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CCNA

The Canadian Consortium forN d ti d A i

CCNA

Neurodegenerationand AgingDr. Howard Chertkow,

Professor, Dept. of Neurology, McGill University;Physician, Division of Geriatric Medicine,

Dept. of Medicine, Jewish General Hospital; Director, Bloomfield Centre for Research in Aging,

Lady Davis Institute, Jewish General Hospital.

CCNA OverOveOverviewOVOVEROverview of Presentation

CIMA-Q CCNA- General ApproachThe teamsThe PlatformsThe PlatformsThe novelty of the approachThe cross-cutting cores

-Training-Knowledge Transfer-Women and Dementia core-ELSI

International collaborationGovernanceCIMA-Q and CCNASummary

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CCNA CIMA

CIMA‐Q  plan and deliverables

Creating a registry of AD, MCI, SCI  (Subjective Cognitive Impairment)Clinical, neuropsychology, imagingBiosamples

CCNA PLATEFORMES ET AXES MÉTHODOLOGIQUES

1. Banques de cerveau (amélioration des critères cliniques)2. Génotypage3. Neuroimagerie4. Biomarqueurs5. Marqueurs cognitifs/comportementaux (détection et progression)6 Modèles animaux6. Modèles animaux

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CCNA PLATEFORMES ET AXES MÉTHODOLOGIQUES

7. Cohortes cliniques8 Plateforme de colonies de rongeurs et8. Plateforme de colonies de rongeurs et de phénotypage9. Transfert de connaissance (e.gCDKTN)10. Harmonisation (critères, outils utilisés, banque de données, etc.)

CCNA FRSQ AD Research pg. 2 –autresaspects-

High Risk Pilot projects P4.Biomarqueurs, qP5. Marqueurs cognitifs,P6.Modèles animauxEt les themes: 1. Mécanismes biologiques2. Prévention3. Détection précoce 4. Thérapeutiques innovantes:

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CCNA Modèle méthodologique

Expert group Expert group Expert group Expert group

Neuro-imaging

Cognitive/behavioural symptoms

Biomarkers Risk and protection

factors

Population cohort (NuAge)

Clinicalcohort

Brainbank

CCNA

Cohort:50 Mild Alzheimer’s Disease subjects150 Mild Cognitive Impairment subjects100 Subjective Cognitive Impairment subjects50 Normal subjects

Deliverables: Cognitive, neuropsychiatric markers• Identification of a psychometrically reliable and valid battery of cognitive measures.• Harmonized web-based training and quality control procedures for administration and scoring of those proceduresprocedures.• Cognitive data from 350 older individuals.• These results will establish a battery of cognitive and clinical tools for the early-stage identification of AD

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CCNA CIMA-QCIMACIMAImaging Deliverables:•7 MRI and 3 PET qualified platforms • quality control records for MRI and PET platforms • 170 MRI scans for healthy older adults, SCI, MCI and AD subjects, with accompanying pre‐processed images and medial temporal lobe volumetric information • 35 PET scans for SCI, MCI and AD subjects, with accompanying qualified reports •Advanced protocols for standardized MRI and PET acquisitions • The first worldwide platform for PET reader training 

CCNA ICRSAD Goals

1Primary 

1Primary 

2Secondary

2Secondary

3Quality

3Quality

preventionprevention preventionprevention Of lifeOf life

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CCNA WhOur Expression of Interest (EOI) included:• 37 principal applicants 4 from B.C.,

CCNA-Who we are:

5 from Alberta, 1 from Saskatchewan, 13 from Ontario, 11 from Québec,3 from Nova Scotia.

9 are junior researchers•9 are junior researchers• 285 other researchers•Steering committee: Chertkow (PI)Theme leaders, co-leaders, (Rylett, Hogan, Black, Masellis, Rockwood) Feldman, Gauthier

CCNA The CCNA application• Work in progress- grant due Dec. 2nd

• National in scope- still in process of recruiting researchers from Manitoba, New Brunswick, Newfoundland

• Budget in flux crucial role of partners especially for• Budget in flux – crucial role of partners- especially for platforms

• About 45 million dollars for 5 years• Leveraging/harmonization with other groups to maximize

productivity and save costs- Canadian Long. Study of Aging – biobanking, normal

control group- Ontario Brain Institute – cohorts, MRI- FRQS/Pfizer CIMA-Q (Québec) – cohorts, imaging-other provincial plans and agencies.

