www.ccna-ccnv.ca

CCNA: What students in Aging research

need to know..SPA 2021

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Disclosure slide• Faculty: Dr. Howard Chertkow

• Relationships with commercial interests:• Dr. Chertkow is co-investigator on pharma-sponsored

clinical trials of Roche, Immunotec, Lilly, Anavex Life Sciences, and Abbvie.

•Previous Industrial Support over five years for clinical trials, research studies, speakers boards, advisory boards, received from:•Pfizer Inc.•Bristol Myers Squibb• TauRx

•No Funding support has been received for this presentation

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Funding Support for Dr. Chertkow• Dr. Chertkow is supported by a research chair from

Baycrest Health Science and University of Toronto.

• Canadian Institutes for Health Research• MOP 10392• MOP 29342• Foundation Grant Award 2015-22• CIHR: PI of operating grant for CCNA,plus “BRAIN” big data

and dementia operating grant

• Weston Foundation• The 11 partners of the CCNA contribute to the national

program.

Mitigating Bias: All recommendations for clinical therapy have been suggested by the Canadian Consensus Conference on Diagnosis and Treatment of Dementia

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CCNA Basics

• Established following Canada’s commitment to tackle dementia

following G8 Summit in 2012

• Funders : CIHR (Institute of Aging) and partners

• Phase I (2014-2019) = $33 million;

• Phase II (after peer review 2019-24) = $42 million

• Research strategy to accelerate discovery, innovation and adoption of

new knowledge, directed at the prevention, treatment, and management

of the neurodegenerative diseases of aging

• Goal: To improve the quality of life of individual Canadians living

with these diseases

BC 26 AB

30 SK20 ON

118

QC 96

NB4

NS12

MB7

Phase II - 313 CCNA researchers across Canada

Key factors:• Inclusion• Collegiality• Compromise• Willingness to work together

CCNA Phase II at a Glance

PARTNER ORGANIZATIONSPROGRAMSCCNA is a Government of Canada initiative, also supported byseveral national, provincial and non-profit organizations.

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Principles of CCNA

Before CCNA

• Individual Canadian researchers receive individual grants to pursue ideas on their own in a “bottom up” fashion

What CCNA Adds

• Adds a “top down” organized attack on the coming dementia epidemic to avoid funding gaps

• Promotes collaboration and coordination: we are advancing the science strategically and faster

• Adds novel national team funding for specific Canadian “strengths”

• Enhances synergy between neurologists, geriatricians, psychiatrists, psychologists, and basic scientists working together

• Accelerates progress in basic science and therapy

• Catalyzes research on all of the dementias (all neurodegenerative diseases, NDD)

• Provides cohorts and infrastructure not accessible to single research scientists

• Connects with CLSA and scientists working on “normal aging”

CCNA Training and Capacity Building Program

Training and Capacity Building (TCB)

Program Leader: Dr. Manuel Montero-Odasso

▪ The CCNA/ASC specifically funding a set of trainees working under

the supervision of affiliated CCNA investigators

▪ Training will be enhanced by planned professional development

and networking opportunities (workshops, cafés, meetings)

▪ Novel grant support for training opportunities, workshops

▪ Developing on-line modules for “extra” training domains

▪ Building a national dementia student identity

▪ Opening this up to all students working in dementia-related fields,

whether funded directly by CCNA or not

Six Goals of the CCNA in Phase II

Understand subgroups

Develop new treatment molecules

Preventionstrategies

Allow earlier diagnosis

Innovate with new life improvement tools/strategies

Optimize health care delivery

Goal Details 10-15 Year Deliverable

1. Understand Subgroups

2. Develop New Treatment Molecules

3. Develop Prevention Strategies

4. Allow Earlier Diagnosis

5. Innovate Life Improvements

6. Optimize Health Care Delivery

Six Goals of CCNA

Elucidate cause and recognition of novel AD subgroups

Paradigm shift, new subgroup targets for therapies

Develop personalized therapy according to subgroups

New, effective validated therapies for ADRD

Develop evidence-based combination prevention strategies

Strategies for public health policy-makers to implement

Biomarker combinations to recognize subgroups before symptoms are florid

Algorithms for clinical diagnosis.

