Decreasing Alzheimer's Disease and Related Dementias After Delirium- Exercise and Cognitive Training
Phase: NA
Conditions: Delirium, Alzheimer Disease
Sponsor: Indiana University

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Protocol 
 
Improving Recovery and Outcome Every Day after the ICU (IMPROVE) 
IRB #: 1608126693 
 
Grant Title: Decreasing Alzheimer’s Disease and Related Dementias after Delirium- Exercise 
and Cognitive Training (DDD-ECT) 
Grant #: R01AG055391 
 
Babar Khan, MD, MS 
Research Scientist, IU Center for Aging Research 
Associate Professor of Medicine, IU School of Medicine 
Division of Pulmonary/Critical Care 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1.0 
Background and Rationale .......................................................................................... Page 3 
2.0 
Specific Aims .............................................................................................................. Page 4 
3.0 
Inclusion/Exclusion Criteria ....................................................................................... Page 5 
4.0 
Enrollment/Randomization ......................................................................................... Page 6 
5.0 
Study Procedures ........................................................................................................ Page 6 
6.0 
Reporting of Adverse Events or Unanticipated Problems  
involving Risk to Participants or Others ..................................................................... Page 9 
7.0 
Study Withdrawal/Discontinuation ........................................................................... Page 12 
8.0 
Statistical Considerations .......................................................................................... Page 12 
9.0 
Outcome Measures ................................................................................................... Page 14 
10.0 
Privacy/Confidentiality Issues .................................................................................. Page 15 
11.0 
Follow-up and Record Retention .............................................................................. Page 16 
12.0 
References ................................................................................................................. Page 16 
 
 

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1.  Background 
 
The Aging Brain during and after Critical Illness: Critical illness has deleterious consequences on both 
acute and chronic cognitive functions.4-12 Acute cognitive dysfunction manifests itself as delirium in the 
critically ill especially the elderly. Delirium is a complex neuropsychiatric syndrome characterized by 
acute and fluctuating changes in cognition and consciousness.37,38 60% to 80% of critically ill ventilated 
older patients and 30% to 50% of those with less illness severity have delirium for at least one day of 
their ICU or hospital stay.39-43 Chronic cognitive dysfunction manifests as ICU acquired cognitive 
impairment and dementia after critical illness, affects multiple cognitive domains and persists years 
after hospital discharge.9-12 Up to 71% of critical illness survivors have cognitive impairment at one year 
after hospital discharge11 and close to 18% are diagnosed with new dementia including Alzheimer’s 
disease within three years post ICU hospitalization.12 
 
Relationship among Delirium, ICU acquired cognitive impairment and dementia: The presence of ICU 
delirium predisposes ICU survivors to long-term cognitive impairment and dementia.9-12 Studies showed 
that delirium was associated with worse cognitive performance 3 and 12 months after an ICU stay even 
after adjusting for age, education, chronic disease burden, pre-existing cognitive impairment, 
cerebrovascular disease, severity of acute illness, and exposure to neuroleptics.10,11 Similar results were 
observed in a prospective cohort study of 52 delirious patients evaluated locally with only 6 (11.5%) of 
the 52 ICU survivors having normal cognition on a standardized neuropsychological battery at 3 
months.9 Among ICU survivors with cognitive impairment, 70% had cognitive impairment in at least two 
cognitive domains such as memory, executive function, language, or constructional praxis; 16% had 
deficit in memory only; and 14% had deficit in a cognitive domain other than memory.9 Furthermore, a 
study performed by Guerra et al. found that acute neurological dysfunction defined as anoxia, 
encephalopathy or delirium in the ICU was associated with a new diagnosis of dementia or Alzheimer’s 
disease with an adjusted hazard ratio of 2.06 (1.72-2.46) within three years of ICU discharge.12 The 
cognitively impaired survivors frequently also have concomitant emotional and functional 
disabilities.10,44,45 Whereas only 23% of ICU survivors without cognitive impairment are disabled, 100% of 
ICU survivors with cognitive impairment are unable to return to work full-time.44 Despite the high 
prevalence rates of cognitive and functional disability among ICU survivors, the majority of this 
vulnerable growing segment of ICU survivors does not receive post-ICU recovery care.43  
 
Systemic inflammation, astrocyte and microglial activation, and loss of neuroprotective growth 
factors, a connecting link between delirium and dementia:  