• Interactive discussions with partners- nothing set in stone here• Addressing EOI critiques and suggestions

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CCNACanadian Issues:• Rural service delivery•Provincial health care systems•Use of single payer system•cohesion across disciplines•cohesion across disciplines•collaborative structure

International issues:•NDD as global problems•Vascular emphasisVascular emphasis•Gender emphasis•Excellence of researchers•Need for novel molecules, new approaches, three themes

CCNA CCNA – our objectives1. To transform the Canadian NDD community into a synergistic clinical and research

network.

2. To create a novel Canadian dementia research infrastructure that will transform2. To create a novel Canadian dementia research infrastructure that will transform Canada into a single Alzheimer’s Disease Research Centre (ADRC). • clinical assessments •imaging protocols • biobanking protocols • brain banking • biomarkers: all are coordinated, shared and made available for the broadest use.

3. To address issues that are of particular importance within the Canadian landscape, including service delivery challenges, care for indigenous individuals, and addressing challenges of care within different provincial systems.

4. To include Teams focussing on neurodegenerative diseases beyond Alzheimer’s disease: LBD, VCI, FTD, PDD –

• common mechanisms • comorbidities • distinctive and shared pathologies

5. To position this Canadian network to partner globally and to move quickly.

6. Provide a critical link between basic scientists and clinical populations.

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CCNA General plan:

• General plan:• Lean administrative structure• 1/3 to ½ of funds to support 8 platforms• 2/3 of funds to 20 teams in the three themes• Roll over CDKTN to become the KT organ of

CCNA• Training program

T i l “ ”• Two special “cores” –– ELSI (Ethical, Legal, Social) consultancy program– Women and Dementia

CCNATeams- Theme 1Prevention of cognitive impairment and dementiaJane Rylett, David Hogan

Team 1 - Clinical genetics and gene discoveryg g yPeter St. George-Hyslop (U.of T.)Team 2 - Inflammation and Nerve Growth FactorsClaudio Cuello (McGill)Team 3 - Protein MisfoldingNeil Cashman (UBC)Team 4 - Synapses and metabolomicsRobert Bartha (Western)Team 5 - Lipid and Lipoprotein MetabolismCheryl Wellington (UBC)Team 6 - Nutrition, Exercise and Lifestyle in AD preventionCarol Greenwood (U. of T.)

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CCNA

Teams- Theme 2Treatments Sandra Black, Mario Masellis

Team 7 - Vascular illness and its impact on NDDEric Smith (Calgary)Eric Smith (Calgary)Team 8 - Lewy Bodies (PDD and LBD), Aging, and DementiaRichard Camicioli (Alberta)Team 9 - Developing New BiomarkersRoger Dixon (Alberta)Pierre Bellec (U. de Montréal)Team 10 - Cognitive Intervention and Brain PlasticitySylvie Belleville (U de Montréal)Sylvie Belleville (U. de Montréal)Team 11 - Prevention and Treatment of Neuropsychiatric SymptomsNathan Herrmann (U. of T.)Team 12 - Mobility, Exercise and CognitionManuel Montero-Odasso (Western)Team 13 - Frontotemporal dementiaRobin Hsiung (UBC)

CCNA

Teams- Theme 3Quality of Life Ken Rockwood

Team 14 - How multi-morbidity modifies the risk of dementia and the patterns of disease expression

M li A d (D lh i )Melissa Andrew (Dalhousie)Team 15 - Gerontechnology and dementiaAlex Mihailidis (U. of T.)Team 16 - Driving and dementiaGary Naglie (U. of T.)Team 17 - Interventions at the Sensory and Cognitive InterfaceNatalie Phillips (Concordia) Team 18 - Program to improve the effectiveness of dementia caregiversJoel Sadavoy (U. of T.)Team 19 - Integrating dementia patient care into the health care systemHoward Bergman (McGill)Team 20 - Issues in dementia care for rural and indigenous populationsDebra Morgan (U. Saskatchewan)Kristen Jacklin (U. Northern Ontario).