1. Hearing and vision support2. New technologies3. Driverless cars4. Reduced multi-morbidity5. Reduced stigma strategies6. Specific strategies for indigenous populations

Applied to produce better quality of life in individuals with ADRD

1. Delineate best clinical practices across provinces2. Optimize care for dementia in rural setting3.Optimize care for dementia in Indigenous population

Knowledge translation into clinical practice for improved outcomes

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About the Teams

• All teams are national (members from multiple institutions) and topic-based

• Teams play to “Canadian research strengths”

• Five-year research program and budget of the team with deliverables

• Annual meetings to promote interaction and synergy

• Promotion of young researchers: 17 young Canadian researchers in leadership positions

• Leveraging of funding with other agencies

• 14 of the teams will leverage data from the COMPASS-ND cohort

COMPASS-ND = “COMPrehensive ASSessment of Neurodegenerative Diseases”

CCNA Phase II Teams and LeadersTheme 1: Primary PreventionBasic Mechanisms & Prevention of Cognitive Impairment and DementiaLeaders: JoAnne McLaurin (U. of Toronto), Edward Fon (McGill U.)

Team 1 - Clinical Genetics and Gene Discovery

Leaders: Ekaterina Rogaeva (U. of Toronto), Ziv Gan-Or (McGill U.)

Team 4 - Investigating Mechanisms of Alzheimer Disease to

Develop New TherapiesLeader: Robert Bartha (Western)

Team 2 - Inflammation and Nerve Growth Factors

Leaders: Pedro Rosa-Neto (McGill U.), Margaret Fahnestock (McMaster U.)

Team 5 - Diet and Prevention

Leader: Guylaine Ferland (U. de Montréal)

Team 3 - Protein Misfolding

Leader: Neil Cashman (U. of British Columbia)

Theme 2: Treatment and Secondary PreventionDiagnostics & Treatments Leaders: Sandra Black, Mario Masellis (U. of Toronto)

Team 6 – Sleep and Dementia

Leaders: Julie Carrier (U. de Montréal), Andrew Lim (U. of Toronto)

Team 10 - Cognitive Intervention, Reserve and Brain Plasticity

Leaders: Sylvie Belleville (U. de Montréal), Nicole Anderson (U. of Toronto)

Team 7 - Vascular Illness and its Impact on NDD

Leaders: Eric Smith (U. Calgary), Bojana Stefanovic (U. of Toronto)

Team 11 - Neuropsychiatric Symptoms

Leaders: Nathan Herrmann, Krista Lanctôt (U. of Toronto), Dallas Seitz (Queen’s)

Team 8 - Lewy Bodies (PDD and LBD), Aging and Dementia

Leader: Richard Camicioli (U. of Alberta)

Team 12 - Mobility, Exercise and Cognition

Leaders: Manuel Montero-Odasso (Western), Louis Bherer (Concordia U.)

Team 9 - Developing New Biomarkers

Leaders: Roger Dixon (U. of Alberta), Pierre Bellec (U. de Montréal)

Team 13 - Frontotemporal Dementia

Leader: Robin Hsiung (U. of British Columbia), Simon Ducharme (McGill U.)

Theme 3: Quality of LifeDisease Management & Quality of LifeLeader: Katherine McGilton (U. of Toronto)

Team 14 - Multi-Morbidity and Dementia

Leader: Melissa Andrew (Dalhousie U.)