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Delirium can be considered as a cytokine mediated inflammatory syndrome with pro-inflammatory 
cytokines such as interleukin (IL)-1, 6, 8, and tumor necrosis factor (TNF)-α disrupting the blood brain 
barrier with recruitment and infiltration of peripheral leukocytes into the central nervous system 
(CNS).46-48 The resultant microglial activation produces local pro-inflammatory cytokines (IL-1, TNF-α), 
reactive oxygen species, expansion of microglial population49 and activation of astrocytes.50 Astrocyte 
activation and glial dysfunction results in elevated S-100β and glial fibrillary acidic protein (GFAP) 
levels.51-54 The neuroinflammation also promotes cholinergic failure55 culminating in the neurocognitive 
syndrome of delirium. This is compounded by lower levels of neurotrophic growth factors such as insulin 
like growth factor-1 (IGF-1) and brain derived neurotrophic factor (BDNF).56,57 IGF-1 and BDNF have 
neurotrophic properties and provide protection against free radical damage and cytotoxic cytokines.58-60
Both inhibit neuronal apoptosisand promote maintenance, survival, and regeneration of neurons.58-62
Moreover, IGF-1 increases choline acetyltransferase levels and modulates acetylcholine release, the key 
neurotransmitter implicated in delirium.60 Thus a combination of increased neuroinflammation with a 
state of cholinergic failure in the CNS and depleted neurotrophic factors predispose patients to delirium. 
The inflammatory cascade, microglial and astrocyte activation, and loss of neuroprotection could persist 
after surviving critical illness,63 leading to a chronic, persistent state of neuroinflammation,
neurotoxicity, diminished neuroplasticity and cholinergic failure, manifesting as long-term ICU acquired 
cognitive impairment, dementia or Alzheimer’s disease (Figure 1). An intervention modulating the 
aforementioned factors could provide cognitive recovery and may delay onset of Alzheimer’s disease 
and related dementias among ICU survivors.
Neurobiological Effects of Physical Exercise and Cognitive Training: Animal studies: Physical exercise 
induces neural proliferation while cognitive training promotes functional integration of these new 
neural elements into adaptive networks, effects found to be additive in animal studies.64,65 As shown in 
an animal study, combination of physical exercise and enrichment (a surrogate for cognitive training in 
the human model) produced more neurons in adult mice than either intervention alone with each 
superior to a “standard” environment.66 An integrative review of decades of animal research concludes 
that adult neurogenesis occurs in an activity-dependent manner and that both physical and cognitive 
inputs generate plasticity inducing signals to the brain.64 Movement stimulates neural precursor cells to 
proliferate while environments conducive to learning and thinking promote survival of the new cells. 
Physical activity enhances angiogenesis, neurogenesis, release of neurotrophic factors and 
neuroplasticity.16 Only 1 week of exercise resulted in increased vascular endothelial growth factor 
(VEGF) levels in rats by increasing precursors of angiogenesis, leading to new vessel formation.67 Physical 
activity promotes neuronal survival, cell proliferation and raises BDNF and IGF-1 in the somatosensory 
cortex and hippocampus.68-71 This translated to enhanced learning and memory in rats that were 
allowed to exercise freely.69 Human studies: Physical exercise increases cerebral blood flow, oxygen 
extraction and glucose use,72 and reduces inflammation.73 Older patients who perform aerobic exercise 
Figure1:ProposedPathophysiologicModellinkingDeliriumandDementia
(Numberofarrowsdepictingmagnitude)
Neuroinflammation
(ÏÏCRP,IL-1,6,8,TNF-α)
Microglial&
astrocyteactivation
(ÏÏS100β,GFAP)
DecreasedNeuroprotection
(ÐÐIGF-I,BDNF)
Neuroinflammation
(ÏCRP,IL-1,6,8,TNF-α)
Microglial&
astrocyteactivation
(ÏS100β,GFAP)
DecreasedNeuroprotection
(ÐIGF-I,BDNF)
Cognitive
Impairment
&Dementia
ICU
Delirium

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showed the greatest increase in blood volume in frontal and parietal lobe white matter, larger 
hippocampal volumes and better memory, and better white matter integrity.74-78 Physical exercise 
appears to mitigate endothelial dysfunction and vascular wall inflammation, and enhances neural 
substrates BDNF and IGF-1 that maximize the effects of subsequent cognitive stimulation.79,80 Similarly, 
cognitive therapy may exert its favorable effect by increasing levels of BDNF. This was shown in a 
randomized trial of eight weeks of cognitive therapy versus health education among patients with heart 
failure.81 Patients randomized into the cognitive therapy arm showed an increase in their BDNF levels at 
8 weeks compared to baseline levels as well as improvement in working memory, whereas the BDNF 
levels decreased in the education control.81 
 
Evidence that Cognitive Training improves cognition: Cognitive training has been shown to improve 
mental abilities82-85 and functional status in healthy older adults,86 patients with traumatic brain injury 
and stroke,87 and patients suffering from mild cognitive impairment (MCI).88 The largest and most 
rigorous investigation of the efficacy of cognitive training in improving cognition and delaying functional 
loss is the ACTIVE study.88 ACTIVE enrolled 2,802 community-dwelling adults (65 years and older) 
without Alzheimer’s disease and related dementias, and randomly assigned them to one of four groups 
(Memory, Reasoning, Speed of Processing training or a no-contact control group). Each ACTIVE 
intervention produced an immediate improvement in the trained ability with largest improvements 
observed for the Speed of Processing intervention followed by Reasoning and Memory. Treatment gains 
declined over time but remained significant at the 5-year follow-up. A recent meta-analysis is consistent 
with this notion showing that persons with MCI obtain mild to moderate cognitive benefits (effect size 
range from .27 for working memory to .50 for language domain) from cognitive training that are durable 
through follow-up.89 The moderator analysis suggested no effect of subject age or years of education on 
outcomes and no differences between training delivered by computer versus in-person methods nor 
was there a difference between groups versus individual instruction. 
 
Evidence that Physical Exercise improves cognition: Physical exercise improves cognitive ability,90,91 
brain function,92 and brain structure of adults.91,93 A cross-sectional study of 2,736 older women showed 
that high daytime movement was associated with higher Mini Mental Status Examination (MMSE) 
scores.94 A meta-analysis of 18 studies examining the effect of exercise interventions on cognition in well 
older adults found a net effect size of .31 in favor of exercise over control activities .89 Executive 
cognitive ability showed the largest response to exercise as compared to other cognitive domains. Gains 
were also greater for training that lasted 30-45 minutes (versus longer or shorter) and older subjects 
(versus ones that were age 55-65). Favorable cognitive effects of physical activity have also been 
demonstrated for patients with mild cognitive impairment, Alzheimer’s disease, stroke, COPD, and 
traumatic brain injury.95-101  
 
