Early Cognitive Training and Rehabilitation to Improve Long-term Cognitive Outcomes in Older Hospitalized Adults With Delirium
Phase: NA
Conditions: Delirium, Cognitive Decline, Dementia
Sponsor: Vanderbilt University Medical Center

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Early Cognitive Intervention in Delirium (ECID) 
Co-Principal Investigators 
Jin H. Han, MD, MSc 
James C. Jackson, PsyD 
Co-Investigators 
Eduard E. Vasilevskis, MD, MPH 
Maria C. Duggan, MD, MPH 
Rameela Chandrasekhar, PhD 
Manus Donahue, PhD 
Lorraine B. Ware, MD 
E. Wesley Ely, MD
NCT04740567

 
 
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Table of Contents: 
 
Study Schema 
 
1.0 
Background 
 
2.0 
Rationale and Specific Aims 
 
3.0 
Inclusion/Exclusion Criteria 
 
4.0 
Enrollment/Randomization 
 
5.0 
Study Procedures 
 
6.0 
Risks  
 
7.0 
Safety Monitoring, Reporting of Adverse Events or Unanticipated Problems 
involving Risk to Participants or Others 
 
8.0 
Study Withdrawal/Discontinuation 
 
9.0 
Statistical Considerations 
 
10.0 
Privacy/Confidentiality Issues 
 
11.0 
Follow-up and Record Retention 
 
12.0 
References 
 
 

 
 
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1.0 
Background 
Delirium is a form of acute brain failure that afflicts 17% of older emergency department (ED) 
and 25% of older hospitalized patients.1-4  Based upon our work and the work of others, delirium 
is associated with accelerated long-term cognitive decline particularly in patients with 
Alzheimer’s disease and related dementias (ADRD).5-17 Unfortunately, most delirium 
interventions have been ineffective in improving outcomes.18-20  
 
Cognitive training and rehabilitation may be a feasible intervention to preserve long-term 
cognition in delirious patients.21 Cognitive training’s purpose is to prevent and restore cognitive 
deficits acquired during the delirium episode. Cognitive training is the “guided practice on a set 
of standard tasks designed to reflect particular cognitive functions.”22,23  Within a cognitive task, 
there is a range of difficulty levels that can be tailored to each individual, with the goal being to 
“stress” the abilities of individuals enough that they will be challenged but not  overwhelmed.23 
Cognitive rehabilitation’s goal is to improve performance in everyday life activities and in daily 
functioning rather than on cognitive tests.24 It seeks to help individuals by establishing new 
cognitive activity patterns or compensatory mechanisms for impaired neurological systems. This 
is achieved by building on and extending the patients’ existing cognitive strengths25-28 and 
developing effective strategies to compensate for their newly acquired cognitive deficits.26,29,30  
Because GMT is also cognitively demanding, it may also help restore cognitive deficits31 such 
as attention and working memory.32  
  
Cognitive training/rehabilitation or any delirium intervention is unlikely to be effective in all 
delirious patients. Specific delirium phenotypes may be associated with a higher risk of 
accelerated cognitive decline and may benefit more from intervention. Delirium is a complex 
syndrome that can vary by psychomotor activity, arousal, severity, etiology, and 
pathophysiology. Based upon these observable delirium heterogeneity factors, overarching 
delirium phenotypes (or latent classes) may exist which can be uncovered using statistical 
techniques such as latent class analysis (LCA).33 
 
2.0 
Rationale and Specific Aims 
Currently, there is no universally accepted delirium intervention that has been shown to prevent 
long-term cognition decline. Older adults who are acutely ill do not typically engage in cognitive 
activities especially when delirious, and this further hastens the cognitive decline during 
hospitalization.34,35 Cognitive training during hospitalization and cognitive rehabilitation post-
hospital discharge may attenuate delirium’s deleterious effect on long-term cognition. The 
cognitive intervention, however, has not been rigorously evaluated in hospitalized older patients 
with delirium.  Furthermore, its mechanisms also remain unknown. The cognitive intervention is 
also unlikely to be benefit all delirious patients; it may be more effective in a subset of delirious 
patients with a specific phenotype, but these phenotypes are not well-defined.  To address this 
dearth of data, we propose this study which will enroll 350 older delirious patients with and 
without ADRD within 12 hours of ED presentation with the following specific aims and 
hypotheses: 
 
Aim #1: Using a RCT design, determine if early (<24 hours) cognitive training performed twice 
daily during hospitalization and cognitive rehabilitation performed weekly for 12-weeks post-
hospital discharge are associated with improved 4-month global cognition in older delirious 
patients with and without ADRD. We hypothesize that early cognitive training and 
rehabilitation will improve 4-month global cognition in older delirious patients with and without 
ADRD compared with usual care. 
 
Aim #2: In a subset of 50 patients, determine if cognitive training and rehabilitation are 
associated with less disintegration of eloquent brain networks at 4-months as determined by 
functional magnetic resonance imaging (fMRI) compared with controls. We hypothesize that 

 
 
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cognitive training and rehabilitation will lead to improved network connectivity in the 
frontoparietal cortex compared with controls at 4-months. 
 
Aim #3: Using LCA, identify novel delirium phenotypes (latent classes) based on psychomotor 
activity, arousal, severity, etiology, and pathophysiological plasma biomarkers (inflammation, 
endothelial dysfunction, and BBB injury), and explore if they modify early cognitive 
intervention’s effect on 4-month global cognition. We hypothesize that we will establish three 
novel delirium phenotypes using LCA and that one phenotype will benefit more from the early 
cognitive training and rehabilitation intervention.   
 
3.0 
Inclusion/Exclusion Criteria 
Table 1 lists the inclusion criteria for Aims #1, #2, and #3. Patients will be included in the study 
if they are 65 years or older, hospitalized from the ED, can receive cognitive training within 24 
hours of ED presentation, and are delirious. We will enroll patients who are 65 years or older, 
because delirium disproportionately affects older patients, and they are most likely to benefit 
from our research. Comatose patients will be re-evaluated 1 to 2 hours later. If the coma is 
persistent, they will be excluded because delirium cannot be assessed for in these patients. 
Patients who are unable to follow simple commands prior to their acute illness are considered to 
have end-stage ADRD and may not benefit from our intervention. In addition, our delirium 
assessment has not been validated for these patients. 
 
Inclusion Criteria 
Exclusion Criteria 
• 
65 years or older 
• 
Admitted through the ED 
• 
Cognitive training can be initiated 
within 24 hours of ED presentation 
• 
Delirious at enrollment 
 
• 
Comatose 
• 
Not able to follow simple commands or non-
verbal prior to the acute illness (end-stage pre-
illness ADRD) 
• 
Resides in a nursing home 
• 
Prisoner 
• 
Receiving hospice care 
• 
Lives > 100 miles away from the enrolling sites 
• 
Non-English speaking 
• 
Previously enrolled 
• 
Deaf or blind 
• 
Intravenous drug, crack or cocaine, or 
methamphetamine use within the past one year, 
or any condition that, in the investigator’s 
opinion, makes them an unreliable trial patient or 
unlikely to complete the trial. 
• 
Psychotic disorder or suicidal gesture requiring 
hospitalization within the past one year 
• 
Discharged from the ED 
 
Table 1. Inclusion and Exclusion Criteria for Aims #1 to 3 
 
Additional exclusions exist for Aim #2 (fMRI). Patients who have absolute and relative 
contraindications to MRI will be excluded: 
1) Metal foreign bodies such as shrapnel 
2) Cardiac pacemakers or internal cardiac defibrillators 
3) Cerebral aneurysm clips 
4) Deep brain stimulator 
5) Breast expander 

 
 
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6) Ocular, cochlear, and penile implants 
7) Drug infusion devices (e.g., insulin pump) 
8) Claustrophobia significant enough to require a sedative-hypnotic 
In addition, patients will be able to opt-out of the MRI portion of the study. No sedation will be 
provided prior to the MRI acquisition. 
 
4.0 
Enrollment/Randomization 
4.1.  
Screening, Recruitment, and Consent 
Screening and recruitment for this study will be performed by clinical trials associates (CTAs) at 
Vanderbilt University Medical Center and the Tennessee Valley Healthcare System Veterans 
Affairs Medical Center. The CTAs will screen the electronic ED Whiteboards and admission logs 
which provide the patient’s age, location, and length of stay.  Patients who are > 65 years old 
and can receive cognitive training within 24 hours of ED presentation will be approached to 
determine eligibility using the script in Appendix A. While CTAs will approach patients as early 
as possible, most will be approached after the initial clinical evaluation and management have 
been completed to prevent any delays in clinical care.  
 