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CCNA

Theme 1 Theme 3

1. Genetics

2. Inflammation4. Synapse

5. Lipoprotein

6. Exercise,Lifestyle

14. Comorbidity

15. Gerontechnology

16. Driving 18. Caregivers

19. Health CareSystem

20. Rural,Indigenous

ELSI

Women

Theme 2

3. Protein Misfoldy p

7. Vascular

8. Parkinsons9. Biomarkers

10. Cognitive Therapy

11 Neuropsychiatric13. FTD

17. Sensory Interfaceg

Key - Arrows Red – one-way interactionwithin themeBlue – two-way interactionWithin themePink – one-way Interaction across themesGreen – two-way interaction across themes

Platforms: Clinical, Biomarkers, Imaging, Neuropsychology, Genetics, Brain Banks

11. Neuropsychiatric

12. Mobility

CCNA

Teams and Platforms being built together to support each other– hypothesis driven platforms

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CCNA

Cohorts

AD MCI VCI/Mixed LBD FTD Normal

BiosamplesPlatform

Platform

Imaging         

Genetics

Brain Banks

Platform

Platform

Platform

Team 1Genetics

Team 2Inflammatory

Team 3……. Team 20Rural, Indigenous

CCNA

Cohorts

AD MCI VCI/Mixed LBD FTD Normal200150 200 50 50 50

Biosamples Blood •CRP, IL‐1, TNF‐alphaCSF • TrK‐A,Pro‐NGF, GFAP,MMP‐9,ACT,BDNF….

Platform

Platform

Imaging         MRI‐allFDG PET            30PET‐PK11195   30PET Deprenyl 30

Genetics

Brain Banks Pro‐NGF, NGF, BDNF, TrK‐A, MMP‐9, CCL2 TIMP‐1 MMP‐3 MMP‐2

Platform

Platform

PlatformCCL2, TIMP‐1, MMP‐3, MMP‐2, CX3CL1….

Team 2 – Inflammation, Growth factors

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CCNA

•Using C5R Memory Clinics, plus Stroke Clinics, Movement Disorder Clinics

Platform #1 – CohortsEstablishment and Coordination of Clinical Cohorts Coordinator‐Michael Borrie

Diagnosis Minimum Number

Mild AD 400

Mixed AD/Vascular Dementia/VCI ‐Vascular Cognitive Impairment

400

Mild Cognitive Impairment 400

Lewy Body Disease/ 200Lewy Body Disease/Parkinsons Dementia

200

Frontal temporal dementia 200

CCNA

MontrealCalgary TorontoVancouver

Major Clinical Sites for CCNA(red outline = brain banks)

Ed t

Halifax

g y

L dWi i OttEdmonton London

Quebec City Fredericton/Saint John

Winnipeg

St. John’s

Ottawa

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CCNAPlatform #1 – Cohorts Establishment and Coordination of Clinical Cohorts

•Subjects seen at academic (largely C5R) Memory Clinics, and Movement Disorder Clinics across the country• i d di d bj i• Rigorous standardized subject ascertainment•Shared consent procedures•iPAD/tablet clinical data (upload)•Web‐based computerized intake• Agreed on cognitive testing, MoCA, computerized testing•Detailed “deep phenotyping of each research subject”• Longitudinal follow upLongitudinal follow‐up. •Upload via C‐Brain to Montreal Neurological Institute•Coordinated with imaging, biosamples, genetics, Brain bank• Directly upload information into anonymized LORIS database • National clinical registry to support the research agenda of all teams and supply well‐ascertained volunteers for clinical trials. 

CCNA

Pl tf #2 B i I iPlatform #2 – Brain ImagingAlan Evans, Louis Collins, Simon Duchesne

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CCNA

HPC Integration(8 compute installations, 80,000+ core)

CBRAIN National HPC Integration(100,000 processors)

Orcinus - Westgrid (3072 cores)

Colosse - CLUMEQ (7616 cores)

JUROPA & JUDGE – Julich, GER(30000 cores)

Kraken - SHARCNET (3774 cores)

Guillimin - CLUMEQ & Local Servers (16000 cores))GPC - SciNET

(30240 cores))

Mammouth II - RQCHP(2464 cores)