Additive Effects of Combined Physical Exercise and Cognitive Training among older adults: As 
postulated above, it stands to reason that combined physical and cognitive training could have additive 
effects. Two studies conducted in Europe found large effect sizes (0.9-1.3) on cognition from combined 
training versus mental or exercise training alone in well older adults.102,103 One study evaluating 
combined training did not find an effect; however, it had a very small sample size (< 20 subjects per 
group), a low dose of exercise (<60 min of exercise per week), and an intervention focused only on 
memory but not executive function.104   
 
Effects of Combined Physical Exercise and Cognitive Training among ICU survivors: Investigators from 
Vanderbilt and Duke Universities conducted a feasibility trial of combined physical exercise and 
cognitive training among 21 ICU survivors. These ICU survivors were randomized to usual care (n = 8) or 

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12 weeks of at-home combined physical exercise and cognitive training intervention, consisting of six in-
person visits for cognitive training and six telemedicine visits for physical exercise.105 At 3-month follow-
up, the ICU survivors in the active treatment arm tolerated the combined program and had significantly 
better cognition as measured by the TOWER test, which is a timed objective measure of executive 
function (median score: 13.0 vs. 7.5, p<0.01) and functional score as measured by the Functional 
Assessment Questionnaire (median score: 1.0 vs. 8.0, p=0.04). The findings of this study are promising 
and provide rationale for our proposed trial. However, the study did not control for attention, had a very 
small sample size with no power to investigate the impact of the intervention on physical performance 
and it neither measured the ICU survivors overall quality of life nor their depressive and anxiety 
symptoms. Also, the isolated effects of physical rehabilitation or cognitive therapy on neuropsychiatric 
outcomes cannot be evaluated, as both interventions were concurrently administered.  
 
Based on the background above, physical exercise and cognitive training hold promise for improving 
cognitive outcomes of ICU survivors although the current evidence is limited. We plan to further explore 
these findings through an efficacy, randomized, 2x2 factorial design clinical trial with four treatment 
arms, a) physical exercise and cognitive training, b) physical exercise, c) cognitive training, and d) 
attention control. The trial will not only be able to answer the question whether combined physical and 
cognitive therapies are superior to either of them alone as compared to attention control, but will also 
shed light on mechanisms of action of the intervention through use of serum biomarkers. An advanced 
mechanistic understanding of cognitive recovery after delirium will lead to refined interventions to 
prevent progression to dementia and Alzheimer’s disease.  
 
 
2. Rationale and Specific Aims 
 
Two million older Americans suffer from an episode of delirium during their intensive care unit (ICU) 
stay.1-3 Presence of delirium predisposes the elderly to immediate in-hospital complications including a 
longer length of ICU and hospital stay, increased risk of in-patient mortality and elevated costs of care.4-8 
In addition, ICU delirium is associated with long-term post-discharge complications such as development 
of cognitive impairment and dementia.9-12 Current advances in the management of critical illness have 
notably improved the survival rates among this vulnerable segment of older adults.13 However, 
increased survival comes at a cost with as many as 70% of older ICU survivors who had an episode of 
delirium suffering from subsequent cognitive impairment and dementia.9-12 At present, there are no 
effective and scalable recovery models to remediate ICU acquired cognitive impairment and its 
attendant elevated dementia or Alzheimer’s disease risk.  
 
The inability to develop efficacious interventions to reduce ICU acquired cognitive impairment may stem 
from a limited understanding of the link between acute brain dysfunction (delirium) and chronic brain 
dysfunction (ICU acquired cognitive impairment, dementia or Alzheimer’s disease). We propose a 
recovery intervention guided by the pathophysiologic mechanisms implicated in producing critical illness 
delirium and elevated risk of cognitive impairment.14-18 The intervention targets inflammation, glial 
dysfunction and astrocyte activation along with restoration of neurotrophic factors while training 
function directly across multiple cognitive domains to reduce the burden of cognitive impairment 
among ICU survivors of delirium. 
 

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Over the past five years, Indiana University Center for Aging Research has developed a research 
infrastructure focused on delirium and delirium associated cognitive impairment, encompassing the ICU 
and post-ICU periods. This includes developing a bio-repository of serum delirium biomarkers, ICU based 
delirium trials, and post-ICU exercise and cognitive therapy recovery models.9,19-26 Building upon our 
prior work and based on the pathophysiologic mechanisms mentioned above, we now propose a novel 
home-based combined physical exercise and cognitive training program for older ICU survivors to 
improve cognitive impairment. 
 
Our team is proposing a 2x2 factorial design randomized controlled trial (RCT) called “Decreasing 
Alzheimer’s Disease and Related Dementias after Delirium-Exercise and Cognitive Training (DDD-ECT)” 
to evaluate the efficacy of 12 weeks of combined physical exercise and cognitive training on the primary 
outcome of cognitive function among older ICU survivors who experienced delirium or subsyndromal 
delirium during their ICU stay. We propose to deliver these interventions via a facilitator-led, small 
group format using internet-enabled, multiparty-videoconference delivered directly into the 
participants’ homes to achieve the following aims: 
 
Primary Specific Aim: Determine the effect of the combined physical exercise and cognitive training on 
the cognitive function of ICU survivors aged 50 and older. Hypothesis: In comparison to older ICU 
survivors randomized to attention control or either intervention alone, those randomized to 12 weeks of 
combined physical exercise and cognitive training will have higher total index cognitive scores as 
assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)27 at 3 and 
6 months post randomization.  
 
