The Comprehensive Assessment of Neurodegeneration and Dementia Study
Conditions: Dementia, Mild Cognitive Impairment (MCI), Subjective Cognitive Impairment, Parkinson's Disease (PD), Lewy Body Disease(LBD), Mixed Dementia, Frontotemporal Dementia (FTD), Alzheimer Disease (AD), Cognitively Unimpaired, Subjective Cognitive Decline (SCD)
Sponsor: McGill University

COMPASS-ND Study Protocol 
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PROTOCOL FOR THE  
COMPREHENSIVE ASSESSMENT OF 
NEURODEGENERATION AND DEMENTIA 
(COMPASS-ND) STUDY  
CCNA-2015 
The Canadian Consortium for Neurodegeneration in Aging 
Protocol Version [9.6] [15-May-2017] 
Sponsor: Dr. Howard Chertkow 
Lady Davis Institute 
Jewish General Hospital 
3755 Chemin de la Côte Ste-Catherine 
Montréal, Québec 
H3T 1E2 
*Confidentially Statement
The information contained in this document is privileged and confidential.  Any disclosure is prohibited unless such disclosure 
is required by applicable laws and regulations.  Persons to whom the information is disclosed must be informed that the 
information is privileged and confidential and it may not be further disclosed by them.

 
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PROTOCOL APPROVAL PAGE 
 
CCNA2015 
 
The Canadian Consortium for Neurodegeneration in Aging 
         
 
Protocol Version [9.6] [15-May-2017] 
 
 
 
 
                                                                                                 
 
 
                                     
Name                                
 
 
 
  
 
 
Date 
 
 
 
 
                                                                                                                                                                                     
Title, Affiliation 
 
 
 
 
 
 
 
 

 
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INVESTIGATOR AGREEMENT 
The Canadian Consortium for Neurodegeneration in Aging 
 
I have read the protocol and agree that it contains all necessary details for carrying out this study.  I undertake 
to conduct this trial within the time designated. 
I understand that all patient information in connection with this trial is considered confidential information. 
The information includes the clinical protocol, the Case Report Form, technical methodology and basic 
scientific data. 
By my signature below, I hereby attest that I have read, understood and agree to abide by all conditions, 
instructions and restrictions contained in the above protocol.  
 
Investigator: 
 
 
 
 
 
 
 
 
Name 
Signature 
Date 
 
 
 
 
Name and Address of Investigational Site: 
 
 
    
 

 
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TABLE OF CONTENTS   
TIME AND EVENTS SCHEDULE     7 
PROTOCOL SYNOPSIS 
8   
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS   9 
1    INTRODUCTION   11 
1.1    BACKGROUND    11 
1.2    JUSTIFICATION OF PLATFORMS    12 
1.3    RATIONALE FOR STUDY 
14 
1.4    DESCRIPTION OF PLATFORMS 15 
2    OBJECTIVES/ HYPOTHESES    17 
2.1    PRIMARY HYPOTHESIS    17 
2.2    PRIMARY OBJECTIVE    17 
2.3    GENERAL STUDY OBJECTIVES    17 
2.4    DISEASE SPECIFIC OBJECTIVES    17 
3    STUDY DESIGN    19 
4    STUDY POPULATION    19 
4.1    GENERAL INCLUSION CRITERIA (ALL CONDITIONS)    20 
4.2    CONDITION SPECIFIC INCLUSION CRITERIA   20 
4.3    PLATFORM SPECIFIC INCLUSION CRITERIA   21 
4.3.1    NEUROPSYCHOLOGY    21 
4.3.2    NEUROIMAGING    22 
4.3.3    GENOMICS    22 
4.4    GENERAL EXCLUSION CRITERIA (ALL CONDITIONS)    22 
4.5    CONDITION SPECIFIC EXCLUSION CRITERIA    22 
4.6    PLATFORM SPECIFIC EXCLUSION CRITERIA    23 
4.6.1    NEUROPSYCHOLOGY    23 
4.6.2    NEUROIMAGING    23 
4.6.3    GENOMICS    23 
5    STUDY PROCEDURES AT EACH VISIT    23 
5.1    VISIT 1: SCREENING AND DEMOGRAPHICS    23 
5.2    SELF-ADMINISTERED PROCEDURES AND QUESTIONNAIRES TO BE COMPLETED 
BETWEEN VISITS 1 AND 2    24 
5.3    VISIT 2: CLINICAL AND PHYSICAL ASSESSMENT    25 
5.4    VISIT 3: NEUROPSYCHOLOGICAL ASSESSMENT    26 
5.5    VISIT 4: MRI    26 

 
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5.6    VISIT 5: LUMBAR PUNCTURE    27 
5.7    FOLLOW-UP 27 
5.8    ADD ON STUDIES 27 
5.9    STUDY PROCEDURE DESCRIPTIONS 29 
5.10 DATA STORAGE  47 
5.11    PILOT TESTING 47 
5.12    PROCEDURE TRAINING  47 
6 ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING  48 
 
6.1    DEFINITIONS     48 
 
 
 
6.1.1 ADVERSE EVENT  48 
 
 
 
6.1.2 SERIOUS ADVERSE EVENT  48 
 
6.2     CLASSIFICATION   49 
 
 
 
6.2.1 SEVERITY   49 
 
 
 
6.2.2 ATTRIBUTION   49 
 
6.3     PROCEDURES FOR AE AND SAE REPORTING  50 
 
 
 
6.3.1 MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION  50     
7 STATISTICAL METHODS    50 
6.1    INTERIM ANALYSIS    52 
6.2    HANDLING OF MISSING, UNUSED AND SPURIOUS DATA    52 
8    ETHICAL CONSIDERATIONS    52 
78.1    INCIDENTAL FINDINGS 52 
8.2     INSTITUTIONAL REVIEW BOARD    52 
8.3    INFORMED CONSENT    52 
8.4    CONFIDENTIALITY OF SUBJECT RECORDS   52 
8.5    PARTICIPANT BURDEN   53 
8    ADMINISTRATIVE REQUIREMENTS    54 
9.1    PROTOCOL AMENDMENTS    54 
9.2    PREMATURE TERMINATION OF THE TRIAL    54 
9.3    COMPLETION OF CASE REPORT FORMS    54 
9.4    ACCESS TO SOURCE DATA/DOCUMENTS 55 
9.4.1    DATA QUALITY ASSURANCE    55 
9.4.2    RETENTION OF STUDY DOCUMENTS    55 
9.5    PUBLICATION AND DATA ACCESS POLICY    56 
9.6    BIOLOGICAL SAMPLE ACCESS POLICY 56 
9.7    CONFIDENTIALITY    57 
9.8    FINANCING 57 
 
REFERENCES    57 

 
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APPENDIX A – Criteria for Subjective Cognitive Impairment   64 
APPENDIX B – NIA-AA Clinical Criteria for the Diagnosis of MCI due to AD   64 
Appendix C - Criteria for Subcortical Ischemic Vascular Mild Cognitive Impairment   65 
Appendix D - NIA-AA Diagnostic Criteria for Alzheimer’s disease   66 
Appendix E – Criteria for Mixed Dementia 67 
Appendix F  – Revised Criteria for clinical diagnosis of Dementia with Lewy Bodies  68 
Appendix G - Criteria for diagnosis of probable Parkinson’s Disease Dementia 69 
Appendix H- Criteria for Mild Cognitive Impairment in Parkinson’s Disease 69 
Appendix I – Diagnostic criteria for FTD subgroups 70 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TIME AND EVENTS SCHEDULE 
 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
… 
k 
Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Hearing & Vision Acuity 
X 
 
 
 
 
 
X 
 
 
 
 
CDR* 
X 
 
 
 
 
 
 
 
 
 
 
Logical Memory 1 & 2* 
X 
 
 
 
 
 
 
 
 
 
 
CERAD word list recall* 
X 
 
 
 
 
 
 
 
 
 
 
MoCA 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Lawton-Brody IADL scale* 
X 
 
 
 
 
 
 
 
 
 
 
Benson Figure Copy & Recall@ 
X 
 
 
 
 
 
 
 
 
 
 
Mini-Mental Status Exam© 
X 
 
 
 
 
 
 
 
 
 
 
Disease-Specific Inclusion & Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Clinical PPA Features / Clinical bvFTD Features μ 
X 
 
 
 
 
 
 
 
 
 
 
General Sociodemographic Information¥ 
X 
 
 
 
 
 
 
 
 
 
 
General Health Questionnaires¥ 
X 
X 
 
 
 
 
X  
 
 
 
Vital Signs 
 
X 
 
 
 
 
X 
 
 
 
 
Blood, saliva, & urine collection 
 
X 
 
 
 
 
X 
 
 
 
 
Oral Swab 
 
X 
 
 
 
 
X 
 
 
 
 
Fecal sample collection (optional)€ 
 
X 
 
 
 
 
X 
 
 
 
 
Medical/Surgical History 
 
X 
 
 
 
 
X 
 
 
 
 
Concomitant Medications 
 
X 
 
 
 
 
X 
 
 
 
 
Cognitive/Neurological Symptoms 
 
X 
 
 
 
 
X 
 
 
 
 
Physical/Neurological Exam 
 
X 
 
 
 
 
X 
 
 
 
 
Hachinski Ischemic Scale 
 
X 
 
 
 
 
X 
 
 
 
 
Disease Specific Questionnaires¥ 
 
X 
 
 
 
 
X 
 
 
 
 
Neuropsychological assessment,  
 
 
X 
  
 
X  
 
 
 
MRI£ 
 
 
 
X 
 
 
X 
 
 
 
 
Lumbar Puncture (optional) 
 
 
 
 
X 
 
X 
 
 
 
 
Annual Telephone Follow-up 
 
 
 
 
 
X 
 
X 
X 
X 
X 
2 year follow-up 
 
 
 
 
 
 
X 
 
 
 
 
Brain Donation Consent (optional) 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
*: Administered to SCI, MCI, V-MCI, AD, & Mixed Dementia groups only. 
@: Administered to LBD, PDD, PD-MCI, and FTD spectrum groups only. 
©: Administered to PD participants only 
μ: Administered to FTD spectrum participants only 
¥: Part of these questionnaires are completed by the participant & informant at home. 
£: Can be scheduled for anytime in the 3 month period, but must be before the lumbar puncture if consented to. 
€: Sample to be collected by participant at home. 
 
 
 
 

 
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PROTOCOL SYNOPSIS 
Title 
The Comprehensive Assessment of Neurodegeneration and Dementia study 
Sponsor 
The Canadian Consortium on Neurodegeneration in Aging 
Objectives 
PRIMARY OBJECTIVE 
The primary objective is to create a pan-Canadian set of cohorts of subjects with various cognitive 
conditions that will, for the first time, integrate a wide range of experimental, clinical, imaging, and genetic 
expertise to specifically address the causes, identification, management, treatment, and prevention of these 
conditions in the aging population. 
SECONDARY OBJECTIVE 
To create a pan-Canadian set of cohorts of patients with various cognitive conditions wherein the 
biospecimens, imaging, genetics, and brain donations will support the research agendas of 20 associated 
national research teams. 
 
Study Design 
This is a 5-year observational study. Sixteen-hundred (1600) subjects, between the ages of 50 and 90,years 
old, with SCI, MCI, V-MCI, AD, Mixed dementia, LBD, PDD, PD-MCI and FTD, will be enrolled into this 
study from up to 30 centres across Canada. All subjects involved in the study will undergo rigorous 
evaluations at baseline, including clinical assessment, neuropsychological assessment, genomics and 
neuroimaging. Biosamples from blood, saliva, urine, fecal matter, buccal cells and cerebrospinal fluid will 
be collected, stored, and analyzed. Basic follow-up determining if there has been any change in their 
diagnosis will be carried out annually and longitudinal re-evaluation will be carried out after two years.  
 
Study Population 
Subjects must meet the inclusion/exclusion criteria for their condition and then also meet the 
inclusion/exclusion criteria for each platform testing. If patients do not meet the criteria for a specific 
platform they may still participate in the study as long as a minimal amount of data (i.e., diagnosis, 
demographics and MRI) is collected on them. Sex distribution of the cohort will be monitored to insure 
sufficient numbers to test for sex related differences in key outcome studies.  
 
 
 
 
 
 
 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
 
AD 
Alzheimer’s Disease 
ADL 
Activities of Daily Living 
ADNI 
The Alzheimer’s Disease Neuroimaging Initiative  
ALP 
Alkaline phosphatase 
ALT 
Alanine Transaminase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Transaminase 
BAIVI 
Brain Atrophy Ischemic Vasculopathy Index 
BIS 
Behavioral Inhibition Scale 
bvFTD 
Behavioral variant of frontotemporal degeneration 
BVMT 
Brief Visuospatial Memory Test 
C5R 
The Consortium of Canadian Centres for Clinical Cognitive Research 
CBC 
Complete Blood Count 
CBS/CBD 
Cortical basal syndrome/autopsy confirmed cortical basal degeneration 
CDIP 
Canadian Dementia Imaging Protocol 
CERAD 
Consortium to Establish a Registry for Alzheimer’s Disease 
CIHR 
Canadian Institutes of Health Research 
CIMA-Q 
Consortium pour l’identification précoce du Maladie d’Alzheimer du Québec 
COWAT 
Controlled Oral Word Association Test 
CRF 
Case Report Form 
CSF 
cerebrospinal fluid 
CVD 
Cardiovascular Disease 
DCF 
Data Clarification Form 
DKEFS 
Delis-Kaplan Executive Function System 
DNA 
Deoxyribonucleic acid 
DTI 
Diffusion Tensor Imaging 
eCRF 
Electronic case report form 
EOS 
End of Study 
eQTL 
Expression Quantitative Trait Loci 
FA 
Fractional Anisotrophy 
FLAIR 
Fluid Attenuation inversion recovery  
fMRI 
Functional MRI 
FSL 
FMRIB Software Library 
FTD 
Frontotemporal dementia 
FTLD 
Frontotemporal Lobar Degeneration 
GATK 
Genome Analysis Toolkit 
GAD-7 
Generalized Anxiety Disorder 7-item scale 
GCP 
Good Clinical Practice 
GDS-30 
Geriatric Depression Scale 
GWAS 
Genome-Wide Association Studies 
HEENT 
Head, eyes, ears, nose and throat 
iADL 
Instrumental Activities of Daily Living 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medication Journal Editors 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRI 
Interpersonal Reactivity Index 
K-M 
Kaplan-Meier 
LBD 
Lewy Body Dementia 

 
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LONI 
Laboratory of NeuroImaging 
MANOVA 
Multivariate Analysis of Variance 
MCI 
Mild Cognitive Impairment 
MDS-UPDRS 
Unified Parkinson’s Disease rating score 
MITNEC 
Medical Imaging Trial Network of Canada 
MMSE 
Mini Mental State Examination 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging 
NDD 
Neurodegenerative Disease 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NIHSS 
National Institutes  of Health Stroke Scale 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
OBI 
Ontario Brain Institute 
ONDRI 
Ontario Neurodegenerative Research Initiative 
PD 
Parkinson’s Disease 
PD/T2 
Proton Density  
PDD 
Parkinson’s with dementia 
PD-MCI 
Mild Cognitive Impairment in Parkinson’s Disease 
PD-NCI 
Parkinson’s Disease with no cognitive impairment 
PDQ-39 
Parkinson’s Disease Questionnaire 
PET 
Positron emission tomography 
PNFA 
Progressive Non-fluent Aphasia 
PPA 
Primary progressive aphasia 
PSP 
Progressive supranuclear palsy 
PURE-MIND 
The Prospective Urban Rural Epidemiologic 
QA 
Quality Assurance 
QC 
Quality Control 
QLS 
quasi-elastic light scattering 
QoL 
Quality of Life 
qPCR 
Quantitative Polymerase chain reaction 
RNA 
Ribonucleic Acid 
RS-MS 
Revised Self-Monitoring Scale 
S & E 
Schwab & England 
SCI 
Subjective Cognitive Impairment 
SD 
Semantic Dementia 
SNPs 
Single nucleotide polymorphism 
T (Imaging) 
Tesla 
TIA 
Transient ischemic attack 
TSH 
Thyroid-Stimulating Hormone 
V-MCI 
Vascular Mild Cognitive Impairment 
VEGF 
Vascular Endothelia Growth Factor 
Vfi 
Verbal fluency Index 
VOSP 
Visual Object Space Perception 
WAIS 
Wechsler Adult Intelligence Scale 
WASI 
Wechsler Abbreviated Scale of Intelligence 
WES 
Whole exome sequencing 
WHO 
World Health Organization 
WMD 
White matter disease 
 
 
 

 
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1. INTRODUCTION 
1.1. BACKGROUND 
Four years ago, a demographic milestone was reached across North America – the baby 
boomers began to become senior citizens. The proportion of the Canadian population over 
age 65 will climb from 11.6% in 1991 to 16% in 2016, and 23% in 2041. As this 
demographic evolution occurs, the concerns and problems of elderly people will take centre 
stage in Canada. Various reports, most notably “Rising Tide: The Impact of Dementia in 
Canada” have delineated the scope of the dementia problem.  Currently 500,000 Canadians 
have Alzheimer Disease (AD), and this will rise to 1,100,000 within a generation. The 
annual cost to the country is now 15 billion dollars. This will rise to 153 billion dollars 
within a generation1.  A call to action has come internationally from the World Health 
Organization (WHO)2. This report (March 2012) stresses that each country should 
determine a priority research agenda with research evidence underpinning policy and 
clinical actions. Multidisciplinary research is essential and an appropriate balance must be 
struck between basic research on disease mechanisms and applied research dealing with 
pharmacologic and non-pharmacologic approaches to the prevention, treatment, and/ or 
care of those with dementia. The WHO report stresses that significantly more research is 
needed to better understand the causes of dementia and how and when lifestyle factors 
influence the risk of developing it. As a response, the Canadian Institutes for Health 
Research (CIHR) in Canada has organized an “International Collaborative Research 
Strategy for Alzheimer’s Disease” as one of the CIHR’s Roadmap Signature Initiatives3. 
Its focus is AD and related neurodegenerative disorders (NDD). This initiative has 
established the Canadian Consortium on Neurodegeneration and Aging (CCNA) which 
will be the major vehicle to coordinate and strengthen Canadian research on AD and NDD. 
It is intended to foster innovative and collaborative research across Canada.  
NDD refers to a class of disorders characterized by the progressive deterioration of thinking 
ability in areas such as memory, function, and behaviour as the brain becomes 
damaged1.  This study will unite the tremendous resources of clinician researchers, basic 
scientists, social scientists, and allied professionals from across Canada to explore the 
causes and improve the identification, management, treatment and prevention of NDD that 
lead to impairments in memory, cognition, and function. 
AD is the most common form of neurodegenerative disease and contributes to 
approximately two-thirds of cases in older adults. It is a progressive degenerative and fatal 
brain disease1. Vascular dementia (VaD) accounts for 20% of dementia cases, second only 
to AD4. While vascular cognitive impairment is not infrequently the result of a stroke, it is 
more often not preceded by a discrete cerebrovascular event5. Mixed dementia – cognitive 
impairment where multiple brain pathologies are present – represents the most prevalent 
type of cognitive impairment6. FTD (frontotemporal dementia) accounts for 20% of pre-
senile dementia cases. Symptoms can begin to appear on average around 45-65 years of 
age7. Symptoms of FTD progress at a rapid, steady rate. Patients suffering from the disease 
can survive between 2-10 years8. Dementia with Lewy Bodies (DLB) accounts for 10-15% 
of cases of NDD. 

