones as Trustee of the Foundation in accordance to herposition as Director General of Public Health Quality and Innovation of the Ministry of Health, SocialServices and Equality. In addition. Termination of Mr. Ruben Fausto Moreno Palanques andappointment of Mr. José Javier Castrodeza Sanz as Trustee of the Foundation as Secretary Generalfor Health and Consumer Affairs, Ministry of Health, Social Services and Equality, are registered.

External Scientific Advisory CommitteeIn the Board meeting held on March 10, 2014 the composition of the CIEN Foundation External Scientific Ad-visory Committee it is presented and approved. The proposed Committee consists of: Miguel Medina Pa-dilla, who will act as coordinator, Javier de Felipe Oroquieta, José Ramón Naranjo Orovio, FernandoRodriguez Artalejo and Joaquín Arenas Barbero.

Scientific Advisory Committee

In order to improve scientific quality, optimize available resources and exploit the peculiarities of the QueenSofia Foundation and the Alzheimer Center, the creation of a CIEN Foundation Scientific Advisory Com-mittee was approved in late 2013.

From its inception, several joint working meetings between UIPA researchers, members of the CIEN Foun-dation Scientific Advisory Committee and representatives of the Queen Sofia Foundation have taken place.In the last one, on February 19, 2015, H.M. Queen Sofia met with the CIEN Foundation Scientific AdvisoryCommittee. Upon arrival at the Center, the Queen was received by the Director General of the Carlos III


1.6. Vision

The Vallecas Project is the main research projectbeing conducted at the CIEN Foundation, both interms of resources employed as well as in terms of itssocial impact. Once the recruitment of volunteersand the constitution of the cohort study of Vallecasproject was completed in late 2013, second, third,fourth, and fifth visits from volunteers have been oc-curring simultaneously during the year 2015, so that

the half-way point of this 5-year longitudinal studyhas been surpassed, as shown in the following figure.

During this year validation of historical data collec-ted to date by the different areas has been com-pleted and a single integrated and anonymized,newly created database has been established. Thisdatabase is intended to ensure the reliability and se-curity of data while in turn allowing a more effectiveanalysis. The first evaluation of data from the first two

2011 2012 2013 2014 2015 2016 2017 2018

First visit

Second visit

Third visit

Fourth visit

Fifth visit

Institute of Health, Antonio Andreu; the Scientific Director of CIEN Foundation and Network Center for Bio-medical Research in Neurodegenerative Diseases (CIBERNED), Jesus Avila; and the Manager of CIEN Foun-dation and CIBERNED, Maria Angeles Perez.

Therafter, the Queen held a briefing with members of the CIEN Foundation Scientific Advisory Committee,including Miguel Medina Padilla, Deputy Scientific Director of CIBERNED; Jose Ramon Naranjo, a resear-cher at the National Center for Biotechnology of the CSIC (CNB) and CIBERNED; Javier de Felipe, CIBERNEDprincipal investigator and Professor at the Higher Centre for Scientific Research (CSIC); and Fernando Ro-driguez Artalejo, Professor of Preventive Medicine and Public Health at the Autonomous University of Ma-drid.

visits have been submitted to the CIEN FoundationScientific Advisory Committee and members of theQueen Sofia Foundation. In addition to presentingour preliminary results in different conferences andscientific meetings during 2015 the first description ofthe Vallecas project has been published in an inter-national scientific journal (see Section 6 of this re-port). The project is generating great interest amongthe scientific community and we look forward topresenting our results in national and internationalconferences and publishing scientific papers of thefirst longitudinal analysis throughout 2016.

As the project progresses it is producing a number ofincreasingly richer and more relevant informationabout the earliest stages of cognitive impairment insubjects that progress to that state, as well as themost suitable biomarkers (clinical, biochemical andneuroimaging) to characterize and identify the po-pulation at increased risk of developing it.

In the coming months we will initiate the necessarycontacts so that information obtained from assess-ments of the volunteers, their biological samples andneuroimaging studies undertaken could integratewith other national and international cohorts, whichsignificantly will increase the potential of each oneof them and the Vallecas project itself.

In addition to the Vallecas project, the Alzheimerproject will continue to be an essential project forthe Queen Sofia Foundation Alzheimer Center andCIEN Foundation and a growing source of informa-tion (clinical, molecular, neuroradiological and neu-ropathological) on mild and severe dementiastages. This longitudinal study, initaited in 2007, aimsto monitor residents at the Queen Sofia FoundationAlzheimer Centre and users of the Day Center.

In the coming months and years the information ga-thered since the beginning of the project will provideimportant clues on how the two main pathologies

that lead to dementia in our environment, the Alz-heimer's and cerebrovascular disease, interact andresult in defined progression pathways. A better un-derstanding of the various forms of expression ofthese diseases, when presented alone or, morecommonly, in combination, will allow to approachin depth their role in the origin of dementia and toidentify patient groups who require special care orthat can benefit from specific therapies.

The research model implemented in the AlzheimerCenter can be equally applied to other residencesand other Day centers around the Region of Madrid.In fact, the Alzheimer Project model in other socialhealth environments is being put into in Day Centersfrom the Associations of Relatives of Alzheimer pa-tients (AFA) in Soria, León, and other towns, in orderto incorporated subjects diagnosed with mild cog-nitive impairment and mild dementia in future Foun-dation projects.

Moreover, a new study (the Madrid+CIEN project)has been designed in collaboration with the Regionof Madrid General Directorate for the Elder and theEuropean University, aimed at establishing a cohortof hundred-year-old subjects in our Region. The pro-ject aims at establishing the cognitive profile of cen-tenarians who have no dementia, studying cognitiveprofile progression over a period of three years andestablishing a cohort of centenarians in which wouldbe possible to set up studies with non-pharmacolo-gical therapies.



During 2015, CIEN Foundation has continued to implement a management model marked by resource optimization and rationalization of expenditure to fit a budgetary reality marked by a funding crisis,although CIEN Foundation is committed with maintaining investment in research,development and innovation as a guarantee of future and putting results to the service of society. CIEN Foundation promotes the education of their researchers as basic support for quality research as well asstrategic and differential value.

The income budget managed by CIEN Foundationduring the year 2015 slightly surpasses the 2.5 millionEuros, arising mainly from the ISCIII annual contribu-tion, which amounted in 2015 to 825,000 €. It is re-markable, once again, the effort and commitmentof the Queen Sofia Foundation with the researchwork carried out by CIEN Foundation, materializedon an income above 400,000 € in 2015, in addition tothe transfer of use of the building and equipment.

During 2015 CIEN Foundation continues to managethe following actions:

• Cooperation agreement between the ISCIII andCIEN Foundation for the development of thestrategic agenda of the European Union JointProgram in Neurodegenerative diseases,particularly Alzheimer's disease (JPND) throughthe participation of CIEN Foundation in theEuropean Network of Centers of Excellence(COEN). ).

The International Network of Centers ofExcellence in Research onNeurodegenerative Diseases (COEN) hasapproved funding for five "Pathfinder"projects for an amount of around three millioneuros. The Foundation has committed 550,000€ to finance projects selected in this call,which will be carried out by CIBERNED groups.

• Collaboration agreement between theFoundation for Knowledge Madridmasd andCIEN Foundation to regulate the participation ofthe Foundation as host institution in theM+VISION program under the FP7-PEOPLE-2011-COFUND call,. The project funded by theEuropean Union provides for the participation ofhost institutions as legal entities in which theresearchers selected for support within theM+VISION program conduct their trainingthrough research.

The M + VISION project includes two types ofassistance depending on the type of mobilityinvolving: incoming and outgoing. In the

incoming grants researchers enjoy three yearsof funding in Spain. The project, financed bythe European Union, envisages theparticipation of host institutions as legalentities in which the researchers selected forsupport of the project M+VISION conducttheir training. The program offers grants of atotal duration of three years, consisting of ayear of scholarship and two-year contractplus contributions for research expenses andtravel. The first year the researchers receivefunding from the Region of Madrid and thescholarship takes place in a primarilyacademic environment, while the secondand third years are directly employed by hostorganizations, making a more market-oriented research.

2.2. Management of financial and economic resources

The CIEN Foundation is a statewide under the Mi-nistry of Economy and Competitiveness.

Revenues of the institution consist mainly of grants,donations and operating legacies and capital re-ceived from Public Administrations and other institu-tions, companies and individuals.

The Carlos III Institute of Health, exercising their func-tions of planning, development and coordination ofbiomedical and health research and innovation re-solves to grant the CIEN Foundation with a nomina-tive allocation for current expenditure for the year2015 of 675,000 € and a nominative allocation forcapital expenditures of 150,000 €. The allocation co-rresponding to fiscal year 2014, experienced a signi-ficant budget reduction compared to previousyears, due to different factors such as the termina-tion of several cooperation agreements betweenCIEN Foundation and other institutions, which weredistant from the aims of the Foundation. Also, by re-solution of ISCIII a nominative allocation of 50,000 €for 2014 was granted to the CIEN Foundation.

2. MANAGEMENT REPORT

2.1. General management


The breakdown of total revenues in 2015 and 2014were as follows:

The management entrustment for the following twoprojects has terminated during 2014: "Strengtheningthe health system and prevention in the fight againstinfectious diseases in the Amhara-Ethiopia region"(Project Amhara-Eth) and "Reference center forcontrol of endemic diseases of Equatorial Guinea"(CRCE, for its acronym in Spanish). This fact is reflec-ted in a decrease in the revenue amount for 2015.

The item "Cash grants and subsidies" corresponds tothe balance arising from the audit of the II call for re-search projects in Alzheimer's disease and related di-seases and the subprogram INNPACTO (2012 call).

In addition, the Foundation has received additionalincome from the provision of services as a result ofvarious activities:

With regards to expenditure, a proportion similar tothe year 2014 expenditure has maintained during2015. The significant reduction in the item "Monetaryaid and others" is the result of the termination of theentrustment management agreement of the twoprojects listed above (Amhara-Eth and CRCE).

All other items of expenditure experience less noti-ceable decreases as a result of general efforts to re-duce costs, in line with the budgetary reality markedby the financial crisis. The departure of staff increa-ses due to the payment of part of the bonus for De-cember 2012.

2.3. Management of Human Resources

The Department of Human Resources at CIEN Foun-dation manages the scientific and technical staffthat cooperates in conducting the various researchprojects, both those granted by public as private or-ganizations. CIEN Foundation encourages personal

825.000,00 €

89.068,99 €

0,00 €

65.365,39 €

45.074,96 €

423.582,70 €

377.567,78 €

637.018,49 €

110.379,36 €

1.219,24 €

2.574.276,91 €

CIEN Foundation revenues during 2015

2015 2014

50.000,00 €

1.028.109,01 €

733.278,65 €

69.059,16 €

828,61 €

417.818,22 €

311.844,42 €

441.132,26 €

104.587,59 €

6.728,54 €

3.163.386,46 €

ISCIII anual grant

ISCIII grants remaining from previous years

Management entrustments

ISCIII capital subsidies charge to income

Reimbursement of grants and subsidies

Public project grants

Donations and legacies assigned to projects

Others donations and legacies

Sales and other income from commercial activity

Financial income


and collective commitment to the institutional mis-sion as well as the sense of belonging to the organi-zation. It promotes habits and procedures adjustedto the needs and expectations of our researcherswho provide inestimable added value and in whichthe personal satisfaction and talent retention are cri-tical. CIEN Foundation encourages the education oftheir researchers as basic support for quality rese-arch and is committed to maintaining investment inresearch, development and innovation, as a gua-rantee of future and placing results to the service ofsociety.

CIEN Foundation researchers, in addition to carryingout the assigned projects, collaborate with other ins-titutions in educational and social outreach activi-ties related to the latest advances and newtechniques for the prevention of Alzheimer's diseaseand other neurodegenerative disorders. The closecollaboration with Alzheimer associations from diffe-rent Regions help us develop a research of recogni-zed prestige and sensitive to society. CIENFoundation, thanks to the work of its professionals,has become a national and international referencein the investigation of neurological diseases.

Energy productionIncome from performing MRIs and collaborative research projects

Revenues from provison of services during 2015

2015 2014

TOTAL

12.982,68 €

91.748,90 €

104.731,58 €

8.028,32 €

95.093,62 €

103.121,94 €


341.349,65 €

-19.290,78 €

173.885,09 €

850.264,09 €

705.055,86 €

508.305,00 €

0,00 €

84,51 €

2.559.653,42 €

13,34%

-0,75%

6,79%

33,22%

27,54%

19,86%

0,00%

27,71%

6,46%

25,56%

23,61%

16,17%

0,48%

CIEN Foundation breakdown exoenditure 2015

Other operating expenses

Depreciation and amortization

Impairment and gains on disposal fixed assets

Monetary aid and others

Supplies

Personnel costs

2015 2014

Exchange differences

871.813,84 €

203.325,46 €

804.343,96 €

742.897,00 €

508.804,38 €

15.175,15 €

92,53 €

3.146.452,32 €TOTAL EXPENDITURE

% %

Variation in stock of merchandise


CIEN Foundation is aware of working in an increa-singly globalized and dynamic environment, morecompetitive and influenced both by new technolo-gies as well as the new demands of society. There-fore, the true differentiator and success generator inresearch lies in the quality and contribution of theprofessionals that make up your organization. Fromthis perspective, the development of the researchcarried out in our Foundation is subject to their corecompetencies, such as personal effectiveness, lea-dership and management skills. Therefore, from CIENFoundation, we care about the constant develop-ment of all our professionals, always taking into ac-count equal opportunities.

Human resources devoted to carrying out theactivities of the Foundation

The CIEN Foundation, in accordance with its policyattracting and retaining talent, has continued tofocus its selective processes to recruit highly quali-fied staff, whose levels of technical and behavioralcompetencies are appropriate to the published jobprofiles.

All positions offered by the CIEN Foundation are de-fined with a specific profile, required qualifications,position requirements and functions to be perfomed.In addition, there have been procured by an opencompetition process, based on criteria of capacity,merit and publicity, having been published on CIENFoundation, ISCIII and CIBERNED websites, honoringthe principle of free competition and objectivelyevaluating the merits of the applicants. This proce-dure is in accordance with section 6.2 of ISO9001:2008.

During 2015, CIEN Foundation has counted on atotal of 58 employees, 33 of which have been hiredfrom competitive grants, 14 are fellows, 3 in-traininglaboratory and anatomy technicians, 2 volunteerswho have worked selflessly in the activities of the

CIEN Foundation, 1 resident Intern in training and 5have developed their activity thanks to various co-operation agreements signed.

Are also part of the CIEN Foundation staff, the rese-arch and technical support personnel fundedthrough CIBERNED and research collaboration agre-ements signed by the CIEN Foundation.

CIEN Foundation, following its commitment to youngresearchers and collaboration with public and pri-vate institutions participated in the program "Pro-moting Youth Employment and Implementation ofthe Youth Guarantee in R+D+i within the framewokof the State Plan for Scientific and Technical Rese-arch and Innovation 2013-2016" with four contractsawarded in 2015 and one in 2016. It has also signedan agreement with the Community Madrid in colla-boration with the Massachusetts Institute of Techno-logy (MIT) within the M+VISION Project to attractinternational renowned researchers within the CO-FUND program from the EU Seventh framework Programme, under the FP7-PEOPLE-2011-COFUNDcall".

The departments comprising the CIEN Foundation inwhich our professionals, medical, research and ma-nagement staff carry out their work with a high de-gree of commitment are the following:

• Department of Management andAdministration

• Department of Neuroimaging• Department of Neuropathology• Department of Cell Biology Laboratory and

Neuropathology• Multidisciplinary Support Unit (UMA for its

acronym in Spanish)

Human resources devoted to carrying out theactivities of the Foundation during 2015 are reflectedin the following table:


List of CIEN Foundation staff in 2015:

2.3.1 Training Program

Continuous training and updating knowledge andprofessional skills are configured as a training systemthat tries to go with workers in their capacity for per-sonal development and career advancement. Itconstitutes a fundamental support for the competi-tive and innovative capacity of organizations basedon quality human resources.

The main objective of CIEN Foundation with regardsto training is to provide suitable means for the deve-lopment of professional skills in order to effectivelymanage the challenges that each position implies.

Training is an integral part of our culture as an orga-nization and we are aware of the need to conti-nuously improve the knowledge and skills of ourprofessionals.

Among the courses conducted by our staff are thefollowing:

• SPSS application and statistical analysis • Specialized Care in Occupational Therapy • Administrative functions in healthcare

centers• Leadership, teamwork organization and

problem solving• Emergency Studies in Computed Tomography:

skull• Technicians and nosocomial infection

In 2015 CIEN Foundation has offered or participatedin the following training activities:

Courses and events

• “V Course on Neurodegenerative Dementias”.From March 9th to 13th, 2015. UIPA (AlzheimerProject Research Unit, CIEN Foundation- QueenSofía Foundation) and UNED (Basic Psychology IDepartment). Madrid, Spain.

• Course on “Prevention of Occupational Hazardsin MRI rooms for medical use” April 21st to 22nd,2015. National Institute for Safety andOccupational Health, CIEN Foundation. Madrid,Spain.

• “International Day of Radiology” November 8th,2015. CIEN Foundation, Queen Sofia Foundationand Spanish Association of RadiologyGraduates (AETR). Madrid. Spain.

• Course on “Specialized Care in OccupationalTherapy”. Belen Frades Payo. October-December, 2015. Organised by ComisionesObreras.

Internships

• Neuropathology internship. IES Moratalaz. LauraSáiz Auz. From September 2014 until March 2015.Madrid, Spain.



26

57

11

2 AdministrationBT-CIENVallecas ProjectUMANeuroimagingLaboratory

Research personnel by area of expertise

14

9

11DiplomaPhDGraduateTechnician

Research personnel by category

• Neuropathology internship. AutonomousUniversity of Madrid. Valentina GonzálezÁlvarez. June-December 2015.

• PhD program. Autonomous University of Madrid.Neuropathology. Mª Dolores Arrabal Ortiz. July2014 – June 2017. Madrid, Spain.

• Psychology end-of-Master internship. Rey JuanCarlos University. Virginia Chaves Morillo.January – March 2015. Madrid, Spain.

• Psychology end-of-Master internship.Autonomous University of Madrid. Sandra MartínSesma. October 2015 – January 2016. Madrid,Spain.

• Psychology end-of-Master internship. Universityof Santiago de Compostela. Carlos M. NietoDoval and Clara Suárez Varela. September 2014– May 2015. Madrid, Spain.

• Neuroimaging internship. Santa Gema School.Marta Molero Carton.January – February 2015.Madrid, Spain.

• Law internship. Carlos III University.Administration-Neuropathology. LorenaHernández de Cáceres. February – May 2015.Madrid, Spain.

• Neuropathology Residence Internship. La PazUniversity Hospital. Lara Sanz Irene. January –December 2015. Madrid, Spain

Postgrads studies

• End of Master studies. Alcala de HenaresUniversity. UMA. Isabel Faro Burgos. June –September 2015.

• End of degree studies. Complutense Universityog Madrid. Neuropatología. Rebeca PérezRodríguez. February – April 2015.

• End of Master studies. Apolipoprotein E4:Neuropsychological characterization andrelationship with cognitive impairment. Master inPsychology Research conducted by theNational University of Distance Education(UNED). Marina Ávila Villanueva. September2015.

• PhD in Neurosciences, Complutense University ofMadrid (UCM). Doctor of Psychology Degree toMiguel Angel Fernandez Blazquez with thethesis: “Study of the variables associated with

the appearance of the attentional blink”.September 2015.

• End of Master studies on Physical Anthropology(Human Evolution and Biodiversity):“Dermatoglyphic Profile of Alzheimer's disease”.Isabel Lighthouse Burgos. Co-directed byMeritxell Valenti and Esperanza GutierrezRedomero. September 2015. Alcala de HenaresUniversity.

Fellowships

• MAPFRE- Queen Sofía Foundation 2015-2016.Participation in research project onneurodegenerative diseases, for a period of 6months extended for additional 6 months. UMA.Ana Rebollo Vazquez. April 2015 - April 2016.