Secondary Specific Aim 1: Determine the effect of the combined physical exercise and cognitive 
training on physical performance, anxiety and depressive symptoms, and quality of life of ICU 
survivors aged 65 and older. Hypotheses: In comparison to older ICU survivors randomized to attention 
control or either intervention alone, those randomized to 12 weeks of combined physical exercise and 
cognitive training will have higher physical performance as measured by short physical performance 
battery (SPPB)28 and two-minute step test,29 lower mood and anxiety symptoms as measured by Patient 
Health Questionnaire (PHQ-9)30,31 and Generalized Anxiety Disorder (GAD-7) scale,32,33 and higher quality 
of life as measured by the Medical Outcomes Study 36-item short form (SF-36)34-36 at 3 and 6-months 
post randomization. 
 
Exploratory Aim 1: To examine the mechanisms of action of combined training. Hypothesis: At the 
completion of treatment, the combined intervention group will show reduced serum levels of CRP, IL-1, 
IL-6, IL-8, TNF-α, S-100β, and GFAP and increased levels of BDNF, VEGF, and IGF-1 compared to the 
attention control, or either intervention alone groups. 
 
Successful achievement of the aforementioned aims will pave the way for a large effectiveness RCT 
testing the combined intervention to delay time to a clinical diagnosis of Alzheimer’s disease and related 
dementias. 
 
3. Inclusion/Exclusion Criteria 
 
Inclusion Criteria:  
[1] Patients aged ≥ 50 years,  

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[2] admitted to medical and/or surgical ICUs at IU Health locations (Methodist, University, North, West, 
Saxony), Eskenazi hospitals 
[3] discharged home, sub-acute rehabilitation, long-term acute care, or skilled nursing facility,  
[4] able to provide consent or has a legally authorized representative to provide consent,  
[5] access to a telephone (study provides computer and broadband) and finally  
[6] have at least one episode of subsyndromal delirium or delirium as determined by the Confusion 
Assessment Method for the ICU-7 (CAM-ICU).109 The CAM-ICU-7 score is determined by examining the 
patient for (a) acute and fluctuating changes in mental status, (b) inattention, (c) disorganized thinking, 
and (d) altered level of consciousness. A CAM-ICU-7 score is considered to be positive for delirium if the 
patient displays a, b, and c, or a, b, and d, or a, b, c, and d. The CAM-ICU-7 score is considered to be 
positive for subsyndromal delirium if any one feature of delirium (either a, b, c, or d) is positive. The 
CAM-ICU diagnosis of delirium was validated against the DSM-III-R delirium criteria determined by a 
psychiatrist and found to have a sensitivity of 97% and a specificity of 92%.109  
 
Exclusion Criteria:  
[1] diagnosis of cancer with short life expectancy;  
[2] current chemotherapy or radiation therapy (confirmed by electronic medical record);  
[3] history of dementing illnesses and other neurodegenerative disease such as Alzheimer’s disease, 
Parkinson disease, or vascular dementia (confirmed by EMR), or current prescription of anti-dementia 
medication, or ruled out by Functional Activities Questionnaire (FAQ) score defining dementia.   
[4] current alcohol consumption > 5 drinks per day (self reported or confirmed by EMR);  
[5] vision < 20/80 via Snellen card or confirmed by EMR;  
[6] low hearing or communicative ability (examiner rated) that would interfere with interventions and 
outcome assessments;  
  
[7] have any active and untreated American College of Sports Medicine133 absolute contraindications to 
exercise (confirmed by EMR) including: acute myocardial infarctions within the past 2 days, ongoing 
unstable angina, uncontrolled cardiac arrhythmia with hemodynamic compromise, active endocarditis, 
symptomatic severe aortic stenosis, decompensated heart failure, acute pulmonary embolism, 
pulmonary infarction, or deep venous thrombosis, acute myocarditis or pericarditis, acute aortic 
dissection, physical disability that precludes safe and adequate testing, or are unable to obtain provider 
clearance for physical exercise for any contraindication where medical management is unclear;  
[8] have any active and untreated American College of Sports Medicine133 relative contraindications to 
exercise (confirmed by EMR) including: known obstructive left main coronary stenosis, moderate  to 
severe  aortic stenosis with uncertain relationship to symptoms, tachydysrhythmias with uncontrolled 
ventricular rates, acquired advanced or complete heart block, recent stroke or transient ischemia attack, 
mental impairment with limited ability to cooperate, resting hypertension with systolic >200 mm Hg or 
diastolic >100 mm Hg, uncorrected medical conditions, such as significant anemia, important electrolyte 
imbalance, and hyperthyroidism, or are unable to obtain provider clearance for physical exercise for any 
contraindication where medical management is unclear; 
[9] recovering from a skeletal fracture (confirmed by EMR), unless cleared by their physician of record to 
safely participate in exercise,  
[10] Acquired neurologic injury (stroke, traumatic brain injury, cerebral edema/swelling, anoxic brain 
injury, or any other acute/subacute severe neurologic deficit) as the admitting diagnosis or a new event 
during the course of hospitalization (confirmed by EMR) or  
[11] history of drug abuse within the last 3 months confirmed by EMR or self-report with Drug Abuse 
and Screening Test (DAST-10) score ≥ 3].110  
[12] Schizophrenia or bipolar disorder (confirmed by EMR) 

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[13] Have any spinal cord injury with persistent neurologic deficit at the time of study enrollment 
[14]Status post tracheostomy and not eligible for a speaking valve 
[15] Pregnant or nursing 
[16] Incarcerated or homeless at time of study 
[17] Lives outside the greater Indianapolis area 
[18] Illiterate 
 
Study team will be using electronic medical records to verify eligibility status. The study team will make 
all efforts to contact the clinical team when a patient’s eligibility status is unclear.  
 