 
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There is an urgency to be able to identify those who will develop NDD before function is 
compromised, so that treatment may be enacted to maintain independence. It is well 
established that Mild Cognitive Impairment (MCI) represents a significant risk factor for 
dementia9, but it remains a subject for debate what proportion of patients with MCI will 
eventually develop dementia10,11. In recent years there has been increased interest in those 
who have a complaint about their cognition, but no objective impairment. This population 
has been referred as having subjective cognitive impairment (SCI), and there is evidence 
that they are at increased risk of developing dementia12,13 
Therapeutic approaches that are directed at single biological mechanisms or targets may 
be inadequate give the complexity of these multifaceted neurodegenerative disorders14. 
Successful treatment may require a cocktail approach as has been applied in cancer. These 
may vary depending on the stage of the disorder being treated, the genetic predispositions 
discovered to be contributing to an individual’s disease (i.e. the need to consider the role 
of “personalized medicine” with respect to genetic determinants, sex and gendered lives) 
and the possible role of mixed pathologies.  
This study aims to lead to an understanding of the bases, commonalities, and distinguishing 
characteristics of these often devastating conditions.  Through a single unprecedented 
collaboration studying SCI, VCI, AD/Mild Cognitive Impairment (MCI), Mixed 
Dementia, FTD, LBD, we aim to develop and evaluate proactive treatment strategies 
designed to meaningfully modify the course of each.  
By employing a standardized patient approach, we can meaningfully conduct cross-
comparisons amongst these conditions.  Six assessment platforms have been set up to study 
the diseases over 5 years. They are as follows: 
a) Clinical - Demographics, history, and physical exam 
b) Clinical - Neuropsychology 
c) Neuroimaging 
d) Biosamples 
e) Genomics 
f) Brain donation and Neuropathology 
 
1.2 JUSTIFICATIONS OF PLATFORMS 
Clinical (Demographics, history, and physical exam) 
As with all medical conditions, a person’s life experience and past and current overall 
health status can contribute greatly to understanding how neurodegenerative diseases 
emerge and express themselves within an individual. An extensive clinical work-up will 
be administered including medical & social history, physical exam and past & current 

 
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medications, as well as gait assessment, and questions related to cognitive reserve and 
reproductive history. 
Clinical (Neuropsychology) 
Cognitive changes are core features of many neurodegenerative diseases. Specific patterns 
of cognitive strengths and weaknesses, quantified by neuropsychological testing, have been 
shown to help distinguish AD, FTD, Lewy Body Dementia (LBD), and other NDD from 
normal aging and each other. However, the full extent of these differences is still being 
researched as well as their earliest neuropsychological manifestations. We will be 
administering a series of tests assessing multiple domains of cognitive function with the 
goal of furthering our understanding of these diseases and how they affect cognition. 
Neuropsychological testing has minimal risks limited to fatigue and/or frustration 
associated with participating in cognitively demanding testing.  
Neuroimaging 
Over the past decade, magnetic resonance imaging (MRI) and more recently positron 
emission tomography (PET) has taken a greater role in the management of patients with 
dementia15. For example, after diagnosis imaging can be used to increase the certainty that 
AD pathology underlies dementia.  Prior to diagnosis, imaging can be used to establish the 
etiology of disease and may help predict progression to dementia.  Finally, in the pre-
symptomatic phase, markers of amyloid accumulation and neurodegeneration can be used 
to establish pathophysiological changes in the brain16. The benefit of imaging will be in 
the form of the generation of new knowledge related to differential anatomical changes 
among the study cohorts. 
 
Biosamples 
 
Even though, neurodegenerative diseases primarily impact the brain, they also have effects 
on the rest of the body and these effects may be measured in blood17, CSF18, and saliva19. 
Buccal swabs can give an indication of telomere length20. Fecal samples can also be 
collected to study the microbiome21. The importance of this is that it can help us to better 
understand the mechanisms and effects of neurodegeneration, as well as provide potential 
diagnostic markers, which may aid in earlier diagnosis of these diseases in the future. 
Genomics and Epigenetics 
In the past 50 years, there has been considerable progress in delineating the etiologies of 
hereditary neurodegenerative disorders, including familial forms of AD, FTD, and LBD22.  
The rare familial forms are single-gene disorders that result from rare mutations in a well-
defined panel of genes for each disease; these can be detected using DNA sequencing 
methods.  In addition, it is now appreciated that a substantial proportion of patients who 
present with these diseases clinically have a genetic susceptibility component that is the 
aggregate of many common variants of small effect (single nucleotide polymorphisms 
[SNPs]), rare variants of large effect, as well as structural or copy number variants.  The 
results of genome-wide association studies have allowed for genotyping of known SNPs 
to create a genetic risk score as the foundation of genetic susceptibility.  A substantial 

 
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proportion of the genetic susceptibility to these disorders remains unaccounted for, but may 
include epigenetic and mitochondrial effects. 
Brain donation and neuropathology 
In many NDD, a definitive diagnosis can only be made through brain tissue analysis, 
generally acquired at autopsy. Despite advances in diagnostic technologies, such as the 
advent of amyloid imaging, tissue pathology is still the “gold standard” for NDD diagnosis. 
It also represents an important tool to examine epigenetic and proteomic aspects of 
NDD23,24. As part of this consortium, we will be creating a voluntary National Brain 
Donation Program tied to a National Brain Banking Network (NBBN) in order to optimize 
the collection of brain samples and to standardize the handling and analysis of brain tissue 
across the 10 existing brain banks in the country. The benefit of this will be the creation of 
a national resource, which heretofore has not been available within Canada and will allow 
correlations between pathology and longitudinal clinical, neuropsychological and imaging 
data.  
1.3 RATIONALE FOR THE STUDY 
To date, a collaborative approach to research that spans a wide breadth of presumably 
related NDD has rarely been undertaken. Not only will our research plan span a wide range 
of conditions, it will help with the development of standardized assessment protocols, 
which will allow for comparison to be made across disease states. These comparisons will 
allow us to identify common and unique factors across these diseases.  Furthermore, 
creation of core assessment platforms that include multiple modalities will give us a more 
comprehensive evaluation of brain health in each of these disease states that is not currently 
available. Using these multiple modalities will allow us to identify clinical, imaging, 
genetic and other biological markers associated with the different neurodegenerative and 
vascular pathologies in the pathogenesis of adult onset dementia.   
Current therapeutic approaches in neurodegenerative diseases tend to be directed towards 
single biological mechanisms, which may be inadequate given the complexity of these 
multifaceted diseases. Through this integrated discovery approach, we have the unique 
opportunity to identify multiple markers of brain health that will contribute to the 
development of (1) biomarkers for neurodegenerative disease that may ultimately be 
relevant towards the identification of subjects in pre-symptomatic stages, and (2) 
personalized “cocktails” of therapeutic approaches that may be more effective than current 
approaches.  Hence, this well-structured and integrated longitudinal exploratory study has 
the potential to deliver significant impacts on health care in the rapidly growing area of 
neurodegenerative disease. 
This project will provide exceedingly rich research platforms that will allow us to advance 
our current understanding of the clinical, experiential, biological and genetic correlates of 
disabling outcomes in adult-onset neurodegenerative disease that have not been possible 
with the current funding mechanisms available. These data will also lead to development 
of innovative investigative tools (e.g. a mixed disease neurodegenerative gene chip) and 
the evaluation of both novel clinical tools (e.g. metabolomic profiles derived from salivary 

 
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samples) and therapeutic approaches. Therefore data from this project will help to focus 
future basic and translational research efforts.   
1.4   DESCRIPTION OF PLATFORMS 
Clinical 
The clinical assessment will provide information on demographics, past and current 
medical and psychiatric conditions, past and current medications, reproductive history, 
childhood adversity, past and current sleep quality and patterns, past and current pain 
status, nutrition, lifestyle factors including physical and social activity and other domains 
of interest as well. In addition, the clinical items were chosen to overlap as much as possible 
with several large-scale provincial initiatives (Consortium pour l’identification precoce de 
la maladie d’Alzheimer - Quebec25; Ontario Neurodegenerative Disease Research 
Initiative26).  
Neuropsychology 
The neuropsychology platform will provide a characterization of cognitive profiles for 
discriminating dementia types and tracking changes in cognitive processes and systems 
associated with dementia progression. Domains assessed will be broad-based, including 
attention, learning and memory, speech production, language, executive function, and 
visuo-spatial function. In designing the battery of tests, we built upon the recommendations 
of the VCI harmonization standards27 given the stated goal of critically evaluating the 
contributions of vascular disease to each of the targeted disease states. The Movement 
Disorder Society Task Force Guidelines were also used to design the battery of clinical 
tests for Parkinson’s Disease patient cohort. In addition, the test battery was chosen to 
overlap as much as possible with several large-scale provincial initiatives. These included 
the Consortium pour l’identification precoce de la maladie d’Alzheimer - Quebec25; 
Ontario Neurodegenerative Disease Research Initiative26) and several provincial disease-
specific studies (Frontotemporal dementia in British Columbia28 and Parkinson’s disease 
in Alberta29). 
Neuroimaging 
The neuroimaging platform will use MRI to characterize the neuro-anatomical, 
microstructural, and functional profiles of the dementia types and monitor changes in 
these phenotypes as dementia progresses. In the development of the COMPASS-ND 
protocol, our imaging group was able to meet with imaging colleagues across the 
country, to establish a “Canadian Dementia Imaging Protocol, CDIP “ that will be used 
not only in CCNA, but in  multiple other Canadian studies where brain imaging is 
involved. By achieving this cooperation, scientists will maximize the knowledge gained 
from these different studies, and be able to compare the brain images obtained similarly 
across by different research groups. 
 
Specific neuro-anatomical measurements will include hippocampal volume, brain ventricle 
volume, and whole brain volume/cortical thickness, and may be extended to other 

 
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measurements as required for each cohort. White matter hyperintensities observed in MRI 
FLAIR images will provide a measure of the burden of vascular disease and the number 
and location of microbleeds will be directly assessed with gradient echo MRI. The integrity 
of white matter tracts will be assessed by diffusion tensor imaging. Specifically, we will 
measure fractional anisotropy and mean diffusivity that are derived directly from the 
diffusivity of water molecules within the tissue. We will also examine the integrity of 
specific fibre tracts using tractography.  Finally, we will measure the functional 
connectivity of the default mode network using resting state functional MRI. All 
neuroimaging measures have been shown to be affected in one or more dementia cohorts. 
Therefore careful measurement using standardized methodology in the current study will 
allow unprecedented comparison and contrast between the various dementias studied.  
Biosamples 
The biosamples platform will collect blood, urine, and saliva in all participants. We will 
also be asking participants if they would be willing to undergo a lumbar puncture for 
collection of CSF samples. We expect that 25% of the cohort will consent to undergo a 
lumbar puncture in order to provide CSF samples (the anticipated proportion is a 
conservative estimate based on our review of similar observational studies that included 
the option of a lumbar puncture)30. We will also do buccal swabs on 200 participants from 
across the diagnostic groups. The samples will be collected, handled, stored and shipped 
according to rigorously established standard operating procedures. A set of core established 
biomarkers will be assessed for all participants including general measures of health, 
measures of sex-related hormones, inflammation, lipid metabolism, and oxidative stress. 
Further experimental measures will be assessed on sub-samples of participants based on 
the needs of the researchers.  
Genomics 
In patients, the genomics component will use: 1) sequencing (both next-generation based 
candidate gene resequencing and whole exome sequencing) to define the presence of 
mutations in genes causing familial forms of neurodegenerative diseases; and 2) common 
and rare variant assays, predominantly the NeuroX chip (Illumina)31 to evaluate the 
common genetic susceptibility component in our patients.  This will allow all CCNA 
program participants to be characterized as extensively genetically as they will be clinically 
and phenotypically.  Uniquely, we will be able for the first time to test for rare monogenic 
and complex polygenic susceptibility across the full range of patients with 
neurodegenerative disorders.  Familial cases with high opportunity for discovery of novel 
genes and novel variants will undergo whole-exome sequencing. 
Brain donation and Neuropathology 
Assessment of brain tissue post-mortem will provide definitive diagnoses for the various 
types of NDD that we will enroll into the consortium as well as providing a wealth of 
information that can be used to correlate with clinical, neuropsychological and imaging 
findings. In addition, access to brain tissue samples will allow for epigenetic and proteomic 
analyses of NDD. Following workshops, a voluntary national brain donation protocol will 
be set up to catalyze and organize brain donation of CCNA cohort subjects. A standardized 

 
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neuropathology protocol will also be established. All brains will be stored in 1 of 6 
designated national CCNA brain bank centres. 
2. 
OBJECTIVES/HYPOTHESES 
2.1 
PRIMARY HYPOTHESIS 
Degenerative cognitive impairment can be caused by a heterogeneous group of disorders 
in interaction with a heterogeneous set of influences, including life experiences, sex 
differences, and other factors, that can be explained, characterized and predicted using an 
integrated multimodality approach. 
2.2 
PRIMARY OBJECTIVE 
The primary objective is to use a pan-Canadian research consortium that will, for the first 
time, integrate a wide range of experimental, clinical, cognitive, imaging and 
epidemiological expertise to specifically address the occurrence, management, treatment, 
and prevention of acquired cognitive impairment in the aging population.    
Using current diagnostic criteria (see Appendices A-E), our goal is to establish subject 
research cohorts that are well characterised in terms of their demographics, pre-morbid 
history, cognitive function, genetic profile, neural structure and pathology, and important 
biomarkers and biological indices.  These data will then be made available to the research 
teams, allowing them access to a more extensive dataset than is typically possible. 
        2.3        GENERAL STUDY OBJECTIVES 
1. To collect data on medical & social history, physical exam and past & current 
medications, as well as gait assessment and sensory function (audition, vision), and 
questions related to cognitive reserve and reproductive history. 
2. To collect neuropsychological data assessing episodic, associative and 
prospective memory, attention, language, visuoperceptual abilities, processing 
speed and executive function. 
3. To carry out collection of biosamples of blood, saliva, and urine in all 
participants, and CSF collection in at least ¼ of the cohort. 
4. To collect MRI data according to CDIP protocol (described on page 38)  
5. To identify psychosocial issues to inform the development of programmes to 
support patients and families. 
         2.4        DISEASE SPECIFIC OBJECTIVES 
SCI 
1. To determine if clinically meaningful subgroups of SCI (e.g., at high risk for progression 
to MCI and/or dementia) can be created by an integrated, multi-modality approach.  
2. To determine if biomarker abnormalities can be delineated at the SCI stage.  
 