• Madrid-MIT +VISION Scholarship in TranslationalBiomedical Imaging. Neuroimaging. ChristopherLong. November 2014 - November 2015.

• European Scholarship. Psychology internship.Ilaria Giovanelli, Italian student. October -December2015.

Teaching

• Module "Professional profile of theNeuropsychologist”. Master of ClinicalNeuropsychology. January 2015. Higher Instituteof Psychological Studies (ISEP).

• Module "Neuropsychological assessment:attention, gnosis, praxis and executivefunctions." Master of Clinical Neuropsychology.Taught by Miguel A. Fernandez. (UMA). February2015. Institute for Psychological Studies (ISEP).

• Module "Neuropsychological examination,screening tests. Beyond the Mini Mental andworkshop on neuropsychological examination".Course on being up-to-date in the earlydiagnosis of cognitive impairment. Taught byMiguel A. Fernandez (UMA). April 2015. Sanitas.

• Course "Neuropsychological assessment of braindamage". Taught by Miguel A. Fernandez.(UMA). September 2015. School of HealthSciences and Social Care, Government ofExtremadura.


• Module "Adapted Physical Education as aneducational tool in childhood (motor behavior,neurological bases of movement)". Mastercourse on specific needs of educationalsupport. Taught by Miguel A. Fernandez. (UMA).November 2015. University of Vigo.

2.3.2 Prevention of Occupational Hazards

Those activities resulting from the preventive mana-gement carried out during 2015, which contributedto the successful implementation and enforcementof the plan of prevention of occupational risks esta-blished in the organization, are listed below.

In collaboration with the External Prevention Service,an annual program of preventive activities includingactivities such as conducting safety and monitoringvisits, planning of medical examinations or adjus-tment of positions for particularly sensitive workershas been established.

In June the annual emergency drill with completeevacuation of the center, in which all staff membersand volunteers and contributors were involved wascarried out.

In relation to health surveillance, there have been 15specific medical examinations.

The following table lists the different types of medi-cal examinations followed by employees depen-ding on the risks inherent to their activities, underArticle 22 of the Law on Occupational Health andSafety.

Health screenings have included a work history witha detailed description of the job, the time spent onit, the risks identified in the analysis of working condi-tions and prevention measures, anamnesis data, cli-nical examination, biological control andcomplementary studies directed and chosen ac-cording to the risks inherent to the work performed.

2.4. Research projects and grants

CIEN Foundation aims to support, promote and co-ordinate research in neurological diseases. In orderto do this, it focuses its efforts especially in neurode-generative diseases and in coordinating prominentSpanish research groups. Research projects mana-ged by the Foundation seek to foster research andstudy in these fields, especially Alzheimer's diseaseand related disorders.

2.4.1 Research projects

Since its inception CIEN Foundation develops rese-arch projects focused in particular on Alzheimer's di-sease and related conditions. In Spain this diseaseaffects about half a million people and is expectedthat, with increasing life expectancy, by 2050 this fi-gure will double, since age is a major risk factor fordementia. It affects 10% of the population over age65 and nearly half of those over 85.

Aware of the importance of research and collabo-ration between all levels of society, a great effort ismade from CIEN Foundation to translate scientificprogress in basic research to clinical practice, pro-


11

1

3

ME Data Display

ME Biological agents – Data display

ME Biological agents – Data display – Strained positions- Chemicals

Type of medical examinations Nº of employees

moting carrying out of coordinated research pro-jects in neurological diseases and fostering partici-pation in calls for projects by national andinternational funding agencies. The main projectsactive during 2015 are the following:

• Vallecas Project: Multidisciplinary study for earlydetection of Alzheimer's disease. 2015 budget:302.320,12€.

• Alzheimer Project: social health project resultedin a healthcare complex in which Alzheimer'sdisease is approached from three angles:research, training and care services for patients:Budget for 2015: 914,068.99€.

• Research projects awarded under competitivecalls active during 2015:

� PI12/03018: Profile of Alzheimer's pathologyassociated with age (85+CIEN Study). 3-year



project funded by the Carlos III Institute ofHealth and led by Dr. Alberto Rábano.Budget for 2015 adds up to 4.840,00 € (projecttotal budget: 19,965.00€).

� PT-2012-0769-010000: Design and constructionof a system for the diagnosis of Alzheimer'sdisease based on laser raman spectroscopy(INNPACTO program). 3-year project fundedby the Ministry of Economy andCompetitiveness, Directorate General forInnovation and Competitiveness, led by Dr.Alberto Rábano. Budget for 2015 adds up to17.295,00 € (project total budget: 93,320.00€).

� PT13/0010/0045: Biobank Platform. PrincipalInvestigator: Dr. Alberto Rábano. Projectfunded by the Carlos III Institute of Health witha budget of 44.478,26 € for 2015. OnNovember 26, 2014 the Carlos III Institute ofHealth approved the continuity of funding forthe years 2015, 2016 and 2017, always subjectto the existence of appropriate and sufficientcredit.

2.4.2 Fellowships and grants

During 2015 the CIEN Foundation has awarded thefollowing fellowships and grants:

• MAPFRE-Queen Sofia Foundation Fellowship2013-2015. Stay of six months, renewed for asimilar period (maximum 12 months) in theResearch Program in Dementia at theAlzheimer's Disease Center, University of Texas,San Antonio, supervised by Prof. George Perry,and the Case Western Reserve University.Cleveland, Ohio. Gorka Guereñu Lopetegui stayended in January 2015.

• MAPFRE-Queen Sofia Foundation Fellowship2015-2016. On March 18, 2015, the SelectionCommittee decided to grant the scholarship toMs. Ana Rebollo Vazquez, formalizing het hiringas provided in the call.

• PEJ-2014-C-19788. Resolution of 23 October,2015 of the Secretary of State for Research,Development and Innovation of the Ministry ofEconomy and Competitiveness grantingsubsidies for the Promotion of YoungEmployment and Implementation of the YouthGuarantee in R+D+i. Four actions were fundedresulting in the recruitment of two universitygraduates and two technicians. The contractssigned to this effect shall have a minimumduration of two years.

2.5. Quality Policy

Quality Objectives are established annually in orderto achieve continuous improvement in processesand obtaining higher levels of user satisfaction, bothexternal and internal.

The Quality Management System is based on pro-cesses. To do so, the basic processes of the Founda-tion are continuously analyzed, which is a tool thatallows constant improvement to meet user require-ments, applicable laws and regulations, as well asoptimize the resources of the Foundation.

The tools used to carry out the monitoring of theQuality Management System are:

• Audit reports, internal and external. • Evaluation of suppliers. • Complaints, suggestions and customer

information. • Results of studies of customer satisfaction. • Evaluation of corrective and preventive actions. • Indicators of quality of processes. • Quality objectives. • Internal or external modifications that influence

the Quality System..The quality policy of CIEN Foundation seeks to en-sure and optimize processes related to: the orienta-tion to the external and internal user, leadership, staffparticipation, a process-based approach, and con-tinuous improvement.


Department of Management and Administration of the CIENFoundation - CIBERNED


2.6. Personal Data Protection Law

CIEN Foundation has files containing personal data(including information systems, support and equip-ment used to treat them), of which is responsible andshould be protected according to the provisions ofcurrent legislation, Organic Law 15/1999 of 13th De-cember on the Protection of Personal Data [LOPD,for its acronym in Spanish). These files are containedin the Security Document, as well as those involvedin the treatment thereof and the premises in whichthey are located, Valderrebollo, 5; 28031-Madrid.

As the only responsible for the files, CIEN Foundationis committed to fulfilling its obligation of secrecy of

personal data and its duty to guard it, and to takethe necessary measures to prevent alteration, loss,or unauthorized access, taking into considerationthe current state of technology, ensuring com-pliance with the LOPD.


The UIPA consists of four departmental areas: Multidisciplinary Support Unit, Neuroimaging, Neuropathology and Laboratory. During 2015, it has continued working primarily on the Vallecas project, in addition to other research projects such as Alzheimer's Project, the 'Detection of proteins in tears as biomarkers of Alzheimer's disease" project, the '85+CIEN' Studycomo biomarcadores de la enfermedad de Alzheimer’, el estudio ‘85+CIEN’ or the REGISTRY international project on Huntington's disease. Moreover, the BT-CIEN has continued to increase the number of registered donors, which now exceeds 600 people.

Since January 18, 2006, by virtue of an agreementsigned with the Queen Sofia Foundation, the CIENFoundation manages the Alzheimer's Project Rese-arch Unit (UIPA). The UIPA was promoted by QueenSofia Foundation within the framework of a largerproject, namely the Alzheimer Complex, located inVallecas and consisting of a Residence for patientswith Alzheimer's and related diseases, a day-careoutpatient Hospital and a Teaching Unit, in additionto the Research Unit itself. The UIPA began operatingin April 2007, while the healthcare activities startedat full capacity during the second half of 2007.

Since then, the UIPA has set up four departmentswith different functions. Among others, they aim atprocessing and managing biological samples, stud-ying such tissues or conducting neuroimaging rese-arch projects in the field of neurodegenerativediseases with emphasis on Alzheimer's disease andrelated dementias. Genetic and molecular kno-wledge gained from these studies have different ap-plications: illustrate researchers into the pathogenicmechanisms of the disease, can be implemented inthe diagnosis field and hopefully may lead to the de-velopment of better treatments.

However these advances, far from promising a sim-ple solution to the problem of neurodegenerativedementias, anticipate an increasingly complex pic-ture, in which the remedies will be achieved throughsmall goals, and only by the complementary andsynergistic work of many research groups.

The main feature of neurodegenerative diseases isits complexity, since they affect both the biologicalaspect as well as the clinical and personal level.Thus, the psychological and social aspects involvedin dementia need to be taken into account and beaware that ethical and legal issues such as the rightto information and participation in medical decisionsare increasingly gaining prominence every day.

Result of the parallel development of both biologi-cal and clinical aspects has given rise to conceptssuch as translational research in medicine. This is atthe core of the scientific activity at the CIEN Foun-dation: moving progress made in basic research tothe clinical setting. This requires establishing com-munication links to help focus and capitalize on ef-forts.

3.2. Departmental Structure

The scientific activity of UIPA is structured around fourcomplementary research areas:

• Multidisciplinary Support Unit (UMA)• Department of Neuroimaging• Department of Neuropathology• Department of Laboratory

From the clinical aspect, Multidisciplinary SupportUnit (UMA, for its acronym in Spanish) staff maintaindaily contact with patients attending the QueenSofia Foundation Alzheimer Center (CAFRS, for itsacronym in Spanish) and with those people respon-sible for healthcare tasks of these patients as well aswith the cohort of volunteers from the “Vallecas Pro-ject” (study to which we devote a full section in thisreport, please see Section 4). One of the UMA rese-arch lines involves conducting a clinical, syndromic,and etiologic diagnosis of patients staying at theCAFRS either in live-in regime (Life Units) or in daycare (Day Center). In addition, the set of clinicaldata obtained will be very useful for investigations ofthe rest of the UIPA scientific areas.

From the basic research side, UIPA's original projectcontemplated the creation of departments of La-boratory; Neuropathology; and Neuroimaging.These three disciplines bring together the most pro-mising areas in research on the biological processesinvolved in dementia.

3. SCIENTIFIC ACTIVITY

3.1. Overview


UMA members are in continuous contact with theseprofessionals, preparing and contrasting hypotheses,and carrying out research projects. Finally, UMA staffplays a mediating role between basic researchersand patients relatives and caregivers. This role is cri-tical for patients, their relatives and caregivers get-ting to know UIPA's research aims, authorizing andcollaborating with the various research lines.

3.2.1. Multidisciplinary Support Unit

Dementia patients care requires an accurate andearly diagnosis, an assessment of the cognitive areasaffected and the severity of the impairment, alongwith the implementation and monitoring of treat-ment. It is imperative that various medical disciplinesbecome involved, due to the need of following upfurther evolution, the particular treatment, the ob-servation of complications, the application of coun-termeasures and the associated practice ofhealthcare resources.

The Multidisciplinary Support Unit (UMA) was esta-blished in 2007 with a translational vocation to dee-pen the clinical-evolutionary knowledge ofdementia. It stands as a link between basic scienceand clinical fields and social sciences related to he-alth, to advance knowledge about neurodegene-rative dementias and their application. It stands as alink between basic science and clinical and social

science fields related to health, to advance kno-wledge on neurodegenerative dementias and itsapplication. The Unit consists of a team of specialistsin Neurology, Psychiatry, Psychology and Sociology,along with the participation of geriatricians, occu-pational therapists, physiotherapists and social wor-kers from the Center's healthcare area. Evaluationsperformed in the UMA constitute the clinical and so-ciological database, and in addition to its intrinsic in-terest for research, it gives support to the biologicalsamples and neuroimaging data obtained systema-tically at the Center.

Progress in the knowledge of neurodegenerative di-seases, particularly Alzheimer's disease is amongUMA's priorities, from a primarily clinical perspective.The main purpose of the UMA is to advance kno-wledge of the degenerative diseases that cause de-mentia to ultimately get a better treatment for thosewho, directly or indirectly, suffer from these disorders.

Department activities

In addition to the large dedication of UMA profes-sionals to the Valleca 'Project, they systematicallyperform a clinical, syndromic, and etiologic diagno-sis of patients who are in the CAFRS, either in live-inregime (Life Units) or day care (day center). Toachieve this diagnosis, UMA staff together with thepeople responsible for healthcare tasks keep daily

53

35

34

490

40

249

Admissions in Day Centre and Residence

Informed Consents

Baseline Assessments

Clinical Evaluations

Brain MRI Studies

Blood testing

PERIODIC MULTIDISCIPLINARY ASSESSMENTS DURING 2015


close contact with the patients coming to CAFRS.Another role of UMA is the periodic monitoring of thepatients progress, from a multidisciplinary perspec-tive, with standardized contributions of Neurology,Psychiatry, Neuropsychology, Health Sociology, Oc-cupational Therapy, Physiotherapy and geriatrics.

Reviews are conducted every six months, based ona rigorous protocol that enables continuous and sus-tained monitoring of each patient through checksof their quality of life, neurological status and theirmental, affective and functional behavior. The ob-jective of this process is to establish and collect va-riables that allow for a subsequent correlation andanalysis with respect to other analytical, genetic, his-topathological and neuroimaging variables.

In 2015 there were 53 admissions at Day Center andResidence, 35 of whom signed consent to partici-pate in regular multidisciplinary evaluations. Alongwith the 34 baseline assessments, a total of 490 clini-cal evaluations (every six months), 40 brain MRI stu-dies (annually) and 249 blood tests were performed.

Research projects

CIEN Foundation supports the use of new technolo-gies in prevention, diagnosis, prognosis, treatmentand monitoring of neurodegenerative diseases. Withthese and other goals, during 2014, the following re-search projects have conducted:

Detection of proteins in the tear as biomarkers of Alzheimer's disease

Currently, many researchers believe that both thedevelopment of amyloid plaques, and the forma-tion of neurofibrillary tangles (NFT) are relatively lateevents in the course of the disease, which may ormay not reflect the fundamental biochemical-mo-lecular dysfunctions that give rise to the disease. Thisassumption, increasingly accepted, suggests that

the disease has an important systemic componentthat manifests with peripheral alterations years be-fore symptoms appear. Considering that future po-tential therapies have to be implemented in veryearly stages of the disease where clinical diagnosisaccuracy decreases, and currently accepted bio-markers (tau, tau and p-A42) require CSF collec-tion, many research groups are focusing their interestin the search for biomarkers of disease in accessibletissues and fluids such as blood or saliva.

The eye is a structure that is highly innervated by thesympathetic and parasympathetic nervous system.In particular by the parasympathetic nervous system,via the neurotransmitter acetylcholine, controls nu-merous processes such as tear secretion, pupil dia-meter or intraocular pressure (Pintor, 2009).

The parasympathetic nerve terminals, coming fromthe ciliary ganglion, stimulate the main lacrimalgland through the M1 and M3 muscarinic receptors,and as a consequence acetylcholine favors the pro-duction of the aqueous component of the tear se-cretion as well as proteins that are part of this (Dartt,2009).

Therefore, it is hypothesized that AD biomarkers, suchas Tau protein, which has been modified the activityof muscarinic acetylcholine receptors in laboratoryanimals (Gómez-Ramos et al., 2009 Martinez-Eagleet al. 2014), may also be present in human tears andthe same could happen with other AD-related pro-tein markers such as 14.3.3 (Sluchanko NN, 2011, HYQureshi, 2013), β-amyloid 40 and 42 (Van Setten,1996) or some proinflammatory cytokines (Benito MJ,2014, VanDerMeid KR, 2011), among others.

The objectives of the project are:

- Recruitment, characterization andclassification of the participants in the projectthrough a comprehensive neurological and



neuropsychological evaluation to know theclinical and cognitive profile of theparticipants.

- After signing informed consent, sampling oftears (Schirmer technique) in participants(individuals with no cognitive impairment,patients with mild cognitive impairment andpatients diagnosed with mild Alzheimerdisease - Reisberg stages GDS 3 and 4).

- Determination in the laboratory of thebiomarkers.

- Comparison of the results from the three studygroups.

- And developing a database to harbor allassociated patient information / controls andsamples.

All this in order to find biomarkers related to AD thatallow us to make the diagnosis of the disease and toelucidate its evolution and prognosis.

Recruitments of participants begun in 2014 and finis-hed during 2015. It involves the Association of Rela-tives of Alzheimer's patients and other dementias atSoria, Leon Alzheimer's Association, CIEN Foundationand Center of Molecular Biology Severo Ochoa.About 100 samples have been collected in total,which will be analyzed at the Center for MolecularBiology Severo Ochoa throughout 2016.

Among the activities in the areaof Neuropsychiatry of UMA are included

the following:

IDEAL Scale

Participation in "VaIidation of the IDEAL Scale in Spa-nish population: a multicenter study in patients withdementia." The study attempts to validate in Spain ascale that values multiple dimensions of dementia.The aim is to better detect the different needs ofcare for patients with dementia. It is known that dif-ferent patients with dementia have different needs,but there are currently no adequate screening me-

thods that meet all these needs. Information from 20patients attending the Alzheimer Day Centre Foun-dation Reina Sofia Center (CAFRS) with their infor-med consent available has been gathered for thisstudy. Clinical information was obtained boththrough interviews with family members as well aswith the application of different existing validatedscales that assess behavioral and psychologicalsymptoms of dementia (BPSD), caregiver burden,functionality and overall cognition.

Personality in dementia

This research line attempts to relate the previous per-sonality of the patient with the development of dif-ferent BPSD or other cognitive symptoms indementia. For years, during the initial evaluation ofpatients it was included the performance by the re-ference family of the NEO-FFI inventory. This year theHetero-anamnesis Questionnaire of Personality (PAH,in its original Dutch version) has been included afterits translation to Spanish. The goals of this researchare the validation of this scale in Spain, its compari-son with the results obtained in the inventory NEO-FFIand its correlation with clinical data of the patientsunder study.

Longitudinal study of CAFRS patients

It consists of gathering information every other yearfrom all patients at Day Care Centre and the Resi-dence who have provided consent to perform theevaluation tests. There is a longer yearly assessmentheld in the first half of the year, and a shorter assess-ment in the second half. In patients from Residenceinformation is gathered through the reports of thecoordinators of the CAFRS Life Units. In the semesterinformation is collected on the following tests: Neu-ropsychiatry Inventory (NPI), Cornell Scale for De-pression in Dementia, Cohen-Mansfield AgitationScale in Dementia (CMAI), Apathy Inventory (IA),and NH APADEM Apathy Scale. In the second se-


mester information is collected on NPI, IA and APA-DEM-NH. Information from Day Center patients is ga-thered through telephone interviews with relatives ofreference. In the first semester information is collec-ted on NPI, Cornell Scale for Depression in Dementia,CMAI and IA: In the second semester information iscollected on NPI and IA.

This systematic data collection since the patient be-comes part of the study untileither is transferred toanother Day Center or the patient dies, along withsystematic information collected at neurological,neuropsychological and functional level allow thecreation of a clinical database that can be exploi-ted by themselves or in combination with neuroima-ging and/or neuropathology data.