CCNA

Acquisition management Analysis pipelines 

80 man‐years of developmentWeb‐based, secure data transfer of multi‐site dataGeneralized open‐source MYSQL architecture  ‐ flexible, extensibleApplications in development, neurodegeneration (US, Europe, Asia)

cqu s t o a age e tProject management toolsDouble data entry/ range checkingAutomated 3D image QCJava‐based remote 3D image QC150 behavioral instrumentsMANTIS bug‐tracking

External pipelines for analysis (MNI, SPM, FSL , LONI, AFNI)Integrated with grid‐computing networks (CBRAIN, NeuGrid)

LORIS

Repository /downloadData types: behavior, clinical, imaging, geneticOn‐line remote MRI browserData querying GUI (volumes, surfaces, behavior)e.g. NIH database of normal brain development                        

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CCNA

CIMAQ multi-centre neuroimaging platform(Duches

Standardized acquisition/QCTrainingData bank/dissemination

CCNA

DemMETRIX platform

VolMETRIX VasoMETRIXAlzMETRIXMCIMETRIX

101 cm3 Normal subjectMCI stable

sMCI

pMCI

CN

ADVascular load 

3.7 cm3

Patient with ADMCI progressor

134 cm3

Collins  L.

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CCNA

• Platform #3 Biosamples• Platform #3 – Biosamples[CSF/Blood samples/Biomarker resources]. Coordinator-Judes Poirier

CCNA

1 ex

pres

sion

Temporal Cortex

Glial HO‐1 expression in AD and MCI (oxidative stress measure)

Canadian researchershave developed

Ast

rogl

ial H

O-1

Temporal Cortexand published 37 potentialnew  biomarkers forNeurodegenerativeDiseases….never studied inadequate numbers.

Asr

oglia

l HO

-1 e

xpre

ssio

n

Hippocampus

Schipper et al,

NeurobiolAging, 2006

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CCNASpectrum of CCNA Biomarker Team: Breadth and

ImpactPierre Bellec

Louis Collins

Simon Duchesne

Nikolai Malykhin

NeuroImaging NeuroBiological NeuroCognitive NeuroQuantitative

Spectrum of biomarkers under development in Canadian labs

y

Eric Smith

Robert Bartha

Richard Camicioli

Howard Chertkow

Roger Dixon

Angeles Garcia

Vassilios Papadopoulos

Marc PoulinMarc Poulin

Peter Stys

Hyman Schipper

David Westaway

Esther Fujiwara

Scott Hofer

Stuart MacDonald

Doug Munoz

CCNA

Platform #3 – Biosamples[CSF/Blood samples/Biomarker resources/]. Coordinator-Judes Poirier

• CLSA model-multiple tubes of blood, bar coded, shipped for analysis

• F bi k d t t i d b th t f• Focus on biomarkers and tests required by the teams for their research program

• Coordinated acquisition of blood, csf, and (eventually) brain biomarkers from all cohort members.

• Tests carried out by relevant team experts Theme 1• CSF- Poirier/Breitner national centre for t-tau, p-tau,

csfamyloid levels.• Genetics (next slide)• Allows measurement of test sensitivity (MCI, AD),

specificity (LBD, FTD).• Allows analysis of clusters and subgroups• Allows comparative assessment of different biomarkers

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CCNAPlatform #3a -Normative Controls and Biobanking

• There are important Canadian population cohorts of elderly subjects: CLSA (Canadian Longitudinal Studyelderly subjects: CLSA (Canadian Longitudinal Study of Aging), Victoria Aging Study (Dixon), NuAge(Gaudreau).

• CCNA will partner to leverage “normal elderly subjects” – shared biosamples, cognitive testing, even MRI protocols.

• Will leverage off CLSA biosample collection andWill leverage off CLSA biosample collection and anonymizing system, and large biobank in Hamilton.