4. Enrollment/Randomization 
 
Recruitment Targets: 
344 older ICU survivors who experienced delirium or subsyndromal delirium in the ICU will be enrolled. 
 
Clinical Settings and Study Population: The target population for our trial is adults aged 50 and older 
who have survived a critical illness in the ICU and had a delirium/subsyndromal episode during their ICU 
stay at Indiana University School of Medicine affiliated hospitals and IU Health hospitals as listed in 
performing organizations.   
 
Screening and Enrollment: 
Study personnel will screen for eligible subjects each day using the ICU census. Eligible individuals (those 
who meet inclusion criteria and do not meet any exclusion criteria) will be screened up to twice per day 
for delirium until ICU discharge using the CAM-ICU-7. Patients who screened positive on the CAM-ICU-7 
(either with study personnel or patient’s care team) and survived the ICU stay will be approached for 
enrollment into the study. CAM-ICU-7 screenings will continue until hospital discharge for patients who 
enroll in the study.  
 
Study approach and consent may take place post-discharge if patient is released from the hospital 
before study personnel have the opportunity to meet the patient. Study brochures may be used to aid 
recruitment. Surrogate consent may be required for patients who are unable to provide consent. All 
patients consented via surrogate will be re-consented once deemed competent.111  
 
[During COVID-19 health crisis, CAM-ICU/CAM-ICU-7 screenings will be conducted by ICU healthcare 
personnel only. Screening outcomes will be obtained from EMR. Study approach will be completed by 
study personnel via phone. Informed consent will be obtained following the IU IRB Flexible Consent 
Procedures:  https://research.iu.edu/compliance/human-subjects/guidance/informed-consent.html. 
No study procedures will be completed prior to receiving the signed consent and authorization forms 
from the subject.] 
Randomization: 
After obtaining an informed consent, study staff will complete a baseline assessment consisting of 
measures of cognition, physical function, depression and anxiety, and quality of life (see measures 
section 4.3.l. below). Blood samples will also be collected from the participants at the time of baseline 
assessment. Baseline may be completed at subject’s home after hospital discharge if unable to complete 
full assessment in the hospital. After initial assessment, study subjects will be randomized to study 
groups. Randomization will be stratified by discharge location (home, other facility) and managed by the 
IU site  

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[During COVID-19 health crisis, baseline assessments will be completed via phone; abbreviated 
measures of cognition, and no measures of physical function will be obtained due to the limitations of 
phone administration. Blood samples will not be collected.] 
 
5. Study Procedures 
 
Enrolled subjects randomized to the experimental intervention will receive cognitive training via 
computer-accessed online training modules 45 minutes per session, 2 days per week for 3 months; and 
physical exercise delivered by trained facilitators to participants in their homes via internet-based single 
or multi-party (2-6 per group) videoconference 45 minutes per session, 3 times per week for 3 months 
(Figure 3). 
 
Cognitive Intervention: 
The cognitive portion of 
the combined 
intervention consists of 
a suite of 24 programs 
called Brain HQ 
developed by Posit 
Science, Inc. The 
modules are designed to 
improve time-order 
judgment, visual 
discrimination, spatial-
match, forward-span, 
instruction-following, 
and memory. The 
program systematically reduces stimulus presentation time to maintain an 85% accuracy rate and 
launches each new session based on the stopping point of the preceding session.  
 
Cognitive Control: This consists of up to 20 minutes of puzzles and games, 2 days per week for 3 months. 
We will use on-line Brain HQ Control Games developed by Posit Science, Inc.  
 
Physical Exercise Intervention: The physical exercise portion of the combined intervention consists of 45 
minutes of multi-modal physical exercise focused on seated aerobic and progressive resistance training 
designed to improve aerobic capacity, muscular strength and endurance consistent with current 
exercise recommendations.112,113 We will deliver 3 sessions per week for 3 months. Each physical 
exercise session will be divided as follows: 5 minutes of warm-up, 10 minutes of upper-body, 10 minutes 
of core, 10 minutes lower-body, 5 minutes of upper-body and lower-body, and 5 minutes of cool-down 
and flexibility exercises. All exercises are conducted from a seated position in a solid backed chair. We 
will provide participants with a heart rate monitor watch or pulse oximeter and have participants report 
their heart rate and oxygen saturation. Their heart rate should be above 55% but not to exceed 70% of 
their age-adjusted maximum heart rate thus providing moderate-intensity exercise for each participant. 
Due to limited heart rate response for participants on beta-blocker medications, we will also use the 
Rating of Perceived Exertion scale (RPE). Participants will be advised to exercise at the RPE level of 5 to 6 
on a 10-point scale. Generally, for adults over the age of 40 years, moderate-intensity is 5 to 6 on a 10-

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point exertion scale.114 Participants will also be given Velcro weight bands specific for the wrists and 
ankles that are color-coded by weight to allow the Interventionist to check that the appropriate weight 
is used by each participant during video-conference sessions. The initial wrist weights will be 1 pound 
and the ankle weights will be 2 pounds, although the participants will have the option of 1-pound weight 
or no weight. Although small group (e.g., 2 to 6) format is the goal, we will start with one-on-one 
training with escalation into a group. We will continue one-on-one in cases of difficult adherence or 
unique physical abilities.                                                                                                                                 
 
Physical Exercise Control: This consists of up to 10 minutes of gentle stretching. We will deliver 3 
sessions per week for 3 months. This stretching module was designed specifically as a control condition 
for exercise trials and was used as such in the NIH-funded LIFE exercise trial.115 Heart rate, oxygen 
saturation and RPE will be collected as in the Exercise Intervention.  
 