Because delirium is key inclusion and only occurs in 10% of patients,36 its assessment will be 
incorporated to the screening process (prior to informed consent) in those who meet the other 
inclusion criteria and do not have any exclusion criteria. We will use the 4AT (Appendix U) for 
non-mechanically ventilated patients and the or Confusion Assessment for the Intensive Care 
Unit (CAM-ICU, Appendix C) for mechanically ventilated patients which are brief (<1 minute) 
and pose minimal risk. We have previously incorporated similar brief delirium assessments into 
the screening process in the DELINEATE study which similarly enrolled older patients with 
delirium.37  
 
If the subject meets eligibility criteria, including the presence of delirium, the CTA will review the 
informed consent document with the patient and/or their legally authorized representative (LAR). 
They will describe the proposed study protocol in lay terminology and allow time for questions to 
be answered. Because patients with delirium may have cognitive impairment significant enough 
to affect capacity, there is a possibility that the patient may not be capable of providing informed 
consent. In these cases, informed consent will be obtained from the LAR. The determination of 
whether or not a patient can provide informed consent will be determined by the study team. 
They will be trained to determine who is not consentable through clinical judgment and direct 
patient interaction (Appendix D).  Patients will be deemed capable of consenting if: 1) they are 
able to carry a normal adult conversation and 2) they are able to recall aspects of the consent 
(e.g. Can you tell me what the purpose and risks of the study are?”).  The patient will be asked 
questions about the study to ensure they comprehend study procedures.  If they are unable to 
adequately answer these questions, then consent will be obtained from a LAR.   
 
If a LAR is not available in the ED or hospital, then the CTAs will attempt to contact the LAR by 
phone. If phone contact is made, then CTA will use the LAR script in Appendix A.  If the LAR is 
interested in having the patient participate, then we will follow the procedures listed in Figure 1. 
If possible, the research staff will electronically deliver the informed consent document to the 
LAR via REDCap or e-mail.  After receipt, the research staff will review the informed consent 
document with the LAR. If the LAR agrees to have the patient participate in the study, then they 
will digitally sign the informed consent document.  If they are unable to sign the informed 
consent document digitally, then they will physically sign the document and return it to 
Vanderbilt via e-mail or mail. If the LAR does not have internet access or does not want to 
receive the informed consent electronically, then the research staff will review the informed 
consent document with the LAR over the phone. If the LAR verbally agrees to have the patient 

 
 
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participate in the study, then the research staff will mail the informed consent document to the 
LAR with a self-addressed and stamped envelope.   
 
For LARs who are not in the ED and unable to sign the informed consent document digitally, we 
are requesting an alteration by initiating the study procedures, including randomization, after the 
LAR verbally agrees for the patient to participate in the study over the phone. This is requested 
for several reasons: 
1) The cognitive training intervention is time sensitive and must be started as soon as 
possible (<24 hours) to enhance its potency and maximize outcomes.  
2) Cognitive intervention is a behavioral, non-pharmacological intervention that poses 
minimal risk for the patient. 
3) Patients with LARs who are unable to come to VUMC within 12-hours of ED 
presentation and do not have internet access likely represent a vulnerable patient 
population. These are likely patients who come from disadvantaged socioeconomic 
backgrounds and/or low education attainment. These patients may most benefit from the 
intervention, and their exclusion may pose an ethical dilemma.  
Every effort will be made for the LAR to sign the informed consent document. If the LAR does 
not sign the informed consent document, the patient may also sign if he/she regains capacity to 
provide consent. If no one is able to sign the informed consent document prior to hospital 
discharge, then all post-hospital study activities (e.g., cognitive rehabilitation at home and 
follow-up) will not be performed until the informed consent document is signed. 
 
Is the LAR going to be in 
hospital within 12 hours 
of ED presentation?
Review ICD when LAR 
arrives to hospital.
Does the LAR have 
internet access?
No
Yes
Is the LAR willing to sign 
the ICD via REDCap 
electronic signature?
Yes
Send LAR REDcap link.
Review ICD over phone.
Sign ICD electronically.
Yes
No
Is the LAR willing to 
receive the ICD by 
e-mail?
No
Does the LAR have 
internet access?
No
E-mail ICD.
Review ICD over phone.
Have LAR digitally sign ICD or  
physically sign the ICD and e-mail 
or mail it to study site.
Yes
Review the ICD over the phone.
If the LAR agrees to have subject enrolled, then mail ICD 
to LAR.
No
No
If LAR provides consent for the subject to be enrolled, but does not return a signed ICD, then we will 
continue with the in-hospital data procedures. We will wait for the LAR to arrive to the hospital to 
sign the ICD. If the patient regains his/her ability to provide informed consent, we will obtain consent 
from the patient. If the patient or LAR are unable to sign the informed consent document before 
hospital discharge, then we will stop any further study activities. 
 

 
 
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Figure 1. Consent procedures if the legally authorized representative (LAR) is not available to 
sign the informed consent document (ICD) in the emergency department (ED). If the LAR 
requests to receive the ICD by e-mail, the script in Appendix T will be sent. 
 
A subset of patients (25 cognitive intervention and 25 usual care) will be enrolled in Aim #2.  
Because of the 1:2 random allocation, one out of two controls will be randomly selected to 
participate in the fMRI aim. Patients will be able to opt-out of the fMRI portion of the study. 
 
4.2. Randomization 
After the patient or authorized surrogate provides informed consent, the cognitive training and 
rehabilitation intervention versus usual care will be randomly assigned at a 1:2 allocation ratio. 
Computerized randomization will occur after informed consent has been obtained using a 
permuted-block randomization scheme with varying block size. We will use adequate allocation 
concealment using a computer-generated, permuted-block randomization scheme with varying 
block size. The block size and randomization list will only be known to the independent 
biostatistician creating the randomization list and will not be shared with trial investigators or any 
other study personnel, as this information could make it easier to correctly guess the next 
treatment allocation. This list will be directly uploaded into REDCap’s randomization module.38 
 
5.0 
Study Procedures 
5.1 Cognitive Training and Rehabilitation Intervention 
Cognitive training and rehabilitation will be administered by a 
Cognitive Intervention Specialist who will be trained and 
supervised by Dr. James Jackson (Co-PI). During 
hospitalization, enrolled patients assigned to the intervention 
arm will undergo two 20-minute cognitive training sessions 
daily, 7 days a week. The first 
session will occur within 24 
hours of ED presentation. If an 
unanticipated delay with the 
initial cognitive training session 
occurs (e.g., patient leaves for 
a procedure or radiographic 
procedure), the cognitive 
training will be administered as 
soon as feasibly possible. The 
Cognitive Intervention 
Specialist will primarily 
administer the cognitive 
training Monday through 
Friday from 8A to 4P. If the 
Cognitive Intervention 
Specialist is not available (e.g., 
weekends), then cognitive 
training will be administered by trained CTAs.  
 
The cognitive training program and its degree of difficulty will be tailored to the patient’s current 
level of cognitive functioning. Patients will be asked to work through progressively more 
challenging exercises pertaining to orientation, attention, problem solving, and memory (Table 
2). These cognitive training exercises will be significantly difficult, but when they can be 
completed easily (>85% mastery), their difficulty will be increased, and this process will be 
repeated as appropriate.  They will also perform puzzles, games, or cognitive tasks related to 
Table 2. Cognitive training 
during hospitalization 
Orientation exercise 
Forward and backward digit span 
Memory and problem solving  
Reverse digit spans 
Letters-numbers 
Puzzles, games, hobbies 
Table 3. Key Components of Goal Management Training 
I. Slip-Ups 
Overall Introduction; Psychoeducation; Define 
Goals and Absentminded Slips; Raise 
Awareness of Consequences of Slips. 
II. Stop the 
Automatic 
Pilot 
Define Automatic Pilot and How Leads to Errors; 
Learn how to “STOP” Automatic Pilot. 
III. The Mental    
Blackboard 
Define the Mental Blackboard; Learn How to 
“STOP” and Check Mental Blackboard. 
IV. State your 
Goals 
Define Goals; Learn How to State Goals; 
Practice “STOP” and “STATE.” 
V. Making 
Decisions 
Define Competing Goals; Learn How to Split 
Goals; Practice “STOP-STATE-SPLIT.” 
VI. Splitting 
Tasks into 
Subtasks 
Define Overwhelming Goals; Learn How to Split 
Goals; Practice “STOP-STATE-SPLIT.” 
VII. Checking 
(STOP) 
Learn How to Recognize Errors in “STOP-
STATE-SPLIT” Cycle; Review How to Use 
“STOP” to Monitor Daily Tasks; Wrap-Up. 

 
 
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their hobbies (based on a brief survey that gauges patient’s hobbies and interests) and will 
participate in simple second language learning (likely Spanish, unless already conversant).39,40 
For patients with severe delirium and are unable to fully engage in the cognitive task, the 
Cognitive Intervention Specialist will engage them with relatively simpler, less demanding tasks 
such as reorientation or following simple 1 or 2 step commands. For mechanically ventilated 
patients (<3% of our cohort), patients will provide written responses. If unable to write, they will 
be presented with a booklet from which to indicate correct answers for each exercise.41 To 
assess uptake, the Cognitive Intervention Specialist will record what tasks were performed and 
session length for each interaction. The subject’s cognitive deficits will also be recorded, 
especially after the delirium has resolved, to help tailor the cognitive intervention. 
 
