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Joint Programming Neurodegenerative Diseases Research Exemplo pioneiro de Programação Conjunta Iniciativa liderada pelos Estados-Membros, 26 países (EU e terceiros) Aumentar a capacidade de Investigação da UE em DN Reduzir a fragmentação e a duplicação dos esforços de investigação através da coordenação da investigação Melhorar os resultados e cuidados de saúde na Europa Inv. Básica Modelos animais Biobancos Cohortes/registos Patologia da doença Melhorar os resultados e cuidados de saúde na Europa Clinica Diagnóstico precoce Prevenção Ensaios clínicos Social Prestação de cuidados de saúde Automação em casa Economia dasaúde Ética 3 grandes domínios

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Joint Programming

Neurodegenerative Diseases ResearchExemplo pioneiro de Programação Conjunta

Iniciativa liderada pelos Estados-Membros, 26 países (EU e terceiros)

• Aumentar a capacidade de Investigação da UE em DN

• Reduzir a fragmentação e a duplicação dos esforços de investigação através da

coordenação da investigação

• Melhorar os resultados e cuidados de saúde na Europa

Inv. Básica

• Modelos animais• Biobancos• Cohortes/registos• Patologia da

doença

• Melhorar os resultados e cuidados de saúde na Europa

ClinicaDiagnóstico precoce

• Prevenção• Ensaios clínicosSocial

• Prestação de cuidados de saúde

• Automação em casa

• Economia dasaúde• Ética

3 grandes

domínios

Resumo das Actividades (últimos 2 anos)

Coordination Action - JUMPAHEAD - financiada pelo FP7, onde PT participa como Associado não beneficiário. 2 milhões de euros / 2anos – termina final 2012.

- Workshops (2011): áreas básica, clínica e cuidados de saúde

- Mapeamento a nível nacional (2011): identificação i) financiamento de projectos (nas áreas de investigação básica, clínica e cuidados de saúde), ii) infra-estruturas existentes (biobancos, Redes imagem, etc), iii) estudos com cohorts e iv) políticas de saúde dos países participantespaíses participantes

- Preparação da Agenda Estratégica: lançamento Fevereiro 2012

-Concurso para apresentação de projectos de investigação transnacionais em ‘Optimização e Harmonização de Biomarcadores em ND’- Set 2011 –

DEMTEST / BiomarkAPD

- Rede de Centros de Excelência em Doenças Neurodegenerativas - CoEN

-

http://www.neurodegenerationresearch.eu/home/

Agenda

Estratégica(Fev 2012)

Implementação

Prioridades científicas / temáticas identificadas:

• A origem das doenças neurodegenerativas (DN)

• Mecanismos de doenças e modelos:

• Definição de doenças e diagnóstico:

• Tratamentos e prevenção:

• Cuidados em saúde e assistência social

Actividades de capacitação

• Conhecer a nossa capacidade de investigação

3

• Conhecer a nossa capacidade de investigação

• Infraestruturas e plataformas de apoio:

• Trabalhar em parceria com a indústria:

• Trabalhar com organizações reguladoras

• Parcerias internacionais para além da Europa

• Capacitação

• Educação e formação

• Ligação aos decisores políticos

• Comunicação e divulgação

A first-phase JPND Implementation Plan (period of 2012-2014)

The plan has three major action areas:�Annual Calls for Proposals

�Action Groups to determine research needs and opportunities

�Action Groups to promote engagement, commitment and partnerships

Annual Calls for Proposals

JPND intends to launch Calls for proposals each year to address high priority areas in neurodegenerative disease research.neurodegenerative disease research.

