5-Cog Battery to Improve Detection of Cognitive Impairment and Dementia
Phase: NA
Conditions: Dementia, Cognitive Impairment, Mild Cognitive Impairment, Neurocognitive Disorders
Sponsor: Albert Einstein College of Medicine

IRB NUMBER: 2018-9140 
IRB APPROVAL DATE: 12/12/2022 
i 
Protocol Template, Version 2.0 
 
 
 
 
 
 
5-Cog Battery for Detecting 
Cognitive impairment and 
Dementia 
NCT03816644 
12/12/2022 

IRB NUMBER: 2018-9140 
IRB APPROVAL DATE: 12/12/2022 
i 
Protocol Template, Version 2.0 
 
 
5-Cog Battery to improve detection of cognitive impairment and dementia: UH3 
Protocol 
 
 
Principal Investigator: 
 
Dr. Joe Verghese M.B.B.S. 
 
 
Supported by: 
 
The National Institute of Neurological Disorders and Stroke (NINDS) 
(Grant Number: 5UG3NS105565-02) 

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5-Cog UH3 Protocol, Version 1.5 
 
 
TABLE OF CONTENTS 
Page 
 
PRÉCIS ......................................................................................................................................... iv 
Study Title .................................................................................................................................. iv 
Objectives ................................................................................................................................... iv 
Design and Outcomes ................................................................................................................ iv 
Interventions and Duration ......................................................................................................... iv 
Sample Size and Population ....................................................................................................... iv 
STUDY TEAM ROSTER ............................................................................................................. 1 
Principal Investigator: Joe Verghese .........................................................................................1 
Co-Investigators ...........................................................................................................................1 
PARTICIPATING STUDY SITES...............................................................................................1 
1 
Study objectives ..................................................................................................................... 2 
1.1 
Primary Objective ........................................................................................................... 2 
1.2 
Secondary Objectives ...................................................................................................... 2 
2 
BACKGROUND AND RATIONALE ................................................................................. 2 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................... 2 
2.2 
Study Rationale ............................................................................................................... 2 
3 
STUDY DESIGN ................................................................................................................... 2 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................. 3 
4.1 
Inclusion Criteria ............................................................................................................. 3 
4.2 
Exclusion Criteria ............................................................................................................ 3 
4.3 
Study Enrollment Procedures .......................................................................................... 4 
5 
STUDY INTERVENTIONS ................................................................................................. 4 
5.1 
Interventions, Administration, and Duration ................................................................... 4 
5.2 
Handling of Study Interventions ..................................................................................... 5 
5.3 
Concomitant Interventions ...............................................................................................5 
5.3.1 Allowed Interventions ................................................................................................. 5 
5.3.2 Required Interventions ................................................................................................ 5 

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5.3.3 Prohibited Interventions .............................................................................................. 6 
5.4 
Adherence Assessment .....................................................................................................6 
6 
STUDY PROCEDURES ....................................................................................................... 6 
6.1 
Schedule of Evaluations .................................................................................................. 7 
6.2 
Description of Evaluations .............................................................................................. 8 
6.2.1 Screening Evaluation ................................................................................................... 8 
6.2.2 Enrollment, Baseline, and/or Randomization .............................................................. 8 
6.2.3 Follow-up Visits .......................................................................................................... 9 
6.2.4 Completion/Final Evaluation .....................................................................................10 
7 
SAFETY ASSESSMENTS .................................................................................................. 10 
7.1 
Specification of Safety Parameters ............................................................................... 10 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ..... 10 
7.3 
Adverse Events and Serious Adverse Events ................................................................ 10 
7.4 
Reporting Procedures .................................................................................................... 11 
7.5 
Follow-up for Adverse Events ...................................................................................... 11 
7.6 
Safety Monitoring ......................................................................................................... 11 
8 
INTERVENTION DISCONTINUATION ........................................................................ 11 
9 
STATISTICAL CONSIDERATIONS ............................................................................... 12 
9.1 
General Design Issues ................................................................................................... 12 
9.2 
Sample Size and Randomization ................................................................................... 12 
9.2.1 Treatment Assignment Procedures .............................................................................12 
9.3 
Interim analyses and Stopping Rules ............................................................................ 12 
9.4 
Outcomes ....................................................................................................................... 13 
9.4.1 Primary outcome ....................................................................................................... 13 
9.4.2 Secondary outcomes .................................................................................................. 13 
9.5 
Data Analyses ................................................................................................................ 13 
10 DATA COLLECTION AND QUALITY ASSURANCE ................................................. 13 
10.1 
Data Collection Forms .................................................................................................. 13 
10.2 
Data Management ..........................................................................................................14 
10.3 
Quality Assurance ..........................................................................................................14 
10.3.1 
Training ................................................................................................................. 14 
10.3.2 
Quality Control Committee ................................................................................... 14 
10.3.3 
Metrics ................................................................................................................... 14 

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10.3.4 
Protocol Deviations ............................................................................................... 14 
10.3.5 
Monitoring ............................................................................................................. 14 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY .................................................. 14 
11.1 
Institutional Review Board (IRB) Review .................................................................... 14 
11.2 
Informed Consent Forms ................................................................................................15 
11.3 
Participant Confidentiality..............................................................................................15 
11.4 
Study Discontinuation ....................................................................................................15 
12 ETHICAL CONSIDERATIONS ....................................................................................... 15 
13 COMMITTEES ................................................................................................................... 15 
14 PUBLICATION OF RESEARCH FINDINGS ................................................................ 15 
15 REFERENCES .................................................................................................................... 16 

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PRÉCIS 
 
Study Title 
 
5-Cog Battery to improve detection of cognitive impairment and dementia 
 
Objectives 
 
Despite the availability of numerous cognitive assessment tools, cognitive impairment 
related to dementia is frequently under-diagnosed in primary care settings, and is a more 
prevalent problem among older African-Americans and Hispanics than among older 
whites. To overcome the technical, cultural and logistic barriers of current cognitive 
screens and dementia care in primary care settings we propose to validate a 5-minute 
cognitive screen (5-Cog) coupled with a decision tree to identify persons at high risk of 
developing dementia in multi-ethnic primary care populations with socio-economic 
challenges. The primary objective is to test the ability of the 5-Cog battery and decision 
tree paradigm to improve dementia care in primary care patients with cognitive concerns. 
The 5-Cog battery includes the Picture based Memory Impairment Screen (PMIS),1 
Motoric Cognitive Risk Syndrome (MCR) diagnosis,2-4 and a brief non-memory picture 
based test (Symbol Match). Our cognitive assessment algorithm will sort patients with 
‘cognitive impairment’ from those with ‘no cognitive impairment’. Moreover, it is 
coupled with a decision tree to guide clinicians through the follow up on any 5-Cog 
results. 
 
Design and Outcomes 
We propose to conduct a single-blind randomized clinical trial (RCT) in 1,200 primary 
care patients age 65 and older presenting with cognitive complaints. Non-medical 
professionals will administer the 5-Cog in the intervention group and a 5-minute health 
literacy and grip strength assessment in the active control group. 
 
Interventions 
The interventions will be given after randomization and before the patients sees the 
physician. After completing the intervention or control assessments, the tester will 
provide results to the treating physician with follow-up recommendations based on the 
decision tree. 
 
Participants randomized to the active control will receive a health literacy questionnaire, 
the Short Assessment of Health Literacy (SAHL) and grip strength assessment to match 
time (5 minutes), tester exposure and decision tree procedure in the 5-Cog arm. To 
parallel the study procedures and flow in the 5-Cog arm, a decision tree for the active 
control arm will also be created. Results of the control screen and the decision tree will 
be presented to the physicians at the same visit. 

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Sample Size and Population 
Our testing will be carried out in an urban, multi-ethnic Bronx patient population. We 
will use a randomized block design to place 1,200 patients into either 5-Cog or control 
groups. Patients will be stratified by gender and age (< or >75 years). 

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STUDY TEAM ROSTER 
Administrative Core: 
Principal Investigator (Dr. Verghese): will head the Management Team and its Cores. He will 
assign responsibilities to team members and integrate their feedback to ensure timely progress. 
To this end, he will chair regularly scheduled, full-team meetings with standing agendas and 
predictable cycles of reports. Dr. Verghese will also hold smaller, Core meetings in order to 
manage specific concerns and unforeseen issues. If necessary, he will also meet individually with 
team members on an ad hoc basis. Dr. Verghese manages programs by promoting a sense of 
participation and ownership by all investigators and staff. He is strongly committed to an open 
management style, encouraging staff to identify problems and propose solutions. 
Project Manager (Emmeline Ayers): will assume fiscal and administrative management, 
including supervising budgets, tracking adherence to timelines, and maintaining collaborative 
relationships among the PI, investigators and cross-consortium coordinating team (CCCT) 
members. She will also be responsible for coordinating with members of the CCCT to conduct 
pilot studies and facilitate sharing of data and paradigms. She will prepare reports for the NIH 
and the IRB. 
Study Coordinator will supervise daily operations of this project. He/She will coordinate patient 
recruitment and scheduling of screening days with the research assistants. The coordinator will 
be responsible for protocol development, procedure implementation and personnel management 
of the research assistants and office coordinators. He/She will monitor and back-up databases, 
conduct quality control audits and clean as well as prepare datasets for the statistical core and for 
institutional and other advisory board reports. 
 