Cognitive rehabilitation, using GMT, will be administered in subjects randomized to the 
intervention arm within 1 week after hospital discharge at their place of residence. We will 
administer the cognitive rehabilitation in post-acute care facilities (~30% of enrolled subjects) by 
leveraging our existing relationships with over 40 skilled-nursing facilities from previous and 
current research studies. The Cognitive Intervention Specialist will administer GMT, 
representing a meaningful cognitive challenge, using the key components listed in Table 3 once 
a week for 12-weeks; each session will last approximately one hour. In summary, GMT will (1) 
teach patients compensatory strategies such as “stop” techniques [e.g., to “stop and think” 
about consequences of a decision before making it]; (2) help them to take complex tasks and 
divide them into manageable subtasks to increase the likelihood of completing the task; and (3) 
enable them to learn to regain cognitive control when their behavior becomes incompatible with 
their intended goals. GMT is anchored in “sustained and vigilant attention theory,” and it enables 
patients to actively attend to “higher order” goals critical to functioning. GMT is tailored to the 
individual needs of the patient. During the initial session, the Cognitive Intervention Specialist 
will meet with the subject and their family member or caregiver to identify these functional and 
cognitive deficiencies. Using this information and the cognitive deficits identified during 
hospitalization, Dr. Jackson and the Cognitive Intervention Specialist will tailor the GMT protocol 
to the subject’s unique disabilities. Thereafter, each session will build on the previous one, so 
that a “dose” of rehabilitation is delivered. Between each session, patients (with assistance from 
their caregiver if needed) will also complete relevant homework assignments emphasizing real 
world applications of the techniques learned. The cognitive rehabilitation will be discontinued if 
the patient dies, is transitioned to hospice care, is persistently unable to follow simple 
commands after hospital discharge for 4 consecutive GMT sessions, or withdraws. If the patient 
is re-hospitalized, we will temporarily stop the intervention. After the subject is discharged from 
the re-hospitalization, we will reinitiate cognitive rehabilitation until the patient completes a total 
of 12 sessions.  
 
To assess uptake and fidelity of the cognitive training and rehabilitation, we will record the 
number of sessions, time taken per session, and what tasks were completed. The Cognitive 
Intervention Specialist will also assess patient engagement at hospital discharge and at the end 
of the cognitive rehabilitation intervention using the Hopkins Rehabilitation Engagement 
Rating Scale (Appendix E).42 All sessions may be audiotaped (with patient consent). Dr. 
Jackson will listen to selected cognitive training and GMT sessions within one week of their 
completion to (1) ensure the continued validity of the intervention of interest and (2) ensure high 
levels of consistency among all individuals delivering the intervention. Dr. Jackson will provide 
feedback if the intervention administration appears suboptimal. Initially, Dr. Jackson will review 
all recorded sessions early in the study. Once the Dr. Jackson feels that the Cognitive 
Intervention Specialist develops mastery with cognitive training and rehabilitation protocols, spot 
checks will occur (~5% of recorded sessions).  He will also review recorded sessions that may 
had issues or been problematic. 
 

 
 
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Due to COVID-19 pandemic, patients may not feel comfortable with face-to-face evaluations 
even after the pandemic is over.  As an alternative, the cognitive training and rehabilitation 
intervention may be done over videoconferencing (e.g., Skype, Zoom, WebEx, FaceTime, etc.). 
In addition, patients or their families may not feel comfortable with research staff coming into 
their place of residence.  Patients will have the option to come to the medical center to have 
their cognitive rehabilitation completed. Post-acute care facilities may also restrict visitation, 
even after the pandemic is over. We will attempt to do the intervention via videoconferencing in 
the post-acute care facility case. If not feasible, then cognitive rehabilitation will start after the 
patient is discharged home.  These alternatives will be available to the subject for the entirety of 
the study.  Even when the pandemic is over, some may patients or families or skilled nursing 
facilities may continue to have these concerns. 
 
5.2. Prospective Data Collection – The data collected prospectively in the ED, hospital, 12-
weeks post-hospital discharge, and 4-months are summarized in Table 4.  
Prospective Data Collection 
Source 
Duration 
ED 
Hospital 
12-weeks 
post-
discharge* 
4-months 
follow-up 
Brief Confusion assessment Method 
(bCAM, Appendix B) 
Patient 
1 min 
X 
X 
 
 
Confusion Assessment Method for the 
Intensive Care Unit (CAM-ICU, 
Appendix C) 
Patient 
1 min 
X 
X 
 
 
Delirium Assessment Battery 
(Appendix G) 
Patient 
5 min 
X 
X 
 
 
Richmond Agitation Sedation Scale 
(RASS, Appendix H) 
Patient 
Observ-
ation 
X 
X 
 
 
Delirium Motor Subtyping Scale-4 
(DMSS-4, Appendix I)  
Patient 
Observ-
ation 
X 
X 
 
 
Confusion Assessment Method 
Severity (CAM-S, Appendix J)  
Patient 
Observ-
ation 
X 
X 
 
 
Blood and urine# 
Patient 
5 min 
X 
X 
 
 
Demographics, education, substance 
abuse, sensory impairment, recent 
hospitalization, region of residence, 
highest occupation, height, weight,  
hospitalization in past 6-months. 
Patient / 
Informant 
5 min 
X 
 
 
 
Quick Dementia Rating Scale (QDRS, 
Appendix K)   
Informant 
3 min 
X 
 
 
 
Everyday Cognition (eCOG, Appendix 
U) 
Informant 
5 min 
X 
 
 
 
Montreal Cognitive Assessment 
(Appendix V) 
Patient 
5 min 
X 
Xo 
 
X 
Older American Resources and 
Services Activities of Daily Living 
Scale (OARS ADL, Appendix L)  
Patient / 
Informant 
5 min 
X 
 
 
X 
Mini-Nutritional Assessment (Appendix 
M) 
Patient / 
Informant 
2 min 
X 
 
 
 
Clinical Frailty Scale (Appendix N) 
Patient 
Observ-
ation 
X 
 
 
X 
Hopkins Rehabilitation Engagement 
Rating Scale (Appendix E) 
Patient 
Observ-
ation 
 
X* 
X* 
 
Life Space Assessment (Appendix F) 
Patient/ 
Informant 
5 min 
X 
 
 
X 
Repeatable Battery for the 
Assessment of Neuropsychological 
Status (RBANS, Appendix O) 
Patient 
30 min 
 
 
 
X 

 
 
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Table 4. Prospective data collection schedule. o MOCA to be performed at 120 hours or at hospital discharge, 
whichever comes first. $hospital discharge only.  *To be performed at hospital discharge and after the cognitive 
rehabilitation sessions are completed. #, Blood and urine will be collected at enrollment and 72 hours; 120 hour 
blood and urine is optional.  ^Home writing samples will be used to calculate propositional density. 
“Observation” in the “Duration” column indicates that these measures are obtained by observing the patient 
during routine research activities.  
 
5.2a. Delirium will be assessed for in the ED at screening and 3-hours, and once daily 
throughout the hospitalization if enrolled for 10 days and at discharge, whichever comes first. 
Trained CTAs will perform the modified Brief Confusion Assessment Method (bCAM, 1 
minute, Appendix B) in non-mechanically ventilated patients or the Confusion Assessment 
Method for the Intensive Care Unit (CAM-ICU, Appendix C). The modified bCAM can be 
reliably performed by our non-physician research staff. It is 82% to 86% sensitive and 93 to 96% 
specific for delirium with a kappa of 0.87 indicating excellent interobserver reliability.43 The 
CTAs will also perform the Delirium Assessment Battery (Appendix G, 5 minutes) to capture 
additional delirium assessments such as the CAM, 3D-CAM, and 4AT for our sensitivity 
analyses.44-47  
 
5.2.b. Delirium Heterogeneity Factors 
Delirium heterogeneity factors will be collected once daily in the ED and hospital to help identify 
delirium phenotypes using LCA (Aim #3). These heterogeneity assessments do not require any 
additional patient interaction and arousal, psychomotor activity, and severity can be observed 
while performing the delirium assessments. Arousal will be determined with the Richmond 
Agitation Sedation Scale (RASS, Appendix H)48,49 Patients will be categorized as having 
delirium with normal arousal (RASS = 0), decreased arousal (RASS < 0) or increased arousal 
(RASS > 0). Psychomotor activity will be assessed  by using the Delirium Motor Subtyping 
Scale-4 (DMSS-4, Appendix I).50 This observational scale is an abbreviated version of the 
more complex 11-item Delirium Motor Subtyping Scale (DMSS) with very good agreement (κ = 
0.63 to 0.92).50,51 Patients will be categorized into hypoactive, hyperactive, mixed, and no 
psychomotor subtype delirium. Delirium severity will be determined by the short form 
Confusion Assessment Method Severity (CAM-S, Appendix J) and will be categorized as 
none (0 points), low (1 point), moderate (2 points), or severe (3 to 7 points).52  
 