Team 17 - Interventions at the Sensory and Cognitive Interface

Leaders: Natalie Phillips (Concordia), Walter Wittich (U. de Montréal)

Team 15 - Issues in Dementia Care for Rural populations

Leaders: Megan O’Connell, Debra Morgan (U. of Saskatchewan)

Team 18 - Issues in Dementia Care for Indigenous Populations

Leader: Jennifer Walker (Laurentian U.), Lindsay Crowshoe (Ucalgary)

Team 16 - Driving and Dementia

Leaders: Gary Naglie, Mark Rapoport (U. of Toronto)

Team 19 - Integrating Dementia Patient Care into the Health Care System

Leaders: Howard Bergman, Isabelle Vedel (McGill U.)

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Synergies Built Over Time

CCNA promotes cross-

fertilization, synergy, and

interaction between

teams

Neurodegenerative Disease Groups

Frontotemporal dementia

Alzheimer’s

Parkinson’s

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CCNA allows

comparison between

Neurodegenerative

Disease groups

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Women, Sex, Gender and Dementia Cross-cutting Program

First national dementia initiative to bring the “sex and gender lens” to all aspects of dementia research

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Issues in Indigenous Dementia Care

1.4 million Indigenous Peoples in Canada have 3X the incidence of dementia in old age relative to other Canadians

• Why?

➢ Genetics?

➢ Stress? Poverty?

➢ Vascular disease and vascular risk factors?

➢ Epigenetics to be worked out?

➢ Other factors?

• Can we find more accurate ways to detect and diagnose dementia in this population?: Development of CICA - The Canadian Indigenous Cognitive Assessment

• Can we find ways to combine “Western” medicine approaches with traditional medicine to best give treatment?

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Promotion of Research in Indigenous Populations

Dr. Jennifer WalkerCRC Chair In Indigenous Health

School of Rural and Northern HealthLaurentian University

CCNA Lead of ICH

Indigenous Cognitive Health (ICH) Team and Program

Goals:

• Building Capacity - we need more researchers from Indigenous communities

• Building appropriate training

• Building our ability to do research in Indigenous communities, and sensitivity to cultural issues

• Interaction with all the teams

Impact of CCNA over Past 7 Years

General Existence Effects

• CCNA has created a national dementia research community

in Canada now based on interactive and collaborating teams

rather than individual researchers

• Impressive interaction at meetings, webinars – there is really

now a Canadian dementia research community

• Leveraging has occurred

• Synergy has occurred

COMPASS-ND Information Leaflet

Recruitment at 29 sites across Canada

Recruitment Targets for COMPASS-ND

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Diagnosis Number

Subjective Cognitive Impairment 200

Mild Cognitive Impairment (MCI) 300

Subcortical Ischemic Vascular MCI 200

Mild AD 150

Dementia of mixed etiology 200

Lewy Body Disease/Parkinson's

Dementia/Parkinson's MCI200

Frontotemporal dementia spectrum

(behavioural variant, primary progressive aphasia, progressive supranuclear palsy, corticobasal syndrome)

60

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MCI

SCI

AD

LBD

FTDVCI

Mixed

If narrowly-focused criteria,

will produce homogeneous

groups that represent a

small fraction of the

dementia population

May exclude co-morbidities

and mixed dementias

ADNI example

Choice of Inclusion and Exclusion Criteria

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Choice of Inclusion and Exclusion Criteria

MCI

SCI

AD

LBD

FTD

VCI

Mixed

Broadly inclusive

criteria will produce

heterogeneous groups

that cover the entire

dementia population

Include almost all co-

morbidities and mixed

dementias

More ecological and

“real-life” dementia

=Approach we are

using in COMPASS-

ND

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Clinical Cohorts Study Flow

1. Recruitment

into CCNA

2. Informed

Consent

Signed

3. History,

Physical &

Cognitive

Evaluation

▪ Assess inclusion/exclusion criteria

▪ Demographics, medical/surgical history

▪ Sensory Assessment (Hearing, Vision,

Olfaction)

▪ Grip strength & Gait Assessment▪ Physical/Neurological examination

4.