Clinical Core: 
Supervisors (Drs. Ehrlich and Zwerling): will oversee training of personnel administering the 5- 
Cog, and protocol implementation within a primary care setting. They will be responsible for 
administrative discussions with partners at Montefiore. Dr. Ehrlich is the Associate Chief of the 
Division of Geriatrics at Montefiore Medical Center and the Medical Director of Montefiore’s 
Home Health Agency. Dr. Zwerling is the Associate Director of the Montefiore-Einstein Center 
for the Aging Brain and has experience developing programs to enhance health professionals’ 
capacity to screen, diagnose and develop personalized plans of care for cognitively impaired 
patients within the Montefiore Health System. 
Operations manager (Dr. Ansari): Dr. Ansari is Medical Director of the primary care clinic 
where our trial is based. He will act as a guide on the logistical side of the operation working 
with clinic staff and the project manager to develop and implement protocols in the clinics. 
Trainer (Dr. Chalmer): is a board certified geriatrician and experienced clinician-educator who 
will train the research assistants involved in this study as well as liaise with the doctors to 
identify barriers and facilitate implementation of the paradigms. 
 
Cognitive Core: 
Neuropsychologist (Dr. Weiss): has experience conducting pilot studies on the utility of brief 
neurocognitive/neuropsychological evaluations in the clinical assessment of older adults. 
Consultant (Dr. DeGutis): will guide us in refining our diagnostic tools for cognitive impairment 
in older adults. 
 
Statistical Core: 
Biostatistician (Dr. Wang): will be responsible for choosing proper analytical tools to determine 

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the statistical relevance of data generated in each of the research aims. Dr. Wang is a 
biostatistician who has participated in a range of studies including multiple clinical trials and 
several large epidemiological studies. 
Healthcare Economist (Dr. Rasekh) is a Healthcare Analyst at Montefiore and will be 
responsible for overseeing the cost effectiveness analysis of this proposal. 
 
Data Management Core: 
Records Manager (Dr. Malik): Dr. Malik is a board certified geriatrician, and has a wealth of 
experience utilizing our electronic medical record (EMR) system (EPIC) for research purposes. 
She will liaise with the EPIC systems programmer to extract relevant patient information. 
Database programmer: will be responsible for the development, upkeep, and maintenance of a 
centralized database in which all project data will be stored. They will work with the EPIC 
programmer and EPIC data analyst to integrate data collected from the EPIC system with study 
data. 
 
Health-disparities Core: 
Test Development (Dr. Walker): has been conducting NIH-funded translational research in 
underserved populations for over 25 years. She will advise us on health disparities issues in 
implementation as well as in analysis. 

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1 
STUDY OBJECTIVES 
 
1.1 Primary Objective 
The 5-Cog battery and decision tree will improve dementia care in primary care settings for 
patients with cognitive concerns. Improved dementia care will be measured by new Mild 
Cognitive Impairment syndrome (MCI) or dementia diagnoses, laboratory investigations to 
rule out reversible causes of cognitive impairment, new dementia medication prescriptions, 
and specialist referrals for dementia care, and will be tracked using the electronic medical 
record (EMR) system. 
 
1.2 Secondary Objectives 
Utilization (emergency room visits and hospitalizations) for patients in both arms will be 
tracked and reviewed at regular intervals throughout the study period. Utilization is defined 
in terms of specialty visits, emergency room visits, and hospitalizations up to 12 months 
following the screening visit. This will be tracked via the EMR in both groups. 
 
2 
BACKGROUND AND RATIONALE 
 
2.1 Background 
Cognitive impairment related to dementia is frequently under-diagnosed in primary care 
settings despite the availability of numerous assessment tools.5-7 Missed detection delays 
treatment of reversible conditions as well as provision of support services and critical 
planning.8 This problem is more prevalent among older African-Americans and Hispanics 
than among older whites.5-7 
 
Picture Memory Impairment Screen (PMIS): A major limiting factor in identifying 
dementia in health disparate populations are the lack of cognitive screens that account for 
cultural differences and variable literacy rates. Also, many cognitive screens are lengthy 
and not designed for non-specialist use, limiting their application in primary care. The 
Memory Impairment Screen (MIS) is a brief, 4-item delayed free- and cued-recall test that 
was developed and validated in an urban U.S. population,9 and recommended for dementia 
screening.10-12 However, the MIS requires minimum reading skills, which limits its use in 
low literacy populations.11 To address limitations of the MIS and other language-based 
cognitive screeners,10 we developed the PMIS that uses pictures. The PMIS minimizes 
educational bias, and expands the scope of dementia screening to low literacy populations. 
In our validation study in India,1 the PMIS discriminated between cognitively normal older 
adults and those with dementia, regardless of age, sex, education or depression.1 
The PMIS takes 4 minutes, which includes a minimum 2-minute delay period between 
picture presentation and recall. During this delay, another cognitive test can be given as an 
interference task, which prevents patients from using strategies such as mentally rehearsing 
items that may lead to false negative ‘normal’ performance. In the 5-Cog, we will fill the 2- 
minute interference period with the MCR diagnosis and paper-based Symbol Match Test. 
We developed highly reliable alternate forms of the PMIS, which enable repeated 
administration.12 Professionals and non-professionals (health aides with 10 years 
schooling) successfully administered the PMIS in rural and urban populations in India and 
USA.13, 14 High inter-rater reliability was seen between administration of PMIS by 
clinicians and nurses.15 The PMIS picture items were administered on a computer screen 

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and using cards.16 These findings support the feasibility of using the PMIS in various 
settings and by personnel with different levels of expertise. 
 
Motoric Cognitive Risk Syndrome (MCR): Many pre-dementia syndromes based on 
cognitive tests or biomarkers have been proposed17, 18 but their requirement for specialized 
equipment and medical professionals to conduct examination limits feasibility in resource- 
poor primary care settings. Increasingly, the simultaneous existence of motor and cognitive 
impairments has been recognized as an important clinical marker of brain pathologies. 
Hence, incorporating measures of motor function (gait speed) into dementia risk 
assessments may improve predictive power.19 We described the MCR syndrome; 
characterized by cognitive complaints and slow gait.4, 20 The MCR criteria are similar to 
those used for Mild Cognitive Impairment syndrome (MCI).21, 22 We substitute the 
cognitive test criterion in MCI with gait speed in MCR, but retain the remaining MCI 
criteria (cognitive complaints and absence of dementia). MCR diagnosis is easy to 
implement because it only requires verification of cognitive complaints and a stopwatch to 
measure gait speed over a fixed distance. 
In a multi-country study of over 26,000 persons aged 60 and older, MCR affected 1 in 10 
participants.20 Advancing age was associated with MCR but there were no sex differences 
in prevalence. Participants with MCR had a higher disease burden and performed worse on 
cognitive tests than non-MCR participants.20 MCR was associated with a 70% increased 
risk of developing cognitive decline (on MMSE).20 The association of MCR with cognitive 
impairment was robust even when the analysis was restricted to cognitively healthy adults 
(Mini-Mental State Examination scores ≥28), supporting MCR as a very early clinical 
marker of cognitive decline.20 MCR diagnosis in older adults was associated with deficits 
in executive function, attention and language as well as overall cognitive status.23 In 4 
longitudinal cohort studies, participants with MCR were twice as likely to develop 
dementia, and were at 2.2 times the risk of developing Alzheimer’s disease specifically.20, 
24, 25 MCR predicted dementia with greater accuracy than its individual components of 
either slow gait or subjective cognitive complaints.20 Because MCR is diagnosed 
independently of cognitive tests, we avoid redundancy (diagnostic circularity) by not using 
the same tests to define both pre-dementia and dementia syndromes. In our multi-country 
study, clinical overlap between MCR and MCI cases was only 39%; indicating that the 
presence of either syndrome alone failed to identify a large pool of at-risk seniors.2 
From a diagnostic perspective, MCR offers several benefits over other pre-dementia 
assessments. Gait speed has high reliability between different protocols,26, 27 excellent 
validity in predicting health outcomes,26, 27 and is recommended as a geriatric vital sign.28 
Non-professionals can easily be trained to measure gait speed in a minimal amount of time 
and without expensive equipment, making screening cheap and efficient in clinical settings. 
Hence, timing gait and asking brief cognitive questions to define MCR is practical and 
feasible in resource-poor settings, and can help streamline high-risk individuals for further 
investigations. The entry criteria for our study requires presence of cognitive complaints. 
Hence, MCR diagnosis procedure in the 5-Cog arm only requires measurement of timed 
gait over a fixed distance, and determination of slow gait using previously established 
cutscores in our population. 
 
Paper-based Symbol Match Test: Match is a tablet-based test of executive functions and 
speed developed by the CCCT at University of California San Francisco (UCSF). Our team 
has created a paper-based version of the Symbol Match stimuli to act as a screening tool 

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which may identify patients with cognitive impairment who were not identified by the 
PMIS or MCR. 
 