5.2.c. Establishing Pre-Ilness Cognition and Intelligence 
To account for pre-illness cognition, we will obtain the Quick Dementia Rating Scale (QDRS, 
Appendix K) and Everyday Cognition (eCOG, Appendix U) scales from a qualified informant 
(caregiver, offspring, spouse, sibling, or having known the patient >5 years). A qualified 
informant is present in 97% of delirious ED patients. Pre-existing ADRD will be defined as a 
DKEFS Proverbs (Appendix P) 
Patient 
4 min 
 
 
 
X 
DKEFS Color-Word Interference 
(Appendix Q) 
Patient 
3 min 
 
 
 
X 
DKEFS Category Switching (Appendix 
R) 
Patient 
3 min 
 
 
 
X 
Trails A and B (Appendix W) 
Patient 
5 min 
 
 
 
X 
EQ-5D-5L (Appendix S) 
Patient / 
Informant 
5 min 
 
 
 
X 
Death, nursing home placement, or 
rehospitalization 
Patient / 
Informant 
/ Medical 
record 
2 min 
 
 
 
X 
Brain MRI 
Patient 
45 min 
 
 
 
X 
Propositional density 
Patient 
writing 
sample^ 
None 
X 
 
 
 

 
 
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QDRS > 5.0, ADRD documented in the medical record, or prescribed an acetylcholine esterase 
inhibitor (galantamine, donepezil, and rivastigmine) before randomization. 
 
We will also account for pre-morbid intelligence, which is considered a measure of cognitive 
reserve, by calculating propositional density using the patient’s writing samples written prior to 
the acute illness. Propositional density is the number of propositions per 10 words, and its 
measurement early and late in life has been shown to be strongly associated with future 
dementia status.53,54 We will use the Computerized Propositional Idea Density Rater (CPIDR 
version 3.2, Athens, GA) to calculate propositional density automatically.55,56 While propositional 
density remains stable over time even in patients with dementia,57 We will attempt to collect the 
earliest writing samples available. Based on our pilot study, approximately 90% of older ED 
patients with a qualified informant will have writing samples available for analysis.  
 
5.2.d. Additional prospective data collected at enrollment.  
To ascertain pre-illness function, we will collect the Older American Resources and 
Services Activities of Daily Living (OARS ADL, 2 min, Appendix L) at enrollment from the 
patient or qualified informant.58 Scores range from 0 (completely dependent) to 28 (completely 
independent. Nutritional status will be determined by the Mini-Nutritional Assessment 
(MNA, Appendix M).59 The MNA ranges from 0 (malnourished) to 14 (normal nutritional status).  
We will also determine pre-illness frailty using the Clinical Frailty Scale (Observational, 
Appendix N) which is based upon comorbidities, functional status, and cognition. This scale 
ranges from 0 (no frailty) to 9 (terminally ill). Patient demographics, including age, race, sex, 
marital status, years of education, highest occupation, weight, height, and place of residence 
will be recorded. Hospitalization within 6 months, substance abuse history, and hearing or visual 
impairment will also be obtained.   
 
5.3. Medical Record Review for Index Hospitalization 
Medical Record Variable 
Description 
Elixhauser comorbidity index61   
Summarizes the prognostic significance of 31 predefined 
comorbidities. Higher scores represent higher comorbidity. 
Acute Physiology Score (APS) of the Acute 
Physiology and Chronic Health Evaluation 
(APACHE II)62  
The APS is based upon the initial values of 12 routine 
physiologic and laboratory measurements. Higher scores 
indicate higher severity of illness. 
ADRD documented in the medical record or 
prescribed an acetylcholine esterase inhibitor 
(galantamine, donepezil, and rivastigmine) 
prior to randomization. 
This data will be used to help define pre-existing ADRD. 
Drug Burden Index (DBI)63 
Characterizes the patient’s home exposure to 
anticholinergic and sedative medications. The DBI 
incorporates the principles of dose-response and maximal 
effect.63 
Medications given in the ED and hospital 
Daily benzodiazepines, opiates, and medications with 
anticholinergic properties given in the ED and hospital will 
be recorded.64-66 
Interventions received in the ED and hospital 
Interventions such as physical, occupational, and speech 
therapies, consultations (psychiatry, geriatrics, or 
neurology), surgeries or procedures, and treatment for 
delirium etiologies will be recorded. 
ED, ICU, and hospital length of stay 
The length of stay in the ED, ICU, and hospital will be 
quantified by hours. 
Hospital discharge disposition 
The patient’s hospital discharge disposition will be 
classified as discharged to home, assisted living, post-
acute care facility, nursing home, or expired. 
Table 5. Variables to be collected during medical record review. 

 
 
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Delirium etiology during index hospitalization will be determined using the Delirium Etiology 
Checklist (Appendix T) which classifies delirium etiologies into 13 categories.60 Using medical 
record review, delirium etiology will be independently determined by two physician reviewers 
who have expertise in delirium; any disagreements will be adjudicated by a third physician 
reviewer. If the inter-rater reliability between the emergency physician and physician reviewers 
is good (kappa > 0.60), then the emergency physician’s delirium etiology rating will be used for 
the LCA. For the purpose of our analysis, delirium etiologies will be collapsed into the following 
categories based upon our preliminary data: (1) CNS, (2) metabolic, (3) systemic infection, and 
(4) other. The physician reviewers will also record what treatments were provided and 
determine if the delirium etiologies were treated adequately. 
 
Additional data will be collected from the medical record and is summarized in Table 5.  
 
Outcome Variable 
Description 
Source 
Length  
Primary Outcome 
Repeatable Battery for the 
Assessment of 
Neuropsychological Status 
(RBANS, Appendix E)67 
A neuropsychological battery for 
global cognition which evaluates 
immediate and delayed memory, 
attention, visuospatial 
construction, and language. It 
has been validated in subjects 
with mild cognitive impairment, 
moderate to severe traumatic 
brain injuries, vascular 
dementias, and Alzheimer’s 
disease.67-71 Scores range from 
40 to 160, and the population 
mean (SD) is 100 (15). 
Patient 
30 mins 
Secondary Outcomes 
Delis–Kaplan Executive 
Function System (D-KEFS) 
Proverbs subscale 
(conceptual flexibility, 
Appendix F), the DKEFS 
Color Word Interference 
(inhibition, Appendix G), and 
DKEFS Verbal Fluency 
Category Switching subscale 
(monitoring, Appendix H)72     
This neuropsychological battery 
will be used to quantify executive 
function. It assesses conceptual 
flexibility, inhibition, and 
monitoring which are the 
cornerstones of executive 
function.72  An executive function 
composite score will be 
calculated from these three 
DKEFS subscales. 
Patient 
10 mins 
Older American Resources 
and Services Activities of 
Daily Living Scale (OARS 
ADL, Appendix I)58 
It is based upon 7 basic and 7 
instrumental activities of daily 
living. Scores range from 0 
(completely dependent) to 28 
(completely independent). 
Patient or 
informant 
5 mins 
EQ-5D-5L (Appendix J)73-75 
EQ-5D-5L characterizes quality 
of life and contains 5-dimensions 
(“5D”) related to everyday living: 
mobility, self-care, usual 
activities, pain/discomfort, and 
anxiety/depression. The EQ-5D-
5L asks patients to grade their 
current global health status from 
0 (worst health you can imagine) 
to 100 (best health you can 
imagine). 
Patient 
5 mins 

 
 
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5.4. Outcome Variables for Aim #1 (randomized control trial)  
Four months (3 to 7 months) after randomization, subjects will return to the local site for 
outcome ascertainment.  For those who are unable to travel, a member of the 
neuropsychological team will travel to the patient’s home.  The primary and secondary outcome 
variables to be collected at 4-months (range 3 to 7 months) are listed in Table 4.  We will also 
investigate the effect of cognitive training on index hospital outcomes as part of our secondary 
analyses. We will collect delirium duration using the modified bCAM, and hospital length of stay, 
ICU length of stay, and post-discharge disposition (e.g., skilled nursing facility) to be collected 
via medical record review. Based upon the neuropsychological raters’ observations, they will 
also determine the Clinical Frailty Scale (Appendix N). They will also collect the Mini-
Nutritional Assessment (Appendix M) for covariate adjustment. 
 