Project REGISTRY

REGISTRY is an international multicenter observatio-nal study conducted by the European Group onHuntington's disease (EHDN, for its acronym in Spa-nish) with the following objectives:

- Obtain data from the natural history of thedisease in a large spectrum of peopleaffected by Huntington's Disease (HD).

- Develop new measurement instruments tomonitor or predict the onset and progressionof the disease as well as improve existingtools.

- Determine how the environmental andgenetic factors influence both the onset ofsymptoms and progression of the disease anddetermine the family variability of thesefactors.

- Accelerate the identification and inclusion ofparticipants in clinical trials.

- Planning future observational or interventionalresearch studies aimed at better controlsymptoms and delay the disease onset orslow the progression of Huntington's disease.

The strength of the REGISTRY study lies in its collabo-rative nature. We can all participate: subjects withgenetic mutation and symptoms, subjects with thegenetic mutation without symptoms, subjects des-cended from a family with a history but they ignorewhether they have the mutation, subjects descen-ded from a family with a history but have a negativegenetic study, subjects who are not descendedfrom a family with affected people... Starting fromthe information gathered, a large database of bio-logical and clinical data (blood and urine) will becreated to enable:

- Better understand the natural progression ofHuntington's disease and the factors involved,besides the Huntington gene, at its onset,presentation and progression.

- Identifying disease modifiers at the genetic,biological and environmental level.

- Identify more accurate and reliable HDbiomarkers.

- Review the drugs used in the management ofsymptoms of HD.

- Assessing co-morbilities with HD. - Study the less frequent types of Huntington

disease (as juvenile EH). - For many people it is a chance to participate in

future clinical trials and intervention studies.

REGISTRY is being carried out in 173 centers from 20European countries and has already registered morethan 12,000 subjects. Among these centers is theCIEN Foundation, where 33 participants were regis-tered during 2014.

Since the second half of 2015, REGISTRY is graduallytransitioning to ENROLL-HD, a prospective registrystudy of a global cohort with HD (Europe, USA, Ca-nada, Argentina, Chile and others).


Team

The UMA team is composed of the following profes-sionals with multidisciplinary expertise:

Area of Neurology

� Teodoro del Ser Quijano (Dr. Medicine, Neurology). Coordinator ofNeurology. Collaborator.

� María Ascensión Zea Sevilla (Dr. Medicine, Neurology).

� Meritxell Valentí Soler (Grad. Medicine, Neurology).

� Javier Olazarán Rodríguez (Dr. Medicine,Neurology) (until April 2015).

Area of Psychiatry

� Jorge López Álvarez (Grad. Medicine, Psychiatry) (until June 2015).

Area of Neuropsychology

� Miguel Ángel Fernández Blázquez (Dr. Psychology, Neuropsychology) Coordinatorof Neuropsychology Neuropsicología.

� Marina Ávila Villanueva (Grad. Psychology, Neuropsychology).

� Belén Frades Payo (Grad. Psychology,Neuropsychology).

� Ana Rebollo Vázquez (Grad. Psychology,Neuropsychology) (Since April 2015).

� María García Otero (Grad. Psychology,Neuropsychology) (since December 2015).

UMA Administration

� Francisca Martínez Lois (Administrative Assistant).


Collaborators

The following CAFRS staff also collaborated during2015:

� Irene Rodríguez Pérez (Occupational therapist).� Almudena Pérez (Occupational therapist).� Inmaculada Barrero Rodríguez (Occupational

therapist, Day Center).� Cynthia Pérez Muñano (Technician in training

and Occupational therapist).� Emma Osa Ruiz (Physiotherapist). � Álvaro Sanabria Luque

(Physiotherapist, Residence).

� Carolina Mendoza Rebolledo (Grad.Psychology, Neuropsychology).

� Gema Melcón Borrego (Social worker).� Lidia Espada Raboso (Social worker). � Belén González Lahera

(Grad. Medicine, Geriatrics).� Rubén Díaz Campos (Physiotherapist, Day

Center) (until September 2015).� Irene Gamarro García (Physiotherapist, Day

Center) (since September de 2015).



UMA’s team

3.2.2. Department of Neuroimaging

Knowledge of the morphological variations occu-rring in brain structure throughout life is essential toassess the corresponding pathological changes thatoccur in neurodegenerative diseases. Currently,neuroimaging in any form, and combined, is one ofthe areas of greatest progress in the understandingof various aspects of Alzheimer's disease and otherneurodegenerative diseases: etiology, early diag-nosis and differential functioning of brain areas, me-tabolism, neurotransmission.

In this regard, neuroimaging techniques such asmagnetic resonance imaging (MRI) have led to sig-nificant progress in understanding brain changes as-sociated with age. MRI is a noninvasive tool thatallows the study of normal aging individuals at diffe-rent times of his life. However, conventional MRItechniques are unable to detect and quantify mi-crostructural changes dependent on age who havebeen described in post-mortem studies of brain tis-sue.

For this reason, the Department of Neuroimaging hasa state-of-the-art 3 Tesla (T) MRI equipment as wellas a collaboration agreement for research with thesupplier: General Electric. The main objectives De-partment of Neuroimaging are:

• Promotion and development ofneuroimaging research projects in the field ofneurodegenerative diseases with specialinterest in AD and related dementias.

• Acquisition and postprocessing of MR imagesfor UIPA ongoing research projects.

• Dissemination of knowledge on neuroimagingtechniques related to neurodegenerativediseases.

• Personnel training related to obtaining,postprocessing or interpretation of advancedneuroimaging techniques.


UIPA's Department of Neuroimaging primarily dealswith the acquisition of MR data (and, where appro-priate, the performance of other imaging techni-ques such as PET or CT through externalcollaborations) and post-processing and analysis ofthe data obtained. All studies are monitored and re-ported by a neuroradiologist.

In addition, the Department provides technical as-sistance to both the rest of the scientific areas of theUIPA and external research groups. It also searchesfor new resources and promotes the UIPA researchprojects and the post-processing of images serviceamong other research groups.

This activity complements the internal seminars andexternal courses, both nationals and internationals,on specific neuroimaging techniques.

During 2015 the Department of Neuroimaging hasparticipated in MRI studies in the following clinicaltrials:

• “Lilly” (Multicentric, European). Extension “Eli LillyProtocol H8A-MC-LZAO”. Effect of passiveimmunization on the evolution of Alzheimer'sdisease: LY2062430 against placebo.Sponsor: EliLilly.

• “Optimise”. Optimization of Treatment andManagement of Schizophrenia in Europe. PI: R.Kahn. University Medical Center Utrech. 2011-2013. CIBERSAM.

• “Clozapine in early outbreaks of schizophreniaas potential preventive treatment from brain



and clinical impairment". Reference protocol:CLOZAPINE-1, Nº EudraCT: 2006-00200-34. PI: Dr.Francisco Javier Sanz Fuentenebro. 2010-2013.CIBERSAM.

• “ABE_4869g” A phase II randomized, double-blind, placebo-controlled, parallel group,multicenter to evaluate the efficacy and safetyof MABT5102A in patients with moderateAlzheimer's disease". Code EudraCT: (2010-021926-37). GENENTECH, Inc.

• “NAC” Phase III study: "Effect of Adjuvanttreatment with N-acetylcysteine for 48 weeksover the loss of gray matter and oxidativemetabolism in patients with early onsetpsychotic episodes". Randomized, Double-blind,placebo-controlled Clinical Trial Code: FIBHGM-ECNC002-2012, EudraCT Number:2012-005435-87. Promoter Center: Foundationfor Biomedical Research Gregorio MaranonHospital. PI: Celso Arango.


0 500 1000 1500 2000 2500

CURSOSDOPAMINE

BP28248TENSOR 64

LILLYUOD

CLOZAPINA1PVALLECAS5

ABE_NAC

PVALLECAS2FMRI_QA

NEUROPATOLOGÍANEUROTREMOR

OPTIMISE_BRAINAGES

RESIDENTESMETSY

PVALLECAS3PVALLECAS4 2.264

1.344413

360235

165154

120108108

6860362821181615122

Number of studies by project 2015

• “BP28248” A Phase III, multicenter, randomized,double-blind, parallel group, placebo-controlled trial to investigate the safety andeficacy of RO4602522 added to backgroundtherapy with acetylcholinesterase inhibitors,donepezil or rivastigmine in patients withmoderate Alzheimer's Disease". Protocol Nº BP28248, Promoter F. Hoffmann-La Roche Ltd.

During 2015 the acquisition of MR images from atotal of 963 subjects has been completed. Overall,5,744 MRI studies have been performed distributedamong the different research projects.

A total of 43,864 MRI sequences have been con-ducted since the creation of the department, distri-buted by year and type of sequence.

Provision of services

The Department of Neuroimaging has a 3T MR scan-ner (GEHC, HDxt) system equipped with dual gra-dient system of up to 50mt/m, 3 antennas for brainstudies (transmitter/receiver quadrature antenna, re-ceiving 8 channels antenna and 16 channels recei-ving antenna) and small antennas for rats and mice.Data is stored in PACS with direct recovery capacityfor five years of work.

For Functional MRI studies the Department has anaudio/video system compatible with 3T MRI. A va-riety of software packages is used, mainly SPM12and FSL.

Sequences

Image acquisition of 3D isotropic studies with T1 se-quences for VBM. Image acquisition of T2 sequen-ces, DWI, ASL, BOLD and spectroscopy.

Team

The Department of Neuroimaging team, led by Dr.Bryan Strange (MD, PhD, Clinical Neuroscience), hasa highly multidisciplinary nature and consists of thefollowing personnel:

Research fellows

� Alba Sierra-Marcos (MD, Neurology).

� Dr. Christopher Long (PhD, Engineering, Specialist in BiomecialImaging, Madrid-Massachusetts Institute ofTechnology Vision Program).

� Eva Dueñas Moreno (BSc, Biology). Since December 2015.

� María Molina Matas (BSc, Physics). Since December 2015.

Radiodiagnostics

� Mabel Torres Llacsa (MD, Radiodiagnostics).

Image Acquisition

� Eva Alfayate Sáez (Technical Coordinator Técnico inRadiodiagnostics).

� Felipe García Fernández (Advanced Technician in Diagnostic Imaging).

� Carmen Rojas Obregón (Technician in Radiodiagnostics).

Administration

� Arantza Narciso (Administrative Assistant).

� Corina Ghinea (Administrative Assistant).


Other Collaborators

� Roberto García Álvarez (PhD, Physics).

� Emily R. Lindemer (PhD Student, Laboratory forComputational Neuroimaging Harvard-MITDivision of Health Sciences & Technology).



Neuroimaging team

3.2.3. Departament of Neuropathology

Neuropathology is a specialty in continuous progresswith capacity for contrasting clinical judgment andperformance of any diagnostic test with the finaldiagnosis ("gold standard"). However, research-wisetheir work goes beyond that and provides essentialinformation about the molecular components of thecharacteristic lesions, the pathogenic mechanismsof the disease, and potential biomarkers, especiallyin the field of neurodegenerative diseases.

The neuropathology of dementia landscape hasdramatically changed in recent years. The incorpo-ration to the neuropathological diagnosis of new an-tibodies for immunostaining and new moleculartechniques has helped establishing the boundariesand internal heterogeneity of entities such as de-mentia with Lewy bodies and frontotemporal de-mentia, and has also led to the discovery of newentities in this area (DFT-TDP. DFT-FUS, etc.).

Also, the definition of diagnostic criteria from largeseries of brains has allowed to address the problemof combined and mixed pathology, specifically re-garding Alzheimer's disease. The evolution of thediagnostic criteria (eg, new diagnostic classificationcriteria for Alzheimer patients, National Institute ofAging, 2012) and molecular techniques are turningthe histological diagnosis in a critical element in theprocess of classifying dementia, definite or quasi-de-finite in some cases, but partial or probabilistic inmany others.

As demonstrated by the clinicopathological ses-sions, the final classification of a case requires inte-gration of all clinical, neuroradiological,neuropathological and molecular, when available.

A need for research in dementia is the provision ofbrain tissue perfectly diagnosed, classified and pre-

served. This need can be met by the brain banks,and CIEN Foundation has one of the major brainbanks in the country, the Tissue Bank CIEN (BT-CIEN).

Neuropathology also provides significant support tothe studies of neurological diseases based on animalmodels, both for histological evaluation of transge-nic animals as well as to search for natural models ofdisease.


The core activity of the UIPA Department of Neuro-pathology corresponds to the BT-CIEN, both to its or-ganizational and logistical components as well asthe neuropathological diagnostic work and the ma-nagement of biological samples.

The Department also participates in numerous co-llaborations in external research projects and carriesout its own internal projects, mainly based on seriesof cases from post mortem donation.

Among the active lines of research in the Depart-ment are the following:

• Neuropathological and molecular study oftauopathies, including Alzheimer's disease.Pathogenic significance and spread ofassociated cellular lesions.

• Clinicopathological profiles in advanceddementia. Characterization of cerebral smallvessel vascular disease.

• Distinctive features of Alzheimer-type pathologyin nonagenarians and centenarians.

• Characterization and pathogenic study ofdementia-associated hippocampal sclerosis.

• Advance age-associated brain pathology inother animal species. Search for natural modelsof Alzheimer in primates and other mammaliangroups.



Among the funded research projects in this area thefollowing can be highlighted:

• Age-associated Alzheimer's pathology profile(The 85+CIEN Study). Project funded by FIS,2013-2015.

The segment of population over 85 years is the onewith the highest relative growth in recent decadesand will increase even more in the next, especially inSpain, which will become the country with the oldestpopulation in the European Union. Several contro-versies have focused in recent years the study of de-mentia and healthy cognitive profile in thesepopulation group. Overall, clinical and pathologicalstudies suggest that Alzheimer's disease shows spe-cific clinical, neuropathological and genetic be-yond age 85, with greater involvement of vascularpathology and similar phenomena are observed inother neurodegenerative disorders (synucleinopa-thies, tauopathies). This project aims to address thisset of issues in a large series of post-mortem brainsfrom donations to four biobanks from three SpanishRegions. More than 500 brains with associated basicclinical information, and in a proportion of cases (75estimated cases) with detailed cognitive data fromtheir last year of life, will be studied. Clinical, neuro-pathological, neuropsychological gathered will beanalyzed according to the main diagnostic groups,associated pathologies, observed stages in the dif-ferent diseases and age groups at death and at di-sease onset. Clinical-pathological correlation offindings in relation to dementia in the subgroup ofcases with cognitive tracking information will beanalyzed. Results will provide a neuropathologicaland clinical-pathological profile of cognitive disor-ders observed in tissue donors, particularly in casesof the oldest-old.

The Department also participates in the projectbelow, funded by BBVA Foundation:

• Complete genome analysis of 'splice' variants inHuntington's disease. Principal Investigator: JoséJavier Lucas Lozano (Centro de BiologíaMolecular "Severo Ochoa", CSIC).

Provision of services

The range of activities undertaken by the depart-ment derives from the ability of its members to co-llect, process, evaluate and diagnose brain tissuesample from human or animal origin.

• Neuropathological autopsies of donors braintissue, from both the Region of Madrid, asneighboring Regions.

• Management of a biobank of neurologicalsamples. Transfer of samples to researchersaccording to the BT-CIEN standard operatingprotocols.

• Diagnostic consultations of neuropathologicalcases. Among the external consultations thosemade in support of other neurological samplesbiobanks (Murcia, Salamanca and Cordoba)can be highlighted.

• Perfoming neurohistological andimmunohistochemical techniques inneurological samples of human andexperimental origin.

• Evaluation of new antibodies in human braintissue.

• Collaboration in research projects from otherinstitutions

CIEN Foundation Tissue Bank (BTCIEN)

Since its opening in May 2010, the CIEN FoundationTissue Bank (BT-CIEN) has traveled a path of growthand consolidation in the field of Spanish Neuros-cience, supporting national and international rese-arch groups and maintaining close contact withneurological disease patients and relatives associa-tions.


3. ACTIVIDAD CIENTÍFICA DE LA UIPA

The number of registered donors in the BT-CIEN re-gistry has continued to grow every year, as has thetissue donations made at our Center within our In-ternal Donation Program, which involves residents ofthe Queen Sofia Foundation Alzheimer Center(CAFRS), and the External Donation Program, that in-volves donors from the Region of Madrid and otherRegions.

There is also an increasing number of researchgroups applying for biological samples from BT-CIEN,especially groups from the Center for Networked Re-search in Neurodegenerative Diseases (CIBERNED).

One of the missions of BT-CIEN is to promote the cre-ation of new neurological samples biobanks whe-never they are demanded by donors andresearchers. The Region of Murcia Brain Bank(BCRM), the Neurological Tissue Bank from the Insti-

tute of Neuroscience of Castilla y León (BTN-CyL)and the of Queen Sofia University Hospital Biobankfrom Cordoba are active examples of this commit-ment.

In 2013, the BT-CIEN has been accredited by theCouncil of Health of the Region of Madrid, accor-ding to what is established in the Royal Decree1716/2011 on Biobanks, and registered in the Natio-nal Registry of Biobanks of the Carlos III Institute ofHealth.

In January 2014 the Biobanks National Network Plat-form (PRNBB, for its acronym in Spanish), promotedand funded by the Carlos III Institute of Health (2014-2017) was constituted, with participation of the mainbiobanks in the country, both hospital and non-hos-pital, including BT-CIEN. PRNBB mission is to create astable organizational structure that allows the coor-



Distribution of donation cases by origin in 2015

Internal donation Consultations External donations

0

30

60

90

120

150

3

2007

7

2008

119

2009

12

14

28

2010

9

42

48

2011

12

53

57

2012

8

47

48

2013

12

43

60

2014

14

42

69

2015

dinated activity of participating biobanks in the co-llection, management and transfer of biologicalsamples of human origin. Moreover, the BT-CIEN hasrenewed its ISO 9001/2008 quality certification.

The BT-CIEN registry had over 600 registered donorsby December 31, 2015.

125 cases were processed in the Neuropathology la-boratory during 2015, with the following distributiondepending on the origin:

• 69 donations from the External Program.• 14 donations from the Internal Program.• 42 consultation cases.

Hence, the number of donation cases extractedand processed entirely at the UIPA during 2015 wentup to 83. It is thus observed a stabilization of the num-ber of studied cases at the BT-CIEN around 120, anddonations extracted in the BT-CIEN in the range of60-75 per year, with an upward trend.

In 2015 the average post-mortem interval obtainedis six hours, slightly longer than the average of pre-vious years, mainly due to the higher rate of externaldonations coming from different Regions.

The research centers that have received samplesfrom BT-CIEN during 2015 have been:

• Karolinska Institute, Stockholm, Sweden.• National Center of Microbiology, ISCIII, Madrid.• Center for Molecular Biology "Severo Ochoa",

CSIC, Madrid. • Center of Biomedical Technology, Technical

University, Madrid.• Faculty of Medicine, University of Castilla-La

Mancha, Ciudad Real.• Institute of Neurobiology Ramón y Cajal, CSIC,

Madrid.

• Institute of Research in Health SciencesGermans Trias i Pujol, Badalona.

• CEU San Pablo University, Madrid.• Institute of Neuroscience, Autonomous University

of Barcelona.• Príncipe Felipe Research Center, Valencia.

By the end of 2015, the accumulated number of theBT-CIEN donations was 405, of which about 50% arecases of Alzheimer-type pathology.

Team

During 2015, the Department of Neuropathologystaff was composed of the following professionals:

� Dr. Alberto Rábano (Grad. Medicine, Pathology), Head ofDepartment and BT-CIEN.

� Elena Gómez Blázquez (Pathology Technician).

� Izaskun Rodal González (Pathology Technician).

� Mario Lozano Enguita (Pathology Technician). Since December 2015.

Collaborators (autopsies):

� Luis Javier Martín Lentijo (Pathology Technician).

� Ana Sánchez de Castro (Pathology Technician).