2.2 Study Rationale 
Our group has two decades of experience developing tools to detect dementia in health 
disparate populations. Notably, we developed the PMIS, which is a brief cognitive screener 
that relies on culture fair pictures and does not need to be administered by a medical 
professional.1 The PMIS demonstrated sensitivity of 95% and a specificity of 99% for 
detecting dementia in a low-literacy population in India.1 We also validated the MCR 
diagnosis in multiple cohorts in many countries.2-4 This highly accessible clinical test relies 
on the presence of slow gait and cognitive self-complaints to identify individuals at high 
risk of converting to dementia. Both the PMIS and the MCR are highly sensitive and 
specific first-line assays that can be followed up with more thorough and complex 
cognitive testing.2-4 
 
Building on our work, we propose to validate a 5-minute screen (5-Cog) to identify persons 
with or at high risk of developing dementia, and to flag them for further evaluation. We 
propose to do this in multi-ethnic Bronx primary care populations with socio-economic 
challenges. The 5-Cog battery will include the PMIS, MCR syndrome diagnosis, and brief 
non-memory picture based test, Symbol Match. 
 
The 5-Cog will sort out patients with or at high risk of developing ‘cognitive impairment’ 
from those with ‘no cognitive impairment’. The 5-Cog battery will overcome many of the 
implementation barriers of previous cognitive screens;13, 29, 30 it will be fast, low cost, easy 
to implement (requires only pen, paper and stopwatch), administered by non-clinicians 
(research assistants) after minimal training, not educationally or culturally biased, not 
confounded by depression and will not require informants. 
 
3 
STUDY DESIGN 
We propose to conduct a single-blind RCT to validate the 5-Cog battery and decision tree 
(Fig. 1). The trial will span 42 months and involve an ethnically diverse Bronx primary 
care population of 1,200 older patients with cognitive concerns (Fig. 2). We chose an active 
control (health literacy and grip) to balance time and tester exposure in the 5-Cog group. 
Our primary outcome is improved dementia care, which is an outcome that informs health 
decisions and is valued by primary care clinicians, older patients and their caregivers. We 
bring together an inter-disciplinary team with major aging and clinical trial experience. We 
have developed partnerships with clinicians in our primary care clinic site. 
 
Design considerations: We will take a pragmatic, real world approach in our trial. We will 
not ask physicians to deny patients any procedures offered routinely. For instance, 
clinicians have access to the PMIS and other cognitive screeners (not included in the 5-Cog 
screen) in our EMR. We will not ask clinicians to avoid using these screeners in enrolled 
patients. But we will track cognitive screener use by clinicians in control and 5-Cog arms 
via the EMR. We hypothesize that time constraints and other barriers as well as the absence 
of the MCR and Symbol Match procedure in the EMR will limit use and efficacy of 
cognitive screeners by primary care physicians. The proportion of older women is higher 
than men in our clinics and aging studies.3, 14, 31 Consistent with our pragmatic approach, 

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we will not strive for equal sex distribution within a study arm, but balance sex distribution 
by selecting gender as a stratification variable. There is no trial design without weakness 
and we will clearly state these in any publications. 
 
Recruitment: We will 
enroll 1,200 older patients 
with cognitive concerns 
(reported by patient or 
noted by caregivers or 
clinic staff) over 30 
months; estimated 
enrollment rate is 8-10 per 
week. This enrollment rate 
conservatively assumes a 
>50% refusal rate from 
potentially eligible 
participants. Our 
enrollment rate in our pilot 
study at the same clinical 
site was about 6-8 per 
week when participants 
were asked to complete a 
longer battery of 
assessments. While we 
anticipate that many 
potential participants may 
be attending our primary 
care clinics for their 
Medicare Annual Wellness 
visit,12 we will also recruit 
patients attending the 
clinics for other medical 
reasons. Montefiore 
Medical Center is the main 
healthcare system for 
Bronx county; one of the most ethnically diverse communities in the nation with an elderly 
population of 140,000 (U.S. census data). Patients age 65 and older account for >20,000 
primary care visits at Montefiore annually; ensuring an adequate pool for recruitment. The 
non-clinician tester will approach all patients age 65 and over attending our primary care 
clinic sites. Those expressing interest will be screened at the same visit to determine 
eligibility. Information regarding demographics, socio-economic status and medical 
illnesses will be collected. 
 
Primary Outcome: Our primary outcome is improved dementia care. This outcome is 
collected prospectively from EMR and related medical records by data analysts (blinded to 
study arm allocation and test results), and do not require patient interviews. This primary 
outcome is defined as meeting any one of the following endpoints within 90 days of the 
clinic visit at which the patient was randomized. Similar composite endpoints to define 

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dementia care have been used in several prior clinical trials in cognitively impaired 
patients.32-36 
1. New diagnosis of dementia (relevant ICD-10 codes) or MCI (331.83) documented in the 
EMR. The recent DSM-V criteria37 include categories of ‘major neurocognitive 
disorder’ and ‘mild neurocognitive disorder,’ which overlap with dementia and MCI. 
These categories will also be included but a recent internal audit indicated that they are 
as yet not in widespread use in our primary care clinics (cf. specialty clinics). 
2. Tests ordered for reversible causes of cognitive impairment as recommended by the 
published guidelines of professional societies (e.g. thyroid function tests, B-12 level, CT 
or MRI scans).15, 38-41 
3. New prescriptions for dementia medications in EMR. 
4. Referral for cognitive/dementia evaluation by specialists (Neurology, Geriatrics or 
Psychiatry) in EMR. 
 
Secondary/exploratory outcomes: Health care utilization data (secondary outcome) is 
abstracted from EMR. Additional tests (described below) take approximately 60 minutes of 
participants’ time. To avoid interrupting clinic flow, these tests will be done at the same 
visit as the enrollment, but after the patient sees their clinician. These tests are exploratory 
outcomes used to generate new hypotheses or provide insights into 5-Cog efficacy. 
 
a) Health care utilization (secondary outcome). Utilization (emergency room visits and 
hospitalizations) for patients in both arms will be tracked up to 12 months from the clinic 
visit at which the patient was randomized and reviewed at regular intervals by data 
analysts throughout the study period. The data analysts will have no participant contact 
and be blinded to study assignment. The EMR system is in place in our institution. All 
visit notes and diagnoses are to be entered within 48 hours of the encounter. A series of 
electronic reminders is sent to clinicians to complete delinquent entries. Patients in both 
arms will be covered by risk or shared savings reimbursement arrangements Montefiore 
has with private health insurance companies or will be fee-for-service Medicare 
beneficiaries attributed to the Montefiore Next Generation Accountable Care 
Organization.42-44 Montefiore either processes or has access to claims data for these 
patients, enabling analysis of encounters and costs through the Montefiore EMR and 
reports received monthly from CMS. The detailed claims-level data will allow for 
tracking and analysis of the utilization of numerous healthcare services. A significant 
amount of data on care and services that patients receive from providers outside of 
Montefiore will also be available for inclusion in our analyses. 
b) Neuropsychological Battery (exploratory outcome): The battery will take 60 minutes 
to complete and will include the measures below (Table 1). The tests are selected from 
those used for diagnostic testing in our dementia clinic, and with established norms for 
different ethnic groups and educational levels.14 The battery will be supervised by Dr. 
Weiss (Cognitive Core); blinded to 5-Cog results. The battery is administered in 
English or Spanish to probe general mental status (MoCA) as well as specific cognitive 
domains, particularly memory (Hopkins Verbal Learning Test-R45), processing speed 
(Symbol Digit Modalities Test46), language (letter fluency,47, 48 category fluency,48 
Boston Naming Test48), and visuo-spatial abilities (clock drawing12).49For ethical 
reasons, if results from the neuropsychological testing are in the dementia range, Dr. 
Weiss will inform the treating physician after the 90-day window to determine 
improved dementia care outcomes. 

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Table 1. Neuropsychological Assessments 
Domain 
Mental Status 
Tasks 
MoCA 
Premorbid Estimate/ 
Reading ability 
Wechsler Test of Adult Reading (WTAR)/ Word 
Accentuation Test (TAP) 
Memory 
Hopkins Verbal Learning Test- R(HVLT-R) 
Naming 
Boston Naming- Short Form 
Fluency 
Controlled Oral Word Association Test (FAS); 
Animals 
Timed Transcription 
Symbol Digit Modalities Test 
Clock 
Clock Drawing Test 
Mood 
Geriatric Depression Scale-30 item 
 
c) Advance care planning (exploratory outcome): We will explore whether 5-Cog 
screening leads to higher rates of advance care planning such as referrals to social work 
or Alzheimer’s Association or having health care proxies or living wills recorded in the 
EMR. 
 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
Our target population is seniors with cognitive concerns in primary care clinics. While we 
anticipate that many potential participants might be attending Medicare Annual Wellness 
visit, we will also recruit eligible patients who will be attending the primary care clinic for 
other medical reasons. 
 