2012-2014 - JPND will launch calls to address each of the following priority areas:

o Genetic, epigenetic & environmental risk factors

o Cell and animal models for the identification of mechanisms underlying NDo Cross-disease analysis of pathways (network analysis in different ND & other chronic diseases)

o Preventive strategies

o Evaluating healthcare policy strategies and interventions

o Systematic Review(s) of ‘pathways to care’o Palliative and end-of-life care

Concursos 2012 (projectos em fase de avaliação)

“European Research projects for the identification of genetic, epigenetic and environmental risk and protective factors for Neurodegenerative Diseases”

“EU research projects for the evaluation of health care policies, strategies and interventions for Neurodegenerative Diseases”

5

An integrated translational genetic approach towards early-onset dementia - TRANSGENED

• 1 national group (Coimbra+Lisbon)

Main goals:WP1: harmonization of the collection of EOD patients plus their biosamples WP2: use of next-generation-sequencing tools to characterize EOD patients and to identify novel genes WP3: investigate correlations between genetic profiles and metabolite-based biomarkers WP4: use of epigenetic approaches to identify signatures associated with EOD WP5: perform prospective clinical follow-up studies in EOD families

Actividades 2013

- Reunião MB em Zagreb (6-7 Junho):

Decisão acerca de pagamento de fees para financiar estruturaDecisão acerca da participação no concurso 2013

- Reunião MB em Lisboa (10-11 Outubro)

- Four expert-led Action Groups (research needs and opportunities)� Longitudinal Cohort Studies (with workstreams addressing both disease-based and

population-based cohorts)� Animal and Cell Models (MJS-IBMC & Paula Alves-IBET)� Assisted Living Technologies (Workshop 20 Junho)� Assisted Living Technologies (Workshop 20 Junho)� Palliative Care - Need answer regarding ongoing regional, national and international

initiatives with a relevant research focus on palliative/end-of life care.Each Action Group will recommend the most appropriate approach to be adopted by JPND for implementation of each of these research priorities.

- Action Groups to promote engagement, commitment and partnershipsThe JPND EB are leading specific actions to promote engagement, commitment and partnerships towards implementation of specific

� Engagement and Partnership with Industry� Engagement and Partnership with the European Commission and other international

initiatives� Linking and alignment of national plans and initiatives� User and Public Involvement in neurodegenerative disease research

2013 – Actividades a nível Nacional-

- 20-21 Maio : ALM participação na reunião ESTRUTURAÇÃO DO PLANO NACIONAL DE INTERVENÇÃO EM PERTURBAÇÕES DEMENCIAIS com coordenação do Prof. Joël Ménard, Presidente da Comissão de redacção do Plano Alzheimer França 2008-2012

- 11 Julho – Reunião JPND-PT: apresentação de resultados dos projectos em curso e divulgação das actividades (participação outros stakeholders)

DinâmicasDinâmicas de de InvestigaçãoInvestigação emem DemênciaDemência

Anjos L. MacedoAnjos L. Macedo

FCTFCT--UNLUNLIsabel Santana

CHUC

curso e divulgação das actividades (participação outros stakeholders)

-Actividades anteriores com CC – PTIdentificação dos investigadores/equipas a trabalharem na área em PT

Março 2010 – Reunião Informal | Doenças Neurodegenerativas/Alzheimer Disease. Investigação a

decorrer em Portugal & Apresentação da Iniciativa de Programação Conjunta EU. Coimbra, CNC , promovida pelo CCCVS.

Recolha de informação relativamente à actividade científica de cada grupo

- internacionais – PT/ESWorkshop FCT-ISCIII, Instituto de Salud Carlos III, 4-5 Julho 2011, Centro Científico e Cultural de Macau. Identificação de acções de colaboração futura no âmbito do JPND e ao nível das plataformas em rede

JPI “Ambient Assisted living”

IniciativasIniciativas EuropeiasEuropeias de de programaçãoprogramação conjuntaconjunta

relacionadasrelacionadas com JPNDcom JPND

- Aumentar o tempo de vida das pessoas no seu ambiente preferido Novos produtos&serviços ICT / envolvimento de empresas / possibilidade de negócioEstimulo à investigação orientada para os resultados / aplicadaEnvolvimento do utilisador no teste ao produto final