Neuropathology team

3.2.4. Department of Laboratory

From a neuropathological point of view, Alzheimer'sdisease (AD) is a neurodegenerative disease that af-fects specific areas of the brain, altering the circuitsinvolved in the catecholaminergic, serotonergic andcholinergic transmission. AD pathophysiology inclu-des the presence of neuritic amyloid plaques, neu-rofibrillary tangles, neuronal loss and neurochemicalabnormalities.

Neuritic plaques contain extracellular deposits of β-amyloid peptide surrounded by dystrophic neurites,activated microglia and reactive astrocytes. Thesepeptides derive from the β-amyloid precursor pro-tein (APP) through the sequential processing by dif-ferent proteolytic complexes called β andγ-secretases.

Neurofibrillary tangles (NFT) are intraneuronal bodiescomposed of paired and helically wound filaments(paired helical filaments, PHF) of a hyperphosphory-lated form of the microtubule-associated protein,tau. The NFT appear in many of the dystrophic neu-rons around amyloid plaques. Currently, many rese-archers believe that both the development ofamyloid plaques and NFT formation represent relati-vely late events in the progression of the disease,which may or may not reflect the fundamental bio-chemical-molecular dysfunctions that trigger the di-sease.

The clinical manifestations of AD are preceded byan asymptomatic preclinical phase, after which thefirst symptoms appear in the prodromal phase of thedisease characterized by mild cognitive impairment(MCI). In this regard, AD can be viewed as an on-going process that evolves from the asymptomaticphase to the dementia stages. This progression is lar-gely determined by genetic risk variants and is asso-ciated with biochemical changes that may ideallyserve as early markers of the disease.


The Department of Laboratory is focused on thestudy of biomarkers and susceptibility genes for Alz-heimer's disease. This study has the following primaryobjectives: to gain further insight into the molecularbasis of the disease and to develop predictive al-gorithms that combine information on genetic, bio-chemical and neuroimaging markers withdiagnostic, prognostic or responsive to disease-mo-difying therapies markers.

For this purpose, the Department's research is con-nected with the activities of the Multidisciplinary Sup-port Unit, and the Departments of Neuroimaging,Neuropathology and BT-CIEN on the two main rese-arch projects in the CIEN Foundation and QueenSofia Foundation: the Alzheimer project and the Va-llecas project.

Because of its location in the CAFRS, the UIPA is bestplaced for obtaining biological samples from pa-tients with minimal discomfort for them and their fa-milies.

The Alzheimer Project

The Alzheimer Project focuses on regular and proto-col-based monitoring of a cohort of CAFRS patientswith dementia, ether as residents at the Center or at-tendants at the Day Center, with the main objectiveof investigating the final stages of Alzheimer's dise-ase. Patients are recruited into the monitoring pro-gram after signing an Informed Consent by a familymember or guardian. The Alzheimer Project programconsists of i) a biannual clinical and neuropsycholo-gical assessment by the Multidisciplinary Support Unit(UMA. for its acronym in Spanish), ii) a biannualblood sampling, coincident with the usual one takenat the residence, iii) conducting an annual cranialMRI if the patient's condition allows it, and iv) dona-tion of brain tissue after patient's death.


The CAFRS takes care of 156 patients in residence,and 40 patients in the Day Centre.

The Alzheimer project monitoring program includesobtaining a blood sample biannually coinciding withthe one routinely performed at the Center for con-ventional analytics. Thus, performing a venipuncturein the patient for research purposes only is avoided.After extraction, each blood sample is processed atonce, resulting in 14 aliquots comprising various he-matologic derivatives (whole blood, plasma, serum,etc.), including extraction of DNA for genetic studies.

Aliquots obtained from blood samples are incorpo-rated into the CIEN Tissue Bank (BT-CIEN, for itsacronym in Spanish) collection according to the pro-

tocols of the biobank. The total number of samplesincorporated to the BT-CIEN so far, corresponding tothe Alzheimer project monitoring program, adds upto 2,084 (13.7% patients corresponding to the DayCentre), which have resulted in a total of 29,176 ali-quots.

Consistent with other studies, the analysis of theAPOE gene polymorphism in CAFRS patients revea-led a high presence of allele ε4, that in this popula-tion appears to be more prevalent in men. Also, thephenomenon of advancement of the age of onsetof Alzheimer's disease associated with the ε4 allele,observed in other cohorts, is noted as it is the reversephenomenon of delayed age of onset associatedwith the ε2 allele.

239

211

196

165149

124 118106 107

97

67 6254 56

33

91

6145

3223

156 5 3 2 1 1 0 0 0

1ª 2ª 3ª 4ª 5ª 6ª 7ª 8ª 9ª 10ª 11ª 12ª 13ª 14ª 15ª

Residence Day care center

Evaluation

Sam

ples

Samples obtained up to December 31, 2015 according to the number of semiannual evaluations

130

16ª

1 0

17ª



The Vallecas Project

It is currently known that the pathological processesthat determine Alzheimer begin many years beforethe disease leads to the first noticeable symptoms inpatients. Years before that future drug treatmentspreventing or slowing down disease progressioncould be applied to the "population at risk" who hasdeveloped these subclinical lesions, or has an higherrisk of developing it than the rest of the population.

In this context it is framed the Vallecas Project, whichis constituted as a 5-year longitudinal study specifi-cally aimed at discovering the factors that wouldallow us to detect this "population at risk" in a phaseof potentially treatable pathology.

The phase of recruiting volunteers for participation inthe study was finished in December 31, 2013, with itscorresponding baseline assessment (n = 1,213). Theproject includes activities from the MultidisciplinarySupport Unit (UMA), Neuroimaging, and Laboratory.During 2015 we have studied 22 volunteers to com-plete the second follow-up study, 245 volunteers onthe third visit, 445 on the fourth visit, and 5 from thethird visit.

Of all patients recruited in the study and having aninformed consent, a blood sample is collected andimmediately transferred to the laboratory for frac-tionation into aliquots following the so-called ViennaInstitute of Neurology protocol, which allow differenttypes of analysis, as well as classification and sto-rage (see Figure below). Additionally, one bloodtube (BD-CPT citrate Vacutainer) for the isolation ofmononuclear leukocytes, together with anothertube lacking anticoagulant to obtain serum are pro-cessed.

Within the department of laboratory, the VallecasProject activity in figures is shown in the attachedtable.

Primary aliquots in duplicate are collected for the fo-llowing fractions:

• Whole blood (ST, for its acronym in Spanish)• Platelets-rich plasma (PRP)• Platelets-free plasma (PFP)• Buffy Coat (BC)• Red blood cells (RBC)• Serum (Suero, in Spanish)• Mononucleate leukocytes (LM, for its acronym in

Spanish)

Genomic DNA was extracted from whole blood ofall participants who have signed informed consentto it and the APOE gene, an important marker of ge-netic risk for Alzheimer's disease, was analyzed. The


Genotypes APOE

Distribution of APOE genotypes in the CAFRS patients cohort

ε3/ε313548%

ε3/ε411140%

ε4/ε4218%

ε2/ε21

0%

ε2/ε39

3%ε2/ε4

21%


Vienna Institute of Neurology Protocol for blood processing in various fractions for the search for biomarkers and susceptibility genes

10ml Whole Blood

2x0.5 ml backup aliquot( -80ºC)

9 ml centrifugation (2280g)

WHO proposal Institute of Neurology Vienna

~ 4ml PRP 2x1.3 ml aliquots

1.3 ml centrifugation (14000 rpm)

1 ml aliquot platelet-free plasma( -80ºC)

( -80ºC)

~ 1ml BC 2x 0.25 ml aliquots (WHO)( -80ºC)

2x 0.25 ml aliquots (genotyping)( -80ºC, separately)

~ 4 ML RBC 2x 1.7 ml aliquots ( -80ºC)

PRP: platelet-rich plasmaBC: buffy coatRBC: red blood cells

FIGURE 1

Evaluation

Samples

2015 samples

1º 2º 3º 4º TOTAL

1.169

0

829

22

577

245

15

441

2.633

757

The Vallecas Project activity in figures

5º

0

5

Total 1.169 851 822 456 3.3905

Aliquots 16.366 11.914 11.508 6.384 47.46070


comparison of the frequency of APOE allele ε4 ca-rriers between CAFRS patients and 'Vallecas Project'volunteers confirms the risk to suffer from Alzheimer'sdisease with an OR = 4.2 (p <0.01). Also, in order todefine different subpopulations of genetic risk, otherpossible genetic susceptibility genes have also beenanalyzed in a subset of participants (see below).

It is also important to emphasize that the samples ob-tained from Vallecas Project volunteers aged bet-ween 70 and 85 years that include a comprehensiveassessment of cognitive, sociological and neuroi-maging state are optimal for its use as a control po-pulation in various projects related toneurodegenerative diseases, especially Alzheimer'sdisease. The monitoring for a period of 5 years willallow us to detect early, even before clinicalsymptoms manifestation, susceptibility factors and

biomarkers associated with Alzheimer's disease.In this sense, we are currently working on three diffe-rent research projects based on the joint use of bio-chemical markers and genetic data to defineendophenotypes. Specifically, funding has been ob-tained for the following research lines:

• Vascular dysfunction associated withAlzheimer's disease (FIS project).

• Diagnosis of rapidly progressive dementia basedon biomarkers (EU Joint Programme –Neurodegenerative Disease Research).

• Development of diagnostic tools for Alzheimer'sdisease (R&D&i grant, INNPACTO program).

• Epigenetic mechanisms involved in the etiologyand progression of rapidly progressiveneurodegenerative dementias (CIBERNEDcooperative project).

Also during this year, CIEN Foundation has joined theDementia Genetics Spanish Consortium (DEGESCO),in which several Spanish groups bring together ge-netic data for achieve greater power in genetic stu-dies on dementia and especially Alzheimer'sdisease. As a result of this collaboration, an interes-ting study on the association of the MAPT H1 ha-plotype gene APOE allele non-carriers ε4 has beenpublished.

Besides the study on the APOE gene, using samplesfrom the Vallecas Project (controls) and the Alzhei-mer Project (AD cases), it have been conducted ge-netic association studies of key AD-associated genesincluding SORL1, LDLR, BIN1, CLU, ABCA7, CR1, PI-CALM, BACE1 and PRNP. These association studies,in addition to serving to reproduce in a Spanish po-pulation studies conducted in other populations, en-able us to determine the most important geneticfactors in the development of cognitive dysfunctionin our Vallecas Project cohort and define endophe-notypes based on genetic variations and specific,measurable features of patients and controls based


Distribution of genotypes of APOE gene in the population of volunteers from the

'Vallecas Project'

ε3/ε3828

73%

ε3/ε418816%

ε4/ε4121%

ε2/ε2 40%

ε2/ε310910%

ε2/ε49

1%

Genotypes APOE

on clinical, neuroimaging, biochemical or patholo-gical outcomes (see Figure below).

Designing and building of a Raman laserspectroscopy-based system for diagnosing

(INNPACTO Program)

This project represents a technological developmentplan and implementation of an innovative diagno-sis system for Alzheimer's disease. It is led by BiocrossSL and supported by a consortium of researchersfrom various scientific institutions such as the CSICand CIEN Foundation.

The project's starting point previous is the work of aresearch team consisting of researchers from CSIC(Institute of Structure of the Matter and Cajal Insti-tute), CIEN Foundation, the Carlos III Institute of He-alth and 12 de Octubre Hospital in Madrid. These

studies demonstrated the potential usefulness ofblood analysis using spectroscopic techniques(which are not normally used in the in vitro diagnos-tics) to distinguish samples from AD patients andcontrol samples (cognitively healthy). According tothis previous study, it has been determined that ap-proximately 9% proteins in control population havebeta structure versus 14% in AD patients. This changereflected in the spectroscopic properties of samplesallowed to classify the samples from cases and con-trols with an accuracy approaching 90%.

The project is organized into two main integratedand complementary lines, whose main goals are:

• Validate Raman laser spectroscopy-basedtechnology to detect Alzheimer's disease (AD)in blood samples.



Exploration of risk factors

Prediction of the disease

Diagnostic or predictive marker

The construct of endophenotype

Epigenetics

Environment

Genes

AD -related Abnormalitiesin cognitively

normal subjects

ADdementia

Illustration of the concept of endophenotypes for defining homogenous populations based on certain genetic variants and biomarkers

in Alzheimer's disease. Modified from During et al. 2011

• Develop a new "ultra-compact" Raman-lasertechnology equipment, specifically designed formarketing in vitro diagnostics (clinical analysislaboratories, hospitals, etc.).

The combination of a new system (with unique fea-tures by leveraging the know-how of previous deve-lopments in the field of the aerospace industry)along with the validation of Raman-laser spectros-copy-based diagnostic markers represents an op-portunity to enter a solution in the market forinnovative diagnostics and clearly differentiatedfrom the competition.

This project builds on the Biocross's and CIEN Foun-dation's experience in developing biomarkers for thediagnosis of Alzheimer's disease. This innovative pro-ject will create a multidisciplinary platform wherecompanies and research centers join together, allo-

wing the development of a diagnostic system for asocially very relevant disease like Alzheimer's.

In connection with the study of biomarkers and thecollaborative context with Biocross as well as variousSpanish hospitals, this year we have published an im-portant metabolomic study in plasma of people withAlzheimer's disease, mild cognitive impairment, orwith no cognitive dysfunction. The obtained resultsshow the possibility of classifying cases and controlsthrough a blood sample with high accuracy, evenat early stages of the disease. These results are nowin the process of validation in a larger multicenterand international cohort.

Within the framework of CIBERNED cooperative pro-ject SIGNAL led by Dr. Alberto Lleó, this year we havealso published a paper in which we have been ableto identify new AD markers, and to suggest that in-



Samples of cerebrospinal fluid (CSF) obtained post-mortem since 2008

0

20

40

60

80

4

2008

11

2009

33

2010

38

2011 2012 2013 2014 2015

55

38

5761

flammation in the central nervous system increaseswith normal aging, and signs of inflammation can bedetected in preclinical stages of Alzheimer's diseaselong before the first symptoms appear.

Contribution to the BT CIEN

The Laboratory department also contributes to theBT-CIEN with processing of various samples, and co-llaborates on several external projects focused onAlzheimer's disease and other neurodegenerative di-seases.

In the context of research focused on the study ofbiomarkers and genetic susceptibility factors, theUIPA Laboratory department is responsible for co-llecting, processing and storing biological samplesfor research related to various projects or for its de-posit in the BT CIEN, whose ultimate purpose is to usein different research areas on neurodegenerative di-seases.

Currently, the department contributes to BT-CIENwith various biological samples including 160 CSFsamples from donor's brain.

Team

During 2015, the team of the Laboratory Departmentwas composed of the following personnel:

� Miguel Calero Lara (PhD, Chemistry), Head of Department.

� Olga Calero Rueda (PhD, Biology).

� Ana Belén Pastor López (Laboratory Technician).

� Alicia Jalvo Sánchez(Laboratory Technician). Since novemeber 2014.

� Juana San Emeterio Mardomingo(Laboratory Technician).April-November 2015.

� Andrés Rodríguez Martín (Laboratory Technician, CIEN Foundation-Biocross).




Lab team

During 2015, the 'Vallecas Project' has brought numerous new features,surpassing the half way point of the study. The second, third, fourth or fifth visit, as appropriate for each specific case, of the 1,213 volunteers enrolled in this project have been carried out, focusing on the early diagnosis of Alzheimer's Disease.In addition, the work performed by our researchers has already began to translate into scientific publications, which is expected to continue during 2016.

V

Dementia is a clinical syndrome characterized by aprogressive cognitive impairment severe enough toaffect personal and social functioning of an indivi-dual.

Alzheimer's disease (AD) is the leading cause of de-mentia in our environment. According to the Natio-nal Epidemiology Center, 7.3% of the populationover 65 years could suffer from this disease nowa-days. In total, AD constitutes about 75% of the etio-logy of dementias, either alone or in combinationwith cerebrovascular disease. As a result of increa-sed life expectancy and the progressive aging of thepopulation in Western countries, dementia repre-sents a huge challenge for public health systems. Inour country, it is estimated that by 2050 a third of thepopulation will be over 65 years, so that approxima-tely one million Spaniards could have dementia bythen.

According to the Survey of Disability, Personal Auto-nomy and Dependency Situations developed bythe National Institute of Statistics, the rate of disabi-lity stands at ninety dementia cases per thousand in-habitants. However, the impact of dementia is notonly produced directly on the patient, but also has agreat impact on his/her family and social environ-ment with regards to affective, organizational andeconomic aspects. In this sense, dementia should beunderstood as a social problem that must be ap-proached in a comprehensive manner.

The transition from a cognitively healthy stage to anAD-type dementia is a continuum in which some in-termediate stages, preclinical and prodromal canbe recognized. These stages are characterized bythe presence of an incipient cognitive impairmentwhich increases the probability of conversion to de-mentia in the future. An effective therapeutic inter-vention in these phases prior to AD could eventuallyslow the progression of deterioration and thus re-duce the prevalence of the disease. For this reason,

one of the challenges currently faced by research isthe development of useful tools that allow earlydiagnosis of AD.

Currently, there is no reliable method to safely pre-dict which individuals in these preclinical stageshave an increased risk of converting to dementia.The emergence in the last decade of various diag-nostic neuroimaging techniques (eg, brain PET amy-loid) has led to considerable progress in research,although its use in regular clinical practice is not fe-asible due to its high cost.

The main objective of the population-based study"Vallecas Project" for Early Detection of Alzheimer'sDisease, is to elucidate, through tracking of progres-sion, the best combination of clinical parametersand complementary tests (imaging and laboratory)that allow deciphering at medium- and long-termfeatures that distinguish those who will develop me-mory impairment (MCI and dementia) from thosewho will not. Thus, it intends to identify various mar-kers to eventually determine the potential risk thateach individual could have to develop the diseasein the future.

4.2. Background: Pilot project

A pilot study was conducted between June 2010and February 2011, prior to the final project, whosefirst preliminary results are presented in this report.The aims of this study were:

• To verify the feasibility of the workingprocedure, the cooperation of the targetpopulation and the adequacy of screeningprotocols to the study objectives.

• To obtain early and sufficient information onthe characteristics of the recruited volunteersand those that could not be recruited, as wellas the limitations of the actualsamplingcompared to the intended one.

4. VALLECAS PROJECT

4.1. Introduction


• To get experience in the implementation ofthe different elements of the protocol and toestimate the burden of the evaluator and theevaluated.

• To promote the Project to achieve theparticipation of volunteers and attractingenough funds to carry out the VallecasProject.

A total of 175 volunteers were involved in this phaseof the project, of which:

• 95 people were able to participate in theproject.

• 80 people were unable to participatebecause they met at least one exclusioncriterion.

4.3. The Vallecas Project

Following the completion and analysis of the pilotstudy the protocol was amended based on the ex-perience gained and a volunteer recruitment stra-tegy was established (social awareness campaignin the media, visits to centers for seniors, contactpensioner's organizations, etc.). In September 2011,after the "Global Summit on Alzheimer Disease Re-search" held in Madrid and with the financial supportof the Queen Sofia Foundation.

The Vallecas Project is being carried out in theQueen Sofia Foundation Alzheimer Center ResearchUnit by researchers from the CIEN Foundation (Car-los III Institute of Health). It aims to develop a proba-bilistic algorithm to identify individuals at risk for AD-type dementia over the course of a fewyears. Such an algorithm will be based on a combi-nation of socio-demographic, historical, clinical,neurological and neuropsychological, biological(from blood tests) and neuroimaging (various formsof 3T MRI).

The participant recruitment phase for the Vallecasproject lasted from October 2011 to December2013. By then, a total of 1,213 individuals of both gen-ders, aged 70-85 years were recruited and evalua-ted at baseline. Once included in the study, theproject conducts an annual follow-up for five yearsin order to assess the evolution profile of all partici-pants, specifically identifying those that developcognitive impairment and/or dementia. At the endof 2015, we are at the end of the third visit for the en-tire cohort and about the middle of the fourth visit(see figure in section 1.3 of this Report).

4.3.1. Baseline evaluation

Before entering the study, volunteers interested inparticipating in it were subjected to an initial assess-ment to determine whether they meet the criteriafor inclusion and/or whether an exclusion criterionexists. Overall, all volunteers were required to meetfour inclusion criteria in order to be considered forentering the study:

• Signing an informed consent.• Be aged between 70 and 85 years old. • Availability and ability to reach the Alzheimer

Centre for visits.• Visual and hearing abilities that allow

conducting the study tests.