5.5. Outcome Variables for Aim #2 (MRI) 
Functional magnetic resonance imaging (fMRI) will be performed at 4 (range 3 to 7) months 
after randomization at the Vanderbilt University Institute of Imaging Science (VUIIS). Because of 
the 1:2 random allocation, one out of two controls will be randomly selected to participate in the 
fMRI aim. Patients will be scanned using dual-channel body coil radiofrequency transmission 
and SENSE-array 32-channel reception with the following protocol: 
a. Functional MRI. Whole-brain gradient echo blood oxygenation level-dependent (BOLD) fMRI 
will be performed using a single-shot EPI multiband (factor=2.0) readout with spatial 
resolution=2x2x2 mm3 and TR/TE=1000/35 ms. The acquisition will be performed during 
a face/scene delayed matching task76 during fMRI acquisition using standard seed-based as 
well as minimum spanning tree (MST) analysis. This face/scene delayed matching task 
evaluates selective attention and working memory, and is designed to target medial temporal 
lobe and frontal and parietal cortices.77  
b. Perfusion imaging. We will perform pseudo-continuous arterial spin labeling (pCASL) to 
obtain quantitative perfusion maps (ml blood / 100g tissue / min). Here, we will apply 
Hanning-windowed block pulse labeling (pulse-train duration=1600 ms) followed by post-
labeling delay=1800 ms with TR=4.1s. Labeling will occur 90 mm inferior to the AC/PC line. 
We will apply a 3D GRASE readout (spatial resolution=3x3x5 mm3; SENSE (Phase)=3; 
SENSE (Slice)=2; turbo direction=slice) with background suppression. A TR=20s equilibrium 
magnetization (M0) image with identical geometry as pCASL but with labeling removed will 
also be acquired.  
c. Anatomical. T1-weighted (MPRAGE; spatial resolution=1.0x1.0x1.0 mm3; TR/TE=8.2/3.7 ms), 
T2-weighted FLAIR (spatial resolution=0.9x1.1x3.0 mm3; TR/TI/TE=11000/2800/120 ms), T2*-
weighted (spatial resolution=0.5x0.5x1mm3; TR/TE1/ΔTE=31/7.2/6.2 ms), and intracranial 
and extracranial time-of-flight MR angiography (TOF-MRA; intracranial: spatial 
resolution=0.5x0.8x1.4 mm3, TR/TE=18.6/3.2 ms; extracranial: spatial resolution=0.9x0.9x3.0 
mm3; TR/TE=18.6/3.2 ms).  
Rehospitalization and nursing 
home placement 
While attempting to contact the 
subject or surrogate, we will 
determine if the patient was 
rehospitalized or placed in a 
nursing home. 
Patient or 
informant 
1 min 
Death 
To be ascertained via medical 
review, subject or surrogate 
contact, obituary searches, and 
National Death Index. 
Informant, 
electronic 
health record 
1 min 
Table 6. Four-month outcome variables to be collected. 
 

 
 
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The brain MRI data will be interpreted by Dr. Donahue’s staff at the Vanderbilt University 
Institute of Imaging Science using the following approaches:  
a. Functional MRI. BOLD data will be corrected for motion, baseline drift, and slice-time and 
will be analyzed using standard seed-based functional connectivity and more novel MST 
following previously-reported standard procedures in eloquent functional networks known to 
be affected by delirium.78,79 Individual-subject t- and z-statistic connectivity maps will be 
calculated, along with betweenness centrality and degree (from MST analysis); maps will be 
warped using FSL FLIRT and FNIRT80 to a 2 mm MNI atlas using a T1-weighted anatomical 
image as an intermediate template. 
b. Perfusion imaging. pCASL data will be corrected for motion and baseline drift, surround-
subtracted,81 and normalized by M0 to generate a difference magnetization map (ΔM/M0); 
these values will subsequently be converted to CBF in absolute units upon application of the 
flow-modified Bloch equation82 and transformed to the standard atlas using identical 
procedures as outlined for BOLD. 
c. Anatomical. Tissue volume will be quantified from the T1-weighted images using Freesurfer 
and quantitative metrics of tissue volume in all brain lobes will be recorded.  
 
5.6. Plasma biomarkers of inflammation (IL-6 and CRP), endothelial dysfunction (PAI-1), 
and BBB injury (S100B) using blood specimens collected at enrollment.  Within 1 hour of blood 
draw, the blood will be centrifuged, processed, and stored in a -80o Celsius freezer. These 
plasma biomarkers will be batch measured in years 3 and 4 at the Lorraine Ware Laboratory 
using Electrochemiluminescent assays (IL-6, CRP, and PAI-1, Meso Scale Discovery; Rockville, 
MD) and sandwich ELISAs (S100B; Millipore; Billerica, MA). Plasma biomarkers will be 
measured in blood collected at enrollment and 72 hours. Additional blood may be collected at 
120-hours for future analyses, but will be optional; some patients no longer have routine blood 
draws by 120-hours. Additional blood will be collected at enrollment for future genetic analysis. 
Urine will also be collected at baseline, 72-hours, and 120-hours for future analyses. 
 
5.7. Database management  
This study will use REDCap for data collection, transmission, and storage. REDCap is a secure, 
web-based application for building and managing online databases. Vanderbilt University 
Medical Center, with collaboration from a consortium of institutional partners, including the 
Vanderbilt Institute for Clinical and Translation Research (VICTR) Informatics Core, developed 
and manages a software toolset and workflow methodology for electronic data collection and 
management of research and clinical trial data. All study data will be entered via a password-
protected, study unique REDCap database website. REDCap servers are housed in a local data 
center at Vanderbilt University Medical Center, and all web-based information transmission is 
encrypted. REDCap was developed specifically around HIPAA-Security guidelines and is 
recommended by both the Vanderbilt University Medical Center Privacy Office and Institutional 
Review Board. REDCap has been disseminated for use locally at other institutions and currently 
supports > 140 academic/non-profit consortium partners and 11,000 research end-users 
(www.projectredcap.org).  
 
Whenever possible, data will be directly entered into electronic case report forms (eCRFs) 
within REDCap.  When paper-based surveys or forms, such as the RBANs, are collected, these 
forms will be entered or uploaded into REDCap. The paper CRFs will only have the patient’s 
unique identification number and initials. These case report forms will then be stored in a locked 
cabinet in a secure office space.  All paper case report forms will be kept according to 
Institutional Review Board (IRB) policies.   
 

 
 
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All research materials will only be accessible by IRB approved research personnel.  Principal 
investigators, co-investigators, study coordinators, Cognitive Intervention Specialist, CTAs, and 
neuropsychological raters will have access to individually identifiable private information. Such 
access is necessary for conducting medical record review and follow-up. The rest of the study 
team (e.g., biostatisticians) will only have access to de-identified data. 
 
5.8. Reimbursement 
We will provide $75 for patients to complete the ED, hospital, and 12-week post-discharge 
assessments. We will also provide participants financial compensation ($75) the 4-month follow-
up. Patients will receive an additional $50 in they participate in the brain magnetic resonance 
imaging (MRI) study. For patients who develop significant functional impairment or are unable to 
travel (~30% of cohort), the neuropsychologists will go to their homes to conduct the long-term 
cognitive and secondary outcomes assessments. These patients will be reimbursed $25. 
 
6.0 
Risks 
There are several risks associated with this R01:   
1) Risks associated with the collection of protected health information.  Collection of 
protected health information for research involves a small risk of the loss of patient 
confidentiality.  To minimize this risk, at no time will we reveal subject identities in any 
manner, whether in presentation, description, or publication of the research for scientific 
purposes. Most data will be directly entered into a HIPAA compliant REDCap electronic 
database.  These data will be stored on a secure network on Vanderbilt’s computer 
servers. While data will be entered electronically whenever possible, paper-based case 
report forms may still be used to collect neuropsychological data (e.g., figure drawing 
and recall).  The paper-based case report forms will have the patient’s study 
identification number and initials only; no other patient identifiers will be present. All 
paper-based case report forms and questionnaires will be stored in a locked cabinet in 
office space only accessible to the study team.  All case report forms will be kept for 3 
years as per Vanderbilt’s IRB policy; afterward, all paper documents will be shredded. 
2) Fatigue, frustration, and distress. Subjects will undergo cognitive training, cognitive 
rehabilitation, and a neuropsychological examination that can take up to 45 minutes to 
perform. Some of the tasks related to the cognitive intervention and testing are also 
cognitively demanding. Therefore, there is a small risk that the patient may become 
fatigued, frustrated, or distressed during the cognitive intervention or assessments. In 
these cases, we will immediately stop the assessment or tasks, and allow the patient to 
rest. Afterward, we will ask the patient and their families if we can continue with the 
study assessments or cognitive training or rehabilitation session, or if we should come 
back later in the day or the next day. Occasionally, patients and their families may get 
visibly frustrated and distressed if the patient is unable to perform the cognitive tasks. 
We will reassure them that these tasks can be difficult to perform and that such 
difficulties are common. If the patient or his / her family continues to be distressed after 
this reassurance, we will skip that task or stop the assessment altogether.   
3) Phlebotomy. All participants will have blood drawn for research purposes. As almost all 
participants will have intravenous lines placed for clinical purposes, the risk of blood 
draws is essentially nil, as blood can be easily obtained from these lines. In the rare 
case an intravenous line is not present, the risks of drawing blood are uncommon and 
include bleeding and bruising. Commonly, drawing blood is painful, and rarely, drawing 
blood can lead to infections at the site of the blood draw. To minimize this risk, we will 
prep the phlebotomy site with chlorhexidine (antiseptic fluid) and use the smallest gauge 
needle possible. We will also minimize the number of attempts.     