• Will supply needed normal control groups

CCNA

Platform #4 DNA Sequencing and GenotypingPlatform #4-DNA Sequencing and GenotypingPlatform/Team coordinated by Peter St. George-Hyslop

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CCNA

AD AD UofT/UBC

FTLDFTLDUBC

DLBDLBUofT

PDPDUBC

ALSALSMcGILL

Expert nodes withexisting samples and genetic data

Genetics Platform#4– New Sample & Data Collection 

•NeuroX chip SNP screen• Whole Exome/Whole Genome Sequencing• RNA‐Seq• Bioinformatics •Methylome•HistoneMark CHIP‐SEQ

• Genetic data (SNP, mutations, InDels, CNV, ROH)• Epigenetic changes 

Common platformswith disease‐specificexpert curation and cross‐disease comparison

Data sharing 

• Gene Expression Profile  

• New Genes•Gene:Gene Interactions  •Gene:Environment Interactions •Genotype:Phenotype Correlation • Genetically Specified Cohorts•Gene:Biomakrer Correlations   

Output  

CCNA

•IlluminaNeuroX Chip assessment providesa) all known mutations (~1 000) in genes known to cause

What the NeuroX Chip measures

a) all known mutations ( 1,000) in genes known to cause neurodegenerative diseases;

b) b) ~10,000 key tagging SNPs for all genome‐wide significant loci published in human GWAS for PD, FTLD, ALS, AD and stroke together with the top ~1,000 SNPs just below genome‐wide significance;

c) c) ~240,000 coding sequence variants with a frequency of ) ) , g q q y>1% in the human genome;

d) d) ~5,000 novel coding variants currently detected by whole exome sequencing of familial cases affected by different neurodegenerative disorders;

e) e) ~1,000 eQTL markers. 

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CCNA

Platform #5-Brain Banking core of CCNA Coordinator-Sultan Darvesh

CCNA

To collect well characterized brain tissues and to make them available for researchers to understand the causes of neurodegenerative disorders

Response ‐ Establish A Canadian NDD Brain Bank Network  Currently – not enough brain collection in Canada

Alzheimer’s DiseasePick’s Disease

Alzheimer’s DiseaseNormal

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CCNA Brain Banking core of CCNA Coordinator-Sultan Darvesh

Plan – establish within 12 months a “Canadian Brain Bank Network” – 4 or 5 BB’s in consortium with secondary banks as well.Standardize structure and procedures$ combination funding: Local, regional, other funders (such as Brain Canada), plus CCNA: total 300,000 /bank/yearbrain donation – national coordination structureNational brain exam protocolDatabasing of results, linked to CCNA cohortsAlso: collection of normal brains from CLSA?

CCNA Platform #6-Support for Transgenic Colonies Coordinator-David Westaway

• Basic science labs across Canada currently underfunded for support of Transgenic animal models

• CCNA will vet requests for extra support of these crucial colonies

• Will supply $15,000 /year for each TG colony used for NDD research.y

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CCNA

Platform #7-National Platform on Experimental Therapies. Coordinator-Howard Feldman Goals:

To integrate a national program for therapeutic drug development that will - develop innovative candidate therapies for AD and other- develop innovative candidate therapies for AD and other

neurodegenerative diseases- optimize preclinical and clinical development phases

Preclinical development- Inventory and coordinating role of assets and skill sets- Models of disease - Close coordination with Themes 1 and 2

Cli i l d l tClinical development- Innovative designs and advanced methodologies- Efficiencies in trial execution- National (C5R, CSC) and global networking (NYAS, ADCS, One

Mind, JPRD)

CCNA CCNA Preclinical Drug Development Development

■ Develop an inventory of resources and units across the consortium with capabilities for preclinical drug discovery

T t id tifi ti ( Th 1 d 2 th )- Target identification ( Themes 1 and 2, others) - High throughput screening with compound libraries (academic

units, pharma partners, specialized facilities CDRD, PQ- Target validation: animal models, cellular models, novel systems

pluripotent stem cells (iPSC)- Pharmacology units with ability to establish Pk, PD, dose modelling

towards phase 1 dose selection- Toxicology (GLP, outsourced, local)

Deliverables:■ Deliverables: - Preclinical package for IND and first in human phase 1 trials- Novel validated targets - Repurposed drugs with preclinical package that have potential

application to targets in neurodegeneration

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CCNA

• What is unique about the platforms?

CCNAPathological Diagnosis of Dementia

Criteria 1 Criteria 2

AD 75% 39%AD 75% 39%VaD 3% 1%LBD 9% 3%Other 13% 13%Mixed AD/VaD 20%Mixed AD/LBD 19%Mixed AD/Other 5%

44%

Source:Munoz,et al.