In addition, a number of exclusion criteria were es-tablished, including the following: i) suspected ordiagnosed dementia; ii) inability to perform neuroi-maging studies; iii) alcohol abuse; iv) mental retar-dation; or v) history of certain psychiatric orneurological diseases (eg schizophrenia, stroke, se-vere head trauma, Central nervous system infec-tions, uncorrected vitamin deficiencies, etc.

In the table below some global data from the co-hort of approximately 1,213 individuals evaluated todate are indicated.


4.3.2. Sociodemographic profile

The following variables are collected through semi-structured interview: gender, date of birth, maritalstatus, number of children, type and amount of in-come, primary occupation and education level,hobbies and leisure activities, etc.

In addition, each year volunteers also must com-plete a scale of quality of life and subjective well-being (mobility, personal care, daily activities,

pain/discomfort, anxiety/depression, perceived he-alth status).

4.3.3. Clinical evaluation

At each visit relevant information is collected fromeach volunteer by applying a semi-structured clini-cal interview:

• Vascular risk factors: blood pressure, diabetesmellitus, smoking, heart disease, stroke.

4. VALLECAS PROJECT


1.213

47 (3,87%)

74,46 años

671 (55,32%)

379 (31,24%)

163 (13,44%)

10,35 años

4 (0,34%)

60 (5,11%)

154 (13,11%)

389 (33,11%)

282 (23,99%)

286 (24,34%)

780 (64,30%)

433 (35,70%)

THE VALLECAS PROJECT IN FIGURESRecruited sample

Excluded at baseline

Age

Sample mean

Age gorup 69-74

Age gorup 75-79

Age gorup > 80

Gender

Females

Males

Schooling

Sample mean

Illiteracy

Read/Write

Minimum studies mínimos (numeracy skills)

Primary Education

Senior High School / Proffesional Training

University Education

• Neurological history: mental retardation,head injuries, etc.

• Consumption and/or toxic addiction:alcoholism/level of regular alcohol intake,addiction/consumption of other psychotropicsubstances.

• Psychiatric pathology: depression, dysthymia,bipolar disorder, psychotic disorders, anxietysyndromes.

• Other relevant systemic diseases: hepaticfailure, renal failure, Obstructive Sleep ApneaSyndrome (OSA)...

• Family history with special attention to thehistory of dementia or movement disorders,developmental delay or psychiatric disorders.

• Regular drug treatment during the last 5years.

4.3.4. General examination

All subjects undergo a general and neurologicalstandard examination: cranial nerves, muscle ba-lance, coordination, extrapyramidal system, gait, os-teotendinous reflexes, midline release reflexes, etc.The following parameters are analyzed in a specialway:

• Gait disturbance.• Handwriting.• Instrumental activities of daily living.

4.3.5. Neuropsychological examination

The assessment protocol was designed in order tocomprehensively assess neuropsychological func-tioning of study participants. Starting from the appli-cation of different measuring instruments (screeningand cognitive assessment tests, scales and ques-tionnaires) information is collected from both the glo-bal neuropsychological functioning and the specificcognitive processes, especially in information pro-cessing speed, attention, episodic memory, proce-dural learning, language, visoconstruction andexecutive functions. Furthermore, neuropsychologi-

cal assessment is completed by a self-reported sub-jective memory complaints, a scale to assess theperformance of instrumental activities of daily livingand other scales to assess anxiety and depressionsymptoms.

Mini Mental State Examination (MMSE)

This is a test of global cognitive assessment. It con-sists of 20 items that gather a rough information onthe level of orientation, attachment, attention, cal-culation, recall, language and viso-constructive pra-xis of the subject. The score for this test is made overa maximum of 30 points to the extent that all itemsare answered correctly. Cognitive impairment diag-nosis is performed based on a score of 24 points asthe cutoff.

Memory Complaints Scale (UIPA)

This scale is based on a self-reported test comprising11 items to assess memory complaints from studyparticipants.

Functional Activities Questionnaire (FAQ)

It is a classic questionnaire to assess autonomouslyperforming of instrumental activities of daily living.The questionnaire should be answered by a reliableinformant. It consists of 11 items with 4 response op-tions to assess the degree of dependence or inde-pendence of the subject in different daily tasks(managing finances, shopping, doing housework,preparing meals, pay attention and discuss news, re-membering dates, managing medication or goingout alone on the street). The diagnosis of Alzheimerdisease occurs from a score of 6 as the cutoff point.

Rey complex figure test

Is a classic neuropsychological evaluation task con-sisting in performing a copy of a complex pattern


(the time it takes for copying is recorded) and sub-sequent immediate recall (within 3 minutes), afterperforming a distraction task, delayed (after 30 mi-nutes) and a recognition task. This test allows to eva-luate a large number of cognitive processes related

to planning, visoconstruction, impulsiviness, episodicmemory, incidental learning, etc. It has also beenadapted and rated in the Spanish population over60 years of age.


4. VALLECAS PROJECT

Free And Cued Selective Reminding Test (FCSRT)

It is based on the assessment of learning ability andverbal episodic memory. The test consists of the con-secutive presentation of 4 sheets with 4 words writ-ten each (a total of 16 words) that the subject mustlearn.

To facilitate this task, the examiner provides a key foreach of the words that will be helpful later to recallmore items. After a simple 20 seconds task interfe-rence people are asked to remember as manywords as possible spontaneously. After 90 seconds,clues to help the memory of those words that did notrecalled by himself/herself will be provided. Then thewords he/she could not recall with the help of theclue are reminded of and another interference taskis proposed. This procedure is performed three times,so that there are three free recall tests and three fa-cilitated recall through the clues. After 30 minutesthe delayed free and with clues recall condition iscarried out. The indexes that are considered in thistest are the total free recall, the total learning, freedelayed recall and the overall delayed recall. Thetest has Spanish ratings.

Semantic lexical evocation

The task consist in providing the highest number ofwords beginning with a certain letter (P, M, and R)or belonging to a specific category (animals,fruits/vegetables, and cookware) for one minute.Furthermore, in the case of phonological evocationthe contribution of people names or words thatshare the same lexical root is not allowed. The num-ber of responses that the subject provides in periodsof 15 seconds is recorded, as well as the total num-ber of correct responses, intrusions and persevera-tions in the minute-long test. This task allows thesystematic assessment of both the language profi-ciency as the semantic system of the subject. More-

over, it must be highlighted that this task has beenvalidated and rated on Spanish population over 60years.

Clock drawing test

It is an easily applicable screening test to evaluateboth the visoconstructive ability as the semanticcomponent associated with the knowledge of thehour. The subject is asked to draw the face of aclock, with all numbers in the correct place and withthe hands pointing to 11 and 10. The score of thedrawing is based on criteria related to the quality ofthe clock face, the presence and sequence of num-bers, as well as the presence and location of thehands. The maximum score corresponds to 10, con-sidering 6 as a cutoff for the diagnosis of cognitiveimpairment.

Reading test of intelligence (TELEI)

This test provides a measure of the level of pre-mor-bid intelligence of the patient through a reading taskcontained 60 words in the dictionary of the RoyalSpanish Academy. An important feature of this testis that the items have a low frequency of use in ourcountry, those who should carry written accent donot carry it and foreign words are also included bet-ween them.

The subject's task is to read the words in the rightway, for what is allowed to rectify if deemed appro-priate. The test raw score is the number of wordsread correctly.

Wechsler Adult Intelligence Scale (WAIS)

This is part of the WAIS scale for assessing intelli-gence. Natural numbers from 1 to 9, each of themassociated with a different symbol, are presented on


4. VALLECAS PROJECT

a test sheet. Below appear random numbers from 1to 9 without any associated symbol.

The task of the subject is to write the symbols foreach number as quickly as possible for one minute.To avoid interference of possible memory alterationson test performance, the model with numbers andsymbols for each of them remain in the top of thesheet. This test provides a measure of informationprocessing speed and procedural learning ability tothe extent of it will become less necessary for thesubject to look at the model because unconsciouslearning.

Global Depression Scale(GDS-15)

Is a self-reported scale to evaluate depressivesymptoms. It consists of 15 questions related to thestate of mind to which the subject must respond di-chotomously (yes/no). The cutoff point beyondwhich the likelihood of major depressive disorder in-creases is 5.

State-Trait Anxiety Inventory (STAI)

This self-reported test evaluates anxiogenicsymptoms related to both a specific time and inten-sity variable period (anxiety state) as well as a morestable personality pattern tending to perceive situa-tions as threatening (anxiety trait). Thus, there aretwo scales of this test, each consisting of 20 itemswith 4 response options (scored by a Likert type scaleof 0-3). The total score is the sum of the individualscores for each item. Spain has recently adaptedthis test in nonclinical populations. After the secondvisit the neuropsychological examination protocolsuffered a slight transformation in order to optimizecollection of cognitive information. For this purpose,a series of assessment tests that allow to obtain moreinformation on attention, language, praxis and exe-cutive functions from all selected study subjects.

Forward and reverse digits(subtest Wechsler Adult Intelligence Scale, WAIS)

This test allows to evaluate the hearing attentionalamplitude and the individual's central executive ofthe working memory. The subject's task consists in re-peating the growing sequences of numbers that theevaluator presents at one digit per second. The testis divided into two separate subtests, so that repeti-tion of the first digit is applied in the same order ofpresentation (Direct digits) and then in reverse order(Inverse digits). The task ends when the subject is notable to repeat two sequences of the same length ofdigits. In both subtests, the number of correct repe-titions and the maximum amplitude of digits that thesubject is able to repeat are counted.

Boston Naming Test (15 items version)

It is a reduced version of the classic subtest includedin the Boston test for the diagnosis of aphasia. TheBoston Naming Test is used in clinical consultationsto assess the ability of naming visual stimuli by visualconfrontation. The subject's task is to name each ofthe 15 drawings that are presented, for which he/sheis given a maximum of 20 seconds per image. If thesubject does not give the correct answer spontane-ously, the examiner provides a semantic or phono-logical clue if the above is not enough. Total score isthe sum of correct spontaneous responses and thenumber of drawings called using the semantic hint.The correct answers after the phonological key areconsidered as an indicator of the kind of difficulty toname drawings.

Symbolic gesture (Revised Barcelona Test)

This test explores performing of a series of symbolicgestures of communication. They are simple, intran-sitive gestures made with a single upper limb. The pri-


mary endpoint of the test is the body position in re-lation to space and the body.

Imitation of bilateral postures (Revised Barcelona Test)

This test consists in the imitation by the subject of anumber of postures that the examiner performedwith both hands. This test evaluates the integrity ofideomotor praxis.

Rule Change (Behavioral Assessment of theDysexecutive Syndrome BADS subtest)

This test involves the presentation of a sequence of21 cards from the French card deck. The subjectmust respond "yes" or "no" as fast as he/she can andas accurately as possible according to a rule that isin plain view. In the first part of the test rule is to res-pond "yes" when the card is red and "no" when isblack. The second part introduces a variation of thefirst rule that the subject must respond "yes" when thecard is the same color as above and "no" when it isa different color. The number of errors made by thesubject in the second part of the test is registeredand the score based on such errors is recorded. Thistest assesses the ability to fulfill one simple rule and the subject flexibility to adapt to a new different rule.

Test of the five points: This is a test that measuresthe subject's cognitive flexibility regarding the

ability to design novel visual shapes

A DIN A4 sheet of paper with 40 identical matricesof 5 dots arranged in eight rows and five columns is-provided. The subject's task is to produce for 3 minu-tes as many figures as possible by connecting thedots within each matrix and the following rules: i) thefigures may not be repeated; ii) only straight lines inany direction (horizontal, vertical or diagonal) canbe used to connect the dots; and iii) it is not neces-sary to join the 5 points of the matrix.

4.3.6. Neuropsychiatric Examination

Psychiatric symptoms are part of the evolution of de-mentia. The concept of "behavioral and psycholo-gical symptoms of dementia" (BPSD) refers to allthose psychiatric manifestations and behaviors thatmay occur in the context of cognitive impairment ordementia.

According to various studies, these BPSD could notonly manifest themselves in the phase of already es-tablished dementia, but may also appear in prodro-mal stages or even in preclinical stages prior tocognitive decline.

Specifically, in recent years the interest in both de-pressive symptoms and apathy in the absence ofdepression has increased, in order to establish theirrelationship with the development of dementia. TheVallecas Project includes a specific exploration ofboth major psychiatric disorders as the most com-mon BPSD to collect more information regarding thefactors related to the onset of Alzheimer's disease.

4.3.7. Identification of biomarkers

It is currently widely accepted that the molecularchanges associated with AD, including the forma-tion of amyloid plaques and neurofibrillary tanglesbegin many years before the appearance of clini-cal symptoms. It has been a great interest of thescientific community during recent years in the de-velopment of new biomarkers of AD and its utility inrisk assessment and early diagnosis of the disease.

Thus, blood samples will be collected within the Va-llecas Project for the study of a number of geneticand biochemical markers. Samples are obtainedaccording to the protocol "Collection and Proces-sing of Human Blood Samples in the Vallecas Project"and processed to obtain the fractions indicated inthe protocol, which will be stored at -80 ° C. On one


4. VALLECAS PROJECT

hand, DNA is extracted from blood cells to deter-mine, by PCR and sequencing techniques, geneticmarkers associated with the various polymorphismsof the following genes: APOE, CR1, BIN1, CLU, PI-CALM, ABCA7, SORL1, PRNP, GRM8, BACE1.

Furthermore, the blood samples collected and deri-vatives are used to determine a number of bioche-mical markers among which the following are ofspecial interest:

• Vascular damage markers, cytokines andchemokines involved in human lipidmetabolism and proinflammatory.

• The following molecules:: MMP-9, SerpinE1/PAI-1, E-Selectin, ICAM-1, VCAM-1, IL-1beta, IL-6, CXCL8/IL-8, CCL2/MCP-1, TNF-alpha, Adiponectin/Acrp30, CRP, P-Selectin yMMP-3.

The utility of these biomarkers complements the in-formation derived from the study of genetic risk mar-kers mentioned above and can define risk factorsmade evident in previous studies.

Samples collected and processed to date are sum-marized in the table below:

4.3.8. Neuroimaging studies

Knowing the morphological variations occurring inbrain structure throughout life is essential to assessthe corresponding pathological changes that occurin neurodegenerative diseases. In this context, neu-roimaging techniques such as magnetic resonanceimaging (MRI) have led to significant progress in un-derstanding brain changes associated with age.

MRI is a noninvasive tool that allows the study of nor-mal aging individuals at different moments of his life.However, conventional MRI techniques are unableto detect and quantify age-dependent microstruc-tural changes who have been described in post-mortem studies of brain tissue. Accordingly, theproject aims to conduct a series of studies based onvarious MRI modern techniques that can provide vo-lumetric quantitative indexes of the morphologicalchanges.

In this regard VBM (voxel-based morphometry tech-niques), based on creating statistical comparisons ofgray and white matter patterns are the method ofchoice in research. The discriminatory power of vo-lumetry in degenerative pathologies such as Alzhei-mer's disease (volumetric reduction in amygdala,hippocampus, entorhinal cortex, etc..) decreases ifage-dependent morphological changes are notwell established in control samples, so that it is criticalto have large, well quantified samples.

• Structural Study (3D volumetry, T2 and FLAIR)Determining the progressive loss of brainvolume during aging, especially in whitematter provides volumetric quantitativeindexes of the morphological aging-associated changes. In this sense, the VBM(Voxel-Based Morphometry) techniques,based on creating statistical comparisons ofgray and white matter patterns constitute themethod of choice, and allows us to


1.169

851

822

456

5

3.390

First visit

Second visit

Third visit

Fourth visit

Fifth visit

Total

determine the volume reduction of theamygdala, hippocampus, entorhinal cortex,etc.

• Diffusion Study (b: 800)White matter, partly due to Walleriandegeneration and partly to reducedconnectivity by decreased cortical activity,presents ultrastructural changes that can bedetected with diffusion techniques (DTI).

• Brain Perfusion StudyCerebral perfusion related to cortical activitymay be assessed -without needing to injectcontrast-through MR sequences (Arterial SpinLabelling, ASL) and therefore hypofunctioningareas will present decreased perfusion.

Throughout 2015 all Neuroradiology reports fromevery subject and each of the visits from the 'Valle-cas Project' have been incorporated in the singleproject database. Text reports have been encoded,incorporating each item to the database, as well asattaching the report of each visit in pdf format, en-abling viewing and downloading to all researcherswho have access to the database.

On the other hand, we have organized MRI data co-rresponding to the 'Vallecas Project' and QueenSofia Foundation Alzheimer Center subjects, con-verting the data obtained directly from MRI equip-ment into the appropriate format for analysis.A collaborative project with CESVIMA (Supercom-

puting and Visualization Center of Madrid), a centerfrom the UPM (Technical University of Madrid) hasalso been established.

As a result, a VBM analysis of T1 sequences from visits1 and 2 of the subjects 'Vallecas Project' has beenperformed. The results of this analysis have beenused to present a paper at the last meeting of the'Society for Neuroscience (Neuroscience 2015 “MRIin the healthy elderly predicts subsequent develop-ment of mild cognitive impairment", Chicago, 17 to


4. VALLECAS PROJECT

18

224

377

6

625

Second visit

Third visit

Fourth visit

Fifth visit

Total

NEUROIMAGING ACQUISITIONS

Second visitThird visitFourth visitFifth visit

34%62%

3%

Vallecas Projectactivities during 2015

24258469

6

1%

Number of fi�h visit assessments

Number of second visit assessments Number of third visit assessments Number of fourth visit assessments

21 October 2015).

4.3.9. Current State

The Vallecas Project is the main research projectconducted at CIEN Foundation, both in terms of re-sources and social impact. In late 2013, the projectcompleted the recruitment phase and the baselinefirst visits of volunteers. During 2015, we have combi-ned the second, third, fourth and fifth visits from vo-lunteers, already surpassing study's half point.

The following table shows the status of clinical eva-luations conducted to date.

In order to ensure the reliability of the data collec-ted so far in the context of the Vallecas Project,throughout 2015 we have continued with the vali-dation process of all information registered by thevarious departments. The first analysis of data from

the first two visits have been designed to assess threedifferent but complementary aspects. First, we stu-died the possible correlation between the informa-tion obtained from medical records (gender, age,medication, past illnesses, ApoE genotype, etc.) ofthe volunteers with the appearance or not of mildcognitive impairment (MCI). Secondly, we have alsoexamined the possible association between cogni-tive complaints expressed by the volunteers on thefirst visit and its role as an early marker of progressionto MCI a year later. Finally, we have carried out acomparative study of magnetic resonance imagingof the volunteers who have transitioned from a cog-nitively healthy status to show signs of MCI in the se-cond visit of 'Vallecas Project'. The purpose of thisstudy was to try to identify changes in brain structurethat can be determined by neuroimaging techni-ques. Some of these results have been submittedand are pending publication in scientific journals.In addition to continuing with ongoing studies, new


1.175

47

966

836

484

6

395

30

17

31

317

VALLECAS PROJECT CLINICAL EVALUATIONS (OCTOBER 2011-DECEMBER 2015)

First visit

Excluded at baseline

Second visit

Third visit

Fourth visit

Fifth visit

Drop outs

Do not comply with inclusion criteria

Deceased

Diagnosis of neurological disease

Volunteer withdrawal

lines of research will open around the 'Vallecas Pro-ject' during 2016. Among other studies, we will exa-mine the effect of drugs on neuropsychologicalperformance of the elderly; the role of bilingualismand cognitive reserve as protection mechanismsagainst possible cognitive impairment; or finding

new neuropsychological markers in combinationwith neuroimaging techniques to discriminate indivi-duals at risk of developing cognitive impairment.