 
 
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4) Distress secondary to fMRI. A subset of 50 patients will undergo fMRI examination which 
can take 45 minutes to perform.  There is a small risk of distress secondary to 
claustrophobia. To minimize this risk, patients will have an opportunity to opt-out of the 
fMRI portion, especially if they are claustrophobic.  If the subject is in the MRI scanner 
and cannot tolerate it, then the MRI will be stopped immediately.  We will ask the subject 
if they will be able to proceed with the MRI. If they are unable to continue, we will 
withdraw the patient from this portion of the study.   
 
7.0 
Safety Monitoring, Reporting of Adverse Events or Unanticipated Problems 
involving Risk to Participants or Others 
Because the cognitive training and rehabilitation is a non-pharmacologic intervention, the 
intervention poses minimal risk to the patient.  Therefore, we will not have a formal DSMB. 
However, Dr. Babar Kahn (Indiana University) will independently serve as the data and safety 
monitor; he is not part of the study team and will not participate in any study or publication 
activities related to this R01. He will also review all data relevant to safety (including all clinical 
outcomes, SAEs, and unexpected AEs) in once a year during prospective enrollment. He will 
have access to unblinded data in order minimize potential for bias while maintaining appropriate 
safety monitoring. After this safety review, Dr. Kahn will provide a written report to the PIs. The 
PIs will provide this to the Vanderbilt IRB and the National Institute on Aging.   
 
8.0 
Study Withdrawal/Discontinuation 
If patient or caregiver declines participation at the outset or does not meet inclusion criteria, they 
will not be included in the study. If patients wish to discontinue taking part in the study, they will 
be instructed to contact principal investigator or the research staff and let them know that they 
wish to withdraw.  At that time, no further data will be collected on the patient. All health data 
previously collected before they withdraw their consent will still be used for reporting and 
research quality.  
 
9.0 
Statistical Considerations
=
Cognitive training /
rehabilitation 
intervention
+ premorbid cognition + premorbid intelligence
+ covariates 
+ pre-existing ADRD*cognitive intervention
Aim #1 Formula
4-month global cognition 
 
9.1. Data analysis for Aim #1 (cognitive training/intervention RCT and 4-month global 
cognition): The primary analysis for Aim #1 will be an intention-to-treat comparison of 4-month 
global cognition between those who receive and not receive the cognitive training and 
rehabilitation intervention. Though randomization theoretically accounts for group imbalances 
and possible confounding, adjusting for strong risk factors for outcomes reduces measurement 
error, which may increase statistical power.83 Therefore, we will use multivariable linear 
regression using the formula below and adjust for pre-illness cognition and other covariates 
listed in Table C8.1.a: 
 
Covariates that occurred after randomization (e.g., interventions provided during hospitalization) 
will not be adjusted for because they may potentially be affected by the cognitive intervention 
and be on the causal pathway. We will also determine if pre-existing ADRD modifies any 
association between cognitive intervention and 4-month outcomes by incorporating a two-factor 
interaction (pre-illness ADRD*cognitive intervention) into the model. In the event of significant 
missing covariate data, multiple imputation will be used.84-86 After the initial analysis has been 
completed, we will also evaluate if there is any effect modification of baseline severity of 
illness (APS), race, sex, and initial delirium psychomotor, arousal, severity, etiology, and 
pathophysiological subtypes. To determine if using a delirium assessment affects our 
conclusions, we will also perform a sensitivity analysis where the multivariable linear 

 
 
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regression model is re-run in a subset of patients who are positive for other delirium 
assessments (CAM, 3D-CAM, 4AT).44-47 
 
Secondary analyses will also be performed. We will 
perform a per protocol analyses; for the multivariable linear 
regression model, the dose of the interventions (total 
duration of cognitive training and total duration of cognitive 
rehabilitation) will be the primary independent variables 
instead of treatment assignment (cognitive 
training/rehabilitation versus placebo). We will determine if 
early cognitive training and rehabilitation are associated 
with our 4-month secondary endpoints such as the 
individual RBANS cognitive domains (immediate and 
delayed memory, attention, language, and visuospatial 
construction), executive function, functional status, 
rehospitalization, nursing home placement, and death. We 
will also determine if early cognitive training reduces 
delirium duration, hospital length of stay, and discharge to 
a post-acute care facility. We will also explore if there are 
specific interventions that potentiate the cognitive 
intervention’s effect such as time-to-cognitive training, 
discharge to a post-acute care facility, and physical activity 
during cognitive rehabilitation (mean Life Space 
questionnaire scores). We will explore if these factors 
modify the association between the cognitive intervention 
and 4-month global cognition. 
 
9.2. Data analysis for Aim #2 (fMRI). To test if frontoparietal network connectivity, as 
characterized by BOLD fMRI, improves with cognitive training/rehabilitation compared with 
controls, we will apply the co-registered z-statistic maps in a mixed effects model to evaluate 
regions that differ in activation between the two groups, after separately modeling age, sex, and 
pre-illness QDRS. Group-level z-statistics and corrected p-values will be reported. As a 
supplementary analysis, we will also explore whether (i) regional tissue volumes at the imaging 
MRI time point vary between groups and (ii) cortical perfusion quantified from pCASL varies 
between groups. For these 
comparisons, a Wilcoxon rank-
sum test or Student’s t-test will 
be applied. With a sample size 
of 50 (25 per group), we will 
have sufficient power to detect a 
30% improvement in 
frontoparietal cortex network 
connectivity with 80% power and 
a two-sided alpha of 0.05. 
 
9.3. Data Analysis for Aim #3 
(identify novel delirium 
phenotypes using LCA): Aim 
#3 will use LCA to identify 
hidden groups based on the 
observed delirium subtypes 
 
Primary Independent  
Cognitive intervention 
 
Pre-illness Cognition / Intelligence 
Pre-illness ADRD 
Pre-illness QDRS 
Propositional density 
 
Other Baseline Covariates 
Sex 
Race 
Education 
Pre-illness function (OARS ADL) 
Severity of illness (APS) 
Comorbidity Burden 
 
 
df 
1 
 
 
1 
1 
1 
 
 
1 
1 
1 
1 
1 
1 
Interactions (Maximum) 
ADRD* Cognitive intervention 
 
 
1 
 
Total Degrees of Freedom (df) 
 
11 
Table C8.1.a. Covariates and interaction 
terms for multivariable linear regression. 
Figure C8.3.a. Three hypothetical latent classes or phenotypes for 
delirium.  

 
 
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(arousal, psychomotor, severity, etiology, and pathophysiology) and separate them into mutually 
exclusive classes. This technique can be used to obtain phenotypes of delirium and determine if 
these novel phenotypes are associated with 4-month global cognition. Based upon our 
preliminary study (Section C1.5), pre-existing ADRD may strongly influence these delirium 
latent classes and will be considered for the LCA. The “best” number of latent classes is usually 
determined a priori by the researcher and we hypothesize that the cohort will be represented by 
three delirium phenotypes (Figure C8.3.a): no or mild, moderate, or severe 4-month cognitive 
impairment. The sensitivity of this hypothesis, model fit, and identification of the correct number 
of unique delirium phenotypes will be evaluated by comparing the models assuming different 
number of classes using the bootstrapped likelihood ratio test, which is a parametric bootstrap 
method that uses bootstrap samples to estimate the distribution of the log likelihood difference 
test statistic.87  
Once the latent classes have been identified, we will explore if the delirium phenotypes 
identified by LCA modify the association between the cognitive training and rehabilitation 
intervention and 4-month global cognition using multivariable linear regression as described in 
Section C8.1a using the formula below: 
 
=
Cognitive training /
rehabilitation 
intervention
+ premorbid cognition + premorbid 
intelligence + covariates + 
cognitive intervention*phenotypes 
Aim #3 Formula
4-month global cognition 
Phenotypes identified 
by latent class analysis
+
 
The multivariable linear model for Aim #3 will be adjusted for the covariates listed Table C8.1.a. 
 
10.0 
Privacy/Confidentiality Issues 
The patient’s information, without identifiers, may be shared with other institutions or 
universities. Dr. Han, his co-investigators, and their staff will comply with any and all laws 
regarding the privacy of such information.  There are no plans to pay the patient for the use or 
transfer of their de-identified information or specimens.   
 