 

 
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V- MCI 
1. To define clinical, neuroimaging, neuropsychological and biological fluid biomarker 
profiles in patients with V-MCI and evidence of a clinically unrecognized, “silent” 
potential vascular contribution to MCI based on neuroimaging evidence of silent brain 
infarcts or extensive ischemic white matter disease. 
2. To determine factors, beyond age and stroke severity, that predict cognitive dysfunction in 
vascular populations using a multi-modal approach – e.g. MRI parameters, genetic burden, 
life experiences (e.g., education, SES, gender). 
3. To determine if cognitive decline can be predicted by an integrated, multi-modality 
approach.   
4. To identify protective factors which allow patients to be less cognitively impacted 
5. To identify novel targets for intervention that may improve the functional status and 
cognition of patients after TIA. 
MCI 
1. To determine if clinically meaningful subgroups of MCI can be created by an integrated, 
multi-modality approach. 
AD 
1. To determine if clinically meaningful subgroups of AD can be created by an integrated, 
multi-modality approach. 
LBD/PDD/PD-MCI/PD-NCI 
1. To determine the prevalence of non-motor symptoms across the spectrum of these 
disorders. 
2. To identify vascular risk profiles in Lewy-body related disorders and identify if patients 
are obtaining treatment for these. 
3. To determine whether LBD patients with a greater “genetic load” (as determined by the 
presence of genetic risk factors for LBD, PD, other neurodegenerative diseases, vascular 
diseases, neuroinflammation) have cognitive and other clinical phenotypic differences 
from those lacking these factors (i.e. “reverse phenotyping”). These studies will serve as a 
basis for important future basic mechanistic studies on the links between these 
mutations/polymorphisms and LBD pathologies. 
4. To carry out an evaluation of the specific MRI imaging profile and MRI/ symptom 
correlation of patients with LBD. 
5. To determine the impact of non-motor symptoms and vascular comorbidity on key medical 
and health outcomes such as falls, hospitalization, nursing home placement and death. 

 
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FTD 
1.   To develop a longitudinal cohort of patients with FTD to obtain integrated clinical, genetic, 
blood, CSF, and neuroimaging (MRI and PET) data to study the natural history and 
biomarker characteristics of FTD and its subtypes as the disease progress. 
2.  To carry out collection of biosamples of blood and saliva in patients with FTD for 
genetic/genomic/proteomic/biomarkers studies. 
3.   To establish a nationwide clinic registry of FTD to expedite recruitment for future clinical 
studies. This registry would also allow the first national survey of FTD and its prevalence. 
At present, there isn’t funding to undertake this. It will be pursued once funding is 
available.  
  
3. 
STUDY DESIGN 
This is an observational cohort study. The recruitment of this cohort will be carried out 
over 3 years. Assuming sufficient funding is available, there will be longitudinal follow-
up 2 years after the initial assessment. Sixteen-hundred (1600) subjects, with SCI (n=300), 
V-MCI (200), MCI (400), AD/Mixed dementia (n=300), LBD/PDD/PD-MCI (n=200), 
FTD/PPA/CBD/PSP (n=200) will be predominantly enrolled into this study from up to 35 
centres across Canada – Memory Clinics affiliated with the Consortium of Canadian 
Centres for Clinical Cognitive Research (C5R), select Canadian Stroke Clinics, and select 
Canadian Movement Disorders Clinics. Patients will be 55-85 years of age and recruited 
based on the normally occurring sex distribution of the condition.  
Subjects involved in the study will undergo comprehensive evaluations at baseline, 
including clinical and neuropsychological assessment, biospecimen collection genomics 
and MRI neuroimaging. Participants may still continue to be a part of the study if they 
decline to undertake some procedures. The minimum level of participation required for 
study inclusion is the MRI scan and clinical assessment.  
 
4. 
STUDY POPULATION 
1600 subjects with SCI (n=300), MCI (400), V-MCI (200), AD/Mixed dementia (n=300), 
LBD/PDD/PD-MCI (n=200), FTD/PPA/CBD (n=200) are to be enrolled. The sex 
distribution of participants will be monitored to ensure that sufficient numbers of each 
sex are being recruited to allow evaluation for potential differences between them on key 
study outcomes. 
 The specific inclusion and exclusion criteria for enrolling subjects in the study are 
described below. 

 
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4.1 
GENERAL INCLUSION CRITERIA (ALL CONDITIONS) 
Subjects must meet each of the following criteria for enrolment into the study: 
1. Written informed consent must be obtained and documented (from the patient or, where 
jurisdictions allow it, from their legally appointed agent).  
2. Sufficient proficiency in English or French to undergo clinical and 
neuropsychological assessment.  
3. Willing to be audio-recorded for certain assessments and to have the audio-recordings 
available without identifying information for analysis for 25 years. 
4. Geographic accessibility to the study site. 
5. Must have a study partner who can participate as required in the protocol (provide 
corroborative information). Study partner must have regular contact with the 
participant (at least one interaction per week). 
 
4.2 
CONDITION SPECIFIC INCLUSION CRITERIA 
For patients with: 
SCI 
1. 60-90 years of age 
2. Subject must meet SCI criteria (see Appendix A). 
 
MCI 
1. 60-90 years of age 
2. Subject must meet NIA-AA core clinical criteria for amnestic or multiple domain Mild 
Cognitive Impairment (see Appendix B) 
3. Select causes of impaired cognition ruled out by standardized work up for dementia 
including brain imaging (e.g., significant cerebrovascular disease, mass lesion) and blood 
work (e.g. vitamin B12 deficiency, hypothyroidism, chronic kidney disease) 
 
Vascular MCI 
1. Age 60-90. 
2. Subject meets criteria for amnestic or multiple domain MCI as defined in Appendix B 
3. No history of previous symptomatic stroke (asymptomatic MRI or CT evidence of silent 
brain infarction is not an exclusion) 
4. Clinical or research CT or MRI showing either: a) 2 or more supratentorial silent brain 
infarcts, OR b) extensive white matter disease defined as score >=2 on the ARWMC scale 
for MRI or CT (see Appendix C for details) 
 
AD 
1. 60-90 years of age 
2. Subject meets the NIA-AA core clinical criteria for Alzheimer’s disease (see       
       Appendix D) 
3. Non-AD causes of dementia ruled out by standardized work up for dementia  
       including brain imaging and blood work 

 
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Mixed Dementia 
1. 60-90 years of age 
2. Subject meets the NIA-AA core clinical criteria for Mixed Etiology dementia (see       
       Appendix E) 
 
LBD 
1.  50-90 years of age 
2.  Subject meets LBD criteria (see Appendix F) 
 
Parkinson’s Disease Dementia (PDD)  
1. 50-90 years of age 
2. Subject meets the MDS core clinical criteria for Parkinson’s Disease Dementia (see       
       Appendix G) 
 
Mild Cognitive Impairment in Parkinson’s Disease   
1. 50-90 years of age 
2. Subject meets the MDS core clinical criteria for Mild Cognitive Impairment in  
      Parkinson’s Disease (see Appendix H) 
 
FTD 
1. 50-90 years of age 
2. Subject meets the FTD subtype criteria for PPA or possible or probable bvFTD or 
corticobasal syndrome, or PSP (see Appendix I) 
 
4.3 
PLATFORM SPECIFIC INCLUSION CRITERIA 
Subjects must meet specific criteria to participate in the platform. Subjects may still 
participate in study even if excluded from a specific platform (other than the clinical 
assessment and neuroimaging). 
4.3.1 NEUROPSYCHOLOGY 
Subject has sufficient vision and hearing to participate in testing based on screening 
measures.   
a. 
Pure-tone hearing thresholds will be tested in each ear at 25 dB HL at 1000, 2000 
and 4000 Hz.  Participants whose hearing does not meet these minimum thresholds in at 
least one ear with correction will be provided with an assistive listening device (e.g., a 
Pockettalker®) during clinical interview and neuropsychological testing.  
b. 
Visual acuity (both eyes) will be assessed via a question on ability to read standard 
newsprint with or without the aid of corrective eyewear. If the response is negative they 
will be excluded from neuropsychological testing.  

 
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4.3.2 NEUROIMAGING 
All subjects will be eligible. 
4.3.3 GENOMICS 
Must be willing to provide blood. 
4.4 
GENERAL EXCLUSION CRITERIA (ALL CONDITIONS) 
Subjects who exhibit any of the following conditions are to be excluded from the study: 
1. 
The presence of other significant known chronic brain disease such as: moderate to 
severe chronic static leukoencephalopathy (including previous traumatic injury), 
multiple sclerosis, a serious developmental handicap, malignant tumors, 
Parkinson’s disease (other than for the Parkinson’s/ LBD cohort), and other rarer 
brain illnesses 
2. 
Ongoing alcohol or drug abuse that in the opinion of the investigator may interfere 
with the subject’s ability to comply with the study procedures. 
3. Subject does not have a study partner who can provide corroborative information. 
4. 
Individuals where English or French is not sufficiently proficient for clinical 
assessment and neuropsychological testing. 
5. Total score on the MoCA<13 
6. Symptomatic stroke within the previous year 
7. 
Unable to undergo MRI scan due to medical contraindications or inability to 
tolerate the procedure. 
 
4.5 
CONDITION SPECIFIC EXCLUSION CRITERIA 
For patients with: 
SCI 
1. Age younger than 60 
2. Major surgery within last 2 months 
3. History of intracranial surgery 
4. Serious comorbid condition that, in the opinion of the study investigator, is likely to 
result in death within a year. 
MCI 
1. Age younger than 60 
Vascular MCI 
1. Subjects with history of symptomatic stroke (CT or MRI evidence of silent brain infarcts 
is allowed).  
2. History of planned carotid revascularization (if enrolled with TIA). 
AD/Mixed Dementia 
None. 

 
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LBD/PD MCI/PDD 
None 
 
FTD 
1. Subjects with probable Alzheimer’s disease (and only possible FTD) or history of 
multiple head traumas, lifelong schizophrenia, or chronic depression 
 
4.6 
PLATFORM SPECIFIC EXCLUSION CRITERIA 
Subjects must meet specific criteria to participate in the platform.  Subjects may still 
participate in the study even if they are excluded from certain specific platforms (all 
participants must undergo a clinical assessment and neuroimaging). 
4.6.1 NEUROPSYCHOLOGY 
All enrolled subjects will be eligible. 
4.6.2 NEUROIMAGING 
All enrolled subjects will be eligible. 
4.6.3 GENOMICS 
N/A 
4.6.4 BIOSPECIMENS 
If a subject is on anticoagulants, they are excluded from undergoing lumbar puncture. 
5. 
STUDY PROCEDURES AT EACH VISIT  
All study evaluations and procedures are provided in the Time and Events schedule.  The 
total expected duration of subject participation is approximately 5 years. Beside each visit 
in brackets is the estimated time for the visit and beside each procedure in brackets is the 
proposed administrator of the procedure and who it will be administered to.  
5.1 
(VISIT 1) SCREENING & DEMOGRAPHICS (ESTIMATED TIME: 2 - 2.5HOURS) 
The following study procedures will be performed: 
 
Written informed consent prior to study procedures (study investigator or delegate of 
investigator; participant and study partner) 
 
Assess inclusion/exclusion criteria (study coordinator or nurse; participant and study 
partner) 
 
Hearing and Vision assessment (study coordinator or nurse; participant)  
 
Logical Memory 1 & 2 from Wechsler memory scale32 (for SCI, MCI, V-MCI, AD, 
Mixed) (psychometrician; participant, audio-recorded) 

 
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 
Clinical Dementia Rating scale33 (for SCI, MCI, V-MCI) (study coordinator or nurse; 
study partner and participant)  
 
CERAD word list Recall34 (for SCI, MCI, V-MCI, AD, Mixed) (psychometrician; 
participant; audio-recorded) 
 
MoCA35 (all groups. SCI must have a score ≥ 25; all participants must have a score >13) 
(investigator or nurse; participant, audio recorded) 
 
Lawton Brody IADL scale36(for SCI,  MCI, & Vascular MCI)) (investigator or nurse; 
study partner) 
 
Benson Figure Recall37 (for FTD, PD) (psychometrician; participant) 
 
Clinical PPA and bvFTD features from NACC Uniform Data Set FTLD Module38 
(FTD) (physician or nurse; study partner) 
 
Geriatric Depression scale & Generalized Anxiety Disorder 7 item Scale 
Some sociodemographic and physical activity information will be collected in between 
LM 1 & 2 for SCI, MCI, V-MCI, AD, and Mixed Dementia participants and the 
Generalized Anxiety scale will be administered between CERAD 1 & 2. The 
sociodemographic information will be collected prior to the Benson Figure Copy & 
Recall test and physical activity information will be collected between the Benson 
Figure Copy & recall in the PD spectrum and FTD spectrum groups (coordinator or 
nurse; participant or study partner) 
 Audio recorded conversation between participant and study partner (optional) 
 
Take home packet provided 
Day 1 will be the date the consent is signed and all follow-up visits will be scheduled 
based on this.  There will be a 12-week window from time of consent to complete all 
screening and baseline procedures. 
 
5.2 
SELF-ADMINISTERED PROCEDURES AND QUESTIONNAIRES TO BE COMPLETED 
BETWEEN VISITS 1 AND 2 
- 
Fecal sample collection: the participant will be provided with a fecal swab 
collection and preservation kit. They will be asked to use the swab to collect a 
sample of feces from toilet paper they have used after a bowel movement. They 
will then store swab in the preservation tube and return it at their next visit. 
- 
Hobbies and leisure activities (participant or study partner if the local investigator 
or staff determines that the participant is unable to complete the questionnaire) 
- 
Tobacco and alcohol consumption (participant or study partner if the local 
investigator or staff determines that the participant is unable to complete the 
questionnaire) 
- 
Activities of Daily Living (study partner) 

 
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- 
Quality of Life (participant) 
- 
End of Life Care (participant or study partner if the local investigator or staff 
determines that the participant is unable to complete the questionnaire) 
- 
Social network, support, & activities (coordinator; participant or study partner if 
the local investigator or staff determines that the participant is unable to complete 
the questionnaire) 
- 
Adverse childhood experiences questionnaire (optional) (take home) (participant or 
study partner if the local investigator or staff determines that the participant is 
unable to complete the questionnaire) 
- 
MDS-UPDRS, parts IB – II (LBD, PDD, PD-MCI, PD-NCI & FTD spectrum only) 
(study partner) 
- 
PDQ-39 (LBD, PDD, PD-MCI, PD-NCI & FTD spectrum only) (study partner) 
- 
Behavioral Inhibition Scale (FTD spectrum only) (study partner) 
- 
Interpersonal Reactivity Index (FTD spectrum only) (study partner) 
- 
Revised Self-Monitoring Scale (FTD spectrum only) (study partner) 
- 
Neuropsychiatric Inventory - Questionnaire (study partner) 
- 
Apathy Inventory (FTD spectrum only) (study partner) 
5.3 
VISIT 2: CLINICAL AND PHYSICAL ASSESSMENT (ESTIMATED TIME: 2.5 -3.5 HOURS) 
At visit 2 the following information will be gathered and study procedures performed:  
- 
Physical Measurements (nurse; participant) 
- 
Fasting blood collection (nurse; participant) 
- 
Saliva collection (nurse; participant) 
- 
Urine collection (nurse; participant) 
- 
Buccal Swab 
- 
Health perception, fatigue, falls history & balance assessment (nurse; participant) 
- 
Walking speed (4 and 6m)(nurse or coordinator; participant) 
- 
Grip strength(nurse or coordinator; participant) 
- 
Vision assessment (nurse or coordinator; participant) 

 
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- 
Hearing assessment(nurse or coordinator; participant) 
- 
Olfaction assessment(nurse or coordinator; participant) 
- 
Nutrition (nurse or coordinator; participant) 
- 
Oral Health (nurse or coordinator; participant) 
- 
Sleep (coordinator; participant or study partner) 
- 
Cognitive fluctuations (coordinator; study partner) 
- 
Caregiver burden assessment (coordinator; study partner [and participant if in a 
caregiving role]) 
- 
Current and past medications (coordinator or nurse; participant or study partner) 
- 
Medical, mental health, and surgical history (coordinator or nurse; participant or 
study partner) 
- 
Family history (coordinator or nurse; participant or study partner) 
- 
Initial Disease Symptoms (coordinator or nurse; participant or study partner) 
- 
Disease course (coordinator or nurse; participant or study partner) 
- 
Signs and Symptoms (physician; participant) 
- 
Physical examination (physician; participant) 
- 
Neurological examination (physician; participant) 
- 
Hachinski Ischemic Scale39 (physician; participant) 
- 
Clinical Diagnosis (physician)  
 
5.4 
VISIT 3: NEUROPSYCHOLOGICAL ASSESSMENT (ESTIMATED TIME:  3 HOURS) 
At visit 3, the following information will be gathered and study procedures performed: 
- 
Neuropsychology: IQ estimate, Verbal Memory tests (RAVLT, Digit symbol 
recall, Envelope test), Attention, Working Memory, processing speed tests, 
Visuoperceptual and construction tests (psychometrician; participant) Visual 
Memory tests (BVMT, Face-Name Matching), Language tests, Complex attention, 
executive, theory of mind tests, Neuropsychiatric scales (psychometrician; 
participant). This session will be audio recorded. 