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CCNA Platform- Novel approach: We will embrace the complexity of NDD

We will be both radical “lumpers” and “splitters” for the major dementias. We will entertain and test general hypotheses that are both of these in innovative fashion:both of these in innovative fashion:

– We will “lump” dementia cases together for molecular analyses, assessing AD/ Vascular/Lewy Body loads along a continuum rather than strict AD vs. Vascular dementias

– Allows us to look at risk factors, biomarkers, therapy response in real life “messy” and mixed dementia cases

– We will entertain the possibility of mixed/multiple therapy trials in years 3-5.– Brings vascular assessment VCI vascular risk factors to centre stageBrings vascular assessment, VCI, vascular risk factors to centre stage.

– We will also have the power to look at cluster analyses of AD – to assess for AD subgroups in terms of genetics, imaging, biomarkers, clinical, and eventually brain tissue, over a five year period. Data driven foray into “AD subtypes” is overdue. We will pursue novel hypotheses that significant subtypes of AD exist and can be established – we will lead as “splitters”.

CCNA

• Platform Hypotheses

Subtypes of Frontotemporal dementia

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CCNA Cross-cutting theme-training

• Building capacity is an urgent priority • Need development of front line health care professionals

with expertise in cognitive impairment and dementia. • CCNA direct support- partnering commitments for a “CCNA

training partnership program” that will fund at least 22 research fellowships across Canada on an annual basis in the area of dementia and cognitive impairment.

• These “CCNA Fellows” will carry out research projects in labs and clinics across the country as part of a CCNA team.

• Novel aspects of their training: menu-driven access to p gselected areas of interdisciplinary training (e.g. business training, use of new technologies, ethics), internships and training in industry settings, and web-based learning and virtual classroom opportunities.

• Tracking of all Fellows along with postdoctoral fellows • CCNA to catalyse their transition to independent researcher.

CCNA Knowledge transfer in the CCNA

• KT will be at the centre of CCNA. We will build on the momentum achieved by the Canadian Dementia Knowledge Transfer Network (CDKTN), whose funding is ending this year. (C ), ose u d g s e d g t s yea

• Ken Rockwood, the director of CDKTN, will sit as Theme 3 leader on the CCNA and will oversee the transition of CDKTN into the KT arm of CCNA

• On-line contact between members of the Canadian dementia research community within CCNA.

• Relevant basic and clinical research developments within CCNA, new initiatives, and collaboration opportunities will all be shared online.

• Monthly newsletters to our research community. • Organizing an annual CCNA meeting• Organizing an annual CCNA meeting. • KEY: Hosting smaller workshops/webinars to bring key members of

multiple teams together on a monthly basis.• Contact with stakeholders and partners such as the various levels of

government and the community at large will be regularly maintained. S• A dementia educational initiative targeted at physicians and care

providers will be developed. • Seek out potential new researchers in dementia annually.

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CCNA Theme 1: KT Education & TrainingThe Canadian Dementia Resource and Knowledge Exchange

(CDRAKE) is a free, virtual network for exchange in dementia

• Focus on dementia specific knowledge translation

• Learning modules to foster the development of KT skills

• KT tools and resources for researchers

© CDKTN 2012

researchers

www.DementiaKT.ca

CCNA

Theme 1 Theme 3

1. Genetics

2. Inflammation4. Synapse

5. Lipoprotein

6. Exercise,Lifestyle

14. Comorbidity

15. Gerontechnology

16. Driving 18. Caregivers

19. Health CareSystem

20. Rural,Indigenous

ELSI

Women

Theme 2

3. Protein Misfoldy p

7. Vascular

8. Parkinsons9. Biomarkers

10. Cognitive Therapy

11 Neuropsychiatric13. FTD

17. Sensory Interfaceg

Key - Arrows Red – one-way interactionwithin themeBlue – two-way interactionWithin themePink – one-way Interaction across themesGreen – two-way interaction across themes

Platforms: Clinical, Biomarkers, Imaging, Neuropsychology, Genetics, Brain Banks

11. Neuropsychiatric

12. Mobility

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CCNA Cross-cutting theme-training – KTHow the teams will communicate