4. VALLECAS PROJECT


In recent years, CIEN Foundation has fostered its relations with international organizations to further promote research excellence in the field of neurological diseases, and especially Alzheimer's disease. Its participation in the Joint EU Programme in Neurodegenerative Diseases Research and its integration into the Network of Centers of Excellence in Neurodegeneration are two clear examples. International scientific collaboration is essential for further

The world population is aging. Improvements in he-alth care in the last century have helped people tohave longer and healthier lives. However, this has re-sulted in an increase in the number of people withage-related diseases, including neurodegenerativediseases. Neurodegenerative diseases are responsi-ble for mitigating states, largely untreated and areclosely linked with age. Among these disorders, de-mentias are responsible for the greatest burden ofdisease, with Alzheimer's disease and related disor-ders the causes of impairment of approximatelyseven million people in Europe. This figure is expec-ted to double every 20 years, as the populationages.

Currently, care and treatment of patients with someform of dementia in Europe accounts for a cost ofaround 130,000 million euros a year, according to es-timates by the Joint Programme of the EuropeanUnion for Research in Neurodegenerative Diseases.This comes to show that age-related neurodegene-rative disorders are one of the leading medical andsocial challenges facing our society.

Although primarily affecting older people, demen-tia is not a normal part of aging. Dementia is asyndrome mainly of chronic or progressive nature,caused by a variety of brain illnesses that affect me-mory, thinking, behavior and the ability to performactivities of daily life. Dementia is devastating notonly for those who suffer from it but also for their ca-regivers and family. Worldwide, it is one of the lea-ding causes of disability and dependence amongthe elderly. In most countries somehow there is a lackof awareness and understanding of dementia, cau-sing stigmatization, barriers to diagnosis and care,and impacts on caregivers, family and society, bothfrom the physical as well as psychological and eco-nomic point of view.

International scientific collaboration increases moreand more, not only because of the availability of in-

ternational funding and the drive of modern com-munication technologies, but also because scienceitself has become a truly international collaborativeactivity. In particular, the scope and scale of the pro-blem of neurodegenerative diseases in today's so-ciety require a global response to confront this greatchallenge and thus has been recognized by variousinternational institutions such as the European Union(EU), the Organization for Economic Cooperationand Development (OECD), the World Health Orga-nization (WHO), etc.), and the industrialized countriesthat constitute the G8. This global concern has ledto the creation of the World Dementia Council(WDC) with the aim of collectively spur actionagainst dementia worldwide in the areas of rese-arch, clinical care and social awareness.

The leaders of governments, businesses and acade-mia also recognize the need for a coordinated stra-tegy to address this major global challenge forhealth systems. There is consensus among all stake-holders on the need to build capacities, infrastruc-tures and R&D resources in the field ofneurodegenerative diseases. As a result, WHO hasdecided to establish a global observatory on de-mentia to monitor the prevalence of the conditionand resources to care for patients in Member Statesas well as to track the establishment of nationalplans and policies against dementia.

There is also a pressing need for global participationand a commitment to a significant increase in in-vestment in skills and resources to reduce the dura-tion of these chronic brain pathologies and/or thenumber of people at risk. This budgetary effort shouldbe accompanied by sound policies and legislativeinitiatives to encourage public-private partnerships.History has shown that collaboration between aca-demic researchers, government agencies and phar-maceutical and biotechnology companies is anessential ingredient in promoting this type of ambi-tious initiatives,especially when resources are limited.

5. INTERNATIONAL RELATIONS

5.1. Introduction


Supporting research in Alzheimer's disease and rela-ted disorders has been and is one of the workingpriorities of the Queen Sofia Foundation since 2002,the year that promoted the construction of theQueen Sofia Foundation Alzheimer Center (CAFRS,for its acronym in Spanish), and from which it hascontinued to support the work of the institutions re-lated to this dementia, both financially as well aswith the invaluable drive and personal interest ofQueen Sofia. In this context, in recent years CIENFoundation together with the Network Center forBiomedical Research in Neurodegenerative Disea-ses (CIBERNED, for its acronym in Spanish) has givena boost to its relations with international organiza-tions in the area of research in neurodegenerativediseases such as the EU Joint Programme for Rese-arch in Neurodegenerative Diseases (JPND) and theNetwork of Centers of Excellence in Neurodegene-ration (COEN), among other initiatives. These and other internationalization activities carried out during 2015 by CIEN Foundation are detailedbelow.

5.2. EU Joint Programming on Neurodegenerative Disease Research (JPND)

The EU Joint Programming for Research in Neurode-generative Diseases (JPND) is an innovative colla-borative research initiative created to address thegrowing challenges posed by these disorders. TheJPND is a pioneering example of joint programmingfor the promotion of research within the EuropeanUnion aimed at scientific challenges requiring a res-ponse that exceeds the capacity of a singlecountry, based on the alignment of national rese-arch programs devoted to these challenges.

Its objective is to enhance the impact of research byaligning existing national research programs and theidentification of common objectives whose scopewould benefit from joint action. The JPND Scientific

Advisory Committee has significant participation ofthe CIEN Foundation Scientific Director, Drs. JesúsAvila.

The Research Strategy designed by JPND provides aframework for future investments and shows that theresearch effort within the European Union can be le-veraged to improve care on prevention, diagnosisand treatment of patients suffering from these dise-ases.

To achieve impact there is a need to encouragenovel as well as multidisciplinary approaches, and tostrengthen and extend existing capabilities acrossthe full spectrum of basic, clinical, health and socialcare, and translational research. To that end, a num-ber of priority areas for future research have beenidentified: The origins of neurodegenerative disea-ses; Disease mechanisms and models; Disease defi-nition and diagnosis; Treatment and prevention;Health and social care.

This Research Strategy also provides a framework ofopportunities for countries involved in JPND and wi-lling to participate in joint actions, which will be im-plemented through co-operative activities thatrealign or link national investments to achieve incre-ased impact, and the provision of new funding. Aguiding principle for its delivery will be that the rese-arch to be supported is of the highest scientific qua-lity.

In this regard, during 2011 took place the first call forEuropean research projects JPND. Under the theme"Optimization of biomarkers and harmonization oftheir use in the clinic", four transnational projectswere awarded for the period 2012-2015, one ofwhich has the participation of CIEN Foundation:

DEMTEST: Biomarker based diagnosis of rapid pro-gressive dementias-optimisation of diagnostic pro-tocols.


Total Funding: 2,2 M€ (approx.)Start Date: May, 2012Duration: 3 years Coordinator: Inga Zerr, University Medical

Center Göttingen, GermanyCIEN Foundation participation: Miguel Calero

Project partners:

• Inga Zerr, University Medical CenterGöttingen, Germany

• Carsten Korth, Heinrich Heine UniversityMedical School, Düsseldorf, Germany

• Hans Kretzschmar, Ludwig-Maximilians-University, Munich, Germany

• Jean-Louis Laplanche, Hopital Lariboisiere AP-HP, France

• Olivier Andreoletti, UMR-INRA-EVNT, France• Theodoros Sklaviadis, Aristotle University of

Thessaloniki, Greece • Stefano Ruggieri & Maurizio Pocchiari & Anna

Ladogana, University “Sapienza”, Rome, Italy • Pawel Liberski, Medical University of Lodz,

Poland• Catarina Resende Oliveira, University of

Coimbra, Portugal • Eva Mitrová, Slovak Medical University

Bratislava, Slovakia • Gorazd Bernard Stokin, University Psychiatric

Hospital, Ljubljana, Slovenia • Miguel Calero, Carlos III National Health

Institute, Spain• Pascual Sanchez-Juan, IFIMAV and CIBERNED,

University Hospital, Spain• Anna-Lena Hammarin, Swedish Institute of

Communicable Disease Control, Sweden• Adriano Aguzzi & Herbert Budka, University

Hospital Zürich, Switzerland• John Collinge, University College London,

United Kingdom • Robert G. Will, Western General Hospital,

United Kingdom

DEMTEST has established a large European and glo-bal collaboration between national surveillanceunits and dementia research centres, facilitating co-

operation between neurologists, neuropathologistsand neuroscientists.

Our goals are:

• To harmonize the protocols involved in patientdocumentation, biomaterial sampling/ storage,biomarker testing/assay analysis and datasharing.

• To standardise a more precise diagnosis inpatients with rapidly progressive dementia byanalysis of the biochemical markers in thecerebrospinal fluid and blood.

• To improve CSF based diagnosis in dementia byapplication of new methodologies.

In DEMTEST we work on standardisation of tests thatare currently available and harmonise their use bet-ween centers worldwide. We define standards forbiochemically based diagnosis in most relevantrapid progressive dementia such as CJD and rapidlyprogressive Alzheimer’s disease. We will improve in-novative methods for amplification assays for mis-fol-ded proteins and introduce their use into clinicalroutine. As an add-on value, we will define criteriafor early differential diagnosis between rapidly pro-gressive neurodegenerative or potentially reversibledementia.

The DEMTEST collaboration allowed us to perform agenome wide association study (GWAS) in prion di-seases. Because of that, we published in 2012 an as-sociation between MTMR7 gene and susceptibility tonew variant Creutzfeldt-Jakob disease (CJD); thisstudy was followed by an attempt of sequencing ourtop candidate genes where we found a risk variantin PLCXD3 gene. In 2014, we finalized the secondpart of our analysis; we performed a GWAS and re-plicated the results with samples from sporadic CJDpatients from all partner countries. We have suc-



cessfully replicated an intronic SNP in GRM8 gene as-sociated to sporadic CJD risk. In collaboration withour JPND partners (ISCIII Miguel Calero), we sequen-ced the exons of that gene in a large sample of Spa-nish cases. In parallel, we correlated genomic datawith CSF markers in a sample of German patientsfrom the group of Dr Zerr. Results of these analyseswere published during 2015.

The other main results from this project were fruit ofdirect collaborations with the coordinator of theconsortium, Dr. Inga Zerr. We carried out studies eva-luating new biomarkers for rapidly progressive de-mentia (desmoplakin) and analysis of clinical datato generate new diagnostic algorithms for otherprion disorders like fatal familial insomnia.

5.3. Network of Centers of Excellence in Neurodegeneration (COEN)

An important hurdle for the advancement of rese-arch on neurodegenerative diseases is the relativelack of common rules and mechanisms for valida-tion of potentially relevant results in preclinical andclinical studies as well as in population-based stu-dies. One approach to addressing these challengeson a large scale is through a more effective use oflarge research centers and institutes, where there isalready the necessary critical mass of resources andexpertise. Increased collaboration between natio-nal centers of excellence must also provide the op-portunity to accelerate progress in understandingthe basic mechanisms of the disease.

To this end, on June 10, 2010, the Canadian Institutesof Health Research (CIHR), the German Centre forNeurodegenerative Diseases (DZNE, Germany) andthe Medical Research Council (MRC, UK) launcheda funding initiative to establish a collaborative ap-proach to research in neurodegenerative diseases,called "Centers of Excellence in Neurodegeneration(COEN)". These founding members were later joined

by other European institutions and thus, in Decem-ber 2011 the COEN membership application by CIBERNED-CIEN Foundation was approved, recogni-zing the scientific excellence in both basic and clini-cal science of the institution which became part ofthe COEN Oversight Group. In 2012, CIEN Founda-tion and CIBERNED joined this Committee to partici-pate actively in the design of the future COENscientific strategy. Both institutions are representedby Dr. Miguel Medina, member of the CIEN Founda-tion Scientific Advisory Board and CIBERNED DeputyScientific Director. During 2015 the French AgenceNationale de la Recherche (ANR) has also beenacknowledged as a new COEN member.

Current COEN members are:

• Canadian Institutes of Health Research (CIHR) • Deutsche Zentrum für Neurodegenerative

Erkrankungen (DZNE, Germany) • Medical Research Council (MRC, United

Kingdom)• Flanders Institute of Biotechnology (VIB Flanders,

Belgium) • Health Research Board (HRB) / Science

Foundation Ireland (SFI), Ireland • Ministero della Salute (MDS, Italy)• Centre of Excellence for Brain Research,

Slovakia• CIBERNED-CIEN Foundation, Spain• Agence Nationale de la Recherche (ANR),

France

The overlapping of the COEN group members withthose of the JPND will ensure that their complemen-tary objectives progress in close cooperation witheach other. This is accomplished through a two-stepprocess, involving expert workshops for the analysisof needs, followed by a call for proposals for colla-borative teams between PIs within the participatingnational Centers of Excellence.

Since 2012, CIBERNED and CIEN Foundation are partof the Oversight Group to be actively involved in the


design of COEN future scientific strategy. Dr. MiguelMedina, CIBERNED Deputy Scientific Director andmember of the Scientific Advisory Committee of theCIEN Foundation, represents both institutions in theCOEN Oversight Group.

Phase II of the initiative was launched during theyear 2013, with the aim of catalyzing collaborativeresearch between centers with a critical mass of re-sources and expertise to thus promote a radicalchange in research on neurodegeneration. To dothis, the countries participating in COENs contribu-ted a total amount of 5.5 million € (of which Spainhas provided 600,000 €) in this call to establish an in-novative and progressive research program to ad-dress the major challenges in this field. The call wasintended to encourage the community to think out-side the pre-established frameworks and stimulatenew and creative approaches and solutions to thechallenges of research in neurodegeneration.

This call of Pathfinder projects intends to combinethe strengths of research groups through Centers ofExcellence in at least two partner countries to pro-vide a truly collaborative effort and value that willadvance our approach to research neurodegene-ration. The projects would address issues that are noteasily financed through standard grant mechanismsfrom CoEN partners, and is expected to further co-llaboration between Centers of Excellence, the pro-jects would also serve to provide a platform forfuture collaboration with industry.

5.4. International Congress in Research and Innovation on Neurodegenerative Diseases (CIIIEN)

During 21st to 23rd September 2015, it was held inMalaga the Third International Congress on Rese-arch and Innovation in Neurodegenerative Diseases(CIIIEN), promoted by the Queen Sofia Foundationin collaboration with CIEN Foundation and CIBER-

NED. The main objective of CIIIEN is providing aforum in which to share progress and information ofinterest on neurodegenerative diseases among thescientific community.

CIIIEN was created in 2013 and consolidates themerger of the two major scientific conferences onneurodegenerative diseases in general and Alzhei-mer's disease in particular, organized in Spain: the XIInternational Symposium Advances in Alzheimer's Di-sease, promoted annually by the Queen Sofia Foun-dation and CIEN Foundation, and the 9th CIBERNEDScientific Forum, which brought together every yearmore than the 58 research groups constituting theCIBER in Neurodegenerative Diseases.

Unifying both congresses is a first step in creating anew operating structure in the two main institutionsdevoted to research on neurological and neurode-generative diseases in Spain: CIEN Foundation andCIBERNED, both under the Ministry of Economy andCompetitiveness through the Institute of Health Car-los III. This new structure seeks greater effectivenessand efficiency in research, promoting the interac-tion of the different research groups.

This third edition of CIIIEN was once again chairedby Her Majesty Queen Sofia and the scientific pro-gram consisted of three plenary sessions and fivescientific sessions. Among the invited speakers at theconference can be highlighted some internationalresearchers who are leaders in their field of researchsuch as Zaven Khachaturian, President of the US2020 Alzheimer’s disease Prevention Campaign;Martin Rossor, Clinical neurologist from the British Na-tional Health System, an expert in prevention of de-mentia, especially Alzheimer’s disease; or DavidRubinsztein, Deputy Director of the Medical Rese-arch Council in Cambridge, a scientist pioneer inproposing autophagy positive feedback (a processthat plays a role in the elimination of toxic proteinsabnormally accumulated in the brain of patients) as


a potential therapy in neurodegenerative diseases.Rui Costa, a scientist from the Champalimaud Foun-dation (Portugal) and Angel Cedazo-Minguez, fromthe Karolinska Institute (Sweden), completed the in-ternational presence, focused on the study of theconnectivity between different brain areas and theeffects of its dysfunction, the first, and pathologicalmechanisms associated with known risk factors, thesecond.

The remaining scientific sessions addressed variousaspects of frontier research in neurodegenerative di-

seases. In addition, less common neurodegenerativediseases such as Charcot-Marie-Tooth were also dis-cussed during the congress, as were topics such asneuroimaging techniques, research in glial cells,neuronal plasticity in Huntington's disease or neuro-nal signaling in Parkinson's disease. Moreover, in linewith the interest to boost the training of CIBERNEDyoung researchers, the Young Researcher (basicand clinical research) Prizes were awarded duringthe Congress to Marta Fernández-Nogales and JuanFortea, respectively, who made presented the stu-dies which have been granted such recognition.



Ultimately, this event establishes in its third edition asa meeting point for the world's leading experts inneurodegenerative diseases, enabling sharing ofknowledge, working methods, new advances anddiscoveries in a field in which international coopera-tion between different institutions is becoming incre-asingly important to obtain optimum results inresearch.

5.5. Other activities of international cooperation Champalimaud Foundation

On February 28, 2015 H.M. Queen Sofia visited theChampalimaud Foundation in Lisbon, a Portugueseinstitution devoted to advanced biomedical rese-arch. Joined by José Luis Nogueira, Secretary of theQueen Sofia Foundation and María Ángeles Pérez,Manager of CIEN Foundation and CIBERNED, the visitaimed at looking for new avenues of research inneurodegeneration.

Received on arrival by Leonor Beleza, Chair ofChampalimaud Foundation, Queen Sofia was joi-ned during Her visit to the Foundation facilities (in-ternationally renowned for its work in oncology andneuroscience) by the Scientific Director and NobelLaureate Zvi Fuks, Professors Carlo Greco, Rui Costaan Carlos Cordón-Cardo, and the Managing Direc-tor of the Foundation, Joao Silveira.

During the day a series of scientific meetings, mainlyon neuroscience, were held where research projectswere reviewed and in which the participating enti-ties (Queen Sofia Foundation, CIEN Foundation, CI-BERNED, and Champalimaud Foundation) focusedon identifying joint collaboration and research linesto foster the knowledge of both countries in a fieldstill as unknown as neuroscience.

At these meetings, also attended the Scientific Di-rector of CIEN Foundation and CIBERNED, Dr. Jesús

Ávila de Grado, and CIBERNED Deputy Scientific Di-rector, Dr. Miguel Medina Padilla. Dr. Avila interve-ned by reviewing the scientific activity that theinstitution carries out as part of the Alzheimer Projectof the Queen Sofia Foundation, which focusesmainly on knowledge of neurodegenerative disea-ses (with particular emphasis on Alzheimer's disease),confluent with the priorities and knowledge of theChampalimaud Foundation.


In 2015, researchers from CIEN Foundation have maintained the trend followed in previous years in terms of scientific productivity with 46 publications, although the average impact factor of the original articles within first or second quartile has increased by 8%. More than 78% of the articles have been published in journals classified in these categories.

A significant and steady growth in the scientific pro-ductivity of CIEN Foundation has been confirmed inrecent years, largely due to the strong commitmentmaintained by the Foundation to research and thegeneration of scientific knowledge in improvingdiagnosis and treatment of neurodegenerative di-seases.

During 2015, the CIEN Foundation researchers haveproduced a total of 46 publications, of which 45have been published in scientific journals of nationaland international recognition (38 original articles,three reviews, three proceedings, and one editorial)and a clinical guideline.

The analysis of these publications has allowed stud-ying, through a series of quantitative indicators, boththe CIEN Foundation scientific activity as the pro-duction, topic, and degree of collaboration and im-pact of scientific publications. Through this analysiswe can note, for instance, that the average impactfactor of publications within the first and secondquartile has increased from 4.367 in 2014 to 4.718 inthe year 2015.

The following table shows output indicators of pro-duction (number of publications), quality (publica-tions in journals ranked within the first and secondquartile of their subject category), impact (determi-ned by the accumulated and average impact fac-

tor of the journals in which it has been published)and degree of collaboration at national and inter-national levels.

Among 2015 milestones we can highlight that theCIEN Foundation researchers have published 46scientific papers, of which 40 (86.7%) have been injournals under the coverage of the Science CitationIndex Expanded, accessible through the Web ofScience portal (WoS, Thomson Reuters) and 36(78.3%) have been published in journals ranked wi-thin the first and second quartile in their category.Considering the type of document, 84.4% of the pu-blications in scientific journals (38) correspond to ori-ginal articles.