4.1 Inclusion Criteria 
1) Age 65 and older. 2) Presence of cognitive concerns expressed by patient or caregiver or 
identified by health care providers. 3) Registered as patient at Montefiore Medical Center 
and have a primary care doctor appointment that day. 4) Able to see and hear well enough 
to complete intervention or control assessments. 5) English or Spanish speaking. 
 
4.2 Exclusion Criteria 
1) Prior diagnosis of dementia or MCI as ascertained by ICD-10 codes or the presence of 
prescription for anti-dementia medications (cholinesterase inhibitors or Memantine) in 
EMR. Patients with a diagnosis containing any of the following terms will be excluded: 
a. “Dementia” 
b. “Mild Cognitive Impairment” 
c. “Alzheimer’s Disease” 
d. “Creutzfeldt-Jakob Disease” 
e. “Major Neurocognitive Disorder” 
f. “Minor Neurocognitive Disorder” 
Patients with any of the following medications documented in their EMR will be excluded 
(generic = brand): 

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Flyer Questions: 
“Are you concerned about your memory?” 
Yes □ No □ 
“Are your loved ones concerned about your memory?” 
Yes □ No □ 
a. Donepezil = Aricept 
b. Memantine = Namenda 
c. Rivastigmine = Exelon 
d. Galantamine = Razadyne 
e. Donepezil and Memantine = Namzaric 
2) Adults who are permanent residents of a nursing facility. 
3) Patients who do not speak English or Spanish. 
4) Patients who are not seeing a primary care physician at the clinic that day. 
5) Patients who are blind, deaf or cannot hear loud voice even with hearing aids. 
 
Recruitment, enrollment, and participation of participants in this project are not limited by 
gender, skin color, racial/ethnic group, or economic status. We will monitor recruitment and 
retention patterns to ensure adequate representation of women and minorities. Since this 
study focuses exclusively on geriatric syndromes, it will not include children. 
 
4.3 Study Enrollment Procedures 
Potential participants may be referred by the clinic staff to the non-clinician research 
assistant (RA) by a message sent in the EMR, a phone call to the RA or by approaching the 
RA in person. Once a referral is received the RA will review the patient’s electronic 
medical records or medical chart to determine their eligibility for participation based on the 
criteria above. Next, they will locate the patient within the clinic by asking the clinic staff 
to identify the patient. 
 
Potential participants may also be identified by reviewing the daily clinic schedule on the 
electronic clinic schedule calendar. The RA will review all patients’ charts that are ≥65 
years and older with an appointment at the clinic that day to determine their eligibility 
based on the criteria described above. Next, they will locate the patient within the clinic by 
asking the clinic staff to identify the patient. 
 
After identifying the patient referred by a clinic staff member the RA will confirm the 
cognitive complaint. Before offering a patient enrollment in the study, the RA will ensure 
that they (or their family member or friend, or a clinic staff member) have a cognitive 
complaint or concern about them. This information will be recorded in the database. 
 
If the potential participant was identified by the RA from the daily schedule and 
determined to be eligible based on criteria from the EMR, the RA will greet the patient and 
say “I am X, and I am a RA. We are conducting a research study here at the clinic.” The 
RA will give a study flyer to the potential participant and say, “Would you mind please 
reviewing this flyer and answering the questions on it? I will give you a few minutes, and 
will come back to review it with you. Do you have any questions, or problems reviewing 
 

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this flyer?” If the patient is there with family or friends, the RA can encourage the patient 
to let their family or friend review it with them if they are comfortable. 
 
If the patient says or marks “Yes” to either of the questions on the flyer OR was referred to 
you by another source because of concerns about their memory or cognition, say, “It looks 
like you may be eligible for our study. We are conducting a research study to validate a 
new cognitive screening tool. If you are interested in participating in the study, I will ask 
you to complete some tasks that involve memory, health and mobility. You will receive a 
total of $10 for completing the 5-minute assessment before seeing your doctor. In addition, 
to the 5-minute assessment before seeing your doctor, if you are interested in completing a 
60-minute cognitive assessment after you see you doctor we will pay you an additional 
$10. Are you interested in participating?” 
 
Those expressing interest should be invited to come to the research office to complete the 
informed consent, randomization and the assessments. 
 
COVID-19 amendment to enrollment and recruitment procedures: In response to the 
COVID-19 pandemic the recruitment process described above will be conducted over the 
telephone rather than in person. Below are descriptions of the study enrollment and 
recruitment procedures for the various recruitment and enrollment pathways. 
 
Instead of the RA recruiting the participant through the flyer at the clinic waiting room, the 
RA will reach out to the participant over the phone on the day before their appointment to 
tell them about the study, screen them and conduct informed consent (see section 6.2 for 
details). The RA will ask the same questions as are on the flyer to potential participants 
over the telephone on the day before their appointment. 
 
In a case where the patient was identified to the RA by a clinic staff member or physician, 
the RA will screen them for eligibility through their medical chart and if they have an 
appointment scheduled, they will reach out to the patient on the day before their 
appointment to tell them about the study, screen and conduct the verbal informed consent. 
 
5 
STUDY INTERVENTIONS 
 
5.1 Interventions & Administration 
Intervention arm (5-Cog): The 5-Cog battery coupled with a decision tree is a simple, 5- 
minute procedure that will identify older persons with cognitive impairment in primary 
care settings, and flag them for further evaluation. The 5-Cog battery includes the PMIS,1 
MCR diagnosis,2-4 and the paper-based Symbol Match Test. The 5-Cog battery will be 
given after randomization and before the patients sees the physician. After completing the 
5-Cog screening, the tester will send a message through the EMR system to provide 5-Cog 
results and a decision tree to the treating physician. The cognitive assessment algorithm 
will sort patients with ‘cognitive impairment’ from those with ‘no cognitive impairment’. 
 
Active control: Participants randomized to the active control will receive a health literacy 
questionnaire and grip strength assessment to match time (5 minutes), tester exposure, and 
gait assessment procedure in the 5-Cog arm. The Short Assessment of Health Literacy 
(SAHL) has comparable tests in English and Spanish, with good reliability and validity. 

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Participants are presented with 18 test items. For each term, a key word with related 
meaning and a distractor word unrelated in meaning to the test term are presented. This 
tests the participant’s comprehension as well as pronunciation of health-related terms. The 
test takes 3 minutes and requires minimal training. Grip strength is measured in dominant 
hand with a Jamar handgrip dynamometer.50-52 Grip strength is a validated health indicator 
in aging.50-52 Low grip strength is a component of frailty definitions and predicts 
disability.50-52 To parallel the study procedures and flow in the 5-Cog arm, a decision tree 
will be created. Results and the decision tree will be sent to the physicians through the 
EMR system at the same visit. 
 
5.2 Handling of Study Interventions 
The tester will obtain informed consent, prior to randomizing patients to either the 5-Cog or 
control interventions. We will follow the example of other pragmatic clinical trials of 
dementia screening in primary care clinics53 by randomizing at the patient level rather than 
at the level of providers or clinics. This will minimize effects of unmeasured case mix 
differences and clinic-level clustering. As noted by Fowler et al,53 the risk for “spillover” 
from having participating primary care clinics treat both intervention and usual-care 
patients is likely to be small given low levels of dementia detection.54 The patient-based 
randomization should conservatively bias results in favor of usual care. Dr. Wang 
(Statistics Core) will computer-generate a randomized block design which will be used to 
assign study identification numbers and place patients into either 5-Cog or control groups. 
 
The IRB requires us to disclose the tests to participants in both study arms; therefore, it is 
not feasible to blind patients. Participants and the RA who carries out the 5-Cog or health 
literacy and grip strength assessments are not blinded to group assignment. However, 
investigators, data analysts collecting outcome data of improved dementia care, and the 
statistician remain blinded to individual assignments. 
 
5.3 Concomitant Interventions 
5.3.1 Allowed Interventions 
We will not ask physicians to deny patients any procedures offered routinely. 
Clinicians have access to the PMIS and other cognitive screeners in the EMR. We will 
not ask clinicians to avoid using these screeners in enrolled patients. But we will track 
cognitive screener use by clinicians in control and 5-Cog arms via the EMR. 
5.3.2 Required Interventions 
Not applicable 
5.3.3 
Prohibited Interventions 
Patients with any of the following medications documented in their EMR prior to 
enrollment will be excluded (generic = brand): 
a. Donepezil = Aricept 
b. Memantine = Namenda 
c. Rivastigmine = Exelon 
d. Galantamine = Razadyne 
e. Donepezil and Memantine = Namzaric 

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5.4 Adherence Assessment 
Our primary outcome is based on information from EMR on Bronx-based patients 
receiving primary care in our institution. This will minimize missing data issues. We will 
aggressively implement data management processes (supervised by the Data Core). The 
goals of data management are to ensure (a) data collected during the study are properly and 
accurately entered and documented, (b) data are stored in an electronic format that allows 
easy retrieval and exportation, and c) participant confidentiality. The study programmer in 
collaboration with the statistician manages the data. They will work with other Data and 
Statistical Core team members to correct identified issues and conduct quality audits of 
database. 
 
We realize that not all patients will complete all of the additional tests for exploratory 
outcomes. However, our sample of 1,200 participants is a sufficient pool to conduct 
sensitivity analyses for exploratory outcomes even assuming a refusal rate of 50% for some 
or all of these additional tests used for secondary and exploratory outcomes. 
 