Questionnaires

▪ General and Mental health

▪ Social Network

▪ Nutrition

▪ Sleep

▪ Physical Activity

5.

Psychometric

Testing▪ National battery

6. Biosamples

6A. Blood 6B. Saliva and

fecal sample6C. CSF

7. Sample

Processing

8. Sample

Shipping to

Biobank

9. MRI Imaging

Acquisition

10. MRI IT &

Databasing

C-Brain LORIS

11. Brain

Donation

Program and

follow-up in

Clinic

Repository /download

Data types: behavior, clinical, imaging, genetic

On-line remote MRI browser

Data querying GUI (volumes, surfaces, behavior)

e.g. NIH database of normal brain development

Acquisition management

Project management tools

Double data entry/ range checking

Automated 3D image QC

Java-based remote 3D image QC

150 behavioral instruments

MANTIS bug-tracking

Analysis pipelines

External pipelines for analysis (MNI, SPM, FSL, LONI,

AFNI). Integrated with grid-computing networks (CBRAIN,

NeuGrid)

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80 man-years of development

Web-based, secure data transfer of multi-site data

Generalized open-source MYSQL architecture - flexible,

extensible

Applications in development, neurodegeneration (US, Europe,

Asia)

LORIS

LORIS Database

Clinical Visit – Test Battery

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Core Cognitive Battery for Clinical Cohorts

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=in CLSA

=in ONDRI

=in both CIMA-Q &

ONDRI

Tests used in other groups

=in CIMA-Q

=in both CLSA & ONDRI

=in both CLSA & CIMA-Q

Pre-Morbid IQ WAIS III Vocabulary

Memory RAVLT

Brief Visuospatial Memory test

CCNA-CIMA-Q Face-Name Association

Digit Symbol incidental recall

Envelope test

Executive function DKEFS Colour-Word Interference

DKEFS Phonemic Fluency

CCNA-CIMA-Q sentence inhibition task

Trailmaking

Reaction time test

Language Animal Fluency

NACC Language battery

Attention/Psychomotor speed WAIS-III Digit Symbol-Coding

Digit span F & B

General MoCA

Visuoperceptual Line Orientation

Object Decision test

VOSP letter completion

=in CLSA, CIMA-Q & ONDRI

CCNA Genetics in COMPASS-ND

Genetics Team:

Ekaterina

Rogaeva/Ziv Gan-Or

Kathy

Siminovitch-Clinical

Genomics Centre, Mt.

Sinai, Toronto

▪ Infinium Global Screening Array-24 v3.0 BeadChip for each subject- will analyze 210,000 neurological SNPs.

▪ Data stored in LORIS

▪ Pax tube for RNA-Seq

▪ Epigenomics

Genetics Platform

MRI Imaging

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CDIPCanadian Dementia Imaging Protocol

www.cdip-pcid.ca

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COMPASS-ND will provide

Biosamples for all Canadian

researchers:

▪ Plasma/serum

▪ Saliva

▪ CSF

▪ Urine

▪ Microbiome (fecal, oral swabs)

(Being analyzed by Dr.

Brett Finlay and colleagues at

UBC)

Biosample Storage and Shipping

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▪ Aliquoted biosamples are sent from

sites to the biorepository in

Edmonton via cryoshipper on a

quarterly basis.

▪ Frozen, to be accessed and used

by Canadian scientists and their

students over coming years.

Blood Core Analyses

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▪ General health

• Complete Blood Count• Electrolytes (Na, K, CL, bicarbonate)

• Creatinine, Urea• Liver function (AST, ALT, ALP, bilirubin)• B12

• Calcium• Albumin

• 25-OH vitamin D level• Ferritin

• Glycosylated Hemoglobin

• Insulin level• Glucose

• Homocysteine -increased plasma

homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer's disease

• Cystatin-C-variation in an amyloidogenic cysteine protease inhibitor affect AD risk

• VEGF Vascular endothelial growth factor –role in angiogenesis, neuroprotection.