Intervention Delivery - Computer and Videoconference in the Home: This feature is common to all 
treatment arms. Study staff will initiate contact within 2 weeks post-ICU discharge to set up the 
computer and videoconference system in subjects’ homes. Afterwards, the interaction between the 
interventionists and the subjects will happen remotely through a computer video interface. 
Communication via videoconference can be described as live, interactive television. The participants can 
hear and see one another and the interventionist; and the interventionist can hear and see the 
participants. We will use New Inspiron One 20" All-in-One Desktop Dell computers, which have the 
processor and webcam built-in to the 20” monitor. Internet access will be provided with 4G LTE air cards 
or jet packs will use Zoom for video conferencing provided by Indiana University. The videoconferences 
will be security protected with room access provided on an individual level. Information technology 
support, including computer and software settings, will be reviewed and addressed remotely as needed 
during sessions using TeamViewer software. We have installation, training, and IT support manuals in 
place. At the initial installation, our staff will orient the subject and family caregiver to the operational 
features of the computer and Internet interface. Additional orientation visits can be scheduled at the 
request of the participant or if the Interventionist detects difficulties in a subject’s ability to operate the 
computer. In addition, we have the capability to run the interventions with smaller groups or even single 
participant groups as needed.  
 
[During COVID-19 health crisis, computers will be delivered to subject’s homes following a no-contact 
drop-off protocol. Interventionists will provide instructions via phone on how to set up the computer. 
As long as in-person research activities are restricted, “additional orientation visits” will not be 
conducted.] 
 
Safety: We have incorporated exercise program elements that are associated with lower risks of 
cardiovascular complications and muscular injury. These include warming up, flexibility exercise, 
moderate intensity exercise, and a gradual progression of exercise intensity and duration.112-114 The 
Interventionist will educate subjects about the signs and symptoms of angina, myocardial infarction, and 
muscle/tendon related injuries and how to respond to them; a procedure recommended by the 
American College of Sports Medicine and the American Heart Association as effective means of reducing 
complications to exercise.112,116 The frequency, duration, and intensity of intervention delivery will be 
modified as necessary for enrolled subjects who are medically frail. We have outlined our Data and 
Safety Monitoring Plan including the identification and response to serious cardiac events and 
orthopedic injuries in the Protection of Human Subjects section. Cognitive training is relatively safe but 
anxiety and burden will be monitored. As subjects recover from their ICU hospitalization, they may 
require additional resources to address a variety of ICU survivorship issues. A list of resources will be 

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provided to all subjects after enrollment. Subjects who express needs to the study team will be referred 
to resources on the list. If a participant indicates suicidal ideation on the PHQ-9, the patient’s care team 
will be notified.  Suicidal ideation of participants at IU affiliated institutions will also be reported to Dr. 
Khan and Dr. Sophia Wang (clinical psychiatrist working at IU Center for Aging Research) for additional 
follow up; suicidal ideation of participants at non-affiliated institutions will be reported to the site PI, Dr. 
Khan, and Dr. Wang. 
 
 
Potential Problems and Alternative Strategies: We have measures in place to ensure retention 
including availability of make-up sessions and availability of individual training sessions. We will request 
Cognitive Intervention adherence data from Posit Science. If retention drops below 80%, we will have 
the study staff follow-up with the study participant to troubleshoot any technical issues and1 provide 
coaching. Physical training sessions will be offered throughout the week on varying days and times, 
including the weekends to provide ample training opportunities and make-up sessions. We will use fair 
subject payments contingent on the completion of the 3 and 6 months follow-up assessments to 
maximize participation. Loss of information could occur if subjects are unable to complete outcome 
assessments. To estimate the treatment effect in key domains, a “step-down” battery, consisting of a 
subset of outcome measures, will be administered when a participant is not able to tolerate the full 
outcome assessments. This “step-down” battery may also be administered via phone if subject is unable 
to complete an in-person assessment for the 3 or 6 month outcomes. We also can provide assistive 
devices (glasses, headphones or pocket talker) if a participant’s visual or auditory acuity declines and 
interferes with interventions or outcome assessments. 
 
Outcomes Assessments: Trained and blinded research assistants will complete 3 and 6 months 
outcomes assessments consisting of measures of cognition, physical function, depression and anxiety, 
and quality of life (see Outcome Measures section 9 and Figure 3). Data will be collected using Research 
Electronic Data Capture (REDCap). We will employ multiple techniques to ensure concealment of 
outcomes assessment.117,118 Our research assistants are trained not to inquire about study assignments. 
They will be conducting structured assessments that do not provide room for qualitative interviewing 
that should prevent unblinding. They will not be involved in study assignments and training 
interventions. Subjects will be instructed not to discuss their training intervention with the research 
assistants.  
 
The following instruments will be used during outcome assessments: Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS)27, Trail Making Test Part A and B, Stroop Color and 
Word Test, Short Physical Performance Battery (SPPB), Grip Strength, 2-minutes Step Test, Patient 
Health Questionnaire–9 (PHQ-9), Generalized Anxiety Disorder Scale (GAD-7), Medical Outcome Study 
Short Form (SF-36), and the International Physical Activity Questionnaire (modified). 
 
[During COVID-19 health crisis, outcomes assessments will be completed via phone; abbreviated 
measures of cognition, and no measures of physical function will be obtained due to the limitations of 
phone administration. Blood samples will not be collected.] 
 