Moreover, according to their scientific subject cate-gory 77.8% of the publications within the first and se-cond quartiles, have focused on the followingcategories: Clinical Neurology, Neurosciences, Mul-tidisciplinary Sciences, and Anatomy and Morpho-logy.

As scientific dissemination activities in meetings andnational and international events during the year2015 there have been a total of 23 participations atscientific conferences, nine of which correspond tolectures and oral presentations, and fourteen co-rrespond to written communications in the form ofposters. These communications have been presen-

6. SCIENTIFIC PRODUCTIVITY

6.1. Bibliometric analysis

2015 IndicatorsTotal number of publications................................................................................................................................ 46Total number of publications in the ISI citation index within the first and second quartile............................... 36Cumulative impact factor of publications within the first and second quartile............................................170,384Average impact factor of the publications of the first and second quartilel.................................................. 4,733Number of collaborative publications of all kinds (CIBERNED, other national groups, international groups) within the first and second quartile.......................32 Number of international collaborative publications within the first and second quartile................................. 11Number of national collaborative publications within the first and second quartile ...........................................21Number of collaborative publications with other CIBERs and networks within the first and second quartile.......................................................................................................4


ted at national (16) and international scientific con-ferences (7).

Other noteworthy scientific activities include 20scientific presentations at training courses, a PhD inNeurosciences, an end-of-Master in PsychologicalResearch internship and the co-direction of end-of-Master in Physical Anthropology internship.

6.2. Publications

References of scientific publications from CIEN Foun-dation professionals are listed below according totype of publication: 45 publications in scientific jour-nals (38 original articles, three reviews, three proce-edings and one editorial) and a clinical guide.

6.2.1. Journal articles

• Ahmed-Mohamed K, Rojo-Pérez F, Fernández-Mayoralas G, Forjaz MJ, Martínez-Martin P.Associative participation of older adults andsubjective quality of life: exploring self-selection bias. Ageing Soc. 2015Aug;35(7):1343-63. WOS:000357882800001.

• Alcolea D, Martinez-Lage P, Sánchez-Juan P,Olazarán J, Antúnez C, Izagirre A, et al.Amyloid precursor protein metabolism andinflammation markers in preclinical Alzheimerdisease. Neurology. 2015 Aug;85(7):626-33.PMID: 26180139

• Alonso R, Pisa D, Marina AI, Morato E, RábanoA, Rodal I, et al. Evidence for Fungal Infectionin Cerebrospinal Fluid and Brain Tissue fromPatients with Amyotrophic Lateral Sclerosis. IntJ Biol Sci. 2015;11(5):546-58. PMID: 25892962

• Alonso R, Pisa D, Rábano A, Rodal I, CarrascoL. Cerebrospinal Fluid from Alzheimer's DiseasePatients Contains Fungal Proteins and DNA. JAlzheimers Dis. 2015;47(4):873-6. PMID:26401766

• Ávila J, Perry G, Strange BA, Hernández F.Alternative neural circuitry that might beimpaired in the development of Alzheimerdisease. Front Neurosci. 2015 Apr;9. PMID:

25954151.• Belhassen-García M, Rábano A, Velasco-

Tirado V, Romero-Alegría A, Pérez-García ML,et al. Atypical Progressive MultifocalLeukoencephalopathy in a Patient withAntisynthetase Syndrome. Intern Med.2015;54(5):519-24. PMID: 25758081.

• Bolos M, Llorens-Martín M, Jurado-Arjona J,Hernández F, Rábano A, Ávila J. DirectEvidence of Internalization of Tau by MicrogliaIn Vitro and In Vivo. Journal of Alzheimer'sdisease : JAD. 2015 Nov 28. PMID: 26638867.

• Calero M, Gómez-Ramos A, Calero O,Soriano E, Ávila J, Medina M. Additionalmechanisms conferring genetic susceptibilityto Alzheimer's disease. Front Cell Neurosci.2015 Apr;9. PMID: 25914626.

• Camacho FII, Cabañas-Perianes V, Coll JM,Rábano A, Cuartero-Pérez B, De SampedroJR, et al. CASE REPORT: CEREBRAL LIGHTCHAIN DEPOSITION DISEASE (LCDD).Haematologica. 2015 Jun;100:747-8. WOS:0003612049.

• Cotelo NV, Rodríguez NF, Pérez JA, IglesiasJC, Lago MR. Burden and associatedpathologies in family caregivers of Alzheimer'sdisease patients in Spain. Pharmacy practice.2015 Apr-Jun;13(2):521. PubMed PMID:26131040.

• Cruz-Orduna I, Agüera-Ortiz LF, Montorio-Cerrato I, León-Salas B, de Juan MCV,Martínez-Martín P. Reliability and validity ofthe Severe Impairment Battery, short form (SIB-s), in patients with dementia in Spain. RevNeurologia. 2015 Jan;60(1):1-9. PMID:25522858

• Cubo E,Rivadeneyra J,Armesto D,MariscalN,Martínez A,Cámara RJ, et al. Relationshipbetween Nutritional Status and the Severity ofHuntington’s Disease. A Spanish MulticenterDietary Intake Study. Journal of Huntington'sdisease.2015 Volume: 4 Issue: 1 Pages: 78-85.PMID: 26333259.

• de Pedro-Cuesta J, Rábano A, Martínez-Martín P, Ruiz-Tovar M, Alcalde-Cabero E,Almazán-Isla J, et al. Comparative Incidenceof Conformational, Neurodegenerative


Disorders. PLoS One. 2015 Sep;10(9). PMID:26335347

• Erro R, Picillo M, Amboni M, Moccia M, VitaleC, Longo K, et al. Nonmotor Predictors forLevodopa Requirement in De Novo PatientsWith Parkinson's Disease. MovDisord. 2015Mar;30(3):373-8. PMID: 25648938.

• Gerenu G, Liu K, Chojnacki JE, Saathoff JM,Martínez-Martín P, Perry G, et al.Curcumin/Melatonin Hybrid 5-(4-Hydroxy-phenyl)-3-oxo-pentanoic Acid2-(5-Methoxy-1H-indol-3-yl)-ethyl -amideAmeliorates AD-Like Pathology in the APP/PS1Mouse Model. ACS ChemNeurosci. 2015Aug;6(8):1393-9. PMID: 25893520.

• González-Rosa JJ, Soto-León V,RealP,Carrasco-López C,Foffani G,Strange BA, etal.Static Magnetic Field Stimulation over theVisual Cortex Increases Alpha Oscillations andSlows Visual Search in Humans. The Journal ofneuroscience : the official journal of theSociety for Neuroscience.2015 Jun 17 Volume:

35 Issue: 24 Pages: 9182-93. PMID: 26085640.• González-Vélez AE, Forjaz MJ, Giraldez-García

C, Martín-García S, Martínez-Martín P, SpanishRes Grp Quality L. Quality of life by proxy andmortality in institutionalized older adults withdementia. GeriatrGerontol Int. 2015Jan;15(1):38-44. PMID: 24397787

• Heller S, Rebolledo CM, Blázquez CR, ChillónLC, Muñoz AP, Pérez IR, et al. Validation of themultimodal assessment of capacities in severedementia: a novel cognitive and functionalscale for use in severe dementia. J Neurol.2015 May;262(5):1198-208. PMID: 25740664.

• Ismail Z, Smith EE, Geda Y, Sultzer D, Brodaty H,Smith G, et al. Neuropsychiatric symptoms asearly manifestations of emergent dementia:Provisional diagnostic criteria for mildbehavioral impairment. Alzheimer's&dementia : the journal of the Alzheimer'sAssociation. 2015 Jun 18. PMID: 26096665.

• Llorens-Martín M,Rábano A, Ávila J. The Ever-Changing Morphology of Hippocampal

Number of publications by subject category in 2015

0 5 10

11

1

1

1

1

1

15

11

4

2

2

Neurosciences

Clinical Neurology

Multidisciplinary sciences

Gerontology

Geriatrics & Gerontology

Chemistry, Medicine

Public, Enviroment

Biology

Biochemistry & molecular biology

Medicine, general


Granule Neurons in Physiology and Pathology.Frontiers in neuroscience. 2015 Volume: 9Issue: Pages: 526. PMID: 26834550.

• Lovestone S, Boada M, Dubois B, Hull M, RinneJO, Huppertz HJ, et al. A Phase II Trial ofTideglusib in Alzheimer's Disease. J AlzheimersDis. 2015;45(1):75-88. PMID: 25537011.

• Martínez-Martín P, Rodríguez-Blázquez C,Forjaz MJ, Frades-Payo B, Agüera-Ortiz L,Weintraub D, et al. Neuropsychiatricsymptoms and caregiver's burden inParkinson's disease. Parkinsonism RelatDisord.2015 Jun;21(6):629-34. PMID: 25892660.

• Martínez-Martín P, Rodríguez-Blázquez C, PazS, Forjaz MJ, Frades-Payo B, Cubo E, et al.Parkinson Symptoms and Health RelatedQuality of Life as Predictors of Costs: ALongitudinal Observational Study with LinearMixed Model Analysis. PLoSOne. 2015Dec;10(12). PMID: 26698860.

• Marventano S, Prieto-Flores ME, Sanz-BarberoB, Martín-García S, Fernández-Mayoralas G,Rojo-Pérez F, et al. Quality of life in olderpeople with dementia: A multilevel study ofindividual attributes and residential carecenter characteristics. GeriatrGerontolInt.2015 Jan;15(1):104-10. PMID: 24456126

• Medina M, Ávila J. Further understanding oftau phosphorylation: implications for therapy.Expert Rev Neurother. 2015 Jan;15(1):115-22.PMID: 25555397

• Medina M. Recent developments in tau-based therapeutics for Alzheimer's diseaseand related dementsia. SpringerPlus. 2015Jun;4.

• Moratti S,Strange B, Rubio G. Emotionalarousal modulation of right temporoparietalcortex in depression depends on parentaldepression status in women: firstevidence.Journal of affective disorders. 2015Jun 1 Volume: 178 Issue: Pages: 79-87. PMID:25801520.

• Nachev P,López-Sosa F,González-RosaJJ,Galarza A,Avecillas J,Pineda-Pardo JA, etal.Dynamic risk control by human nucleusaccumbens. Brain : a journal of neurology.PMID: 26428667.

• Olazarán J, Valentí M, Frades B, Zea-SevillaMA, Ávila-Villanueva M, Fernández-BlázquezMA, et al. The Vallecas Project: a cohort toidentify early markers and mechanisms ofAlzheimer's disease. Front Aging Neurosci.2015 Sep;7. PMID: 26483681.

• Olazarán J, Gil-de-Gómez L, Rodríguez-MartínA, Valentí-Soler M, Frades-Payo B, Marín-Muñoz J, et al. A Blood-Based, 7-MetaboliteSignature for the Early Diagnosis of Alzheimer'sDisease. J Alzheimers Dis. 2015;45(4):1157-73.PMID: 25649659.

• Olazarán J, Hoyos-Alonso MC, Del Ser T,Garrido Barral A, Conde-Sala JL, Bermejo-Pareja F, et al. Practical application of briefcognitive tests. Neurologia. 2015 Sep 14.PMID: 26383062.

• Oliviero A, Carrasco-López MC,CampoloM,Pérez-Borrego YA,Soto-León V,González-Rosa JJ, et al.Safety Study of TranscranialStatic Magnetic Field Stimulation (tSMS) of theHuman Cortex.Brain stimulation. 2015 May-JunVolume: 8 Issue: 3 Pages: 481-5. PMID:25595064.

• Oreja-Guevara C, García-López J, Sánchez-Sánchez R, Orviz-García A, González-Suárez I,Rábano A, et al. Inhibition of neurogenesis ina Marburg's variant of multiple sclerosis. MultScler J. 2015 Sep;21:172.WOS:000365729400305.

• Pastor P, Moreno F, Clarimón J, Ruiz A,Combarros O, Calero M, et al. MAPT H1Haplotype is Associated with Late-OnsetAlzheimer's Disease Risk in APOE epsilon 4Noncarriers: Results from the DementiaGenetics Spanish Consortium. J AlzheimersDis. 2015;49(2):343-52. PMID: 26444794.

• Pisa D, Alonso R, Rábano A, Rodal I, CarrascoL. Different Brain Regions are Infected withFungi in Alzheimer's Disease. Sci Rep. 2015Oct;5. PMID: 26468932.

• Rieu I, Martínez-Martín P, Pereira B, DeChazeron I, VerhagenMetman L, JahanshahiM, et al. International Validation of aBehavioral Scale in Parkinson's DiseaseWithout Dementia. Mov Disord. 2015Apr;30(5):705-13. PMID: 25809278.



• Rodríguez-Blázquez C, Martín-García S,Frades-Payo B, Paris MS, Martínez-López I,Forjaz MJ, et al. Quality of Life and HealthStatus in Institutionalized Elderly withDementian. Rev Esp Salud Publica. 2015 Jan-Feb;89(1):51-60. PMID: 25946585.

• Ruiz-Riquelme A, Sánchez-Iglesias S, RábanoA, Guillén-Navarro E, Domingo-Jiménez R,Ramos A, et al. Larger aggregates of mutantseipin in Celia's Encephalopathy, a newprotein misfolding neurodegenerativedisease. Neurobiology of disease. 2015Nov;83:44-53. PMID: 26282322.

• Sánchez-Juan P, Bishop MT, Kovacs GG,Calero M, Aulchenko YS, Ladogana A, et al. AGenome Wide Association Study LinksGlutamate Receptor Pathway to SporadicCreutzfeldt-Jakob Disease Risk. PLoS One.2015 Apr;10(4). PMID: 25918841.

• Schmitz M, Ebert E, Stoeck K, Karch A, CollinsS, Calero M, et al. Validation of 14-3-3 Proteinas a Marker in Sporadic Creutzfeldt-JakobDisease Diagnostic. Molecular neurobiology.2015 May 7. PMID: 25947081.

• Sierra-Marcos A, Álvarez V, Faouzi M, BurnandB, Rossetti AO. Statins are associated withdecreased mortality risk after statusepilepticus. European journal of neurology.2015 Feb Volume: 22 Issue: 2 Pages: 402-5.PMID: 24684345.

• Sierra-Marcos A, Scheuer ML, Rossetti AO.Seizure detection with automated EEGanalysis: a validation study focusing onperiodic patterns. Clinical neurophysiology:official journal of the International Federationof Clinical Neurophysiology.2015 Mar Volume:126 Issue: 3 Pages: 456-62. PMID: 25046981.

• Smits C, Anisuzzaman S, Loerts M, Valentí-SolerM and Heerink M. Towards PracticalGuidelines and Recommendations for UsingRobotics Pets with Dementia Patients.Canadian International Journal of SocialScience and Education. Vol 3, May 2015Page 656. ISBN / ISSN: 2356-847X.

• Storch A, Schneider CB, Klingelhofer L, Odin P,Fuchs G, Jost WH, et al. Quantitativeassessment of non-motor fluctuations in

Parkinson's disease using the Non-MotorSymptoms Scale (NMSS). Journal of neuraltransmission (Vienna, Austria: 1996). 2015Dec;122(12):1673-84. PMID: 26264174.

• Strange BA, Yebra M. The multi-instrumentalisthippocampus: Comment on "The quartettheory of human emotions: An integrativeand neurofunctional model" by S. Koelsch etal.Physics of life reviews. 2015 Jun Volume: 13Issue: Pages: 85-6. PMID: 25921634.

• Valentí-Soler M, Agüera-Ortiz L, Rodríguez JO,Rebolledo CM, Muñoz AP, Pérez IR, et al.Social robots in advanced dementia. FrontAging Neurosci. 2015 Sep;7. PMID: 26388764.

• Valentí-Soler M, M. Heinemann, S.Anisuzzaman, C. Smits,S. D. Vos, A. P. Muñozet al.Picking New Friends: Caregivers andDementia Patients Choices of Robotic Pets.Canadian International Journal of Scienceand Technology. 2 (May 2015): 354-357.

• Zea-Sevilla MA, Bermejo-Velasco P, Serrano-Heranz R, Calero M. Cerebral AutosomalDominant Arteriopathy with SubcorticalInfarcts and Leukoencephalopathy(CADASIL) associated with a Novel C82RMutation in the NOTCH3 Gene. JAlzheimersDis. 2015;43(2):363-7. PMID:25096610.

• Zea-Sevilla MA, Fernández-Blázquez MA,Calero M, Bermejo-Velasco P, Rábano A.Combined Alzheimer's disease andcerebrovascular staging explains advanceddementia cognition. Alzheimer's &dementia :the journal of the Alzheimer's Association.2015 Nov;11(11):1358-66. PMID: 25804997.

• Zhang WI, Antonios G, Rábano A, Bayer TA,Schneider A, Rizzoli SO. Super-ResolutionMicroscopy of Cerebrospinal Fluid Biomarkersas a Tool for Alzheimer's Disease Diagnostics. JAlzheimersDis. 2015;46(4):1007-20. PMID:25881910.

6.2.2. Clinical guidelines

• Forjaz MJ; Ayala A; Frades-Payo C; De CastroE; Díaz A; Fernández-Mayoralas G; et al. Saludy Calidad de Vida de Personas Mayores


Institucionalizadas. Madrid: Escuela Nacionalde Sanidad, Instituto de Salud Carlos III –Ministerio de Economía y Competitividad;2015. N.I.P.O. en línea: 725-15-027-X.

6.3. Funded projects

During 2015 the CIEN Foundation researchers haveparticipated in 8 scientific research projects obtai-ned through various national and international com-

petitive calls and funded by different institutions. Funded research projects are cited below:

• Code FCIEN-005/11Principal Investigator: Dr. Miguel MedinaTitle: Proyecto Vallecas – Early detection of alzheimer's diseaseFunding agency: Queen Sofia FoundationDuration: 2011-2016Total budget: 1,800.000 €2015 budget: 302,320.12 €



• Code: PI12/03018Principal Investigator: Dr. Alberto RábanoTitle: Profile of the age-associated Alzheimer pathology (85+CIEN Study)Funding agency: Carlos III Institute of HealthDuration: 2013-2015Total budget: 19,965 €2015 budget: 4,840.00€

• Code: PT13/0010/0045Principal Investigator: Alberto RábanoTitle: Biobanks PlatformFunding agency: Carlos III Institute of HealthDuration: 2014-20162015 budget: 44,178.26€

• Code: Proyecto IPT-2012-0769-010000(INNPACTO)

Principal Investigator: Dr. Alberto RábanoTitle: Design and manufacture of a system for the diagnosis of Alzheimer's disease based on laser Raman spectroscopyFunding agency: Ministry of Economy and CompetitivenessDuration: 2012-2015Total budget: 720,218 €; CIEN Foundation 93,320€2015budget: 17.295,00€

• Code: Universidad UlhmPrincipal Investigator: Dr. Pablo Martínez Martín y Dra. María Ascensión Zea Sevilla.Title: The multi-site prospective neural history cohort study entitled “Registry”.Funding agency:Duration: 2013-2015Budget: 6.930 €

• Code: PEJ-2014-C-19788 (Youth Employment Plan)

Principal Investigator: Dr. Alberto RábanoTitle: Grants for Promoting Youth Employment and Implementation of the Youth Guarantee in R+D+i within the framewok of the National Plan of Incorporation Funding agency: Ministry of Economy and Competitiveness / Secretary of State for

Research, Development and InnovationDuration: 2015-2017Total budget: 150,000 €2015 budget: 75,000 €

• Code: PEJ2015/BIO/AI-0615Principal Investigator: Dr. Alberto RábanoTitle: Grants for hiring research assistants and laboratory technicians.Funding agency: Ministry of Education, Youth and Sports, Region of MadridDuration: 2016-2018Total budget: 45,000 €2015 budget: 22,500 €

6.4. Patents

During 2015 three patent applicationss remain on-going, active at national and international stages,which have currently a co-ownership agreementwith participation of CIEN Foundation:

• Inventors: Pablo Martínez Martín, PedroCarmona Hernández, Adolfo ToledanoGasca, Miguel Calero Lara, Félix BermejoParejaTítulo: Infrared analysis of fractions obtainedfrom peripheral blood to indicate cognitivedevelopment.Registration Nº: P201131370PCT/ES2012/070613Application date: 08/08/2011Type: National/EuropeanLicensing agreement with Biocross

• Inventors: Pablo Martínez Martín, PedroCarmona Hernández, Adolfo ToledanoGasca, Miguel Calero Lara, Félix BermejoPareja, Marina Molina SantosTitle: Raman analysis, infrared or Raman-infrared of plasma protein structure fromperipheral blood and its relationship to thecognitive development in Alzheimer's Disease.Registration Nº: EP12382330.4PCT/EP/2013/067304


Application date: 20/08/2012Type: National/EuropeanLicensing agreement with BiocrossNational phases for this patent to thefollowing countries have been initiated during2015: Australia, Brazil, Canada, China, USA,Israel, New Zealand, South Africa, Japan andRussia.