▪ Inflammation

• Insulin like growth factor-1

• Tumour necrosis factor-alpha

• Interleukin-6

• C-reactive protein

▪ Lipidomics

• Total Cholesterol

• Triglycerides

• HDL-C

• LDL-C

• apoA-1

• apoB

▪ Synaptic function, plasticity

• BDNF levels

(Being carried out at Jewish General Hospital Clinical Labs)

New: Simoa Serum samples for NfL, serum phospho-tau181, Abeta42/40,GFAP- lab of Dr. Cheryl Wellington, UBC

Blood Core Analyses (cont’d.)

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Hormones Oxidative Stress

• ACTH

• Androstenedione

• Luteinizing Hormone

• FSH

• DHEA-S

• Estrone Sulphate

• Testosterone (total)

• DHT

• Estrone

• Estradiol

• Prolactin

• Cortisol

• SHBG

• TSH

• Vitamin E

• Alpha-1 antitrypsin

• Biliverdin

• ferritin

CSF Core Analyses

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(To be carried out at Judes Poirier’s laboratory at Douglas Mental

Health University Institute)

Abeta 42

Total tau

Phospho tau 181

Alpha Synuclein

Microbiome Analyses

(Being carried out by B. MacVicar and B. Finlay at UBC)

▪ Alteration in the human microbiome in gut and mouth may be an unappreciated factor in various NDD. New frontier.

▪ Reflects inflammatory state

▪ GI tract bacteria can influence host innate-immune, neuroinflammatory-, neuromodulatory- and neurotransmission-functions

▪ Mouth biology and AD risk?

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Big Data on Dementia ̶ COMPASS-ND

COMPASS-ND will provide deeply phenotyped cohorts through:

• Extensive clinical information gathered

• Genetic information: Infinium Global Screening Array-24 v3.0 BeadChip

for each subject. = 240,000 SNP’s (all known neurological genes)

• 3T MRI-standardized MRI imaging protocol via Canadian Dementia Imaging Platform (CDIP)

• Baseline volumetrics, hippocampal volumes

• Neuropsychology → national battery

• Microbiome assessment

• Longitudinal follow-up planned

• Serum biomarkers

• Brain donation program, standardized neuropathology protocol (eventually brain tissue will be available for studies)

5/4/2021

COMPASS-ND Data

• First 400 subjects now released on LORIS database.

• Data on LORIS will be released regularly over coming year.

• Completion of subject recruitment December 2021.

• Release of full dataset to CCNA members by Feb 2022

• There are a set of 100 “quarantined projects” already being written by CCNA writing groups…privileged priority.

• All other topics/questions can be addressed/written by Canadian scientists and their students. 12 months after full release of data there will be “open science” availability to international community.

• Planned longitudinal follow-up of all subjects after three years.

• Brain bank and brain collection protocol now established at Douglas Mental Health University Institute.

• We encourage SPA students to look into LORIS accounts via CCNA member labs.

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COMPASS-ND will provide a

normative comparison group -

elderly subjects screened for

normal cognition - screen out

MCI, SCI…no memory

complaints:

▪ Planned 200 MRI studies within

CLSA sub-cohort (E. Smith)

▪ Planned normal CCNA neuropsych

normative group of 600 (R. Dixon,

N. Phillips to coordinate this)

What we can get from a normal comparison group:

▪ Norms for MRI volumes

▪ Imaging norms

▪ Canadian CCNA neuropsychology battery norms

▪ Biosamples - norms for CSF, for saliva

metabolomics, …

All in appropriate elderly Canadian populations

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Conclusion

•Many opportunities for students interested in dementia within CCNA•Students can join via their lab/faculty member•Some students have joined CCNA independently•Networking, mentorship, access to data and samples

www.ccna-ccnv.ca