 
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5.5 
VISIT 4: MRI SCAN (ESTIMATED TIME: 1 HOUR) 
At visit 4, the following information will be gathered and study procedures performed: 
Magnetic Resonance imaging scan (imaging technician & study coordinator; participant). 
This visit may be scheduled any time after Visit 1. It may be done prior to the clinical and 
neuropsychological assessments but must be done prior to the LP. 
5.6 
VISIT 5: LUMBAR PUNCTURE (ESTIMATED TIME: 1 HOUR) 
At visit 5, the following information will be gathered and study procedures performed: 
Lumbar puncture (if consented to) (physician; participant) 
5.7 
FOLLOW-UP 
All cohort subjects and/or informants will be contacted via telephone on an annual basis 
to insure continued willingness to participate and to request permission to consult their 
treating physician in order to determine if there has been any diagnostic change. 
Assuming sufficient funding is available, 2 years after the initial visit, the participants 
will be invited back to clinic to undergo the same procedures as in visits 2-5.  If brain 
donation has been consented to, upon the subject’s death their brain will be collected 
according to established protocols. If at any time during the follow-up, the participant no 
longer has the capacity to consent to continuing in the study (e.g. they have become 
severely demented), the consent of a substitute decision maker (SDM) will be sought if 
one has been designated. If there is not a designated SDM, consent will be considered 
withdrawn and participation terminated. 
 
5.8 
ADD ON STUDIES 
There are studies planned by researchers in the CCNA that will recruit participants who 
are enrolled in the COMPASS-ND study. There may also be studies that will recruit 
study partners of participants in the COMPASS-ND study. Participation in these add-on 
studies isn’t required to be enrolled in the COMPASS-ND study, although participation 
in the COMPASS-ND study may be a prerequisite to be recruited for some of the add-on 
studies. The data collected within COMPASS-ND may represent the baseline or pre-
treatment data for the interventional trial and will be shared with the interventional trial 
research teams without identifying information attached. The protocols for these studies 
will be presented for review separately, but will be described in summary here along with 
the COMPASS-ND data that will be shared with each one.  
 “SYNERGIC TRIAL” (SYNchronizing Exercises, Remedies in GaIt and 
Cognition); A Randomized Controlled Double Blind Trial  
The proposed SYNERGIC TRIAL is uniquely designed to evaluate the effect of 
aerobic and progressive resistance training exercises, isolated or combined with 
cognitive training and vitamin D supplementation, in older adults with MCI. 
Based on recent literature, after twenty to twenty four weeks (four to six months) 
of supervised multimodal exercise (aerobic and progressive resistance training) 

 
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alone and/or in combination with cognitive training (CT) and/or vitamin D. 
Primary outcome will be global cognitive function, as assessed by primary 
outcome Alzheimer’s Disease Assessment Scale-Cognitive subscale plus (ADAS-
Cog-Plus).  
 
Data shared from COMPASS-ND baseline assessment: All 
clinical, neuropsychological, MRI, and biospecimen data collected 
from the participant. 
 
 
Multifaceted cognitive stimulation to enhance cognitive reserve in older adults 
with subjective cognitive decline. 
 
The aim of the project is to develop and test a multi-faceted intervention program 
meant to increase cognitive and brain reserve by providing cognitive stimulation 
through participation in cognitive training sessions and engaging leisure activities. 
This will be done with a double-blind, randomized, controlled trial in participants 
with subjective cognitive decline (SCD). Exploring Novel Group Activities for 
Geriatric Enrichment (ENGAGE), is a 4-month long, innovative, multifaceted 
program which combines formal education on brain health, formal teaching of 
cognitive strategies to improve attention and memory skills, leisure activities 
known to impact cognition and potentially boost cognitive reserve: music lessons, 
second language (Spanish) lessons, and carefully selected videogames. Ninety 
participants with subjective cognitive decline (SCD)   but no objective 
impairment based on cognitive tests will be recruited in Montreal and randomly 
assigned to either the cognitive program (ENGAGE SPANISH or ENGAGE 
MUSIC) or the active control program (ENGAGE DISCOVERY). Participants in 
the ENGAGE DISCOVERY program will undergo the same amount of activities 
as proposed in the ENGAGE SPANISH/MUSIC programs, but those activities 
will be designed not to be cognitively challenging. The interventions – ENGAGE 
SPANISH/MUSIC or ENGAGE DISCOVERY – will be provided over a 4-month 
period, twice a week for the first 2 months, and then only once a week for the last 
two months. The training will be delivered to small groups of 5 to 8 participants, 
at the Centre de Recherche du l’Institut Universitaire de Geriatrie de Montréal. 
The sessions will be about 2.5 hours long and will be complemented by 
assignments to be completed at home between the class sessions (1 to 2 hours per 
week). Behavioral measures (objective and subjective measures of cognition and 
efficiency in everyday life functioning) as well as neuroimaging measures (fMRI 
scan during a memory task) will be collected at 3 time points: before the 
intervention (PRE), immediately after the intervention (POST-1), and 18 months 
after the intervention (POST-2). 
 
Data shared from COMPASS-ND baseline assessment: All 
clinical, neuropsychological, MRI, and biospecimen data collected 
on the participant. 
 
Nutrition, Exercise and Lifestyle Intervention 
This study investigates how a combination of exercise and nutritional changes effects 
brain health. We will ask 66 participants aged 55 to 80 with memory concerns 
who have 2 of the following conditions: high blood pressure, high cholesterol, 

 
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type 2 diabetes, or are overweight to participate in this study. These 60 
individuals will be randomized into one of two arms: 1) a 6-month combined 
aerobic and resistance exercise intervention with additional Brain Health Food 
Guide (BHFG) counseling (EX+BHFG) and 2) a 6-month aerobic exercise 
intervention with standard of care materials on healthy lifestyle (EX+noBHFG). 
 
Data shared from COMPASS-ND baseline assessment: All 
clinical, neuropsychological, MRI, and biospecimen data collected 
on the participant. 
Participants recruited into one of these add-on studies will have to provide separate 
consent for the add-on component. 
 
5.9        STUDY PROCEDURE DESCRIPTIONS 
INFORMED CONSENT 
The participant and their study partner will meet with the study physician and/or their 
delegated representative to go over the consent form which will include information 
concerning the study purpose and procedures, what would be asked of the participant and 
study partner, the potential benefits and risks of participation, the confidentiality of the 
information being collected, and the rights of the participant to withdraw consent to study 
participation at any point without penalty. If they agree to participate in the study, they will 
be asked to sign the consent form. As part of the consent process for this study, participants 
will be asked if they would be willing to be re-contacted for other CCNA studies they may 
be eligible for. Their willingness to permit this would have no impact on other aspects of 
the consent process. If the participant lacks capacity to consent and has a legally designated 
agent who could consent for them, this person can consent for the participant as long as the 
participant indicates a willingness to participate.   
INCLUSION/EXCLUSION CRITERIA 
Both general and disease specific inclusion/exclusion criteria will be assessed and captured 
in the CRF. 
 
HEARING AND VISION ASSESSMENT 
Vision assessment will consist of the participant being asked if he/she is able to read 
standard newsprint with his/her standard corrective lenses. If the response is no, the 
participant will be excluded from certain elements of the study requiring reading or visual 
processing of stimuli. Hearing will be assessed with a pure‐tone audiometer and assess 
hearing in each ear at 25 dB HL at 1000, 2000 and 4000 Hz. If participant is unable to 
detect a signal at any point, an assistive listening device will be used at all subsequent 
clinical and neuropsychology visits. 
 
SUBJECTIVE MEMORY ASSESSMENT (ADMINISTERED TO SCI COHORT) 
Three questions will be asked to assess the level of subjective memory awareness and 
concern: “Do you feel like your memory or thinking is becoming worse?”, “Does this 
concern you?”, and “Do you feel like your memory or thinking is worse than that of other 
people the same age as you?”  These questions are adapted from the work of Jessen et al.13 

 
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LOGICAL MEMORY I & II (FOR SCI, MCI, V-MCI, AD, MIXED) 
The participant will be instructed to listen to a story and repeat it back after it has been 
read. They will then be asked to recall the story approximately 30 minutes later. 
Administration will be audio-recorded for quality assurance of procedure. 
MONTREAL COGNITIVE ASSESSMENT  (MOCA) 
The MoCA is a 10-minute test that provides a global assessment of cognition, covering 
domains of memory, language, attention, visuospatial, and executive functioning. It will 
be administered and captured in the CRF. Administration will be audio-recorded for quality 
assurance of procedure. 
FUNCTIONAL CAPACITY QUESTION 
Do the participant’s cognitive deficits interfere with independence in everyday activities 
such as paying bills or managing medications? Response is recorded as Yes/No. 
LAWTON-BRODY IADL SCALE (FOR SCI, MCI & VASCULAR MCI ONLY) 
This 10-15 minute scale captures functional ability on 8 instrumental activities of daily 
living (telephone use, shopping, food preparation, housekeeping, laundry, transportation, 
medication management, and ability to handle finances). Each activity has a series of levels 
of capability described, ranging from full capability to no capability. A total score out of 
23 is derived from the levels of capability for each activity with a higher score representing 
better functional capacity. 
CERAD WORD LIST RECALL (FOR SCI, MCI, V-MCI, AD, MIXED) 
This test consists of ten words to be remembered which are repeated over three study-test 
trials, a ten minute retention interval, a delayed recall test, and finally a twenty-word 
recognition test (ten studied and ten unstudied words). Administration will be audio-
recorded for quality assurance of procedure. 
CLINICAL DEMENTIA RATING SCALE (FOR SCI, MCI & VASCULAR MCI ONLY) 
This scale collects information in a standard way from both the study partner and from the 
subject relative to memory, orientation, judgment and problem-solving, community affairs, 
home and hobbies, and personal care. From the information collected, a severity rating is 
derived for each domain, as well as a global dementia severity rating. The rating is a five-
point scale in which CDR-0 connotes no cognitive impairment, and then the remaining four 
points are for various stages of dementia: CDR-0.5 = questionable dementia; CDR-1 = mild 
dementia; CDR-2 = moderate dementia; CDR-3 = severe dementia. 
BENSON COMPLEX FIGURE COPY & RECALL (FTD & PD ONLY) 
The purpose of the test is to assess visuoconstructional and visual memory functions. The 
participant is first presented the figure and instructed to copy it. After they have completed 

 
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the copy, they are told to remember the figure. After 10-15 minutes they are given a blank 
sheet and asked to draw the figure from memory. 
CLINICAL PPA AND BVFTD FEATURES QUESTIONNAIRE FROM NACC UNIFORM DATA SET 
FTLD MODULE (FTD ONLY) 
Gateway questions are asked about the presence of PPA or bvFTD and if the answers 
indicates the presence of one or the other, then the rest of the related questionnaire section 
is filled out. For the PPA section, there are 10 follow-up questions. For the bvFTD section, 
there are 8 follow-up questions. 
SOCIODEMOGRAPHIC DATA 
Sociodemographic data (sex, age, handedness, languages, marital/partner status, living 
circumstances, reproductive history, education, employment history and volunteerism, 
household income, and driving history) will be captured in the CRF. 
PHYSICAL ACTIVITY 
Present levels of physical activity will be assessed with the Physical Activity Scale for the 
Elderly40. Levels of activity throughout the life span will be assessed with The California 
Teachers Study Long Term Recreational Physical Activity Survey41,42. 
GERIATRIC DEPRESSION SCALE43 
Depressive symptoms will be assessed with the Geriatric Depression scale. This is a 15-
item scale of Yes/No questions where each point represents a depressive answer. A score 
over 10 suggests depression and a score over 15 suggests major depression. 
GENERALIZED ANXIETY DISORDER 7-ITEM SCALE44 (GAD-7) 
Anxiety symptoms will be assessed with the GAD-7. The proband is asked how frequently 
they felt the way described in a given item over the last two weeks (choices are “Not at all 
sure”, “Several days”, “over half the days” & “Nearly every day”). If any of the items are 
indicated to have been experienced several days or more, there is a follow-up question on 
how much difficulty this created in being able to work, take care of things at home, or get 
along with other people. The score is based on the frequency of each experienced item with 
“Not at all sure” =0 points, “Several days”=1 point, “Over half the days”=2 points, and 
“Nearly every day”=3 points. A score greater or equal to 10 suggests generalized anxiety.  
AUDIO-RECORDED CONVERSATION BETWEEN PARTICIPANT AND STUDY PARTNER (OPTIONAL) 
At, the end of this visit, if the participant and their study partner have both consented to it, 
they will be audio-recorded while they converse about a topic or topics of their choosing. 
To avoid accidental recording of other people not involved in the study, this will occur in 
a private room with the door closed. If a third party not involved with the study is 
inadvertently recorded, that section or sections of the taped conversation will be erased. 
The taped conversation will be analysed for communication strategies that contribute to 

 
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the resolution or the worsening of misunderstandings in communication. In addition to 
having a conversation taped, the study partner will be asked to complete the Perception of 
Conversation Index – Dementia of the Alzheimer’s Type (PIC-DAT)45. This procedure is 
only being performed in English speaking participants as the PIC-DAT has only been 
validated in that population. 
 
FECAL SAMPLE COLLECTION 
The participant will be given package containing a swab and a capped tube with sample 
stabilising liquid inside. They will be asked to use the cotton swab to collect a sample of 
feces from toilet paper they have used after a bowel movement. They will then put the swab 
in the tube, re-affix the cap and return it at their next visit. 
 
HOBBIES AND LEISURE ACTIVITIES (TAKE-HOME) 
Hobbies and Leisure activities will be captured by a questionnaire developed by Rami et 
al.46 and adapted for French and English by CIMA-Q25. 
SMOKING AND ALCOHOL CONSUMPTION (TAKE-HOME)Smoking and alcohol consumption 
will be captured with a series of questions developed for the ONDRI clinical survey26. 
ACTIVITIES OF DAILY LIVING (TAKE-HOME) 
Function in basic and instrumental activities of daily living will be captured with the 
Modified OARS activities of daily living scale47. 
QUALITY OF LIFE (TAKE-HOME) 
Perceived quality of life will be captured through the QoL-AD scale48. 
END OF LIFE CARE (TAKE-HOME) 
End of life care preparedness will be captured by three Yes/No questions about whether 
wishes on end of life care have been discussed and whether a power of attorney and/or 
advance directive have been completed (and enacted).. 
SOCIAL ENGAGEMENT (TAKE-HOME) 
Social engagement will be captured by assessing the social participation, support, and 
activities of participants. Lifetime & present social network will be assessed by six items 
adapted from the CIMA-Q study25. Social support is assessed by the MOS Social Support 
Survey49 supplemented with items from Rami et al.46 and an item addressing loneliness50. 
Social activities will be assessed using items adapted from the CLSA51. 
 
 

 
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ADVERSE CHILDHOOD EXPERIENCES (OPTIONAL TAKE-HOME) 
Adverse experiences of childhood will be captured through the Adverse Childhood 
Experiences scale52. 
MDS-UPDRS (LEWY-BODY DISEASE, PARKINSON’S DISEASE, & FTD SPECTRUM PATIENTS 
ONLY) 
To capture the extent and severity of Parkinson’s disease symptomatology, the Movement 
Disorders Society Unified Parkinson’s Disease Rating Scale53 will be administered and 
captured in the CRF. Parts IA, III, & IV will be done during the clinical visit with the 
physician; parts IB & II will be done at home by the participant. 
PARKINSON’S DISEASE QUALITY OF LIFE QUESTIONNAIRE (LBD, PD SPECTRUM ONLY) (TAKE 
HOME) 
This is a 39-item questionnaire assessing the impact of Parkinson’s symptoms on quality 
of life. (participant) 
BEHAVIORAL INHIBITION SCALE (FTD SPECTRUM ONLY)(TAKE HOME) 
Part of the NACC Uniform Data Set (UDS)-FTLD Module Version 3.038, the BIS54 is a 7 
item scale that captures the degree of behavioral inhibition exhibited by the participant. 
(Primary informant) 
INTERPERSONAL REACTIVITY INDEX (FTD SPECTRUM ONLY)(TAKE HOME) 
Part of the NACC Uniform Data Set (UDS)-FTLD Module Version 3.038, the IRI is a 14 
item scale designed to capture the level of empathy and perspective-taking of the 
participant. (Primary informant) 
REVISED SELF-MONITORING SCALE (FTD SPECTRUM ONLY)(TAKE HOME) 
Part of the NACC Uniform Data Set (UDS)-FTLD Module Version 3.038, the RS-MC55 is 
a 13 item scale designed to capture the level of the participant’s attention to the impact of 
his or her behaviour on others. (Primary informant) 
NEUROPSYCHIATRIC INVENTORY –QUESTIONNAIRE56 (TAKE-HOME) 
General neuropsychiatric symptomatology of the participant will be captured with this 
instrument. (Primary informant) 
APATHY INVENTORY57(TAKE-HOME) 
This scale assesses the perceived level of interest in activities and interactions with others. 
(Primary informant) 

 
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SCHWAB & ENGLAND ACTIVITIES OF DAILY LIVING SCALE58 (LBD, PD SPECTRUM ONLY) 
This is an instrument to assess participant’s perception of general functional capacity on a 
scale from 100% capacity to 0% capacity. 
CAREGIVER BURDEN ASSESSMENT(TAKE-HOME) 
 