6 
STUDY PROCEDURES 
 
6.1 
Schedule of Evaluations 
Figure 2. Study Flow 

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6.2 Description of Evaluations 
6.2.1 Screening Evaluation 
The RA will review all patients’ charts that are ≥65 years and older with an appointment 
at the clinic on the following day to determine their eligibility based on the criteria 
described above. Next they will reach out to the patient over the telephone. 
 
After identifying the eligible patients the RA will confirm that they have an 
appointment on the following day and describe the study to them and ask them if they 
would be interested in participating. If interested, the RA will confirm the cognitive 
complaint. Before offering a patient enrollment in the study, the RA will ensure that 
they (or their family member or friend, or a clinic staff member) have endorsed a 
cognitive complaint or expressed concern about them. 
 
Consenting Procedure 
Those with cognitive complaints, expressing interest in the study will be invited to 
participate at their appointment on the following day. Consent will be obtained from 
participants through a verbal consent process prior to enrollment. The non-clinician 
tester will obtain verbal consent over the telephone prior to the patient coming to the 
clinic for their appointment when they will also be randomized and receive the study 
assessments. 
 
The consent script describes the purpose of the study, the procedures to be followed, 
and the risks and benefits of participation. A copy of the script can be given to each 
participant and this fact will be documented in the participant’s record. Language in the 
consent form will describe data sharing. For example, “We will store information about 
you in a “bank”, which is a library of information from many studies. This information 
cannot be linked to you. In the future, researchers can apply for permission to use the 
information for new studies to prevent, diagnose, or treat disease. Your information 
may be kept for a long time, perhaps longer than 50 years. If you agree to the future 
use, some of your de-identified health information (not linked to you) may be placed 
into one or more scientific databases. These may include databases maintained by the 
federal government.” 
6.2.2 Randomization & Assessments 
Randomization 
The tester will obtain informed consent, prior to randomizing patients to either the 5- 
Cog or control interventions. We will follow the example of other pragmatic clinical 
trials of dementia screening in primary care clinics53 by randomizing at the patient level 
rather than at the level of providers or clinics. This will minimize effects of unmeasured 
case mix differences and clinic-level clustering. As noted by Fowler et al,53 the risk for 
“spillover” from having participating primary care clinics treat both intervention and 
usual-care patients is likely to be small given low levels of dementia detection.54 The 
patient-based randomization should conservatively bias results in favor of usual care. 

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Dr. Wang (Statistics Core) will computer-generate a randomized block design which 
will be used to assign study identification numbers and place patients into either 5-Cog 
or control groups. Patients will be stratified by gender and age (< or >75 years). Briefly, 
an encrypted file containing the group assignment is prepared for each study 
identification number. The file is stored in RedCap the database program used for this 
trial. The assignments are presented to the RA in sequential order at the time the 
participant is enrolled, following the eligibility assessment, and administer the indicated 
screen. Participants and the RA who administers the tests are not blinded to group 
assignment. However, investigators, data analysts collecting outcome data, and the 
statistician remain blinded to individual assignments. 
 
Assessments 
Intervention arm (5-Cog): This simple, 5-minute procedure will identify older persons 
with cognitive impairment in primary care settings, and flag them for further evaluation. 
The 5-Cog battery includes the PMIS, MCR diagnosis,6-8 and the paper-based Symbol 
Match test. Our cognitive assessment algorithm will sort patients with or at high risk of 
developing ‘cognitive impairment’ from those with ‘no cognitive impairment’. 
Moreover, it is coupled with a decision tree to guide clinicians through the necessary 
steps to follow up on 5-Cog results. Because primary care clinicians and staff may not 
have the time to complete even a 5-minute screen,12, 15, 16 non-clinicians (RAs) will 
administer the 5-Cog and communicate the results to primary care physicians for further 
action. 
 
Active control: Participants randomized to the active control will receive a health 
literacy questionnaire and grip strength assessment to match the time (~5 minutes), 
tester exposure, and gait assessment procedure in the 5-Cog arm. The SAHL has 
comparable tests in English (SAHL-E) and Spanish (SAHL-S), with good reliability and 
validity in both languages. Participants are presented with 18 test items. For each term, 
a key word with related meaning and a distractor word unrelated in meaning to the test 
term is presented. This tests the participant’s comprehension as well as pronunciation of 
health-related terms. The test takes 3 minutes to complete and requires minimal 
training. Grip strength is measured in dominant hand with a Jamar handgrip 
dynamometer.50-52 Grip strength is a validated health indicator in aging.50-52 Low grip 
strength is a component of frailty definitions and predicts disability.50-52 To parallel the 
study procedures and flow in the 5-Cog arm, a decision tree will be created. Results and 
the decision tree will be presented to the physicians at the same visit. 
 
Additional Assessments: In order to avoid interrupting the normal clinic flow, these 
additional assessments, which will be used as covariates or exploratory outcomes in our 
analyses, will be done following the clinician’s assessment of the patient. These 
exploratory measures will help us generate and test new hypothesis and provide insights 
into the effects of the 5-Cog battery. We realize that not all patients will be able to 
complete part or all of the tests due to other commitments. Nonetheless, our overall 
sample size of 1,200 participants provides a sufficient pool assuming a non-completion 
rate of 50%. 
a. Patient characteristics: Demographic, socio-economic status and medical illness 

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burden. 
b. Neuropsychological battery – due to safety concerns with in person visits, as of 
July 27th, 2020 participants will be offered the opportunity to complete the 
neuropsychological evaluation over the phone or via video conference. 
6.2.3 Outcome assessment 
Our primary outcome is improved dementia care. This outcome is collected 
prospectively from EMR and related medical records by data analysts and do not 
require patient interviews. This primary outcome is defined as meeting any one of the 
following endpoints within 90 days of the clinic visit at which the patient was 
randomized. 
1. New diagnosis of dementia (relevant ICD-10 codes) or MCI (331.83) 
documented in the EMR. The recent DSM-V criteria37 include categories of 
‘major neurocognitive disorder’ and ‘mild neurocognitive disorder,’ which 
overlap with dementia and MCI. These categories will also be included but a 
recent internal audit indicated that they are as yet not in widespread use in our 
primary care clinics (cf. specialty clinics). 
2. Tests ordered for reversible causes of cognitive impairment as recommended by 
the published guidelines of professional societies (e.g. thyroid function tests, B- 
12 level, CT or MRI scans).15, 38-41 
3. New prescriptions for dementia medications in EMR. 
4. Referral for cognitive/dementia evaluation by specialists (Neurology, Geriatrics 
or Psychiatry) in EMR. 
 
7 
SAFETY ASSESSMENTS 
Participant safety will be monitored once an individual is enrolled in the study. We do not 
expect any serious adverse events during the non-invasive assessments that will take place 
in both study arms. Answering health questionnaires and cognitive assessments involve 
minimal psychological, social, or other risks. 
 
7.1 Specification of Safety Parameters 
Trained RAs, who will monitor the subject for any adverse events, will perform all 
assessments. The RA will stop the testing procedures if subjects feel stressed or get 
embarrassed by their performance, and relay the information immediately to Dr. 
Verghese or one of the supervising clinicians (Drs. Chalmer, Ansari, Ehrlich, or 
Zwerling). In addition, Dr. Chalmer and Dr. Ansari will be available at the clinic site 
during the conduct of the trial, and Dr. Verghese will be available by cellular telephone at 
all times to address any safety concerns or clinical issues. 
 
All abnormal findings from the clinical, motor, and neuropsychological assessments will 
be documented and the participant and their primary care physician will be informed of 
all clinical results that are relevant to patient care following the 90 day window for 
primary outcome ascertainment. 

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7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
 
7.3 Adverse Events and Serious Adverse Events 
Adverse Events (AEs): Any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (for example, abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the subject’s participation in 
the research, whether or not considered related to the subject’s participation in the 
research. AEs encompass both physical and/or psychological harms. 
Serious Adverse Events (SAEs): An adverse event that meets any of the following 
criteria: 
• Results in death 
• Is life threatening, or places the participant at immediate risk of death from the 
event as it occurred 
• Requires prolonged hospitalization 
• Causes persistent or significant disability or incapacity 
• Is another condition which investigators judge to represent significant hazards 
7.4 Reporting Procedures 
AE Reporting: All AEs will be collected on an Adverse Event Form in electronic format 
and recorded in the RedCap database. All AEs experienced by the participant will be 
reported in Safety Reports sent twice a year to the NINDS Program Official. 
SAEs Reporting: When SAEs occur that are unanticipated (i.e., events other than those 
described in the protocol, consent form and DSMP), and that are related to the 
intervention, they will be reported to NINDS Program Officer within 48 hours of study’s 
knowledge of the SAE. The expedited report will be followed by a detailed, written SAE 
report as soon as possible. Follow up information may be required. 
 