Identificação prioridades de investigação (contribuição para a preparação dos concursos)

European Innovation Partnership - Active and Healthy Ageing

Desafio Sociedade EU

http://ec.europa.eu/research/innovation-union/index_en.cfm?section=active-healthy-ageing

Envolvimento do utilisador no teste ao produto final

ERA-NET ERA AGE 2 (não participamos)http://era-age.group.shef.ac.uk

AGE Platform Europe - European network of around 167 organisations of and for people aged 50+ representing directly 150 million older people in Europewww.age-platform.eu

“FUTURAGE Road Map for European Ageing Research” – agenda de investigação elaborada no âmbito de um projecto FP7:“This document contains the research agenda that will enable Europe to respond successfully to the unprecedented demographic challenges it faces. Its twin starting points are the high priority allocated to population ageing, by Member States and the European Union as a whole, and the fundamental importance of scientific research as the driver of innovations in whole, and the fundamental importance of scientific research as the driver of innovations in

public policy, in a wide range of clinical and other professional practices, and in the development of products and services”.

http://www.futurage.group.shef.ac.uk/assets/files/Final%20road%20map/FUTURAGE%20A%20Road%20Map%20for%20European%20Ageing%20Research%20-%20October%202011.pdf

SHARE - Survey of Health, Ageing and Retirement in Europe (parece fundamental a participação PT na próxima “onda” – a tratar)http://www.share-project.org

Listagem dos projectos financiados 7ºPQ no tópicoHuman Development & Ageing:http://ec.europa.eu/research/health/medical-research/human-development-and-ageing/index_en.html

CNC

IBMC-UP

FCM-UNL

FM-UP

FARM-ID

UC

UM

FCG

FChampalimaud

FC-UL

ICBAS-UP

ICETA-UP

IMM

UBI

Ualg

Básica

Clinica

Social

Ualg

UAv

FC-UP

CEPESE-UP

FCSH-UNL

FADE-UP

HGO

IBET

IT

INSA-RJ

IPVC

IST/UTL

MTCB

MSFT

Distribuição projectos financiados área envelhecimento

2008-2012

Consórcios Internacionais

European Alzheimer´́́́s Disease Consortium (EADC)

Coordinator: Bengt Winblad

Members: 63 centers from 19 EU-countries

Aims:• increase the basic scientific understanding of AD• develop ways to prevent, slow, or ameliorate the symptoms of AD• develop ways to prevent, slow, or ameliorate the symptoms of AD

� Portugal (2 centers):

�Lisboa: Alexandre de Mendonça (joined in 2008)

�Coimbra: Isabel Santana (joined in 2010)

European consortium for early-onset dementia (EOD)

� Launched in August 2011

� Current status – where are we now

� Members: 48 partners (PIs) from 16 EU-countries

� Resources: 2.600 EOD patients

Coordinator, PI: Christine Van Broeckhoven

� Portugal

� Coimbra: Isabel Santana

� Lisboa: Alexandre de Mendonça

� Resources: 2.600 EOD patients

The European Early-Onset Dementia consortium

Aim: � Study early-onset dementia (EOD) at the European level

� Create a platform for high-profile translational clinical and translational

genetic dementia research

Meetings:

� 1st Informal meeting at AAIC2012 Vancouver, Canada

� 2nd Informal meeting at FTD2012 Manchester, UK

� 3nd Informal meeting at AD/PD2013 Florence, Italy

�1st Annual Meeting of the EU EOD Consortium June 13-14th, Antwerp

The European Early-Onset Dementia consortium

� Joint research projects

First joint project:

→→→→ C9orf72 repeat expansion in FTLD and ALS patients

Second joint project:

→→→→ SQSTM1/p62 genetic screening in FTLD and ALS patients

DEMTESTBiomarker based diagnosis of rapid progressive dementias - optimisation of diagnostic protocols

Goals of study:

• Harmonisation of protocols for biochemical CSF and blood tests

• Recommendations for sample collection protocols for biological fluids

• 31 partners from 23 countries within and outside Europe – 1 Pt group

• Recommendations for sample collection protocols for biological fluids

• Definition of standard cut off values for biomarker assays

• Establishment of a worldwide biomaterial bank for RPD

• Recommendations for test selection for RPD diagnosis

• Modification of clinical criteria/consensus reports for most important

differential diagnoses in RPD (i.e. CJD, rpAD and reversible disorders)

• Training for laboratories beginning to implement CSF analysis on RPD

• Validation of novel assays for detection of very low amounts of PrPSc in

biological fluids from CJD - break-through in pre-mortem diagnosis.

DEMTESTBiomarker based diagnosis of rapid progressive dementias - optimisation of diagnostic protocols

Involvement of the Pt group (Coimbra):

WP1: Establishment of a data base and biomaterial bank from Rapid Progressive Dementia (RPD)

• Periodical follow-ups with the clinical sites of samples origin to ensure the update of clinical diagnosis

and the inclusion of autopsy informationand the inclusion of autopsy information

• ≈ 900 samples: 60 sCJD definitive / 150 non-CJD

WP2: Standardization of pre-analytic conditions influencing sample stability and marker degradation

• Temperature of short-term sample storage (days): room temperature or 4°C;

• Delay of freezing at -80°C: within 2h and 1, 2, 3 and 7 days of freezing delay;

• Duration of long-term sample storage before analysis: 1, 2, and 3 years of storage;

• Number of freeze-thaw cycles: 1,2,3,4 or 5 cycles;

WP3/5: Optimisation, standardization and validation of 14-3-3 and tau/p-tau assays for RPD diagnosis

• Test different 14-3-3 isoforms

• Implement a quantitative WB for 14-3-3 and establish reference values

• Adapt and validate the t-Tau assay for this specific type of samples (usually above the detection range)

DEMTESTBiomarker based diagnosis of rapid progressive dementias - optimisation of diagnostic protocols

Involvement of the Pt group:

• Adapt and validate the t-Tau assay for this specific type of samples (usually above the detection range)

WP7: Quality control and biomarker monitoring strategies

• 1st ring trial currently underway

• Implement a sustainable procedure of regular ring trials for RPD markers

Recombinant

14-3-3, ng

50025012562,531.3

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

• 48 partners from 21 European countries – 3 Pt groups (Lisbon, Coimbra, Aveiro)

Main Aim:

• Develop evidence-based guidelines for measurement and use of biochemical biomarkers for AD

(Aβ42, t-Tau and p-Tau) and PD (α-synuclein) in clinical practice.(Aβ42, t-Tau and p-Tau) and PD (α-synuclein) in clinical practice.

Objectives:

• To develop and validate standard operating procedures (SOPs) for pre-analytical sample handling

• To develop qualification algorithms for commercially available biomarker assays

• To develop and validate SOPs for analytical procedures

• To develop SOPs for the use of biomarkers in the diagnosis in clinical practice and in clinical trials

• To implement the SOPs among laboratories and clinicians across Europe

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

BIOMARKAPD

Preclinical stream Clinical stream

CSF biomarkers : lack of standardization

Alzheimer Association Quality Control Program for CSF Biomarkers

Aββββ42 Tau p-Tau

CSF biomarkers : lack of standardization

Mattsson et al, Alz Dementia 2013

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – Confounders:

• In vitro pre-analytical confounders

• In vivo pre-analytical (biological) confounders

• Analytical confounders

CSF lyophilization

CSF manipulation and storage – Inês Baldeiras

Genetics – Madalena Martins

Caffeine – Alexandre de Mendonça

CSF / brain volume

Diurnal rhythm

Clinical phenotype

• Analytical confounders

... that may affect the results of biomarkers for AD and PD

On-going studies

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – issues to consider:

#1: Lumbar puncture – time of day, fasting, location and type of needle#1: Lumbar puncture – time of day, fasting, location and type of needle#2: CSF gradient#3: Type of tubes#4: Spinning conditions#5: Time delay between CSF collection & storage#6: Freeze-thaw cycles#7: Aliquots#8: Freezing temperature#9: Length of storage

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#2: CSF gradient

Mollenhauer B et al. J Neurol Transm 2012;119:739-746

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#3: Type of tubes

Leweczuk P et al. Clin Chem 2006;52:332-3342006;52:332-334

• Aβ42 levels decreases 35% from polystyrene/glass to polypropylene Bjerke M et al. Int J Alz Dis 2010:1-11

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#3: Type of tubes

• Comparison of 11 types of polypropylene tubes

Perret-Liaudet A et al. JAD 2012;31:31-20

Selection of collection and storage tubes by the consortium:• Sarstedt 10 mL, sterile – cat nr: 62.610.018 • Sarstedt 2, 1 or 0.5 mL – cat nr: 72.694.007

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#4: Spinning conditions

• Important for blood contaminated CSF and markers that have higher concentrations in blood in blood

Bjerke M et al. Int J Alz Dis 2010:1-11

• Aβ42 levels decrease in centrifuged samples compared to non-centrifuged

No studies addressing the influence of spinnig temperature or speed

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#5: Time delay before storage

Aββββ42 t-Tau p-Tau

Zimmermann et al. JAD 2011;25:739-745

Aββββ42 t-Tau p-Tau

αααα-Syn

del Campo et al. Biomark Med 2012;6:419-430

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#6: Freeze-thaw cycles

Aββββ42 t-Tau p-Tau

Zimmermann et al. JAD 2011;25:739-745

Aββββ42 t-Tau p-Tau

αααα-Syn

del Campo et al. Biomark Med 2012;6:419-430

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#7: Aliquots

Water

del Campo et al. Biomark Med 2012;6:419-430

No studies with protein-rich

solutions

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – previous studies:

#8: Freezing temperature

• No difference in Aβ42 levels but T-tau and P-tau were significantly lower when CSF samples were frozen at -20 instead of -80°Csamples were frozen at -20 instead of -80°C

#9: Long-term storage

Zimmermann et al. JAD 2011;25:739-745

Aββββ42 t-Tau p-Tau

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – consensus-based recomendations:

del Campo et al. Biomark Med 2012;6:419-430

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – ongoing work:

Aim: focus on pre-analytical confounders that have been less studied for CSF biomarkers

Centrifugation •No centrifugation• For Aβ42 / t-Tau/p-Tau:

Freeze-thaw

cycles

•1•3•5

Centrifugation •No centrifugation•500/2000/3000g, 10 min, 4oC / RT

• For Aβ42 / t-Tau/p-Tau:

Aliquots

•25% tube total volume•50% tube total volume•75% tube total volume

Analyzed at 3 time-points: 1 month, 1 year and 2 years after collection

BIOMARKAPD

Biomarkers for Alzheimer’s disease and Parkinson’s disease

Task D3 – In vitro pre-analytical confounders:

• CSF manipulation and storage – ongoing work:

5 groups working on this sub-task:• Coimbra, Portugal – Catarina Oliveira (coordinator)

• Luxemburg – Fay Betsou• Kuopio, Finland - Sanna-Kaisa Herukka• Kuopio, Finland - Sanna-Kaisa Herukka• Copenhagen, Denmark - Anja Hviid Simonsen• Lyon, France – Armand Perret-Liaudet

Timeline:

1. Protocol finalized in March 20132. March 2013 – June 2013 : sample collection

. 10 samples/center/condition 3. June 2013 – July 2013: biomarker determination

. Each group performs the determinations in the samples they collect

. For each sample, all conditions tested in the same plate4. July 2013 – October 2013: analyze data

. Results will be normalized (relative percentage of baseline)5. October 2013 – December 2013: write an article