Caregiving perception of both the study informant and the participant (if in a caregiving 
role) will be captured by the Caregiving Burden Scale59. 
PHYSICAL MEASUREMENTS 
Measurements will be taken of height, weight, circumference of waist, hip, neck and calf, 
resting blood pressure in the supine, sitting, and standing positions, and orthostatic change 
will assessed 1 and 3 minutes after standing. 
HEALTH PERCEPTION, FATIGUE, FALLS AND BALANCE 
Questions on personal perception of health status and level of fatigue will be administered 
to contribute to assessment of frailty60. Perception of falls and balance will be assessed via 
the Activities specific Balance Confidence scale61,62. 
FASTING BLOOD COLLECTION 
BD Vacutainer tubes (BD Diagnostics, Franklin Lakes, NJ) will be used to collect 
approximately 60 mL of blood by standard venipuncture. The participant will have been 
directed to fast no less than 12 hours beforehand. If the participant has eaten within 12 
hours, it will be noted along with the time of the last meal.  
SALIVA COLLECTION 
OG-500 kits (DNA Genotek, Kanata, Ontario) will be used to collect approximately 4mL 
of saliva by passive drool. The collection protocol will be as follows: 
Pre-collection Steps: 
1. 
Ask participant if they’ve had anything to eat or drink in the last 30 minutes (when 
making appointment to collect saliva, specify that the participant should refrain from eating 
and drinking for 30 minutes prior to the appointment) 
2. 
If they accidentally did eat or drink, ask them to rinse out mouth with water (clean 
cup/disposable Dixie cup), wait 30 minutes 
3. 
If they haven’t had anything to eat or drink, ask participant to wash out mouth with 
water (clean cup/disposable dixie cup), wait 2 minutes 
4. 
Put on gloves so that tester skin cells don’t cross-contaminate specimen 
5. 
Ask participant to use hand sanitizer (voluntary) prior to handling kit 
 
 
 

 
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Collection: 
1. 
Hand participant Oragene collection tube and explain what needs to be done: Point 
out the fill line and explain amount of liquid saliva needed, timeframe (~20 minutes), can 
touch lips to outer rim, but avoid filling the tube completely (make sure there is room at 
top of tube for the liquid in the lid, as the tube can overflow quite easily) 
2. 
Spit until amount of liquid saliva (not including bubbles) reaches the fill line 
3. 
Once saliva reaches the fill line, have the participant return the tube to the tester to 
close the lid by firmly pushing the lid down until a loud click is heard; the liquid in the lid 
will then be released into the tube containing the saliva 
4. 
Unscrew the funnel from the tube (put into disposable bag) and screw the small cap 
tightly onto the tube, all the while ensuring the tube is kept upright, then proceed to invert 
the tube for 5 seconds to ensure the liquids mix adequately 
5. 
Place remaining items in disposable bag for autoclaving (gloves, packaging, etc.) 
URINE COLLECTION 
A urine collection container will be provided for each participant to obtain a random urine 
sample. 
BUCCAL SWAB 
Samples will be collected by rubbing a Norgen swab across the inner cheek for 30 seconds. 
The swab will then be put into a tube containing sample stabilizing fluid and stored at 
ambient temperature..  
WALKING SPEED 
Participants will perform walks along a 6 metre path. Institutions with available pressure 
sensitive mats (GAITRite® system) will perform all walk assessments attempted with the 
mat. 
 
Participants will perform three main tasks: 1) preferred walking speed, 2) dual-task walking 
and 3) fast walking. If participants use assistive aids (cane, walker) then the tester will 
determine the participant’s capacity to walk safely without the use of the aid. If participants 
are willing, they will then perform one test walk without the use of the aid. To ensure the 
safety of participants, they will be accompanied during the performance of gait tasks when 
the risk of falling is judged by the local investigator or staff to be significant. 
The first walking block will measure self-selected or preferred walking. Participants are 
instructed to “walk at a comfortable and secure pace” and it will be  assessed over four63 and 
six64 meters. Participants will be asked to walk twice over a marked, six-metre course at 
their usual walking pace. The time in seconds to get to four meters and six meters will be 
captured.  Each performance will be recorded as the number of metres walked per second 
over four and six metres. 
The second block of trials will be dual-task walking. There will be an initial determination at 
least an hour prior to the walking tasks of the ability of the participant to perform the 

 
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cognitive tasks as outlined. If unable to perform a task, the specific testing will not be done. 
The first dual task will be walking while counting backward by serial 1’s from 100 (100-99-
98…). The second dual task will be walking while naming animals (fluency test). The third 
dual task will be serial 7s in which participants will be asked to walk while subtracting 7’s 
from 100 (100-93-86…). During this trial participants are encouraged to keep walking even if 
they cannot do the subtractions. The evaluator must not on the form how many numbers were 
subtracted or if the participant did no subtractions. Participants are encouraged to continue 
walking during all trials.  
 
The third and final block will include a single walk where the participant is asked to walk as 
quickly as possible as a ‘capacity’ reference for preferred walk velocity. 
 
In all walks, participants will start 1 meters before the start of the 6 meter walk and continue 
1 meter past the end of the 6 meter walk to ensure steady state walking.  
Participants with slow walking speed (i.e., less than 0.6m/s) or participants with lower limb 
disability will be allowed to complete one walk if they are not able to perform the 3 trails. 
GRIP STRENGTH 
Grip strength will be assessed using a Jamar dynamometer. The participant will be asked 
to squeeze the hand-grip as hard as they can. They will have three trials on each hand, each 
of which will be recorded in the CRF. 
VISION ASSESSMENT 
Subjective experience of visual ability will be assessed by a question on perceived visual 
ability and an inventory of visual aids used. Visual contrast sensitivity will be assessed 
with the Mars Contrast Sensitivity Test65. Visual acuity will be assessed with the 
MNREAD Visual acuity chart66. 
HEARING ASSESSMENT 
Subjective experience of hearing ability will be assessed by a question on perceived 
auditory ability and an inventory of audition aids used. Auditory acuity will be assessed 
with the Digits in Noise test67. Perceived impact of hearing loss will be assessed with the 
Hearing Handicap Inventory for the Elderly – Screening version68. 
OLFACTION ASSESSMENT 
Olfaction acuity will be assessed with the Brief Smell Identification Test69. 
NUTRITION 
Nutritional risk will be measured using the abbreviated version of the SCREEN II70. In 
addition, we will collect information on frequency of fast-food consumption, coffee and 

 
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tea consumption, and on food security. Nutrition will be measured using the Short Diet 
Questionnaire (SDQ)71. 
ORAL HEALTH 
Oral health will be measured in the COMPASS-ND using a questionnaire based on the 
Ontario Health Study and studies by Locker et al.72-74 The oral health instrument has six 
items measuring general oral health, chewing problems, and oral care and takes 
approximately two minutes to administer. 
SLEEP 
Sleep quality will be assessed with the Pittsburgh Sleep Quality Index75. In addition, we 
will ask questions about REM sleep behaviour (acting out dreams) and restless leg 
syndrome, both of which are related to neurodegeneration76,77 
COGNITIVE FLUCTUATIONS 
Level of fluctuation in cognition will be assessed with the Mayo Clinic Fluctuations Scale78 
FREEZING OF GAIT QUESTIONNAIRE79 (LBD, PD SPECTRUM ONLY) 
A six-item scale assessing gait freezing. 
CURRENT AND PAST MEDICATIONS 
All prescribed and over the counter medications as well as any natural therapies received 
by the subject following screening must be recorded in the CRF.  As well prior medications 
will also be recorded in the CRF. 
MEDICAL, MENTAL HEALTH, AND SURGICAL HISTORY 
Relevant medical, mental health and surgical history will be captured in the CRF. 
FAMILY HISTORY 
Relevant medical history of first-degree relatives will be captured in the CRF. 
INITIAL DISEASE SYMPTOMS 
Initial symptoms will be captured in the CRF. 
DISEASE COURSE 
Course of the disease will be captured in the CRF. 

 
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SIGNS AND SYMPTOMS 
Presenting neurological, cognitive, and functional symptoms will be captured in the CRF. 
PARKINSON’S DISEASE QUALITY OF LIFE QUESTIONNAIRE (LBD & PDD SPECTRUM ONLY) 
This is a 39-item questionnaire assessing the impact of Parkinson’s symptoms on quality 
of life. 
PHYSICAL EXAMINATION 
A complete physical examination (general appearance, HEENT [head, eyes, ears, nose and 
throat], lung/chest, heart, abdomen, skin, lymph nodes, musculoskeletal, neurological, 
extremities, other) will be performed. 
NEUROLOGICAL EXAMINATION 
A complete neurological exam, assessing level of consciousness, cranial nerves, motor 
strength, cerebellar function, sensory function, deep tendon reflexes, plantar reflexes, and 
gait will be performed. 
HACHINSKI ISCHEMIC SCALE  
The 13 item HIS39 will be captured in the CRF. 
CLINICAL DIAGNOSIS  
Based on the information gathered, the presenting diagnosis will be confirmed or re-
evaluated. 
NEUROPSYCHOLOGY 
To minimize time-of-day effects, neuropsychological assessment will always be conducted 
in the morning, with the final task being completed by 12:00 noon. 
The battery requires between 2 and 3 hours to administer. Testing session will be audio-
recorded for quality assurance of procedures. 
Tests that have been administered clinically in the past 12 months will not be repeated 
(unless there is a discrepancy between test versions). Consent forms for each site will 
include a statement asking participants to allow for their clinical results from tests 
overlapping with the CCNA battery to be entered into the CCNA case report form. If a 
patient was assessed using a different version of the same test used in the CCNA 
neuropsychological battery, the test will be repeated using the version consistent with the 
study. 

 
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Test Battery# 
 
 
 
 
Domain 
Test 
Description 
Battery 
Time 
(min) 
 
 
 
 
 
Premorbid IQ 
WAIS-III 
Vocabulary  subtest 
Expressive 
Vocabulary  
Core 
10 
Attention, working 
memory, 
processing speed 
WAIS-III Digit Span 
forward and backward 
Attention span and 
working memory 
Core 
5-10 
 
WAIS-III Digit Symbol-
Coding 
Processing speed 
Core 
5 
Complex attention, 
executive, theory 
of mind 
DKEFS Phonemic Fluency  
Phonemic (letter) 
fluency 
Core 
5 
 
Reitan Trail making test 
Switching attention 
Core 
5-10 
 
DKEFS Color Word 
Interference 
Inhibition and 
switching 
Core 
7-12 
 
Hayling Sentence 
Completion Test 
Inhibition (verbal) 
Core 
10 
 
NACC Social Norms 
Questionnaire 
Knowledge of 
Appropriate Social 
Mores 
Core 
5 
 
Victoria Longitudinal 
Study on Aging Simple 
and Choice Reaction 
Time Measure 
Reaction Time 
Core 
10 
Visuoperceptual 
and construction 
Object Decision Test - 
Birmingham Object 
Recognition Battery 
(BORB)  
Object perception 
Core 
5 
 
Judgment of Line 
Orientation (split half) 
Visual perception 
Core 
10 
 
Brief Visuospatial 
Memory Test Copy 
Visuoconstruction 
Core 
3 
Speech and 
language 
DKEFS Semantic Fluency 
Semantic (category) 
fluency 
Core 
3 
 
Cookie Theft Picture 
Description  
Spoken Language 
Core 
5 
 
NACC Word Reading Test  Reading of regular 
and irregular words 
Core 
2-3 
 
NACC Semantic Word-
Picture Matching Test 
Word Recognition 
and Comprehension 
Core 
5 
 
NACC Semantic 
Associates Test 
Knowledge of 
Meaning of objects 
Core 
5 

 
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NACC Northwestern 
Anagram Test 
Grammatical 
knowledge 
Core 
10 
 
NACC  Sentence 
Repetition Test  
Oral Repetition 
Core 
1 
 
NACC Noun and Verb 
Naming Subtests 
Naming of objects 
and actions 
Core 
6 
 
NACC Sentence Reading 
Test  
Sentence Reading 
Core 
1 
Memory 
Rey Auditory Verbal 
Learning Test  
Word-list learning 
Core 
5-8 
 
Brief Visuospatial 
Memory Test  
Figure learning 
Core 
10-15 
 
Face-Name Matching 
Associative Recall 
Core 
10-15 
 
Digit Symbol - Incidental 
Recall 
Incidental 
Associative Recall 
Core 
5 
 
Envelope Test 
Prospective 
Memory 
Core 
5 
Behaviour in 
testing situation* 
NACC Social Behavior 
Observer Checklist 
Completed by 
psychometrician 
FTD 
only 
 
*Tests listed in this section will be completed by informants and/or be completed outside of the neuropsychological 
testing session (e.g., at home). As such, they will not require on-site administration time. 
# These tests will be audio-recorded. 
Test Descriptions 
WAIS-III Vocabulary subtest80 
This subtest measures expressive vocabulary and requires participants to verbally define 
an increasingly difficult series of words that are presented visually and aurally. This subtest 
assesses overlearned verbal knowledge (crystallized intelligence). 
WAIS-III - Digit Span80 
This test includes two tasks, Digits Forward and Digits Backward, which  are administered 
separately.  On both tasks, the examiner reads a series of number sequences of increasing 
length. On Digits Forward, the participant is asked to repeat the digits in the same order as 
presented; on Digits Backward, the participant repeats the digits in the reverse order. On 
both tasks there are two trials for each sequence length, and the task is discontinued after 
the subject fails both trials of a given sequence length.  
WAIS-III Digit Symbol Coding task and Incidental Recall80 
This timed task asks participants to pair specific numbers with geometric figures according 
to a defined key. Immediately after the 120 second response period, the defined key is 
removed from view and participants are given another sheet containing just the symbols. 
Participants are then required to recall the symbols which corresponded with each number.  

 
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Delis-Kaplan Executive Function System (DKEFS) - Phonemic Fluency81 
For this task, the participant is asked to generate words that begin with a particular letter 
as quickly as possible, within a 60 second time window. Three trials are given, each with 
a different letter. Participants are not to include names of people, places or numbers. This 
task measures the participant’s ability to produce words in an effortful, phonemic format.  
Reitan Trail Making Test82 
This timed task assesses the participants’ ability to rapidly scan and sequence: (1) a series 
of dots containing numbers (Part A); and (2) a series of dots containing numbers and letters 
in an alternating series (Part B). Errors are corrected prior to the participant moving onto 
the next dot. The time it takes to complete the task is the recorded response, up to a 
maximum of three minutes for Part A and up to a maximum of five minutes for Part B. 
DKEFS - Color Word Interference81 
This timed task requires participants to (1) name a series of colors, (2) read a series of 
words and then (3) name the color of the ink of dissonant color words (i.e., must say 
“green” when the word red is written in green ink). The latter task is a measure of response 
inhibition as participants must inhibit an overlearned verbal response of reading the 
particular word (red) in favor of generating a conflicting response of naming the different 
ink color (green). For the fourth trial, participants must alternate between naming the ink 
color of dissonant color words and simply reading the word and ignoring the ink color. The 
time it takes to complete the task is the recorded response, The maximum time for reading 
for each of the color and word trials is 90 seconds and the maximum time for the response 
inhibition and inhibition switching trials is three minutes. 
Sentence Completion Task83 
This is a computerized task that is a modification of the original Burgess & Shallice (1996) 
task84. Participants hear a series of 30 sentences, presented one at a time, in which the last 
word missing. They are asked to either give a word that fits at the end of the sentence or to 
give a word that is unrelated to the sentence. For the related words condition, responses are 
scored as either correct or incorrect. For the unrelated words condition, responses are 
scored as either totally unrelated, partially related or related. Response time is also 
recorded.  
National Alzheimer’s Coordinating Center - Social Norms Questionnaire38 
The participant is given a list of twenty-two behaviors and asked whether or not the 
behavior is socially acceptable and appropriate in mainstream culture.  Participants are 
asked to consider these behaviors in the context of interactions with a stranger or 
acquaintance, not a family member or close friend. 
 
 

 
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Victoria Longitudinal Study on Aging Reaction Time Measure85 
This computerized task consists of both simple and choice reaction time measures, assessed 
by having participants make a key press to stimuli presented on the screen. 
Birmingham Object Recognition Battery (BORB)- Object Decision Task86 
Participants are shown a series of pictures and asked to identify whether the object could 
be real or unreal. 
Judgment of Line Orientation86 
This task requires participants to match the orientation of two lines to a selection of lines. 
A 15 item split half version will be administered to participants to assess spatial ability. 
Brief Visuospatial Memory Test-Revised87 
On this task, participants are presented with a 2 x 3 array of six line drawings for ten 
seconds. After the display is taken away, participants are asked draw each figure accurately 
and in its correct location on the page. There are three learning trials, a 25 minute delayed 
recall trial, a delayed recognition memory trial and a copy trial. 
Clock Drawing Task88 
Participants are asked to draw a clock, putting in all of the numbers and setting the hands 
to ten past eleven. This is a measure of visuoconstructional abilities, planning and 
organization and abstract thinking. 
BDAE Cookie Theft Picture Description task89 
Participants are presented with a line drawing of a scene where multiple things are 
happening and asked to give a verbal description of the scene. This is a measure of spoken 
language ability and the assessment is recorded.  
National Alzheimer’s Coordinating Center (NACC) Fronto-Temporal Lobe 
Dementia Module (NACC FTLD Module)- Selected subtests38 
Word Reading Test Participants are asked to read 15 regular and 15 irregular words from 
a stimulus card. If the patient does not read the word perfectly, his/her response is 
transcribed verbatim and the type of error is recorded (i.e., semantic error, super-ordinate 
error, subordinate error, within-category errors, thematically related word). This 
assessment is audio-recorded. 
Semantic Word-Picture Matching Test Participants are presented with an array of four 
pictures and asked to point to the picture that matches the word that is read by the examiner. 
The score is the total correct out of the twenty words that are read by the examiner. 