Relatedness: The potential event relationship to the study intervention and/or 
participation is assessed by the site investigator. The comprehensive scale to categorize 
an event is listed below: 
• 
Definitely Related: The AE is clearly related to the investigational procedure – 
i.e. an event that follows a reasonable temporal sequence from administration of 
the study intervention, follows a known or expected response pattern to the 
suspected intervention, that is confirmed by improvement on stopping and 
reappearance of the event on repeated exposure and that could not be reasonably 
explained by the known characteristics of the subject’s clinical state. 
• 
Possibly Related: An AE that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response 
pattern to the suspected intervention, but that could readily have been produced 
by a number of other factors. 
• 
Not Related: The AE is clearly not related to the investigational procedure - i.e. 
another cause of the event is most plausible; and/or a clinically plausible temporal 
sequence is inconsistent with the onset of the event and the study intervention 
and/or a causal relationship is considered biologically implausible. 

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Expectedness: AEs must be assessed as to whether they were expected to occur or 
unexpected, meaning not anticipated based on current knowledge found in the protocol 
and the consent form. Categories are: 
• 
Unexpected: The nature or severity of the event is not consistent with information 
about the condition under study or intervention in the protocol or consent form. 
• 
Expected: The event is known to be associated with the intervention or population 
under study. 
 
Classification of AE Severity: 
• 
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor 
irritant type causing no loss of time from normal activities. Symptoms do not 
require therapy or a medical evaluation; signs and symptoms are transient – i.e. no 
doctor visit or medical treatments were required. 
• 
Moderate: Events introduce a low level of inconvenience or concern to the 
participant and may interfere with daily activities, but are usually improved by 
simple therapeutic measures; moderate experiences may cause some interference 
with functioning – i.e. minimal medical treatment was needed, possible doctor 
visit or physical therapy. 
• 
Severe: Events interrupt the participant’s normal daily activities and generally 
require systemic drug therapy or other treatment; they are usually incapacitating – 
i.e. medical attention was required, possible hospitalization. 
Note: Severity is not synonymous with seriousness. SAEs are a subset of the reported 
AEs. 
 
7.5 Follow-up for Adverse Events 
AEs will be followed until the participant discontinues the study. 
 
7.6 Safety Monitoring 
 
Prior to beginning data collection, we will convene an internal safety monitoring 
committee who will be responsible for monitoring participant safety and study progress. 
The committee will be comprised of investigators on the project team. Before beginning 
recruitment, Dr. Verghese and the safety committee will reconfirm that our sites have 
appropriate safety measures in place. The internal safety monitoring committee will meet 
with the entire research team to review the study protocols. Particular attention will be 
paid to outcome definition, study design, procedures for recording and reporting adverse 
events, informed consent procedures and documentation. 
 
At the initial meeting, the internal safety monitoring committee may recommend 
modifications or clarification of the protocol, and it will formulate its operating 
procedures (e.g., meeting schedule, reports due dates for the study statistician, unblinding 
policy, and what interim data may be released to the investigators). At the initial meeting 
the plans for interim monitoring for efficacy and futility will be presented to the internal 
safety monitoring committee as an aid for monitoring the trial. 
 
We will train competent staff to conduct the assessments, ensure they understand the data 
collection procedures and process, and understand adverse event reporting requirements. 

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Trained clinical assistants, who will monitor the subject for any adverse events, will 
perform all assessments. We do not expect any serious adverse events during these non- 
invasive interventions. The clinical assistant will stop the testing procedures if subjects 
feel stressed or get embarrassed by their performance, and relay the information 
immediately to Dr. Verghese or one of the supervising clinicians (Drs. Chalmer, Ansari, 
Ehrlich, or Zwerling). In addition, Dr. Ansari and/or Dr. Chalmer will be available at the 
clinic site during the conduct of the trial, and Dr. Verghese will be available by cellular 
telephone at all times to address any safety concerns or clinical issues. 
 
8 
INTERVENTION DISCONTINUATION 
Subjects may withdraw voluntarily from participation in the study at any time and for any 
reason. However, participants will continue to be followed, with their permission, as long 
as they completed the 5-Cog or health literacy and grip strength assessments. 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 General Design Issues 
We propose to conduct a single-blind RCT to validate the 5-Cog battery coupled with 
decision tree in an ethnically diverse Bronx primary care population of 1,200 older patients 
with cognitive concerns. We chose an active control (health literacy and grip) to balance 
time and tester exposure in the 5-Cog arm. Our primary outcome is improved dementia 
care. 
 
Primary Outcome: The primary outcome is improved dementia care, defined as meeting 
any one of the following endpoints within one month of the clinic visit at which the patient 
was randomized. 
1. New diagnosis of dementia (relevant ICD-10 codes) or MCI (331.83) documented in 
the EMR. The recent DSM-V criteria include categories of ‘major neurocognitive 
disorder’ and ‘mild neurocognitive disorder,’ which overlap with dementia and MCI. 
We will track these diagnoses but not use these solely to define the outcome as they are 
as yet not being widely used as diagnostic or billing codes in our primary care sites. 
2. Tests ordered for reversible causes of cognitive impairment as recommended by 
published guidelines of professional societies (e.g. thyroid function tests, B-12 level, 
CT or MRI scans). 
3. New prescriptions for medications for dementia or MCI indications in EMR. 
4. Referral for specialist evaluation for cognitive impairment (Neurology, Geriatrics or 
Psychiatry) in EMR. 
 
9.2 Sample Size and Randomization 
This randomized study has 600 subjects for each of the 2 groups. Assuming a non- 
completion rate of EMR entries of 10% over 90 days and that 25%, 30% or 35% of control 
subjects will experience ‘improved dementia care,’ we can detect odds ratios of 1.46, 1.43 
or 1.42, respectively, on the effect of 5-Cog on improving dementia care with 80% power 
using a two-sided test with significance level of 0.05. There is a paucity of studies 
examining efficacy of brief cognitive screens in primary care. One non-randomized trial of 

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screening by medical assistants coupled with a decision tree in primary care clinics showed 
new physician action in 17% of patients with a positive screen in intervention sites 
compared to 1% in control sites. 36 Action included new dementia diagnosis, referral to 
specialist or initiating dementia treatment (similar to our primary outcome). While our 
projected effect size used for sample size estimation is conservatively lower than that 
reported in this previous study,36 the effect size from this previous study was not used to 
calculate power given its preliminary, non-randomized nature but is presented in support of 
our assumptions. A review of 8 studies of detection of mild dementia in primary care 
showed that sensitivity ranged from 9% to 41%.55 Detection rates in clinics are even lower 
for earlier dementia stages such as MCI.56 These observations support our assumptions of 
lower rates of improved dementia care in our control group. 
 
Cohort retention: This is not a major issue for this RCT as primary outcomes are based on 
clinical encounters information collected from EMR and other administrative data sources 
in patients residing in Bronx County and receiving primary care in our institution. Also, 
primary outcomes do not require repeat in-person testing after baseline assessments. 
• Non-completion: We realize that not all patients will complete the additional tests 
described above as covariates or exploratory outcomes. We will complete as many of 
the tests as possible depending on patients’ availability. Nonetheless, our overall 
sample size of 1,200 participants provides a sufficient pool to conduct sensitivity 
analyses assuming non-completion rate of 50%. 
• Over- or under-detecting cognitive impairment: Given the high sensitivity and validity 
of 5-Cog procedures for dementia detection, we do not expect under-detection to be a 
major issue. We will set PMIS cutscores to maximize sensitivity and will improve 
cognitive concern ascertainment. A major consequence of over-detection is the strain 
on limited primary care resources resulting from more dementia assessments. Our 
decision tree provides guidance to primary care physicians regarding next steps in 
cognitively impaired patients. Red flags are built within our decision tree to channel 
patients for specialist evaluations. These steps were developed in consultation with our 
primary care partners. We will carefully monitor clinical, logistical and economic 
impact of introducing 5-Cog in our primary care sites, and make any necessary system 
changes to optimize clinical encounters. It is encouraging that introducing PMIS into 
our local EMR has not resulted in significant bottlenecks or overburdening specialists. 
We have also not observed any significant bottlenecks or negative feedback from 
primary care staff regarding implementing the first phase of the 5-Cog battery at our 
site. 
9.2.1 Treatment Assignment Procedures 
Patients will be assigned to screening using stratified block randomization. Dr. Wang, 
who is not involved in subject testing or interventions will generate a computerized 
block randomization scheme to assign study identification numbers to either 5-Cog or 
control arms. Patients will be stratified by gender and age (< or >75 years). Briefly, 
an encrypted file containing the group assignment is prepared for each study 
identification number. The file is stored in RedCap the database program used for this 
trial. The assignments are presented to the research assistants (RA) in sequential order 
at the time the participant is enrolled, following the eligibility assessment, and 

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administer the indicated screen. Participants and the RA who administers the tests are 
not blinded to group assignment. However, investigators, data analysts collecting 
outcome data, and the statistician remain blinded to individual assignments. 
 
9.3 Interim analyses and Stopping Rules 
Due to the non-invasive nature of the protocol, it is not expected that early termination 
will be required due to adverse events. However, constant monitoring of the participants 
by Dr. Verghese, other investigators, and research staff will be maintained to ensure that 
AEs are not occurring. Early study termination will occur in the event of any 
unanticipated serious adverse event determined to be possibly, probably or definitely 
related to study procedures. 
 