• Constant web-style communication of new results and opportunitiesand opportunities

• Annual meeting of researchers• Frequent small group meetings on topics and sub-

themes• Research Webinars• Integration of new researchers• Policy role

CCNAWomen and Dementia CoreCo-leads – Dr. Gillian Einstein and Dr. Mary C. Tierney, University of TorontoMembers: Dr. Barbara Sherwin and experts across Canada

Background and Rationale– Women account for 70% of cases of dementia– Women have a higher prevalence of Alzheimer’s disease, the

most common cause of dementia– Women are the primary caregivers of people with dementia-

they are more likely to outlive their male partnersthey are more likely to outlive their male partners– Sex and gender issues must be addressed in research on

neurodegenerative diseases– Propose a Women and Dementia Core

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CCNAWomen and Dementia Core

Objectives1. Ensure presence of a research program targeting women and

d i i d ti ll b ti ith th t tgender issues in dementia collaborating with the separate teams • Develop projects addressing critical issues in the etiology of dementia in women,

including for example, the effects of reproductive history, sex hormones, oophorectomy, postmenopausal hormone therapy (HT) use, breast cancer and its treatments, all of which intersect with issues pertaining to primary and secondary prevention and quality of life, including caregiver stress and isolation

2. Provide consultation to Teams on methodology in order to:• optimize assessment of gender and sex variables across the clinical cohorts and

other platforms• optimize studies across the 20 teams so that gender and sex variables are

adequately consideredy• optimize therapy programs (pharma and non-pharma) so that gender and sex

variables are adequately addressed 3. Allocate resources to achieve these objectives

CCNAWomen and Dementia Core

Elements to be incorporated in Shared Resources and Platforms

Clinical cohorts and normal control subjects• gender and sex issues in choice of subjects to study effects of sex hormones,

postmenopausal HT status, oophorectomy, etc.Imaging platform

• sample size affected by sex and genderBiosamples, CSF, genetic samples, biomarker resources, DNA

sequencing and genotypying• sex issues in sample collection, storage and analysis

Transgenic colonies• animal sex as a variable

Academic Clinical Trials and Drug Development• females must be studied in equal numbers as males in therapy trials.

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CCNAELSI (Ethical, Legal, and Social Implications of the research) consultation core

ELSI will be coordinated by Dr. Serge Gauthier, MD, FRCPCM Gill C t f St di i A iMcGill Centre for Studies in AgingDouglas Mental Health Research Institute

• National experts in legal, ethical, social issues surrounding dementia being recruited onto the “Consultation Core”• “Consultation Core” will consult with teams on all• Consultation Core will consult with teams on all ELSI issues• “Consultation Core” will advise Research Executive Committee on all pertinent issues arising, and draw up policy for CCNA.

CCNA International collaborations - Britain

• The Wellcome Trust/MRC/CIHR/DZNE neurodegeneration consortium is coming up forneurodegeneration consortium is coming up for renewal.

• Discussions with researchers from U.K.- Lovestone, Fox, regarding MRC “deep phenotyping” initiative and registry in Britain – coordination of clinical cohorts and genetics.

• A f th ll b ti ill b il bl• An array of other collaborations will become available.

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CCNA

ScientificDirector

Governance structureCIHR

ScientificAdvisory Group

KT Committee

Data/SamplepAccess

Committee

ELSICommitteeChair/ELSI

Management

Training

ResearchExecutiveCommittee

CommunityAdvisoryGroup

PlatformsCohorts

Women

Committee‐Manager‐ Business & Finance officer‐ Community officer

Theme 1Lead

Theme 2Lead

Theme 3

LeadTeams1‐6

Teams7‐13

Teams14‐20

CohortsBiosamplesGeneticsImagingBrainbankingMouse TG modelsClinical trials

CCNAMaintaining focus and priorities issue:

Start with all the teams  (that is, all approved by CIHR)Each team – milestones, and deliverables up frontEach team  milestones, and deliverables up frontTwo year end Report Carda) Deliverables (score /70) – scored for meeting milestones, and for the transformational  potential of the deliverablesScoring by the  International Scientific Advisory Groupb) Networking/Interchange (score/30) – scored for interchange with other groups,  interaction.Scored by the theme leader

The 15 teams with lowest scores are cut by 10%.The 4 teams with the highest scores are increased by 100%

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Québec Involvement in CCNA

*89 researchers whose names are attached to the CCNA EOI are based in Québec.