 
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Semantic Associates Test Participants are presented with two pairs of pictures and asked 
to point to the pair that have a relationship with each other. There are a total of sixteen 
items, eight animals and eight tools. 
Northwestern Anagram Test Participants are presented with a series of pictures 
demonstrating an action and randomly arranged individual magnetic words on a dry-erase 
board. Participants are told that they must arrange all of the words to make a sentence 
describing the picture, beginning with “Who is”. There are a total of ten items, with five 
items representing “Subject Who Questions” and five items representing “Object Who 
Questions”.  
Sentence Repetition Test Participants hear recordings of sentences of increasing 
complexity and are asked to repeat them. There are five sentences, and the score consists 
of the number of completely accurate sentences. In cases where sentences were not 
accurately repeated, the number of words omitted from the sentences, the number of 
semantically related or unrelated incorrect read words and the number of phonologically 
related words or nonword errors are recorded. This assessment is audio-recorded. 
Sentence Reading Test Participants are asked to read the same five sentences, and the 
scoring system is the same. This reading subtest is always to be given after the repetition 
subtest and not given in direct succession. This assessment is audio-recorded. 
Noun and Verb Naming Subtests Participants are asked to name sixteen pictures of nouns 
and sixteen pictures of verbs. Responses are recorded verbatim, but only scored for 
accuracy. Inaccurate responses are not prompted by either semantic or phonemic cues. 
Social Behavior Observer Checklist Completed by the examiner at the end of the testing 
session, this assesses participant behaviour during the testing session within 15 domains. 
DKEFS Semantic Fluency81 
This task asks participants to verbally generate as many words as they can according to 
specific categories (animals and boys names) with a 60 second time period. This test is a 
measure of semantic knowledge. 
Rey Auditory Verbal Learning Test90 
Participants are asked to recall fifteen orally presented nouns after each of five trials. A 
second list of fifteen nouns is then presented and participants are asked to recall words 
from this second list. Participants are then asked to recall words from the initial list, without 
the benefit of additional repetition from the examiner. Recall and recognition for this initial 
list are further assessed after a 20 minute delay. 
Face Name Matching 
On this experimental memory test, adapted from a task developed by Dr. Simona Brambati 
based on her previous work91, a series of faces paired with names are presented for 

 
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encoding and memory for names associated with each face is tested both immediately and 
after a 20 minute delay. 
Envelope Test 
This task is based on the work of Huppert, Johnson and Nickson (2000)92 and assesses 
prospective memory. Participants are told that at a future time, they will be asked to write 
a name and address on an envelope, and that they are also to write their initials on the back. 
There is a ten minute delay, after which participants are given the name, address and phone 
number and asked to write this on the envelope. Whether or not the participant 
spontaneously recalls the additional instruction to write their initials on the back is 
recorded. If they do not spontaneously recall the additional instructions, they are prompted 
for the additional action. 
LUMBAR PUNCTURE (ADAPTED FROM PROCEDURE USED IN THE PREVENT-AD TRIAL93) 
Patients must be lying on the lateral decubitus, at the edge of a, procedure bed, flexed, with 
the back horizontal and perpendicular to the bed throughout its entire length. It is important 
to ensure the patient is as flexed as possible, but shoulders should be perpendicular to bed, 
and knees and ankles should be symmetrically placed. Chorhexidine or iodine aqueous 
solution skin application must start in the site of puncture and continue in a concentric 
motion towards the iliac crest. A sterile swab should be used to wipe off the antiseptic 
solution from the LP site. Sterile drapes should be placed to keep sterile conditions. CSF 
should be collected from the vertebral interspace L3-L4 as indicated by a line joining the 
tips of the iliac crests or L4-L5. The goal is to anesthetize the equivalent of a volume 
equivalent of a radius of 2 cm including the skin and soft tissue adjacent to the 
intervertebral space L3-L4. Lidocaine 1% should be infiltrated subcutaneously and 
immediate tissues with a short (yellow) 25G needle. Following the infiltration, 
subcutaneous lidocaine should be dispersed by gently applying pressure with gauze above 
the infiltration site. Subsequently, local subcutaneous lidocaine administration should be 
repeated with a long (blue) 25G needle. Check the introducer and the 24G sprotte spinal 
needle to make sure that there are no defects. Insert the needle introducer on skin towards 
L3-L4 intervertebral space and subsequently the spinal needle through the introducer. At a 
depth of about 4-7 cm more firm resistance may be encountered as the ligamentum flavum 
is reached. Beyond this one should feel a slight ‘give’ as the needle punctures the dura. The 
stylet should be removed and clear CSF should drip out of the needle. If no fluid appears 
the stylet should be reinserted, the needle partially withdrawn and then advanced with a 
slightly different angle. CSF opening pressure should be conducted and recorded. It is good 
practice to take 4 tubes and to fill them each by at least 1 ml. Up to 40-50 mL CSF can be 
safely removed during a lumbar puncture, assuming the absence of contraindications. All 
tubes and .5 ml polypropylene containers will be labeled with correct bar code for the 
subject. The tubes should be numbered 1 to 4 according to the order they were filled. After 
the CSF collection, the stylet must be reinserted before the spinal needle can be removed. 
Finally, the spinal needle introducer should be removed. It is good practice to swab the LP 
site with saline soaked gauze. CSF samples will be aliquoted into .5 ml polypropylene 
containers and then stored in a -80 fridge until they can be transported via cryoshipper to 
the Canadian Biosample Repository in Edmonton for more permanent storage. 
 

 
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NEUROIMAGING 
2/3 of magnetic resonance imaging will be performed on 3 Tesla systems and 1/3 on 1.5 
Tesla systems. The following image sets will be acquired at 3T: 
1. 
3D T1-weighted MRI (Standardized across platforms) 
2. 
PD/T2-weighted MRI (Standardized across platforms) 
3. 
FLAIR (Standardized across platforms) 
4. 
Gradient Echo (Standardized across platforms) 
5. 
Resting state fMRI (Standardized across platforms) 
6. 
Diffusion Tensor Imaging (DTI) (Standardized across platforms) 
 
The following image sets will be acquired at 1.5T: 
 
1. 3D T1-weighted MRI (Standardized across platforms) 
2. PD/T2-weighted MRI (Standardized across platforms) 
3. FLAIR (Standardized across platforms) 
4. Gradient Echo (Standardized across platforms) 
 
The total test time for the MRI scan will be approximately 1 hour.   
 
BIOSAMPLES 
 
A total of 62 mls of blood will be collected via venipuncture in 10 tubes. A total of 4 mls 
of saliva will be collected by passive drool in 1 tube. A total of 20 mls of CSF will be 
collected via lumbar puncture. The samples will be aliquoted into 500-μL V bottom, 
screw-top tubes (Matrix Tubes, Thermo Fisher Scientific, Carlsbad, CA) and stored in a  
-80 fridge until they can be transported via cryoshipper to the Canadian Biosample 
Repository in Edmonton Alberta under the supervision of Dr. Bruce Ritchie for more 
permanent storage. Core biomarkers will be assessed at 3 labs in Canada: blood and urine 
biomarkers will be assessed at the Clinical Chemistry lab of the Jewish General Hospital 
in Montreal, Quebec under the supervision of Dr. Elizabeth MacNamara; CSF core 
biomarkers will be assessed at the Douglas Mental Health University Institute in 
Montreal under the supervision of Dr. Judes Poirier; saliva biomarker will be assessed at 
the University of Alberta under the supervision of Dr. Roger Dixon. 
GENOMICS 
 
Blood Samples will be sent to the Clinical Genomics Centre in the Mount Sinai Hospital, 
600 University Ave, Toronto, ON M5G 1X5, Canada and will be processed under the 
guidance of Dr. Kathy Siminovitch.  
Biological samples will be handled using Health Canada Level 2 bio containment standards 
and DNA extractions will occur in a containment hood. All DNA must be of high quality, 
as indicated by: UV spectrophotometer 260/280 >1.6; 260/230 >1.7 ratios; no degradation 
on gel; minimum 5 µg for exome sequencing, 250 ng for the NeuroX array, 60 ng for re-
sequencing panel plus extra aliquots for Sanger and qPCR validation studies, including 

 
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0.5-1.0 µg for assessment of C9orf72 expansion for specific probands. Aliquots of plasma 
and extracted RNA will be stored for future use. 
A custom-designed CCNA Neurodegeneration Re-sequencing Panel based on 
IlluminaNextera Custom Enrichment chemistry will be used for all 1600 subjects (familial 
and sporadic) and will be sequenced on the IlluminaMiSeq platform at RRI. We will use 2 
x 150 bp chemistry and will multiplex 12 samples per MiSeq run to achieve a minimum of 
100x coverage. Targets represent candidate gene coding regions and 5’ and 3’ UTR regions 
and will total approximately 700 kilobases of sequence. Re-sequencing data will be 
aligned, annotated and variant calls will be generated at the three analysis sites. 
Standardized workflows on both MiSeq Reporter v2.2 and CLC Bio Genomics Workbench 
v6 will be used for parallel analysis. Both raw and processed data will be posted to the 
LORIS server. 
All samples will be genotyped at the UHN Clinical Genomics Centre (CGC)/University of 
Toronto using the Illumina NeuroX chip suitable for genetic association analysis for all 
neurodegenerative diseases. This chip will provide a cost-effective common, cross-disease 
platform for the discovery of: a) all known mutations (~1,000) in genes known to cause 
neurodegenerative diseases; 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) ~240,000 coding sequence 
variants with a frequency of >1% in the human genome; d) ~5,000 novel coding variants 
currently detected by whole exome sequencing of familial cases affected by different 
neurodegenerative disorders; and e) ~1,000 eQTL markers. All data will be archived in 
LORIS within 72 hours of passing Quality Control. 
If analysis with the NeuroX microarray and the Neurodegeneration candidate gene re-
sequencing panel is inconclusive, there may be a benefit to extend the genomic analysis 
using a more comprehensive method called whole exome sequencing (WES). This might 
require inclusion of family members. The clinical coordinator along with the clinical lead 
and the appropriate genetic lead scientist will discuss the best strategy to select and contact 
additional family members to allow for the most informative and effective use of WES. 
WES will be performed on 100 subjects including family members using best practices for 
exome enrichment and subsequent sequence and in silico analyses. Sequencing of the 
captured exome libraries is carried out on the IlluminaHiSeq 2500 platform using 
Illumina’s 100bp paired-end reads.  Raw sequencing data will be analyzed using the 
bioinformatics pipelines for variant identification and association analyses. Briefly, these 
pipelines include primary analysis (i.e., generation of sequence reads and quality scores 
using Illumina’s CASAVA tool), secondary analysis (i.e., alignment and QA using 
software such as BWA), and tertiary analysis (i.e., variant calling and annotation using the 
Broad Institute’s GATK or similar). The curated sequence (including unaligned regions) 
will be stored for data mining (BAM files) and variants sequentially filtered to remove 
those found in public databases and technology-related false-positives.  All variants will 
be validated by Sanger sequencing and qPCR variant screening in replication cohorts at 
current sites used by members of the genomics team, as these instruments are commonly 

 
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available, with primers designed pertinent to researchers' discoveries and evolving 
directions of research. 
PATHOLOGY 
All participants entered into the study are eligible for the voluntary brain donation program. 
Clinicians are encouraged to discuss with participants and their families the possibility of 
brain donation. This is optional for patients.  If they indicate a willingness to make a 
donation, the participant’s designated agent or next of kin will be asked to provide consent 
for an autopsy limited to the central nervous system at the time of the participant’s death. 
Procedure 
At the time of patient’s death, Brain will be removed and transported to one of 6 hospitals 
(Queen Elizabeth II Health Sciences Centre, Halifax, NS; Douglas Mental Health 
University Institute, Montreal; Sunnybrook Health Sciences Centre, Toronto; University 
Health Network, Toronto; Foothills Medical Centre, Calgary; Vancouver General Hospital, 
Vancouver).  The brain will be divided midsagittally, one half fixed, and the other sliced 
fresh. Blocks from CERAD areas94, or other areas specific for the disease under 
consideration, will be placed on a cassette, labelled, embedded in OCT and snap frozen. 
Corresponding areas will be obtained from the fixed hemisphere.  
5.10 DATA STORAGE 
All data collected in this study will be stored in the Longitudinal Online Research 
Information System (LORIS)95 which is based in the McGill Centre for Integrative 
Neuroscience in Montréal, Québec.  
5.11 PILOT TESTING 
Study procedures (individually and in the aggregate), participant flow, and the burden on 
participants will be carefully evaluated in pilot testing at more than one site before the 
protocol is implemented. 
5.12 PROCEDURE TRAINING 
A series of manual of procedures has been developed describing how to administer each 
procedure undertaken in this study. There have also been videos developed to model the 
proper administration of the tests in the neuropsychology visit, the cognitive tests in the 
screening visit, the sensory assessments, and the gait assessment. For the 
neuropsychological tests and screening visit cognitive tests, research staff are required to 
rate the responses of the research volunteer in the videos and submit their responses for 
review by the neuropsychology data monitor. Research staff are also required to obtain an 
acceptable criterion on a series of multiple choice questions pertaining to each test to 
demonstrate knowledge of testing administration and scoring procedures. If the research 
staff administering the neuropsychological tests is not a certified neuropsychologist, they 
must do a dry run through the test battery (both screening and neuropsychology visit 
measures) with another individual and be observed by a certified neuropsychologist prior 

 
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to testing any actual participants to ensure test administration occurs according to 
standardized procedures. In addition, a certified neuropsychologist will observe the first 
two participant assessments to demonstrate proficiency with administering the tests. If 
there is not a certified neuropsychologist on site to do this observation, research staff will 
be observed by the CCNA Neuropsychology coordinator via an encrypted video streaming 
service. In addition, the entire neuropsychology visit and the cognitive tests in the screening 
visit will be audiorecorded for all participants to facilitate data monitoring. The research 
staff's scoring will be monitored until such a time as the data monitor feels that the research 
staff has reached an acceptable criterion with minimal errors. Following this time, every 
second participant will be monitored by that research staff. 
6.  ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING 
6.1 
DEFINITIONS 
6.1.1 ADVERSE EVENT (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject that may present 
itself during the conduct of a research study and which may or may not have a causal 
relationship with the study procedures.  An AE can therefore be any unfavourable or 
unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease 
temporally associated with a study procedure.  An AE may be a new illness, worsening of 
a sign or symptom of a condition, or an effect from a study procedure. 
6.1.2 SERIOUS ADVERSE EVENT (SAE) 
A serious adverse event (SAE) is any untoward medical occurrence that: 
 
Results in death 
 
Is life-threatening, i.e., the subject was at immediate risk of death at the time of the 
event; it does not include any event which hypothetically might have caused death if it had 
occurred in a more severe form. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalizations and/or surgical procedures that are scheduled to occur during the study 
period, for an illness or disease that existed before subject enrolment in the trial, will not 
be considered AEs provided the pre-existing condition did not deteriorate (e.g., surgery 
performed earlier than the planned date). 
 
Results in persistent or significant disability/incapacity 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate.  In other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 

 
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subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
6.2 
CLASSIFICATION 
6.2.1 SEVERITY 
Adverse events will be classified as mild, moderate or severe in severity as follows: 
 
Mild:  Discomfort noticed but no disruption of normal daily activity. 
 
Moderate:  Discomfort sufficient to reduce or affect normal daily activity. 
 
Severe:  Incapacitating with inability to work or perform normal daily activity. 
The term “severe” is often used to describe the intensity (severity) of a specific event (as 
in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relative minor medical significance (such as severe headache).  This is not the same as 
“serious”, which is based on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject’s life or functioning.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
6.2.2 ATTRIBUTION 
The relationship of the AE to study procedure will be assessed by the investigator to be not 
related, unlikely, possible, probable or definite, as follows: 
 
Not related:  No relationship between the AE and the study procedure, judged 
clearly and incontrovertibly due to extraneous causes such as concomitant medication(s) 
or the subject’s clinical state. 
 
Unlikely:  The AE is more likely due to an alternative explanation such as 
concomitant medication(s), concomitant disease(s) and/or the time relationship suggests 
that a causal relationship is unlikely. 
 
Possible:  The AE might be due to a study procedure.  An alternative explanation 
such as concomitant medication(s), concomitant disease(s) is inconclusive.  The time 
relationship is reasonable therefore the causal relationship cannot be excluded.   
 
Probable:  The AE might be due to a study procedure.  An alternative explanation 
such as concomitant medication(s), concomitant disease(s) is less likely.  The time 
relationship is suggestive, i.e. it is confirmed by de-challenge. 
 