9.4 Outcomes 
9.4.1 Primary outcome 
Our primary outcome is improved dementia care. This outcome is collected 
prospectively from EMR and related medical records by data analysts (Administrative 
& Statistics Cores) and do not require patient interviews. This primary outcome is 
defined as meeting any one of the following endpoints within 90 days of the clinic visit 
at which the patient was randomized. Similar composite endpoints to define dementia 
care have been used in several prior clinical trials in cognitively impaired patients.32-36 
1. New diagnosis of dementia (relevant ICD-10 codes) or MCI (331.83) documented 
in the EMR. The recent DSM-V criteria37 include categories of ‘major 
neurocognitive disorder’ and ‘mild neurocognitive disorder,’ which overlap with 
dementia and MCI. These categories will also be included but a recent internal 
audit indicated that they are as yet not in widespread use in our primary care 
clinics (cf. specialty clinics). 
2. Tests ordered for reversible causes of cognitive impairment as recommended by 
the published guidelines of professional societies (e.g. thyroid function tests, B-12 
level, CT or MRI scans).15, 38-41 
3. New prescriptions for dementia medications in EMR. 
4. Referral for cognitive/dementia evaluation by specialists (Neurology, Geriatrics 
or Psychiatry) in EMR. 
9.4.2 Secondary outcomes 
Health care utilization (emergency room visits and hospitalizations) for patients in both 
arms will be tracked up to 12 months from the clinic visit at which the patient was 
randomized and reviewed at regular intervals by data analysts throughout the study 
period. The data analysts will have no participant contact and be blinded to study 
assignment. The EMR system is in place in our institution. All visit notes and diagnoses 
are to be entered within 48 hours of the encounter. 
 
9.5 Data Analyses 
We will examine data for potential outliers and analyze the robustness of our findings 

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against them. We will perform per-protocol analysis to assess the sensitivity of our findings 
to protocol deviations. Furthermore, the impact of baseline imbalance will be determined by 
comparing the analysis outcomes with and without controlling for baseline attributes. Chi- 
square test will be used to compare ‘improved dementia care’ outcome within 90 days post- 
intervention between the intervention and control groups. Logistic regression model adjusted 
for covariates will also be used. We will use intention to treat analysis.57 Pre-specified 
baseline covariates to account for confounders in the planned analysis include age, gender, 
education, and chronic illnesses. Baseline distribution of covariates will be compared to 
assess adequacy of randomization. We do not discount residual/unmeasured confounding – 
though this is more of an issue in observational studies without randomization. We will 
report adjusted and crude estimates of associations to assess confounding, and discuss 
limitations of the study. 
 
Primary outcome: Chi-square test will be used to compare ‘improved dementia care’ 
outcome within 90 days post-intervention between the intervention and control groups. 
Logistic model adjusted for covariates will also be used. 
 
Heterogeneity of treatment effect (HTE) is the nonrandom, explainable variability in the 
direction and magnitude of treatment effects for individuals within a population. The main 
goals of HTE analysis are to estimate treatment effects in clinically relevant subgroups and 
to predict whether an individual might benefit from a treatment. In this RCT, we will 
specifically address HTE due to gender (male/female), ethnicity (African- 
American/Hispanic/Caucasian) and education (less than high school/ high school graduate). 
Treatment effects in these subgroups will be evaluated using stratified analysis. Alternative, 
an interaction term between the subgroup characteristic and treatment group will also be 
tested. 
 
Secondary outcome: Utilization is defined in terms of specialty visits, emergency room 
visits, and hospitalizations up to 12 months following the screening visit. This will be 
tracked via the EMR in both groups. The rates of utilization will be compared between the 
two groups using analytical approaches described for the primary outcome. We will also 
compare ‘days free of utilization’ (number of days from screening to first episode of health 
care utilization over follow-up) in both groups using linear mixed effect and survival 
models.58, 59 
 
10 
DATA COLLECTION AND QUALITY ASSURANCE 
 
10.1 Data Collection Forms 
During the initial phase, the database programmer will work closely with the project manager to 
establish a centralized database and archiving system. Data collection of baseline assessments by 
the research assistants is in-person and entered in real time into the centralized database which 
will be programmed using RedCap. This system has automated checks for ranges of values and 
logical validity of data entered and imports subject data directly from the computerized test data 
files. This system provides immediate access to individual subject data and can generate a 
summary report of the entire database. The database programmer will also work with the EMR 
programmer and data analyst to integrate data collected from the EMR system with study data. 

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ATLAS, a modern data platform to use clinical and health data from Montefiore patients, will 
also be used to export clinical data for outcomes and integrated with RedCap data. The EMR 
systems programmer will develop reports to easily export relevant data from the EMR system to 
provide to the EPIC systems data analyst. The analyst will check exported data files for data 
integrity and flag in the event of inconsistent or missing data. 
 
Forms or screens will be designed to meet the data collection needs, applying standards for the 
structuring of variables to permit the pooling of shared/common variables across the consortium. 
The database manager will develop a data entry/management system so that the interviewers can 
not only enter the data directly into the computer during the interview, but they can also run 
reports and compute scores during the interview if need be. Data collected from both methods 
will be integrated by the database programmer and stored in the centralized database. 
 
10.2 Data Management 
The project manager will have day to day responsibility for data management, cleaning and 
quality checks, with consultation from Dr. Wang. The project manager will serve as primary 
point of contact for data entry and management needs. 
 
The Statistical Core will work with the Data Management Core on the structure of spreadsheets 
and data tables containing endpoint data to facilitate the merging of such data with clinical 
assessment data. 
 
Hard copies of documents will also be maintained by the Data Management Core and subjected 
to quality control procedures. A codebook will be maintained that contains variable names, 
labels and values for all variables collected. As clean data are accumulated, the project manager 
will re-run data editing programs periodically as a final quality control check. Any 
inconsistencies identified will be validated with the original source and stored in report form for 
evaluative purposes. From the cleaned data, data sets will be compiled for analysis purposes. 
Data sets will be frozen on a semi-annual basis by the statistical team. As projects are completed 
(closed), cleaned data sets, their data dictionaries, and their command files and output files will 
be archived. 
 
The exchange of data across the consortium will be reviewed by the Data Sharing and 
Harmonization Committee of the Cross-Consortium Coordinating Team (CCCT) and handled by 
the Analysis Committee so that files from different studies are merged properly and contain only 
data that have been double entered and verified (see Section 13 for details of committees). 
 
Data sharing: A data sharing agreement with collaborators at Northwestern University will 
account for sharing data across sites which include the following data elements: 
 
Demographic information, including all elements (except years) of dates related to an 
individual (including birthdate, admission date, discharge date, date of death, and exact age 
if over 89) 
 
Data extracted from EHR 

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Financial data about care linkable to clinical data using pseudo IDs 
Healthcare utilization data 
10.3 Quality Assurance 
10.3.1 
Training 
We will train competent staff to conduct the interventions and assessments, ensure they 
understand the nature of the interventions, and understand adverse event reporting 
requirements. All study staff will take the Safety Training Class, an online training 
venue that provides an overview of human subjects safety surveillance and reporting 
requirements in clinical research studies. The intent of the course is to help clinical 
study investigators and staff understand and implement NIA and regulatory 
requirements for safe, high quality clinical research. The topics covered include Good 
Clinical Practice, Human Subject Protections, Adverse Events and Unanticipated 
Problems, Safety Monitoring and Reporting Requirements, Safety Monitoring and 
Oversight: DSMPs and Safety Officers, Regulatory Requirements and Responsibilities 
of PIs, and Data and Safety Monitoring Plans (DSMP). 
 
They will also all successfully complete the required CITI training courses. 
10.3.2 Metrics 
The outcomes are collected prospectively from the EMR and related sources by study 
data analysts and do not require patient interviews. Data analysts who ascertain 
outcomes will have no participant contact and will be blinded to study assignment. The 
EMR system is in place in our clinic and hospital settings, and all aspects of clinic 
visits, emergency room visits or hospitalization in Montefiore Healthcare system are 
captured. All visit notes and diagnoses are to be entered within 48 hours of the 
encounter. A series of reminders are send to clinicians via EMR to complete delinquent 
entries. 
10.3.3 Protocol Deviations 
Protocol deviations will be documented and reviewed in bi-annual reports sent to the 
internal safety monitoring committee. 
10.3.4 Monitoring 
A study protocol, Manual of Operations and DSMP for all study activities will be 
developed during study setup and approved by the IRB and internal safety monitoring 
committee prior to initiating recruitment. Data will be maintained in a Database 
Manager System (RedCap). 
 
The database system will have automated checks for ranges of values and logical 
validity of data entered and will be programmed to import subject data directly from the 
computerized test data files. Imported data files will be checked for data integrity and 
flagged in the event of inconsistent or missing data. Hand entered data will be verified 
using double entry routines to guard against key punch errors. This system will provide 

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immediate access to individual subject data and can generate a summary report of the 
entire database. The database will contain provisions for password protection and 
distribution of analytic data files containing only necessary information on an as-needed 
basis; there will be an interface to export all or selected data from RedCap and transfer 
these to any of the statistical packages (SAS, S-PLUS, Stata, SPSS) used by the project 
investigators. 
 