*6 of 20 teams within the CCNA (30%) are led or co‐led by researchers from Québec (C. Cuello, Inflammation and Nerve Growth Factors; P. Bellec, Developing New Biomarkers; S. Belleville, Cognitive Intervention and Brain Plasticity; L. Bherer, Mobility, Exercise, and Cognition; N. Phillips, Interventions at the Sensory and Cognitive Interface; H. Bergman, Integrating Dementia Patient Care into the Health Care System) 

*2 f th Sh d R Pl tf ill b b Q éb h*2 of the Shared Resource Platforms will be run by Québec researchers (CSF/Genetic samples/Biomarker Resources – J. Poirier; Imaging Platform – A. Evans, L. Collins, S. Duchesne).*The Ethical, Legal and Social Issues (ELSI) Committee will be chaired by a Québec researcher (Dr. S. Gauthier at McGill.)* The Nominated Principal Applicant  (myself) is at McGill

CCNA CCNAICRSAD FRSQ –1.

PlatformsBrain banks: 4 x 100,000 = $400,000 **

‐Banques de cerveau – Douglas–CIMAQ funding

CCNA                   and              CIMA‐Q

$400,000 Biomarkers centre-csfGenotyping Centre

Clinical Cohorts support: $2,000,000 / year

Centre Biomarqueurs‐Douglas/LDI $x/year

Cohortes cliniques a Quebec5x100K

Imaging Centre: $400,000

Administration and Meetings: $300,000

Centre NeuroimagerieEt support – quality control x/yr

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• There will be considerable synergy between CCNA and CIMA Q Imaging platform as example

Synergy between CCNA and CIMA‐Q

CIMA‐Q.‐ Imaging platform as example. • Douglas Hospital Brain Bank. CCNA will actively coordinate and co‐fund a consortium of brain banks across the country, and this will allow complementary funds for the Douglas Brain Bank to come from national as well as provincial dementia strategies.The CCNA will collaborate and build off of the clinicalThe CCNA will collaborate and build off of the clinical cohorts being established under CIMA‐Q. We hope to make the protocols comparable such that subjects enrolled into CIMA‐Q can also be at the same time included into the CCNA cohorts being established.

CCNA

Conclusion 1:This is a  huge and complex construct. Will we be able to integrate it?

Response: This is the biggest  and most ambitious grant ever for NDD in this country.•We will need to train on access to LORIS and data.•We will need to set up communication systems to keep researchers out of silos and  bind teams together.•We will need to bring in informatics and data management experts.•We will need to communicate in ways never previously necessary.W ill d t di t d ll b t•We will need to coordinate and collaborate as never  before.Leadership and management will be key.

The potential pay‐off?‐ Transformational research, break throughs,  and successful deliverables never previously possible.

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Conclusion 2-What is novel and transformative in CCNA?

• We will be constructing national platforms which are hypothesis driven and support the research program of the teams utilizing them.

• Canada is big enough and small enough:– Small enough to include the entire NDD research community- to

connect basic and clinical researchers.– Big enough to study all the Neurodegenerative Diseases- for

shared and contrasting mechanism.• We will become the first country where imaging

algorithms can be made available to clinicians and clinics in a single payer public system in real time.

• We will acknowledge and accept the “real world” dementias, embrace complexity, and study unique cohorts of mixed dementias, where multiple pathologies are at play and multiple therapies may be necessary.

CCNA Conclusion 3-What is novel and transformative in CCNA?

•We will be “lumpers”‐ studying shared mechanisms across• We will be  lumpers ‐ studying shared mechanisms across NDD, as well as “splitters”‐ enunciating subtypes of AD to emerge from cluster analyses of complex data.•We will unite highly characterized cohorts across the country with a unit for Academic Clinical Trials and Drug Development – subgroups classified by pharmacogenomics, imaging, specific biomarkers will be available for pilot studies.p• We will put KT right at the centre of the research plan•First international consortium to focus on gender and women issues.

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Thank youMerci!