11.0 
Follow-up and Record Retention 
The duration of this study is approximately 4 years.  We will try to enroll 500 patients during this 
time.  Data collected will be retained indefinitely.    
 
12.0 
References 
1. 
Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. 
JAMA. 1990;263:1097-1101.  
2. 
Han JH, Shintani A, Eden S, et al. Delirium in the emergency department: an independent 
predictor of death within 6 months. Ann Emerg Med. 2010;56:244-252.  
3. 
Inouye SK, Rushing JT, Foreman MD, Palmer RM, Pompei P. Does delirium contribute 
to poor hospital outcomes? A three-site epidemiologic study. J Gen Intern Med. 
1998;13:234-242.  
4. 
Bellelli G, Morandi A, Di Santo SG, et al. "Delirium Day": a nationwide point prevalence 
study of delirium in older hospitalized patients using an easy standardized diagnostic 
tool. BMC Med. 2016;14:106.  
5. 
Fong TG, Jones RN, Marcantonio ER, et al. Adverse outcomes after hospitalization and 
delirium in persons with Alzheimer disease. Ann Intern Med. 2012;156:848-856, W296.  
6. 
Fong TG, Jones RN, Shi P, et al. Delirium accelerates cognitive decline in Alzheimer 
disease. Neurology. 2009;72:1570-1575.  
7. 
Gross AL, Jones RN, Habtemariam DA, et al. Delirium and Long-term Cognitive 
Trajectory Among Persons With Dementia. Arch Intern Med. 2012;172:1324-1331.  

 
 
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Protocol Date:  02/04/2022 
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8. 
Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia 
in the oldest-old: a population-based cohort study. Brain. 2012;135:2809-2816.  
9. 
Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after 
critical illness. N Engl J Med. 2013;369:1306-1316.  
10. 
Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after postoperative 
delirium. N Engl J Med. 2012;367:30-39.  
11. 
Lundstrom M, Edlund A, Bucht G, Karlsson S, Gustafson Y. Dementia after delirium in 
patients with femoral neck fractures. J Am Geriatr Soc. 2003;51:1002-1006.  
12. 
Bickel H, Gradinger R, Kochs E, Forstl H. High risk of cognitive and functional decline 
after postoperative delirium. A three-year prospective study. Dement Geriatr Cogn 
Disord. 2008;26:26-31.  
13. 
Witlox J, Slor CJ, Jansen RW, et al. The neuropsychological sequelae of delirium in 
elderly patients with hip fracture three months after hospital discharge. Int Psychogeriatr. 
2013;25:1521-1531.  
14. 
Basinski JR, Alfano CM, Katon WJ, Syrjala KL, Fann JR. Impact of delirium on distress, 
health-related quality of life, and cognition 6 months and 1 year after hematopoietic cell 
transplant. Biol Blood Marrow Transplant. 2010;16:824-831.  
15. 
MacLullich AM, Beaglehole A, Hall RJ, Meagher DJ. Delirium and long-term cognitive 
impairment. Int Rev Psychiatry. 2009;21:30-42.  
16. 
Davis DH, Muniz-Terrera G, Keage HA, et al. Association of Delirium With Cognitive 
Decline in Late Life: A Neuropathologic Study of 3 Population-Based Cohort Studies. 
JAMA Psychiatry. 2017;74:244-251.  
17. 
Inouye SK, Marcantonio ER, Kosar CM, et al. The short-term and long-term relationship 
between delirium and cognitive trajectory in older surgical patients. Alzheimers Dement. 
2016;12:766-775.  
18. 
Abraha I, Rimland JM, Trotta F, et al. Non-Pharmacological Interventions to Prevent or 
Treat Delirium in Older Patients: Clinical Practice Recommendations The SENATOR-
ONTOP Series. J Nutr Health Aging. 2016;20:927-936.  
19. 
Abraha I, Trotta F, Rimland JM, et al. Efficacy of Non-Pharmacological Interventions to 
Prevent and Treat Delirium in Older Patients: A Systematic Overview. The SENATOR 
project ONTOP Series. PLoS One. 2015;10:e0123090.  
20. 
Milisen K, Lemiengre J, Braes T, Foreman MD. Multicomponent intervention strategies 
for managing delirium in hospitalized older people: systematic review. J Adv Nurs. 
2005;52:79-90.  
21. 
Jackson JC, Ely EW, Morey MC, et al. Cognitive and physical rehabilitation of intensive 
care unit survivors: results of the RETURN randomized controlled pilot investigation. 
Crit Care Med. 2012;40:1088-1097.  
22. 
Clare L, Woods RT. Cognitive training and cognitive rehabilitation for people with early-
stage Alzheimer's disease: A review. Neuropsychological Rehabilitation. 2004;14:385-
401.  
23. 
Clare L, Woods RT, Moniz Cook ED, Orrell M, Spector A. Cognitive rehabilitation and 
cognitive training for early-stage Alzheimer's disease and vascular dementia. Cochrane 
Database Syst Rev. 2003:CD003260.  
24. 
Wilson BA. Towards a comprehensive model of cognitive rehabilitation. 
Neuropsychological Rehabilitation. 2002;12:97-110.  

 
 
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25. 
Clare L, Wilson BA, Breen K, Hodges JR. Errorless learning of face-name associations 
in early Alzheimer's disease. Neurocase. 1999;5:37-46.  
26. 
Clare L, Wilson BA, Carter G, Breen K, Gosses A, Hodges JR. Intervening with 
everyday memory problems in dementia of Alzheimer type: an errorless learning 
approach. J Clin Exp Neuropsychol. 2000;22:132-146.  
27. 
Hill RD, Evankovich KD, Sheikh JI, Yesavage JA. Imagery mnemonic training in a 
patient with primary degenerative dementia. Psychol Aging. 1987;2:204-205.  
28. 
Backman L, Josephsson S, Herlitz A, Stigsdotter A, Viitanen M. The generalizability of 
training gains in dementia: effects of an imagery-based mnemonic on face-name retention 
duration. Psychol Aging. 1991;6:489-492.  
29. 
Bourgeois MS. Enhancing conversation skills in patients with Alzheimer's disease using 
a prosthetic memory aid. J Appl Behav Anal. 1990;23:29-42.  
30. 
Bourgeois MS. Evaluating memory wallets in conversations with persons with dementia. 
J Speech Hear Res. 1992;35:1344-1357.  
31. 
Ylvisaker M, Hanks R, Johnson-Greene D. Perspectives on rehabilitation of individuals 
with cognitive impairment after brain injury: rationale for reconsideration of theoretical 
paradigms. J Head Trauma Rehabil. 2002;17:191-209.  
32. 
Stamenova V, Levine B. Effectiveness of goal management training® in improving 
executive functions: A meta-analysis. Neuropsychological Rehabilitation. 2018:1-31.  
33. 
McCusker J, Verdon J, Caplan GA, Meldon SW, Jacobs P. Older persons in the 
emergency medical care system. J Am Geriatr Soc. 2002;50:2103-2105.  
34. 
Breuil V, De Rotrou J, Forette F, et al. Cognitive stimulation of patients with dementia: 
Preliminary results. 1994;9:211-217.  
35. 
Small GW. What we need to know about age related memory loss. BMJ. 2002;324:1502-
1505.  
36. 
Han JH, Zimmerman EE, Cutler N, et al. Delirium in older emergency department 
patients: recognition, risk factors, and psychomotor subtypes. Acad Emerg Med. 
2009;16:193-200.  
37. 
Han JH, Vasilevskis EE, Chandrasekhar R, et al. Delirium in the Emergency Department 
and Its Extension into Hospitalization (DELINEATE) Study: Effect on 6-month Function 
and Cognition. J Am Geriatr Soc. 2017;65:1333-1338.  
38. 
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic 
data capture (REDCap)--a metadata-driven methodology and workflow process for 
providing translational research informatics support. J Biomed Inform. 2009;42:377-381.  
39. 
Farrington Leisure Interest Inventory.  
http://www.carepartnermentoring.com/Leisure%20Interest%20Inventory-
Public%20share%20version.pdf. Accessed January 31, 2019. 
40. 
Kolanowski AM, Hill N, Clare L, Marx P. Practical Protocol for Implementing Cognitive 
Stimulation in Persons with Delirium Superimposed on Dementia. Nonpharmacol Ther 
Dement. 2012;2:101-110.  
41. 
Brummel NE, Girard TD, Ely EW, et al. Feasibility and safety of early combined 
cognitive and physical therapy for critically ill medical and surgical patients: the Activity 
and Cognitive Therapy in ICU (ACT-ICU) trial. Intensive Care Med. 2014;40:370-379.  
42. 
Kortte KB, Falk LD, Castillo RC, Johnson-Greene D, Wegener ST. The Hopkins 
Rehabilitation Engagement Rating Scale: development and psychometric properties. 
Arch Phys Med Rehabil. 2007;88:877-884.  