Definite:  The AE cannot be reasonably explained by an alternative explanation 
such as concomitant medication(s), concomitant disease(s).  The time relationship is very 
suggestive, i.e. it is confirmed by de-challenge and re-challenge. 

 
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For the purposes of safety analyses, all SAEs classified with a relationship to a study 
procedure of possible, probable or definite will be considered study-related events. 
6.3 
PROCEDURES FOR AE AND SAE REPORTING 
All AEs experienced by the subject between the signing of the Informed Consent and 
discontinuation of the study will be reported.  All AEs must be recorded in the CRF.   For 
both serious and non-serious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study procedures. 
All SAEs will be recorded in the CRF starting from the time of the signing of the Informed 
Consent up to and including the end of study. 
All SAEs, regardless of the relationship to study procedures, must be reported within one 
working day of site personnel being notified of the occurrence of the event.   
SAE forms will be provided to each study site.  The initial SAE report should include at a 
minimum: subject number, a narrative description of the event, and an assessment by the 
investigator of the intensity of the event and relationship of the event to study drug.  The 
initial SAE report received from the site should be complete as soon as possible.  A 
complete follow-up SAE report must be submitted when the information, not available at 
the time of the initial report, becomes available.  The sponsor (or designee) may request 
SAE follow-up information. 
Any SAE that occurs at any time after completion of the study, which the investigator 
considers to be related to study procedures, must be recorded in the CRF. 
6.3.1 MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION 
All AEs should be monitored to determine the outcome or until the investigator considers 
it medically justifiable to terminate follow-up.  
All SAEs should be monitored until resolved or until the SAE is clearly determined to be 
due to a subject’s stable or chronic condition or intercurrent illness(es). 
 
7.      STATISTICAL METHODS 
Following are the methods that will be used within each of the outlines areas. 
Neuropsychology 
Interim (baseline) analyses will include descriptive statistics, frequencies, score 
distributions, inter-test correlations, MANOVA (domain x diagnostic groups), logistic 
regression (to discriminate between groups), test sensitivity and specificity.  Longitudinal 

 
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analyses will include MANOVA (domains x diagnostic groups x time)). Correlational 
analyses with neuroimaging and genotyping data will be completed. 
Neuroimaging 
Analyses 1 & 2 will be carried out for all scans. Analyses 3, 4, & 5 will be carried out in 
3T scans only. 
1. Core Tissue Classification and Volumetrics. Structural MRI will be performed 
using acquisition protocols that have already been standardized across vendor 
platforms in the PURE-MIND and MITNEC studies and are compatible with the 
current ADNI protocols, the VCI Harmonization criteria, and guidelines for 
detecting Amyloid Related Imaging Abnormalities (ARIA). The core protocol, 
consisting of 3D T1-weighted imaging, dual-echo PD/T2, and FLAIR sequences, 
allows tissue compartment classification, including a sophisticated subtype analysis 
of SH, classified as lacunes, and as lesions in the periventricular or deep nuclei/ 
white matter (not connected to the ventricles). This pipeline has been developed 
over the last decade and combines automatic and user-assisted manual steps. PD/T2 
images are co-registered to the T1-weighted images to perform landmark-based 
parcellation (‘SABRE”), which provides customized 26 regional volumes, not 
dependent on template matching, an important feature in the dementias such as FTD 
where focal atrophy can lead to failed template matching and case exclusion. 
2. Automated Hippocampal Segmentation. A general computerized tool developed 
by CCNA researchers and provided through True Positive Medical Devices Inc.96 
will provide volumetry reports. These reports will contain age- and sex-matched 
measures of brain structures. The analysis will provide quantitative volumetric 
estimates of intracranial capacity, total parenchyma, total grey and white matter, 
cortical and deep grey matter, as well as cerebral spinal fluid.  In addition, it will 
provide grey and white matter volumes for each brain lobe (frontal, parietal, 
temporal, occipital) as well as the cerebellum.  Furthermore, state-of-the-art 
algorithms will provide highly precise volumes of deep grey matter structures 
(thalamus, caudate, putamen, globus pallidus) and medial temporal lobe cortices 
(hippocampus, parahippocampal gyrus, entorhinal cortex, perirhinal cortex, 
amygdala).  
3. Diffusion Tensor Imaging. Preprocessing will initially be based on standard 
approaches using FMRIB Software Library (FSL) that have proven effective in 
measuring significantly preserved white matter integrity in elderly bilinguals versus 
monolinguals (mean age = 70.5 yrs, SD = 3 yrs) based on significant differences in 
fractional anisotropy (FA) and radial diffusivity. Standardised endpoint biomarkers 
will be defined and provided in consultation with the DTI neuroimaging 
researchers. 
4. Resting state fMRI. Preprocessed resting state data sets will be provided within 
CCNA for each subject utilising automated pipelines: 1) with a standard fixed set of 
pipeline steps including adaptive physiological noise correction to eliminate the 
need to obtain external physiological noise measures from all subjects, and 2) an 
individually optimized set of pipeline steps for each subject. Standardised endpoint 

 
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biomarkers will be defined and provided (e.g., network metrics) in consultation 
with the resting state neuroimaging researchers. 
5. Brain Atrophy Ischemic Vasculopathy Index (BAIVI). Using the structural 
imaging core protocol, the clinical neuroradiology team will help develop and 
validate clinical rating scales of hippocampal and global atrophy, regional 
microbleed counts, lacunes and white matter lesions.  
Genomics 
Standard bioinformatic tools will be used for data processing and analysis, including MiSeq 
Reporter v2.2, PLINK, PLINK/SEQ, Applied BiosystemsTaqManGenotyper and 
SeqScape, CLCBio Genomics Workbench v6, ANNOVAR based annotation scripts and 
Ingenuity Pathway Analysis.  
Neuropathology 
A standardized neuropathology protocol to be used on all CCNA subject brains will be 
developed by a group of Canadian neuropathologists and neurologists  in association with 
Platform #6 under direction of Dr. Sultan Darvesh of Dalhousie University. 
7.1 INTERIM ANALYSIS 
No interim analyses are planned 
7.2 HANDLING OF MISSING, UNUSED OR SPURIOUS DATA 
All data will be included in data listings and/or summary tables.  No imputation of values 
of missing efficacy or safety data will be performed. 
 
8.  ETHICAL CONSIDERATIONS 
The current study will be conducted in compliance with the protocol, International 
Conference on Harmonization Good Clinical Practice (ICH-GCP) and the applicable 
regulatory requirements. 
8.1 INCIDENTAL FINDINGS  
All data collected will be reviewed by a qualified reviewer for medically significant 
findings within 90 days of its collection. Any medically significant findings will be 
communicated in writing to the CCNA National Operations Manager (NOM) in Montreal. 
The NOM will link the participant code to his or her identity and the finding will be passed 
on to the study site physician of the participant in question within 24 hours. The study site 
physician will be responsible for determining the significance of the finding, arranging 
appropriate follow-up and informing the NOM and the primary care physician (if provided) 
in writing of the follow-up within 5 days of receiving notice of the finding. . The finding 

 
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and its follow-up will be documented and monitored until it has been resolved or as long 
as the participant remains in the study. 
8.2 INSTITUTIONAL REVIEW BOARD 
All relevant documents for this study will be submitted to an appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) for review.  A signed and 
dated letter documenting IRB/IEC approval must be obtained prior to entering subjects at 
the site. The IRB/IEC must be notified of all subsequent protocol amendments. 
8.3 INFORMED CONSENT 
Prior to any study procedures, it is the responsibility of the investigator to fully inform the 
subject or legally acceptable representative, of all pertinent aspects of the study.  Each 
subject or a legally authorized representative must give written consent prior to the 
subject’s participation in the study.  The method of obtaining and documenting the 
informed consent and the contents of the consent must comply with ICH-GCP and all 
applicable regulatory requirement(s). 
8.4 CONFIDENTIALITY OF SUBJECT RECORDS     
The LORIS system95 will house the data from participating institutions. LORIS is a web-
based database solution for neuroimaging and other research data that is physically located 
at McGill University in Montreal. It will store data that has been processed to remove any 
direct identifiers of an individual study participant. Study subjects will be assigned a unique 
coded study identification number that will be used to store their data.  
The investigator will grant monitor(s) and auditor(s) from CCNA and regulatory health 
authorities access to the subject’s original medical records for verification of the data 
gathered and to audit the data collection process.  The subject’s confidentiality will be 
maintained. Information about study subjects will be made publicly available to the extent 
permitted by the applicable laws and regulations. In CCNA publications, only group data 
will be reported. 
In cases where participant identification is required (e.g. when an incidental finding is 
uncovered on coded data), the recruiting site study investigator for the participant will be 
informed and be given access to only the minimum identifying information required to link 
the participant to the incidental finding and move it towards a resolution.    
8.5   PARTICIPANT BURDEN 
 
The potential burden on participants will be carefully evaluated by pilot testing where 
input from investigators, potential participants and care partners will be sought. The 
protocol will not be implemented until this evaluation is done and all stakeholders agree 
that the burden on study participants is reasonable. The pilot testing will also allow us to 
provide specific information on the likely burden placed on participants for inclusion in 
the consent. 
 

 
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9.  ADMINISTRATIVE REQUIREMENTS 
9.1 PROTOCOL AMENDMENTS 
The Sponsor may modify the protocol at any time during the life of the protocol. Protocol 
amendments will require IRB/IEC approval prior to implementation except when changes 
to the protocol are required to eliminate immediate hazards to the study subjects.  The 
Sponsor and IRB/IEC must be notified immediately after such changes have occurred. 
9.2 PREMATURE TERMINATION OF THE TRIAL 
If the investigator or Sponsor discovers sufficient reasonable cause for the premature 
termination of the study, the terminating party will provide written notification 
documenting the reason for study termination.  The appropriate regulatory agencies and 
IRB/IEC must be notified. 
9.3 COMPLETION OF CASE REPORT FORMS 
Standardised subject demographic and clinical-research meta-data 
Non-imaging data (ie. Demographic, clinical) will be entered directly (or transcribed) into 
the LORIS system. LORIS CDEs will be incorporated into case report forms (CRFs).  
Neuroimaging 
Image Upload: Raw neuroimaging data and experimental meta-data (e.g. QA/QC scans, 
physiological signals, etc) will be de-identified and defaced and uploaded to LORIS for 
secure archive and sharing. 
Open Access Database: Neuroimaging data sets that pass QA/QC will be automatically 
run through standardized, image processing pipelines at True Positive, and the results will 
be linked with their corresponding raw data and metadata. These standardized processing 
results will be provided to researchers without precluding download of raw or intermediate 
processed data for use of alternative (pre)processing strategies under rules to be determined 
by the executive and steering committee. Datasets generated by preprocessing and analysis 
tools at individual sites (i.e., image processing and analysis pipelines) will also be uploaded 
to the LORIS system, as determined by the Executive and Steering committees, using 
standard formats (e.g., NIfTI) where available, and linked with their corresponding raw 
data and metadata.  
At the option of the Neuroimaging platform leaders/researchers, non-standardised 
preprocessing and analyses may be conducted within LORIS’ secure, high-performance 
computing environment. This would allow neuroimaging personnel to connect to 
dedicated high-end servers, virtual machines, and storage over a secure virtual private 
network (VPN) connection to run a selected set of individual analysis tools (e.g., FSL, 
AFNI, Freesurfer) or manage standardized, automated pipelines using the LONI 
workflow management engine. 
Genomics 

 
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Genomic analysis raw data and associated sample and experiment metadata will be de-
identified and uploaded to the LORIS molecular database subsystem for secure archival 
and sharing. Data types will include resequencing (IlluminaMiSeq; approx. 600 samples; 
3 GB/sample), exome sequencing (IlluminaHiSeq; approx. 100 samples; 50 GB/sample), 
genotyping (IlluminaiScan/HiScanexome arrays; approx. 700 samples; 5 MB/sample), as 
well as Sanger sequencing and qPCR/TaqMan assay outputs. 
   Documentation to be provided from the dedicated assay platform teams will be quality 
assurance reports from the assays and instruments and bioinformatics workflows including 
tuning parameters for the analyzed data. For analysis software tools deployed or developed 
centrally at LORIS there will be similar documentation available. 
The investigator and site study personnel will be trained on CRF completion.  The 
investigator is responsible for all entries in the CRF for completeness, accuracy and 
clarity.  The investigator or designee should complete the CRF as soon as possible after the 
information is collected.  The investigator is responsible to endorse all the information 
recorded in the CRF and will provide formal approval of the final submitted data. 
9.4 ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator will permit study related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s), providing direct access to source data/documents. 
9.4.1 DATA QUALITY ASSURANCE 
Study data will be entered in the CRF by trained study personnel.  Data validation edit 
checks will be defined and implemented.  Inconsistent and questionable data detected 
during data entry or data validation process will be queried.  Data clarification forms 
(DCFs) will be generated and any discrepancies will be resolved. 
Standardised subject demographic and clinical-research meta-data 
As quality control for transcribed data, double entry will be performed on a randomly 
chosen subset of 10% of the data from each clinical site over the course of the 
project.  Feedback on detected errors will be immediately provided to each site for ongoing 
QC and data improvement.  
Neuroimaging 
Standardized QC: We will leverage our experience with semi-automated, web-based 
visual image evaluation, and quantitative QC tools (http://www.birncommunity.org/tools-
catalog/) at the Montreal Neurological Institute and the Centre de recherche de l'Institut 
universitaire en santé mentale de Québec within Dr. Collins’ and Dr. Duchesne’s 
neuroimaging groups, respectively. (Dr. Collins & Duchesne to fill in)  
9.4.2 RETENTION OF STUDY DOCUMENTS 
The investigator must retain all study records for 25 years after the notification of the 
IRB/EC regarding the end of the study or according to applicable regulatory requirements. 

 
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If the investigator retires, relocates or withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the 
responsibility.  The Sponsor must be notified in writing if a custodial change occurs. 
9.5 PUBLICATION AND DATA ACCESS POLICY 
In order to access the data generated in this study, researchers must agree to abide by the 
CCNA Publication and Data Access policy, a document prepared by the CCNA Publicaton 
and Data Access Committee (PDAC) and which can be downloaded at www.ccna-ccnv.ca. 
The PDAC is made up of members of CCNA and is chaired by a member of the CCNA 
Research Executive Committee. PDAC members list is available upon request. Access to 
and analyses of CCNA acquired data by CCNA investigators will be granted automatically 
upon request of access to the PDAC. For non-CCNA investigators, CCNA data will be 
embargoed for one (1) year after the entire cohort has been completed, uploaded into 
LORIS, quality-controlled and cleaned, and subsequently locked. After the embargo 
period, non-CCNA investigators may be granted access to CCNA acquired data upon 
submission to the PDAC of background materials and of a project outline supporting their 
data access request. They will only be granted access to data related to the project outlined. 
CCNA partners will have the same access to CCNA acquired data as non-CCNA members, 
although they may ask CCNA investigators to pursue projects on their behalf. 
Prior to submission for publication or for presentation of any data or results obtained in 
this study, notification of the PDAC is required.  Draft manuscripts, abstracts and 
presentations should be submitted to the PDAC for review and approval.  The Participating 
Institutions will retain the ownership of the data obtained in this study.  Authorship of 
publications resulting from this study should accurately reflect the academic contribution 
of individuals to the design and implementation of the trial, analysis of the data and 
preparation of the manuscript. No researcher shall include identifiable personal health 
information in any publication or presentation.  All publications that arise from the use of 
data contributed by the participating institution will give acknowledgement, attribution, or 
co-authorship as appropriate in accordance with the International Committee of Medication 
Journal Editors (ICMJE) standards and any rules established by the data access committee.  
9.6 BIOLOGICAL SAMPLE ACCESS POLICY 
Biological samples will be stored at the Canadian Biosample Repository in Edmonton. 
Approximately half of the samples will be used for planned analyses which will occur at 
the Jewish General Hospital Clinical Laboratory in Montréal, Québec (on blood and urine), 
the laboratory of Judes Poirier at the Douglas Mental Health University Institute in 
Montréal, Québec (CSF), and the laboratory of Roger Dixon at the University of Alberta 
in Edmonton, Alberta. The rest will be available for investigators who wish to perform 
further analyses on the whole cohort or a subset. Access to these samples will be regulated 
by the Biological Sample Access Committee which is made up of members of CCNA 
(members list available on request). Requests for access will be assessed for feasibility, 
scientific rigour, and alignment with the consent of the participants. In order to be granted 
access to samples, investigators must agree that the data they generate from the samples 
will be included in the larger CCNA database on LORIS within 2 years of sample batch 
receipt. Samples will be shared within Canada only for a period of 3 years after the last 

 
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sample has been collected. After that 3 year period, they will be available to international 
researchers, if not already depleted. The full Biological Sample Access policy document is 
under development and will be made available upon its finalization. 
9.7 CONFIDENTIALITY 
All confidential information, verbal and written, provided to the investigator by the 
Sponsor will be kept in strict confidence, and restricted to the study personnel involved in 
conducting the study, except if the information is required by the IRB/IEC or similar 
committees. 
9.8 FINANCING  
Financing will be addressed in a separate agreement with study centres. 
 