• Inventors: José Ramón Naranjo Orovio, BrittMellström, Alberto Rábano Gutiérrez delArroyo. Title: Methods for the prognosis and diagnosisof neurodegenerative diseasesRegistration Nº: EP13382108.2PCT/EP2014/055928Application date: 25/03/2013Type: National/European



CIEN Foundation in 2015 has continued to promote variousactivities to bring to society the latest advances in research on neurological diseases, complemented with specific actions to encourage citizen participation allowing to raise funds for Alzheimer's disease research. Thus, to the more traditional activities, such as the 'tree of memories' or the Vallecas Project Volunteer’s Day, we must add numerous meetings with patient associations, conferences, exhibitions or concerts. This work has been recognized in the year with different awards.

One of the founding goals of the CIEN Foundation isto translate to society in an easy and accessiblemanner the advances and progress made in the re-search in neurological diseases.

For this reason, the responsibles of the CIEN Founda-tion departments have organized, as every year, va-rious activities that allow the dissemination of theresearch work carried out by its professionals. Thisallows them to bring the scientific field to society in akinder way, while translating results and relevant in-formation on the various neurological diseases understudy.

During 2015, CIEN Foundation continued to developactivities to disseminate the research carried out byits professionals, which has been so succesful in pre-vious editions. It is the case of the World Parkinson'sDay. On April 10, 2015, María Ángeles Pérez, Mana-ger of the CIEN Foundation and CIBERNED, partici-pated in the main event, organized by the CatalanAssociation for Parkinson (ACAP, for its acronym inSpanish). During the event, held in CaixaForum, Bar-celona, the Clinic Hospital neurologist and memberof CIBERNED Steering Committee Eduardo Tolosaspoke about the role of the patient and Associationsin Parkinson's research. and three round tables wereheld devoted to complex treatments in fluctuatingParkinson's disease: apomorphine, duodopa, anddeep brain stimulation. A conference reviewing newtreatments and technologies that will shape the fu-ture of research and treatment of the disease, whichaffects between 120,000 and 150,000 people inSpain, also took place.

It is also the case of several meetings organized byInstitutions throughout Spain in which participatedAlberto Rábano, Head for Neuropathology and di-rector of the CIEN Foundation Tissue Bank. An exam-ple is the 'Meeting of Huntington's disease families',held at the San Carlos Hospital in Madrid, on 3 No-vember 2015. Or the "NeuroMeeting: Experts Dialo-

gue on Neurodegenerative Diseases", organized bythe Spanish Alliance for Neurodegenerative Disea-ses (Neuroalianza) on 25 June 2015 at the Ministry ofHealth, Social Services and Equality, and aimed atall those involved in improving the quality of life ofpeople affected by neurodegenerative diseases:responsibles and workers in patient associations, so-cial health professionals, those affected and their re-latives, representatives of the administration, etc. Atthe meeting, public institutions, health authorities, ex-perts, associations and affected individuals analy-zed, on the one hand, the social initiatives that existto protect and improve the quality of life of peopleaffected by neurodegenerative diseases and, se-condly, advances and current research for an inte-grated approach to these pathologies. The aim ofthis meeting was to establish a meeting point andgenerate debate around reality, the current situa-tion and approach to neurodegenerative diseasesin our country, thanks to the participation of themain authorities involved in these pathologies.

The conclusions drawn from the conference willserve Neuroalianza to continue with its mission to re-present and defend the interests of the people itstands in for. The meeting has a discussion or dialo-gue format and there were representatives of theinstitutional and health, social and scientific sectors.

In addition, in May 2015, Dr. Rábano participated inSalamanca at the Third Meeting of the State Groupon Dementias, of which we the Foundation is amember since its inception in 2014. The meeting ad-dressed, among other issues, conclusions and pro-posals to advance the definition of an nationalpolicy on Alzheimer, while the external technicalevaluation report of this disease in Spain was analy-zed. This group was created with the mission to de-velop a of National Cooperation Network onDementias that allows for offering Spanish societywith a response to the social reality of these disordersand the vision to place Spain as an international re-

7. SOCIAL DISSEMINATION


7.1. Outreach activities

ference in the social, health, legal and research ap-proach in dementia through a shared national stra-tegy. The group seeks to promote the exchange ofknowledge, experiences and best practices amongprofessionals. For this, the IMSERSO, which overseesthe State Reference Center of Care for People withAlzheimer's disease and other Dementias (AlzheimerCRE, for its acronym in Spanish) of Salamanca, hascreated the Collaborative Environment. The aim ofthis initiative is to incorporate and classify docu-ments, to be accessible to all participants in thisgroup. CRE Alzheimer will be responsible for incor-porating documents that each group member or-

ganization deemed relevant and will manage andcontrol the uploading of documentation.

Among the outreach activities undertaken duringthe year it also stands out the development of a se-ries of videos of general interest, so that everyoneknows and is involved in the investigations on thebrain that are underway in Spain. This initiative is theresult of the collaboration of CIEN Foundation andthe Spanish Brain Council. In the video devoted toCIEN Foundation, in-house researchers from the fourmajor areas of work, such as Ascension Zea, a neu-rologist at the UMA; Alberto Rábano, Head of the Tis-


sue Bank; Miguel Calero, Head of Laboratory; AlbaSierra, neuroscientist from the area of neuroimaging;and Marina Avila, a neuropsychologist at the UMA,give a clear and concise overview of the work theycarry out in this indisputable reference center.

In addition, a series of activities with the dual aim ofpromoting citizen participation and raise funds for re-search into Alzheimer's disease have been schedu-led during 2015. Among these outreach activitiesraised with this duality, these can be highlighted: twostreet markets from the “Edición Recuerda” (Re-member Edition) and the fifth edition of “The Chris-tmas Tree of Memories”.

“Edición Recuerda” street markets

As part of the “Edición Recuerda” project launchedby the Queen Sofia Foundation, CIEN Foundationand Villa de Vallecas District Council joined forcesagain to set up two “Edición Recuerda” street mar-kets. The first one took place on April 17 and 18 in theDistrict of Villa de Vallecas. Those interested couldbuy vintage products re-manufactured by the par-ticipating Spanish companies. Products with me-mory designed to support and help those who nolonger have it.

On May 9 and 10, again with the intention to re-member and work with those who cannot do it anylonger, CIEN Foundation and the Queen Sofia Foun-dation organized another joint selling of re-manu-factured vintage products, this time in the popularEngines Market, located in the Railway Museum,which opens in Paseo de las Delicias, Madrid, the se-cond weekend of each month.

Christmas tree of memories

Due to the success of the previous campaign, CIENFoundation has once again set up its traditional "Treeof Memories", placed in previous years in the Queen

Sofia Foundation Alzheimer Center, at the Villa deVallecas food market, in an awareness campaignthat, for the second consecutive year, allows for notonly bringing the reality of Alzheimer to society in ge-neral, but also strengthening the role of the Villa deVallecas District in this task.

From December 2, 2015 to January 5, 2016, ever-yone who visited the market could leave a writtenspecial memory about Christmas in previous years,which were then hanged like Christmas tree orna-ments. During the campaign, market traders placedin their shops a small display for the sale of solidaritybracelets. In addition, a space was enabled on themarket for the sale of surplus from the Queen SofiaFoundation “Edicion Recuerda”.

The funds obtained from the sale of these productshave been allocated to research projects on Alz-heimer undertaken by CIEN Foundation as the ma-naging body of the Queen Sofia FoundationAlzheimer Project Research Unit, especially the Va-llecas Project.

Other Outreach Activities

During 2015 the CIEN Foundation has continued todevelop other dissemination actions among whichwe highlight the following.

• On the occasion of the American film "Still Alice"release on January 16, 2015, Grupo Senda andGolem organized few days earlier in Madrid itspremiere and subsequent debate, which wasattended by María Ángeles Pérez, Manager ofthe CIEN Foundation; María Ascension Zea, aneurologist from the UMA; Rosa Brescané,president of the Federation of Associations ofRelatives of Alzheimer patients (FAFAL, for itsacronym in Spanish); and José Luis Nogueira,Secretary of the Queen Sofia Foundation. "StillAlice" has enjoyed box office and reviewssuccess. Julianne Moore, who plays the leading



role, provides a universal vision of how familiesbehave in illness and in facing old age.According to the actress, what most attractedher about the film was "the idea of givingpeople the space to be who they are and notjudge them by what is happening with theirdisease. That was something that really touchedme".

• In March 2015, CIEN Foundation was visited bysecondary school students from the Program onEducational Enrichment for Gifted Students(PEAC, from its acronym in Spanish) of theMinistry of Education, Youth and Sports of theRegion of Madrid (CAM, from its acronym inSpanish). This Program provides students withopportunities to deepen in different areas of


knowledge through experimentation, researchand development, implemented throughvarious methodological strategies. During thevisit, CIEN Foundation researchers taught aseries of lectures and highlt educationalworkshops in different areas: pathology,neuropsychology and neuroimaging.

• Since October 2015, we could enjoy theexhibition "FromBubble", created by DanielBagnon to raise awareness throughout societyof what Alzheimer's disease means in thepersonal, family and social environment,through the interaction of contemporary artwith other scientific and social disciplines.Queen Sofia inaugurated the exhibition onOctober 30, accompanied by the mayor ofMadrid, Manuela Carmena; the Director of theart project, Maria Paz Cotorelo; and the CIENFoundation Manager and member of the Artand Science Project, María Ángeles Pérez, whoalong with the creative artist of this art proposal,Daniel Bagnon, visited the exhibit.

• The exhibition was open to the public untilJanuary 24, 2016 on the third floor of Cultureand Citizenship Cibeles CentroCentro, a City ofMadrid cultural space located at CibelesPalace, which also hosted numerousconferences such as by Dr. Miguel Medina, orJavier de Felipe members of the CIENFoundation Scientific Advisory Committee, aswell as other activities related to Alzheimer'sdisease. Noteworthy among other projectartworks, was the main piece 'Brain', a sculpturelocated in the central room of the exhibition.With FromBubble, Daniel Bagnon drawed aparallel between the Alzheimer's damagedbrain and a bubble element that represents thecomplexity of the disease. In this way, he soughtto show not only the reality of the patient butalso that people who go with them through thisstruggle. In addition, to convey the message ofthis artistic proposal to a much wider audience,FromBubble took to the streets of Madrid. 3,000bubbles were placed in cultural and historicalpoints of the city, creating a route of over seven

kilometers. Manuela Carmena, was responsiblefor placing the first of these bubbles in Plaza deCibeles, in an urban action participated by 100volunteers. These points highlight the 'Performancemultidisciplinary conference' about Alzheimer'sdisease from the scientific and socialperspective of art, delivered at the Plaza deCallao in Madrid by members of the Committeeof Art and Science, including Dr. Miguel Medina.

7.2. Awards and Honours

Candidacy of Her Majesty Queen Sofia to theNobel Peace Prize

For his personal commitment for years with Alzhei-mer's research, Her Majesty Queen Sofia has beenone of the candidates for the Nobel Peace Prize2015, after being selected from the initial 273 nomi-nations presented by national and international or-ganizations.Queen Sofia nomination, proposed by a university inthe southern United States, is due to its continuingthrust to Alzheimer's disease research, a task towhich we at CIEN Foundation, as management of-fice of the Alzheimer Project from Her Foundation,wanted to show our greatest support.

The Vallecas Project receivedthe INESE Award at the XV edition of the

Insurance Solidarity Awards

The Vallecas Project, being conducted by CIENFoundation with the support of the Queen SofiaFoundation, was one of 25 selected out of 243 pro-posals that applied to the fifteenth edition of the In-surance Solidarity Awards 2015, under the topic "Theheart drive us" were awarded on 24 November inMadrid.

Proposed by the Queen Sofia Foundation, the pro-ject has been chosen to be supported by one of the



25 insurance companies participating in the Awards,that provide a prize of 4,500 € to the sponsored pro-ject.

INESE, organizer of the Awards, was the organizationthat supported the 'Vallecas Project', a study laun-ched in 2011 by CIEN Foundation and the QueenSofia Foundation, to find common patterns in theprogression of Alzheimer's disease that advance theidentification of early markers for early diagnosis ofthe disease. The 'Vallecas Project' is studying theevolution of more than 1,200 cognitively healthy pe-ople between 70 and 85 years of age.

The Insurance Solidarity Awards 2015 show the sup-port of the insurance industry towards organizationsworking to improve the quality of life of people fromvarious fields. Thus, 25 NGOs, Foundations and Asso-ciations have received financial contributions by 25insurance and service companies to develop pro-jects concerning children, disability, social exclusion,women, and cooperation in the framework of itsCorporate Social Responsibility.

AEHTF Solidarity dinner

In its fourth edition, held on April 25, 2015, the Fuer-teventura Association of Entrepreneurs of Hotels andTourism (AEHTF, from its acronym In Spanish) electedthe Association of Relatives of Alzheimer's and otherdementias of Lanzarote and Fuerteventura (AFALF,from its acronym in Spanish) and CIEN Foundation asequal beneficiaries of the money raised (8,000 €).The money intended for CIEN Foundation has beenallocated to the Fuerteventura Grant, which finan-ces one of the research lines being carried out toeradicate Alzheimer's pathology.

Vallecas Project Volunteer's Day

CIEN Foundation is aware of the role of the volun-teer, fundamental to carry out our research projects.

Therefore, from CIEN Foundation we feel very grate-ful for the great generosity of each and every oneof the 1,213 people who attended our call and,above all, the fidelity with which year after yearcome to the corresponding visits of the Vallecas Pro-ject. Hence, since 2013, every year we pay them tri-bute through the already established "VallecasProject Volunteer’s Day" and activities organized forthe residents of CAFRS, many of them also volunteersin the Alzheimer Project of the Queen Sofia Founda-tion.

The event, chaired by H.M. Queen Sofia, was heldon 20 February 2015 at the La Latina Theater in Ma-drid. With Irma Soriano as master of ceremonies, thetribute included two actions: the performance of theunique in Spain choir "Voices of Memory", compo-sed by Alzheimer's patients from the Association ofRelatives of Alzheimer of Valencia (FSMA, for itsacronym in Spanish); and the play "Who said love?"by the Forja Theater Company.

Christmas concert "Music of Recycling"

Queen Sofia attended on December 18 a Christmasconcert held at the Queen Sofia Foundation Alzhei-mer Center, home of CIEN Foundation, played by agroup of children and several teachers of the pro-ject "Music of Recycling" by the Oberon Trio.

The project, promoted by Ecoembes and supportedby the Queen Sofia Foundation, educates musicallyand in values 80 children and young people fromthe Villapaz (Pozuelo de Alarcón) Shelter and Nunezde Arenas (Vallecas) public school, who are lear-ning to build their own instruments with and playmusic from recycled materials.

The concert was aimed at Alzheimer patients resi-ding in the Queen Sofía Foundation Alzheimer Cen-ter under the management of the Madrid Region.There are 156 people living with Alzheimer's in the



Center and 40 more patients are cared for throughthe Day Center.

María Ángeles Pérez, Manager of CIEN Foundation,said that "supporting charity projects is a wonderfulway to welcome Christmas in the Queen Sofía Foun-dation Alzheimer Center".

José Luis Nogueira, Secretary of the Queen SofiaFoundation, expressed his gratitude to Ecoembes "toinclude the Queen Sofia Foundation at the wonder-ful initiative" which means the “Music of Recyclingproject”, to CIEN Foundation and the Madrid Regionfor making possible the Alzheimer project of theQueen Sofia Foundation, and the protagonists, whoare the children who take part of the project andtheir teachers, for bringing joy and memories to resi-dents of the Queen Sofía Foundation Alzheimer Cen-ter.

Oscar Martin, CEO of Ecoembes, expressed his gra-titude to the Queen Sofia as "the breath that conti-nues to motivate us to keep this initiative alive everyday"; to the Queen Sofia Foundation for their supportsince the beginning of the project and CIEN Foun-dation and the Madrid Region "for the opportunityto give this concert, aimed at Alzheimer's patients,and for the commendable work done on behalf ofour elders". "We want to spread the joy of Christmas,"he said, "share and celebrate the magic that comesfrom the union of music and recycling".

Her Majesty was also joined during the concert bythe Minister of Social Policy and Family of the MadridRegion, Carlos Izquierdo Torres; Director General ofCare for Dependent and the Elder, Carlos GonzalezPereira; Director General of the Family and Children,Alberto San Juan; Director of the Healthcare Area ofthe Queen Sofia Foundation Alzheimer Center,Laura Fernández Pérez; and the CIEN FoundationManager, María Ángeles Pérez; as well as Javier Urraand Maria Franco, "Music of Recycling" SupportCommittee members

7.3. Presence in media

During 2015 there we produced 46 web contents, 26press releases and we managed up to 28 interviewsin the media, which resulted in the generation of of1,093 impacts in the media, distributed as follows.


2014 2015

Evolution of the impacts in 2015

889

1.093+23%

Digital media (767)

Written press (240)

Press agencies (54)

TV and radio (32)

70%

22% 3%5%

With regards to year 2014, we observed an overallpositive trend, having increased by 23% the numberof hits in the media, thanks to an increase of 109% inprint and 13% on digital media.

7.4. Presence in social networks

CIEN Foundation has an established presence in so-cial networks where it is recognized as a reliablesource of information on research in dementia. Inaddition, its efforts to promote healthy aging and theresults being obtained in the Vallecas project andthe Alzheimer project are particularly appreciated.

The digital presence of CIEN Foundation has esta-blished itself due to the great interest and follow-upof blog posts about researchers’ activities and thegreat interaction through social networks with bothprofessionals in the field and the general public.

Moreover, online public participation in events heldin CIEN Foundation and broadcasted through livestreaming, such as the International Conference onResearch and Innovation in Neurodegenerative Di-seases and the International Day of Radiology is alsoachieved through the web and social networks.Hundreds of people from different countries had thechance of virtually attend both events. Highlightingthe impact obtained with the broadcast for the firsttime the International Day of Radiology: the #IdorS-PAIN conversation got more than 1.5 million impacts,a record of visibility for the benefit of Medical Ra-diology in Spain, where the CIEN Foundation had akey role in hosting this event. In addition, coveragewas also given in real time on Twitter to other confe-rences and events.

In 2015 the CIEN Foundation website was adaptedto a responsive design, optimizing its functionality onmobile devices and thus promoting its search enginepositioning. The site was visited by 100,000 users whoviewed 128,400 pages.

• Facebook:The year 2015 closed with a total de 3,956fans following our page, with a high numberof shared publications, likes and comments.

• Twitter:By the end of 2015 the profile counted on11,800 followers with which has constantinteraction, receiving numerous comments,retweets and publications bookmarked.

• LinkedIn:A profile aimed at a professional audience, inwhich contents of interests in dementias ispublished in various groups, promotingscientific outreach and public debate

• Google+:The CIEN Foundation actively engages insharing its publications both in its profile aswell as in groups related to health, preventionand neurodegenerative diseases. Year 2015ended with a total of 123,329 visits.



Coordination and content management: Miguel Medina PadillaAina Frontera Sánchez

José de Arriba-Enríquez

2015Centro Alzheimer Fundación Reina Sofía

C/ Valderrebollo, 5. 28031 MadridTel.: (+34) 91 385 22 00 Fax: (+34) 91 385 21 18

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