 
6. Reporting of Adverse Events or Unanticipated Problems  
 
PROTECTION OF HUMAN SUBJECTS 

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Risks to Human Subjects:  
Human Subjects Involvement, Characteristics, and Design: As many as 50% of ICU survivors aged 65 and 
older who had an episode of delirium are left with newly acquired “Post-Intensive care Syndrome” 
(PICS) characterized by cognitive, physical, or psychological symptoms that have onset in the peri-ICU 
period and persist among ICU survivors for a long period of time with some patients never recovering 
from such devastating symptoms.  We are proposing a behavioral intervention targeting ICU older 
survivors who have experienced delirium as a means of improving cognitive and functional outcomes. 
ICU survivors with delirium constitute a growing segment of older American who are vulnerable to 
develop post ICU cognitive, physical, and psychological disability. The current system does not offer an 
effective recovery care for this population.   
 
The target population is 344 English-speaking adults aged 50 and older who have been admitted to a 
critical care unit, have had at least one episode of delirium and are discharged home. This intervention 
targets cognitively impaired individuals suffering from delirium and will also include women and 
minorities who meet the inclusion criteria, as these vulnerable populations are at risk of Post-Intensive 
Care Syndrome.   
 
Sources of Materials: During the hospital stay, research assistants will review the medical records and 
conduct delirium screening to assess the eligibility criteria for potential subjects. Furthermore, blinded 
assessors will complete the baseline assessment within the hospital or within the subject’s home as 
necessary. The data obtained from subjects will include self-report of demographics, health history, 
current medications, anxiety and mood symptoms, and quality of life questionnaire. The Assessors will 
also be collecting information on cognitive and physical performance via objective tests and physiologic 
status (blood pressure, height, weight, heart rate, oxygen saturation). Finally, the assessors will also 
conduct a medical record review to assess subject’s chronic conditions (Charlson index) and severity of 
medical illness (APACHE index). In addition to recording attendance, subject’s effort and use of 
modifications, the Trainers will be collecting information on RPE, heart rate and oxygen saturation, while 
Brain HQ will monitor cognitive performance, for each subject at each training session. 
 
Data will be linked to participants through the use of a unique identifying number. Only persons on the 
research team will have access to the data. All data are collected for research purposes only. All data will 
be entered via a password-protected, study specific REDCap (Research Electronic Data Capture) 
database. Case Report Forms (CRFs) will be stored in locked filing cabinets at Regenstrief Institute.  CRFs 
completed at non-affiliated institutions will be stored locally at their facility and, once the subjects are 
off-study, transferred to their long-term storage facility, per their local policy.   
 
Potential Risks:  
 
(1) Fatigue, anxiety, stress, or embarrassment from the training or testing sessions. Emotional distress 
may result from answering health and behavior questions. Testing may also create anxiety, stress, or 
embarrassment at perceived performance. Participants may also become fatigued during the testing 
and/or training sessions.  
 
(2) Falls and/or muscle stiffness and soreness from exercise. The exercise intervention components 
proposed in this study are consistent with standard recommendations for exercise among older adults. 
Based on piloting and published studies, the most common risk associated with increased exercise is 
mild muscle stiffness and soreness. Moderate-intensity physical activities are associated with a very low 

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risk of musculoskeletal complications. There is a low risk of fall given all exercises in the physical 
intervention are seated. 
 
(3) Cardiovascular complications from exercise. The risks of cardiovascular complications do increase 
transiently during periods of strenuous physical activity.  
 
(4) Exposure of confidential information. There is the potential for loss of privacy or confidentiality due 
to the data collection efforts of this study. 
 
(5) Discomfort with biological samples collection. Two blood samples will be collected from each 
participant, one during their hospital stay and the other at 3-months follow-up. Drawing blood could be 
associated with pain, bruising, and anxiety.  
 
Adequacy of Protection Against Risks:  
Recruitment and Informed Consent: Eligible subjects will be identified through the intensive care units 
census to which they are admitted. Study personnel will consent the patient or their legally authorized 
representative (if the patient is unable to consent for themselves) during their ICU hospitalization. If LAR 
provides consent, study personnel will seek consent from subject when capacity is regained, either at 
hospital or home.  
  
Protections Against Risk:  
 
(1) Fatigue, anxiety, stress, or embarrassment from the training or testing sessions. All questions 
planned for this study are part of validated standardized instruments, and we are not asking any 
questions that do not directly relate to the study purpose. Both Interventionists and Assessors will be 
trained in their proper use and in the importance of privacy and sensitivity to the participant’s time. 
They will be trained to be alert and sensitive to signs of fatigue and other symptoms and to take 
appropriate actions when they are present. Breaks from testing will be offered as needed; assessment 
sessions can also be split into two sessions if a participant is tired or physically uncomfortable.  
 
(2) Falls and/or muscle stiffness and soreness from exercise. We have minimized the risk of a fall through 
the use of seated endurance exercise training; the stiffness and soreness from adoption of exercise 
training are minimized by the moderate nature of the exercise program; any soreness that may occur 
early in the training will subside within a few days and be unlikely to occur again with adherence. 
Participants with persistent or very severe soreness will be encouraged to contact their primary care 
provider. In the ~2,000 in-home assessments that we have done in the African-American Health study 
which has an extensive physical exam protocol, we have not had a single fall or other adverse event. We 
attribute this to our very careful training and supervision procedures, which we will also be using in the 
proposed trial. We will have an emergency plan in place to handle any emergencies that might occur.  
 