Full backups of the entire database will be performed daily. For added security, copies 
of the databases are kept in two separate physical locations in locked, fire-resistant 
containers. Database files will be maintained by the Database Management Core and 
subjected to quality control procedures. Summary reports will be generated and 
reviewed by the project manager and PI as requested. 
 
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY 
 
11.1 Institutional Review Board (IRB) Review 
 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB responsible for oversight of the study. 
 
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. The tester will obtain informed 
consent, prior to screening and randomizing patients to either the 5-Cog or control intervention. 
The consent form describes the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy will be given to each participant and this fact will be 
documented in the participant’s record. Language in the consent form will describe data sharing. 
For example, “We will store information about you in a “bank”, which is a library of 
information from many studies. This information cannot be linked to you. In the future, 
researchers can apply for permission to use the information for new studies to prevent, diagnose, 
or treat disease. Your information may be kept for a long time, perhaps longer than 50 years. If 
you agree to the future use, some of your de-identified health information (not linked to you) may 
be placed into one or more scientific databases. These may include databases maintained by the 
federal government.” 
 
11.3 Participant Confidentiality 
This protocol, the informed consent, all recruitment materials, assessments and scripts as well as 
any subsequent modifications to these documents will be reviewed by the IRB prior to study start 
date. Any data, forms, reports, and other records that leave the site will be identified only by a 
participant identification number (Participant ID) to maintain confidentiality. All records will be 
kept in a locked file cabinet. All computer entry and networking programs will be done using 
PIDs only. Information will not be released without written permission of the participant, except 
as necessary for monitoring by the IRB or the NINDS. 
 
As of July 27th 2020, participants will be offered the opportunity to complete neuropsychological 
evaluations over the telephone or via video conference. Interviews collected on video conference 
or over the phone will NOT be recorded. 

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11.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the NINDS or other government agencies 
as part of their duties to ensure that research participants are protected. 
 
12 
ETHICAL CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki and the Institutional 
Review Boards. 
 
To maintain confidentiality all study records will be identified by a coded number. All study 
records will be kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet. Clinical 
information will not be released without written permission of the subject, except as necessary 
for monitoring. 
 
13 
CROSS CONSORTIUM COMMITTEES 
The Consortium for Detecting Cognitive Impairment, Including Dementia (DetectCID), is a 
collaborative network of research programs that are performing cross-site validation of paradigms, 
tools, and protocols that will increase the frequency, and improve the quality of patient evaluations 
for detecting cognitive impairment in primary care and other everyday clinical settings. The 
members of the consortium include Albert Einstein College of Medicine, Northwestern University 
and The Regents of the University of California San Francisco (UCSF). The DetectCID 
Consortium was created pursuant to joint funding from the National Institute of Neurological 
Disorders and Stroke and the National Institute on Aging under grant number UG3NS105557, and 
the exchange of Data is for the research activities of DetectCID. 
 
The committees described below guide cross consortium projects and are not responsible for local 
governance. 
 
Steering Committee 
The Steering Committee is the governing leadership and decision-making body for the project. It 
includes the PI of each project as a voting member, and up to 4 NINDS non-voting members. Co- 
PIs and Project Managers are encouraged to attend all meetings, although only one vote will be 
allocated to each project. This Committee’s primary purview will be to maintain the cross-project 
scientific synergy of the Consortium. They will oversee cross-validation projects, establish 
milestones and timelines, and monitor progress. They will coordinate the activities of and gather 
input from critical stakeholders whose investment and support are important for project success, 
including the Food and Drug Administration, Centers for Medicare & Medicaid Services, 
Alzheimer’s Association, etc. This Committee will review proposals for cross-site projects and 
ensure equitable shared-data publication practices across sites. They will also receive reports from 
and provide scientific, logistical, and administrative governance for the other Committees. The 
Steering Committee will meet via videoconference monthly throughout the project for a minimum 
of 1 hour. These meetings may be extended to 1.5 hours, with one hour dedicated to private 
discussion, and 30 minutes joined in a regular rotation by representatives from one of the other 
Committees or stakeholder groups, who will provide a report of their key activities, issues, and 
recommendations, and receive feedback from the Steering Committee to guide their progress. 

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Analysis Committee 
The Analysis Committee is responsible for study design and statistical analysis. This Committee 
will be dedicated to providing a sophisticated approach to research design and statistical analysis 
plans for the data being collected throughout the Consortium and with an emphasis on cross- 
validation projects. While the exact membership of these Committees will be determined by the 
Steering Committee, this Committee should have at least one expert in statistics, research design 
and/or data science from each site. This Committee will maintain an updated and clear 
understanding of the key scientific goals of the project, as articulated by the Steering Committee, 
and will work with the project leadership to derive specific statistical analysis plans to most 
effectively answer the Consortium’s scientific questions. Regular discussion of analytic plans and 
methods across projects will ensure that the best statistical approaches are shared when common 
problems arise. This Committee will also facilitate sharing of analytic code to reduce redundancy 
and maximize efficiency of data analysis across the Consortium. This Committee may choose to 
meet less frequently (i.e., only quarterly) during the middle years of the project but will likely 
require monthly meetings during early and later project periods. 
 
Data Sharing and Harmonization Committee 
The Data Sharing and Harmonization Committee is responsible for identifying opportunities for, 
and implementing, practices that promote data sharing and harmonization. While the exact 
membership of these Committees will be determined by the Steering Committee, this Committee 
should include a scientist from each site who is familiar with that site’s patient data collection 
practices, and individuals with research technology expertise. Project managers are encouraged to 
attend these meetings, and individuals with administrative/regulatory expertise will be included as 
needed. The team will develop an overview of the protocols, paradigms, and available data 
generated by different Consortium sites, and will provide recommendations, subject to final 
approval by the Consortium Steering Committee, for how those resources would most effectively 
be shared and included in cross-validation studies. This may include potentially harmonizing the 
collection of certain common data elements across sites (e.g., the exact protocol for collection of 
demographic and clinical severity information, etc.) to promote unified datasets for later analysis. 
They will evaluate and may adopt elements of already well-established harmonization schemas, 
such as some of the NACC standards for ADCs. It will be the purview of this Committee to ensure 
maximal data sharing of Consortium data, both within and beyond the Consortium, and to 
investigate and make recommendations about data sharing tools and repositories that would be 
facilitate this sharing. This Committee will likely be responsible for establishing reliance 
agreements across site IRBs to facilitate sharing of de-identified clinical data. This Committee 
may choose to meet less frequently (i.e., only quarterly) during the middle years of the project but 
will likely require monthly meetings during early and later project periods. 
 
Clinical Practice Committee 
The Clinical Practice Committee is responsible for paradigm implementation and maintaining 
relationships with primary care providers, health systems, and health disparities populations. This 
Committee will be responsible for guiding successful strategies for the implementation of 
protocols in everyday clinical settings across health disparities populations, and to guide 
implementation research protocols and benchmarks for success. While the exact membership of 
these Committees will be determined by the Steering Committee, this Committee should include 

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representatives with expertise in implementation science, primary care, and health disparities 
research. Meetings will be monthly to initiate the work, and during the planning phases for the 
implementation projects; frequency may be less often (quarterly at minimum) during other phases. 
 
14 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures developed 
by the Steering Committee. Any presentation, abstract, or manuscript will be made available for 
review by the NINDS prior to submission. 
 
AMENDMENTS 
7/15/2020 – Section 10.1. Data Collection Forms was updated to include that Atlas will be used 
to collect outcome data. 
7/15/2020 – Section 6.2.2 Randomization & Assessments – Additional Assessments was 
amended to include that due to safety concerns about in person visits because of the COVID-19 
pandemic, participants will be offered the opportunity to complete neuropsych assessments over 
the telephone or via video conference. 
7/15/2020 - 11.3 Participant Confidentiality was amended to add that although participants may 
agree to complete the neuropsychological evaluation over the telephone or via video conference 
the interview will not be recorded. 
8/25/2020 – 6.2 Description of Evaluations: Consenting procedure – In light of the COVID-19 
pandemic, we have amended to the protocol to include an oral consent process in order to reduce 
exposure for both the research staff and the participants. 
12/2/2020 - 6.2 
Description of Evaluations: Screening Evaluation and Consenting procedure – 
In light of the COVID-19 pandemic, we have amended the protocol to include that only an oral 
consent process will be used to consent participants (rather than offering a written consent as 
well). In addition, recruitment and screening was amended to describe that these procedures will 
now take place over the phone. 
12/2/2020 - 4.3 
Study Enrollment Procedures: A new section (COVID-19 amendment to 
enrollment and recruitment procedures) is added to the end of this section to describe the 
changes to the recruitment and enrollment procedures that will be made in response to the 
pandemic. 
12/9/2022 - 10.2 Data Management: A data sharing section under data management is added to 
describe the data sharing agreement and what specific data will be shared under the collaboration 
 
 
15 
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