 
 
21 
Protocol Date:  02/04/2022 
 Amendment #7 
43. 
Han JH, Wilson A, Graves AJ, Shintani A, Schnelle JF, Ely EW. A quick and easy 
delirium assessment for nonphysician research personnel. Am J Emerg Med. 
2016;34:1031-1036.  
44. 
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying 
confusion: the confusion assessment method. A new method for detection of delirium. 
Ann Intern Med. 1990;113:941-948.  
45. 
Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: 
validity and reliability of the confusion assessment method for the intensive care unit 
(CAM-ICU). JAMA. 2001;286:2703-2710.  
46. 
Bellelli G, Morandi A, Davis DH, et al. Validation of the 4AT, a new instrument for 
rapid delirium screening: a study in 234 hospitalised older people. Age Ageing. 
2014;43:496-502.  
47. 
Marcantonio ER, Ngo LH, O'Connor M, et al. 3D-CAM: Derivation and Validation of a 
3-Minute Diagnostic Interview for CAM-Defined Delirium: A Cross-sectional Diagnostic 
Test Study. Ann Intern Med. 2014;161:554-561.  
48. 
Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: 
validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 
2002;166:1338-1344.  
49. 
Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU 
patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). 
JAMA. 2003;289:2983-2991.  
50. 
Meagher D, Adamis D, Leonard M, et al. Development of an abbreviated version of the 
Delirium Motor Subtyping Scale (DMSS-4). Int Psychogeriatr. 2014:1-10.  
51. 
Boettger S, Nunez DG, Meyer R, et al. Brief assessment of delirium subtypes: 
Psychometric evaluation of the Delirium Motor Subtype Scale (DMSS)-4 in the intensive 
care setting. Palliat Support Care. 2017:1-9.  
52. 
Inouye SK, Kosar CM, Tommet D, et al. The CAM-S: development and validation of a 
new scoring system for delirium severity in 2 cohorts. Ann Intern Med. 2014;160:526-
533.  
53. 
Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. 
Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. 
Findings from the Nun Study. JAMA. 1996;275:528-532.  
54. 
Engelman M, Agree EM, Meoni LA, Klag MJ. Propositional density and cognitive 
function in later life: findings from the Precursors Study. J Gerontol B Psychol Sci Soc 
Sci. 2010;65:706-711.  
55. 
Covington MA. CPIDR 3 User Manual. 2007; http://ai1.ai.uga.edu/caspr/CPIDR-
Manual.pdf. Accessed October 31, 2019. 
56. 
Brown C, Snodgrass T, Kemper SJ, Herman R, Covington MA. Automatic measurement 
of propositional idea density from part-of-speech tagging. Behav Res Methods. 
2008;40:540-545.  
57. 
Kemper S, Greiner LH, Marquis JG, Prenovost K, Mitzner TL. Language decline across 
the life span: findings from the Nun Study. Psychol Aging. 2001;16:227-239.  
58. 
McCusker J, Bellavance F, Cardin S, Belzile E. Validity of an activities of daily living 
questionnaire among older patients in the emergency department. J Clin Epidemiol. 
1999;52:1023-1030.  

 
 
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Protocol Date:  02/04/2022 
 Amendment #7 
59. 
Kaiser MJ, Bauer JM, Ramsch C, et al. Validation of the Mini Nutritional Assessment 
short-form (MNA-SF): a practical tool for identification of nutritional status. J Nutr 
Health Aging. 2009;13:782-788.  
60. 
Levenson JL. The American Psychiatric Publishing textbook of psychosomatic medicine : 
psychiatric care of the medically ill. 2nd ed. Washington, DC: American Psychiatric 
Pub.; 2011. 
61. 
Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with 
administrative data. Med Care. 1998;36:8-27.  
62. 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985;13:818-829.  
63. 
Gnjidic D, Cumming RG, Le Couteur DG, et al. Drug Burden Index and physical 
function in older Australian men. Br J Clin Pharmacol. 2009;68:97-105.  
64. 
Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor 
for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104:21-
26.  
65. 
Tune LE, Bylsma FW. Benzodiazepine-induced and anticholinergic-induced delirium in 
the elderly. Int Psychogeriatr. 1991;3:397-408.  
66. 
Morrison RS, Magaziner J, Gilbert M, et al. Relationship between pain and opioid 
analgesics on the development of delirium following hip fracture. Journals of 
Gerontology Series a-Biological Sciences and Medical Sciences. 2003;58:76-81.  
67. 
Randolph C, Tierney MC, Mohr E, Chase TN. The Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS): preliminary clinical validity. J Clin 
Exp Neuropsychol. 1998;20:310-319.  
68. 
Duff K, Hobson VL, Beglinger LJ, O'Bryant SE. Diagnostic accuracy of the RBANS in 
mild cognitive impairment: limitations on assessing milder impairments. Arch Clin 
Neuropsychol. 2010;25:429-441.  
69. 
Duff K, Humphreys Clark JD, O'Bryant SE, Mold JW, Schiffer RB, Sutker PB. Utility of 
the RBANS in detecting cognitive impairment associated with Alzheimer's disease: 
sensitivity, specificity, and positive and negative predictive powers. Arch Clin 
Neuropsychol. 2008;23:603-612.  
70. 
Hobson VL, Hall JR, Humphreys-Clark JD, Schrimsher GW, O'Bryant SE. Identifying 
functional impairment with scores from the repeatable battery for the assessment of 
neuropsychological status (RBANS). Int J Geriatr Psychiatry. 2010;25:525-530.  
71. 
McKay C, Casey JE, Wertheimer J, Fichtenberg NL. Reliability and validity of the 
RBANS in a traumatic brain injured sample. Arch Clin Neuropsychol. 2007;22:91-98.  
72. 
Latzman RD, Markon KE. The factor structure and age-related factorial invariance of the 
Delis-Kaplan Executive Function System (D-KEFS). Assessment. 2010;17:172-184.  
73. 
Johnson JA, Coons SJ, Ergo A, Szava-Kovats G. Valuation of EuroQOL (EQ-5D) health 
states in an adult US sample. Pharmacoeconomics. 1998;13:421-433.  
74. 
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann 
Med. 2001;33:337-343.  
75. 
Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development 
and testing of the D1 valuation model. Med Care. 2005;43:203-220.  
76. 
Chen AJ, Novakovic-Agopian T, Nycum TJ, et al. Training of goal-directed attention 
regulation enhances control over neural processing for individuals with brain injury. 
Brain. 2011;134:1541-1554.  

 
 
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77. 
Adnan A, Chen AJW, Novakovic-Agopian T, D'Esposito M, Turner GR. Brain Changes 
Following Executive Control Training in Older Adults. Neurorehabil Neural Repair. 
2017;31:910-922.  
78. 
Woolrich MW, Ripley BD, Brady M, Smith SM. Temporal autocorrelation in univariate 
linear modeling of FMRI data. Neuroimage. 2001;14:1370-1386.  
79. 
van Montfort SJT, van Dellen E, van den Bosch AMR, et al. Resting-state fMRI reveals 
network disintegration during delirium. Neuroimage Clin. 2018;20:35-41.  
80. 
Woolrich MW, Jbabdi S, Patenaude B, et al. Bayesian analysis of neuroimaging data in 
FSL. Neuroimage. 2009;45:S173-186.  
81. 
Lu H, Donahue MJ, van Zijl PC. Detrimental effects of BOLD signal in arterial spin 
labeling fMRI at high field strength. Magn Reson Med. 2006;56:546-552.  
82. 
Alsop DC, Detre JA, Golay X, et al. Recommended implementation of arterial spin-
labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion 
study group and the European consortium for ASL in dementia. Magn Reson Med. 
2015;73:102-116.  
83. 
Hernandez AV, Steyerberg EW, Habbema JD. Covariate adjustment in randomized 
controlled trials with dichotomous outcomes increases statistical power and reduces 
sample size requirements. J Clin Epidemiol. 2004;57:454-460.  
84. 
Moons KG, Donders RA, Stijnen T, Harrell FE, Jr. Using the outcome for imputation of 
missing predictor values was preferred. J Clin Epidemiol. 2006;59:1092-1101.  
85. 
Schafer JL. Multiple imputation: a primer. Stat Methods Med Res. 1999;8:3-15.  
86. 
Sterne JA, White IR, Carlin JB, et al. Multiple imputation for missing data in 
epidemiological and clinical research: potential and pitfalls. BMJ. 2009;338:b2393.  
87. 
Nyland KL, Asparouhov T, Muthen BO. Deciding on the Number of Classes in Latent 
Class Analysis and Growth Mixture Modeling: A Monte Carlo Simulation Study. 
Structural Equation Modeling. 2007;14:535-569.