 
 
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Appendix A: Criteria for Subjective Cognitive Impairment (from Jessen et al., 2014)97 
Core Diagnostic Criteria 
Operationalized as 
Self-experienced persistent decline in 
cognitive capacity in comparison with a 
previously normal status and unrelated to 
an acute event. 
Answer “yes” to both of the following 
questions: “Do you feel like your 
memory or thinking is becoming worse?” 
and “Does this concern you?” 
Normal age-, sex-, and education-adjusted 
performance on standardized cognitive 
tests, which are used to classify mild 
cognitive impairment (MCI) or prodromal 
AD. 
Global CDR=0; Logical Memory 2 
above ADNI education-adjusted 
cutoffs*; CERAD word list recall score 
>5; MoCA total score >25. 
 
Appendix B – NIA-AA Clinical Criteria for the Diagnosis of MCI due to AD (from 
Albert et al., 2011)98 
Core diagnostic criteria 
Operationalized as 
Concern regarding a change in cognition 
Report from patient and/or informant of 
such 
Impairment in one or more cognitive 
domains 
1 or more of the following: 
- 
Logical memory below 
ADNI cutoffs* 
- 
CERAD word list recall 
<6. 
- 
MoCA score 13-24 
inclusive  
- 
Global CDR>0 
Preservation of independence in 
functional abilities 
Score > 14/23 on the Lawton-Brody IADL 
scale 
Not demented 
Global CDR < 0.5 
 
 
 
 
 
 

 
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Appendix C: Criteria for Subcortical Ischemic Vascular Mild Cognitive Impairment 
(based on published criteria from Gorelick et al., 2011 and  Sachdev et al, 2014)4,99 
Core Diagnostic Criteria 
Operationalized as 
Presence of mild cognitive impairment (as 
defined in Appendix A) 
Meets Diagnostic Criteria of Appendix B 
Absence of prior symptomatic stroke 
(silent brain infarcts are allowed). 
No reported history of symptomatic stroke 
Presence of “diffuse, subcortical 
cerebrovascular disease” 
 
 1. Presence of 2 or more silent brain 
infarcts in supratentorial locations (i.e., 
excluding cerebellum or brainstem), OR 
2. Extensive white matter disease, defined 
as Age-Related White Matter Change 
(ARWMC) scale score of 2 or higher 
(indicating “beginning confluence of 
lesions” or greater) in any brain region.  
(See image below) 
 

 
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APPENDIX D – NIA-AA DIAGNOSTIC CRITERIA FOR ALZHEIMER'S DISEASE (AD) 
(from McKhann et al., 2011)100 
Core diagnostic criteria 
Operationalized as 
Gradual progressive change in memory and/or other 
cognitive function over more than 6 months. 
Report from patient and/or 
informant of such 
Objective evidence of significant decline in at least 2 
of the following cognitive /behavioural domains:  
- 
Episodic memory 
 
 
 
 
- 
Reasoning, problem 
solving 
- 
Visuospatial abilities 
- 
Language 
 
- 
Personality/behavior 
2 or more of the following: 
- 
Logical memory 
below ADNI 
cutoffs* 
- 
CERAD word list 
recall <7. 
- 
MoCA score 13-24 
inclusive (with at 
least one point lost 
in a non-memory 
task). 
- 
Positive response to 
the question: Has 
the participant had 
any changes in 
personality or 
behaviour Yes/No 
Impairment of functional abilities 
 
Positive response to the 
question: The cognitive 
deficits interfere with 
independence in everyday 
activities such as paying bills 
or managing medications 
Yes/No 
Non-AD causes of dementia ruled out 
No report or sign of any of the 
following: sudden onset, focal 
neurological features, early 
extrapyramidal signs, 
metabolic abnormalities, 
cerebrovascular disease, or 
MRI T2 or FLAIR signal 
abnormalities, or evidence for 
another concurrent, active 
neurological disease, or a non-
neurological medical 
comorbidity or use of 
medication that could have a 
substantial effect on cognition. 

 
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Appendix E: Criteria for Mixed Dementia (from McKhann et al., 2011)100 
 
Core Diagnostic Criteria 
Operationalized as 
Gradual progressive change in memory 
and/or other cognitive function over 
more than 6 months. 
Report from patient and/or informant of 
such. 
Objective evidence of significant decline 
in at least 2 of the following 
cognitive/behavioural domains:  
- 
Episodic memory 
- 
Reasoning, problem 
solving 
- 
Visuospatial abilities 
- 
Language 
- 
Personality/behaviour 
 
2 or more of the following: 
- 
Logical memory below 
ADNI cutoffs* 
- 
CERAD word list recall <7. 
- 
MoCA score 13-24 
inclusive (with at least one 
point lost in a non-memory 
task). 
- 
Positive response to the 
question: Has the participant 
had any changes in 
personality or behaviour in 
the last year Yes/No 
Impairment of functional abilities 
 
Positive response to the question: The 
cognitive deficits interfere with 
independence in everyday activities such as 
paying bills or managing medications 
Yes/No 
Non-AD causes of dementia may be 
present 
Report or sign of one or more of the 
following: sudden onset, focal neurological 
features, early extrapyramidal signs, 
metabolic abnormalities, cerebrovascular 
disease, or MRI T2 or FLAIR signal 
abnormalities, or evidence for another 
concurrent, active neurological disease, or 
a non-neurological medical comorbidity or 
use of medication that could have a 
substantial effect on cognition 
 
 
 
 

 
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APPENDIX F - REVISED CRITERIA FOR THE CLINICAL DIAGNOSIS OF DEMENTIA WITH 
LEWY BODIES (from McKeith et al., 2005)101 
Core diagnostic criteria 
Operationalized as 
Dementia defined as progressive cognitive 
 decline of sufficient magnitude to interfere  
with normal social or occupational  
function. 
Report from patient and/or informant of 
such over the course of at least one year 
Prominent or persistent memory 
impairment may not necessarily occur in  
the early stages but is usually evident  
with progression. Deficits on tests of  
attention, executive function, and  
visuospatial ability may be  
especially prominent. 
MoCA score 13-24 inclusive on testing 
within the last year. 
Has two or more of the following core 
features by themselves, or one or more if 
at least one suggestive feature (criteria 
below) is present: 
– Fluctuating cognition with 
pronounced variations in 
attention and alertness. 
– Recurrent visual 
hallucinations that are 
typically well formed and 
detailed.  
– Spontaneous features of 
parkinsonism.   
 
Positive responses to 2 or more of the 
following check box items: 
 
- 
Does the participant have 
fluctuating cognition with 
pronounced variations in 
attention and alertness 
Yes/No 
- 
Does participant have 
recurrent visual 
hallucinations? Yes/No 
- 
Does the participant have 
spontaneous features of 
parkinsonism Yes/No 
Has one or both of the following 
suggestive features: 
– REM sleep behavior 
disorder.   
– Severe neuroleptic 
sensitivity.  
Positive responses to 1 or more of the 
following check box items: 
- 
Does the participant move in 
their sleep or act out their 
dreams? Yes/No 
- 
Does the participant have 
severe neuroleptic sensitivity? 
Yes/No/Unknown 
 
 

 
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APPENDIX G: Criteria for Diagnosis of probable Parkinson’s Disease Dementia 
(from Emre et al., 2007; Dubois et al., 2007 & Postuma et al., 2015)102-104 
Core diagnostic criteria 
Operationalized as 
Both must be present: 
 
Meets the International Parkinson and 
Movement Disorder Society clinical 
diagnostic criteria for Parkinson’s disease. 
 
 
Has a dementia syndrome based on MDS 
Task Force proposed criteria: insidious 
onset and slow progression, developing 
within the context of established 
Parkinson’s disease and diagnosed by 
history, clinical, and mental examination, 
and defined as: 
- 
Impairment in more than 
one cognitive domain. 
- 
 Representing a decline 
from premorbid level. 
- 
 Deficits severe enough to 
impair daily life (social, 
occupational, or personal 
care), independent of the 
impairment ascribable to 
motor or autonomic 
symptoms. 
“Yes” response to 8 items of the 
diagnostic rating sheet for probable PD-D 
recommended by the MDS task force: 
 
1. Parkinson’s disease? 
2. Parkinson’s disease developed before 
dementia? 
3. MoCA<20? 
4. Dementia has Impact on ADLs? 
5. Impaired cognition? (For Yes, at least 
of 2 of 4 tests below are abnormal) 
Mark which Tests are abnormal (taken 
from MoCA): 
Sevens backwards; 
Lexical fluency or clock drawing; 
Figure copy; 
delayed word recall less than 3 of 5. 
6. Absence of Major Depression? 
7. Absence of delirium? 
8. Absence of other abnormalities that 
obscure diagnosis? 
 
 
Appendix H: Criteria for Mild Cognitive Impairment in Parkinson’s Disease (from 
Litvan et al., 2012)105 
 
Core Diagnostic Criteria 
Operationalized as 
Diagnosis of Parkinson’s disease as based 
on the IPMDS Criteria 
“Yes” response to check box item on 
diagnosis of Parkinson’s Disease 
Gradual decline, in the context of 
established PD, in cognitive ability 
reported by either the patient or informant, 
or observed by the clinician 
Report from patient and/or informant of 
such 
Cognitive deficits on either formal 
neuropsychological testing or a scale of 
global cognitive abilities  
MoCA 13-24 inclusive 

 
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Cognitive deficits are not sufficient to 
interfere significantly with functional 
independence, although subtle difficulties 
on complex functional tasks may be 
present 
Negative response to the question: The 
cognitive deficits interfere with 
independence in everyday activities such 
as paying bills or managing medications 
Yes/No 
 
APPENDIX I - Diagnostic criteria for FTD subgroups 
Progressive Supranuclear Palsy (PSP) Diagnostic Criteria (from Litvan et al., 
1996)106 
Core diagnostic criteria 
Operationalized as 
Possible PSP 
- 
Vertical supranuclear palsy 
OR   
- 
Both slowing of vertical 
saccades 
& 
postural 
instability with falls < 1yr 
after disease onset 
Probable PSP 
 
                  -    Vertical supranuclear palsy    
                       & postural instability with   
                       falls < 1yr after disease  
                       onset 
a)“Definitely present” box checked on 
Clinical PSP features question on presence 
of supranuclear palsy as determined by a 
qualified clinician 
b) “Definitely present” box checked on 
Clinical PSP features question on postural 
instability with falls < 1 yr after disease 
onset 
c) “Definitely present” box checked on 
Clinical PSP features question on slowing 
of saccades as determined by a qualified 
clinician 
 
Possible PSP= a, or b & c positive 
Probable PSP= a and b positive 
Possible behavioural variant Frontotemporal Dementia (bvFTD) (from Rascovsky 
et al., 2011)107 
Core diagnostic criteria 
Operationalized as 
At least 3 of 6 diagnostic features: 
- 
Disinhibition 
- 
Apathy / Inertia 
- 
Loss of sympathy / empathy  
- 
Perseverative / compulsive  
- 
Hyperorality 
- 
Neuropsychological profile 
- Positive responses on gateway question 
and 3 items of the NACC FTLD module 
bvFTD features checklist OR Positive 
responses on gateway question and 2 
items of the NACC FTLD module bvFTD 
features 
checklist 
and 
evidence 
of 
executive dysfunction on cognitive screen. 
 
Functional disability 
Positive answer to impaired functioning 
on the NACC FTLD module bvFTD 
features checklist. 

 
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Neuroimaging consistent with bvFTD (if 
available). 
Frontal lobe atrophy on MRI or reduced 
frontal lobe metabolism on FDG or 
reduced frontal perfusion on SPECT 
 
Diagnostic Criteria for Corticobasal Syndrome (CBS) (from Armstrong et al., 
2013)108      
Core diagnostic criteria 
Operationalized as 
Possible CBS  
• 
May be symmetric 
• 
1 of: a) limb rigidity or akinesia, 
b) limb dystonia, c) limb 
myoclonus  
• 
plus 1 of: d) orobuccal or limb 
apraxia, e) cortical sensory deficit, 
f) alien limb phenomena (more 
than simple levitation) 
Probable CBS 
• 
Asymmetric presentation 
• 
2 of: a) limb rigidity or akinesia, 
b) limb dystonia, c) limb 
myoclonus  
• 
plus 2 of: d) orobuccal or limb 
apraxia, e) cortical sensory deficit, 
f) alien limb phenomena (more 
than simple levitation) 
a) “Definitely present” box checked on 
Clinical CBS features question on limb 
rigidity and akinesia as determined by a 
qualified clinician 
b) “Definitely present” box checked on 
Clinical CBS features question on limb 
dystonia as determined by a qualified 
clinician 
c) “Definitely present” box checked on 
Clinical CBS features question on limb 
myoclonus as determined by a qualified 
clinician 
 
d) “Definitely present” box checked on 
Clinical CBS features question on 
orobuccal or limb apraxia as determined 
by a qualified clinician 
e) “Definitely present” box checked on 
Clinical CBS features question on cortical 
sensory deficit as determined by a 
qualified clinician 
f) “Definitely present” box checked on 
Clinical CBS features question on alien 
limb phenomena as determined by a 
qualified clinician 
 
Possible CBS= 1 of a-c and 1 of d-f 
present 
Probable CBS= 2 or a-c and 2 of d-f 
present plus symmetric presentation 
 
 
 
 
 
 
 

 
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Primary Progressive Aphasia (PPA), all forms (from Mesulam, 2001)109 
 
Core diagnostic criteria 
Operationalized as 
Insidious onset and gradual progression 
Report of informant of same. 
Must have all 3: 
- 
Language impairment as the 
most 
prominent 
clinical 
feature 
- 
Language difficulty as the 
cause of impaired ADL’s 
 
 
 
 
 
 
- 
Aphasia 
as 
the 
most 
prominent feature at onset 
and in early stages 
 
- 
Report of informant of 
same 
 
 
- 
Positive response to the 
question: The language 
deficits interfere with 
independence in everyday 
activities such as work, 
hobbies, or interacting 
with friends  Yes/No 
 
- 
Report of informant of 
same 
Must not: 
- 
Be better accounted for by 
other 
neurodegenerative, 
psychiatric, 
or 
medical 
disorders  
- 
Have initial episodic 
memory, visual memory, 
and visuoperceptual 
impairments 
 
 
- 
Have prominent initial 
behavioral disturbances 
 
- 
Medical history 
 
 
 
- 
Intact performance on 
clock and figure drawing 
on the MoCA and 
relatively normal Benson 
Figure Recall 
 
- 
Negative response to 
gateway question on 
NACC FTLD module 
bvFTD features checklist.  
 
PPA-Semantic (from Gorno-Tempini et al., 2011)110 
Core diagnostic criteria 
Operationalized as 
Both must be present: 
- 
Impaired confrontation 
naming 
 
 
- 
Impaired comprehension of 
single words 
 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on poor 
object naming; 
- 
“Definitely present” box 
checked on Clinical PPA 

 
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features question on 
impaired word 
comprehension; 
At least 3 of the following 4 features: 
- 
Impaired object knowledge 
 
 
 
 
- 
Surface dyslexia or 
dysgraphia 
 
 
 
- 
Spared repetition 
 
 
 
 
- 
Spared syntax and motor 
speech 
 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on poor 
object/person knowledge; 
 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on 
surface dyslexia and 
dysgraphia; 
 
- 
“Absent” box checked on 
Clinical PPA features 
question on impaired 
speech repetition 
 
- 
“Absent” box checked on 
Clinical PPA features 
question on grammatical 
errors and effortful speech  
 
PPA-Nonfluent/Agrammatic (from Gorno-Tempini et al., 2011)110 
Core diagnostic criteria 
Operationalized as 
At least one must be present: 
- 
Agrammatism 
 
 
 
- 
Apraxia of speech 
 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on 
grammatical errors; 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on 
effortful speech; 
At least 2 of the following 3 features: 
- 
Impaired complex syntax 
 
 
 
 
- 
Spared comprehension of 
single words 
 
 
 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on 
impaired speech repetition; 
 
- 
“Absent” box checked on 
Clinical PPA features 
question on impaired word 
comprehension; 

 
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- 
Spared object knowledge 
 
 
 
 
- 
“Absent” box checked on 
Clinical PPA features 
question on poor 
object/person knowledge 
 
PPA-Logopenic (from Gorno-Tempini et al., 2011)110 
Core diagnostic criteria 
Operationalized as 
Both must be present: 
- 
Impaired word retrieval and 
naming 
 
 
 
- 
Impaired repetition of 
sentences and phrases 
 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on 
impoverished word 
selection; 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on 
impaired speech repetition; 
At least 3 of the following 4 features: 
- 
Impaired complex syntax 
 
 
 
 
- 
Spared comprehension of 
single words 
 
 
 
- 
No apraxia of speech 
 
 
 
 
- 
No agrammatism 
 
 
- 
“Definitely present” box 
checked on Clinical PPA 
features question on speech 
sound/word errors; 
 
- 
“Absent” box checked on 
Clinical PPA features 
question on impaired word 
comprehension; 
 
- 
“Absent” box checked on 
Clinical PPA features 
question on effortful or 
halting speech; 
 
- 
“Absent” box checked on 
Clinical PPA features 
question on grammatical 
errors.