(3) Cardiovascular complications from exercise. We have incorporated exercise program elements that 
are associated with lower risks of cardiovascular complications, such as employing a warm up, flexibility 
exercise, using moderate intensity exercise, and a gradual progression of exercise intensity and duration. 
Supervised exercise programs also have a low rate of complications suggesting that the use of well-
trained exercise instructors will also provide a margin of safety to the participants. Participants and 
interventionists will be instructed in the signs and symptoms of cardiovascular complications and how to 
respond to them both during the exercise sessions and at other times.  
 

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(4) Exposure of confidential information. Indiana University requires certification of training in protection 
of human subjects in research. The investigators, interventionists, assessors, and all key personnel have 
or will have successfully completed training and certification in these courses. All research involving the 
use of these data must be reviewed and approved by the IRB. We will assure the privacy of subjects and 
confidentiality of study data by assigning unique identifiers to track participants’ data (rather than using 
names or hospital or social security numbers) and keep all records under lock with access only by study 
personnel. These procedures have been dutifully adhered to in prior studies. The final data files for this 
study will be merged, maintained, and analyzed on servers managed by the Division of Biostatistics, 
Department of Medicine, Indiana University School of Medicine. This group has extensive experience in 
the handling and security of PHI. None of the individual participant data will be identifiable in published 
reports or manuscripts and the analyzable datasets will not contain the participant’s unique identifier.  
 
(5) Discomfort with biological samples collection. A small amount of blood will be required (maximum 44 
ml over the entire study course) for the specified laboratory analyses. We will attempt to coordinate all 
blood sampling with that done for clinical purposes or from indwelling catheters to avoid added 
venipuncture. Sample collection at 3-month’s follow-up will be performed by an experienced 
phlebotomist. We have collected blood samples at homes of our participants in our other projects and 
have not encountered any serious adverse events. Blood will be stored in de-identified tubes and will be 
transported by personnel who have obtained certification in specimen handling and transfer. In addition 
we are planning to have continuous feedback from the patient, the caregiver, the physician, and the 
nursing staff to discuss any problems encountered during the data collection.  
 
Potential Benefits of Proposed Research to Human Subjects and Others.  
The study participants will be engaged in national health guideline-level physical activity with all its 
attendant positive results (e.g., decreased fall risk, improved cardiovascular function, improved 
strength, improved pulmonary capacity, potentially reduced insulin resistance). Participants will also 
receive small payments for participation. This research could also provide a non-pharmacological 
treatment for cognitive impairment in patients suffering from ICU acquired cognitive impairment. 
Despite the high prevalence rates of cognitive and physical disability among ICU survivors, only ICU 
patients who survived major stroke, traumatic brain injury, or cardiac surgery receive formal cognitive or 
physical rehabilitation leaving a large percentage of ICU survivors with no such rehabilitation and higher 
risk for hospital readmission or death. 
 
The intervention proposed in this study builds on prior research and may hold promise for an effective 
and scalable recovery model for this population. This intervention does require additional resources that 
will cost additional money; however, it is possible that these short-term costs will be offset by 
reductions in overall costs to patients and the healthcare system. Patients enrolled in our study and 
randomized to receive our proposed intervention might have a reduction in post-ICU symptoms and, 
subsequently, may experience improved cognitive and physical function, improved mood, and quality of 
life. Our intervention might also improve other health outcomes such as a lower rate of hospital 
acquired complications, a higher probability of survival, lower institutionalization rates, and decreased 
length of hospital stay, thereby decreasing health care utilization and cost. The intervention may delay 
onset of Alzheimer’s disease and related dementias among ICU survivors. 
 
Importance of Knowledge Gained.  
Up to 70% of ICU survivors aged 65 and older develop long-term cognitive impairment and other 
functional and psychological sequelae of critical illness. Currently there are no effective and scalable 
recovery models to remediate or treat ICU acquired cognitive impairment and its deleterious effects on 

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quality of life and independence of the growing segment of ICU survivors. Our proposed intervention 
may provide a conceptual and scalable recovery model to remediate or treat post-delirium cognitive 
impairment and its deleterious effects on quality of life and independence of the growing segment of 
ICU survivors. 
 
 
 
7. Study Withdrawal/Discontinuation 
 
Participants who wish to withdraw from the study will notify the study team verbally or via letter as 
outlined in the HIPAA authorization document. 
 
8. Statistical Considerations 
 
To verify the comparability of the randomized groups, patients’ baseline characteristics among the four 
groups will be compared using analysis of covariance (ANCOVA) for continuous variables and the 
Cochran-Mantel-Hansel statistic for categorical variables while adjusting for age group. We will examine 
the distributions of continuous variables and use alternative approaches such as transformation or 
nonparametric methods in cases of violation to the normal distribution assumption. We will also 
examine the frequency distribution of all categorical variables and adopt exact inference procedures in 
cases of zero or small cell size. All analyses will be conducted using the SAS 9.4 (SAS Institute, Carey, 
North Carolina). 
  
Primary Specific Aim: Mixed effects models will be used with repeated RBANS scores collected at 
baseline, 3 months and 6 months as the outcome measures, group, time and a group by time interaction 
as independent variables while adjusting for stratification variables and other potential baseline 
covariates found to be significantly different in univariate comparisons. A significant interaction 
between group and time would indicate differences in changes of cognitive functions over time among 
the four groups. Post-hoc comparisons will be conducted following a significant interaction between 
group and time to compare the effect of the combined training group to the other three groups 
(attention control, cognitive training only, and exercise only groups) at 3 month for immediate training 
effect and at 6 month for sustained training effect. Separate mixed effect models will also be used for 
repeated, Trail Making A&B, and Stroop Color and Word Test scores. 
 
Secondary Specific Aim 1: Separate mixed effects models will be used with repeated measures (SPPB, 2-
minutes step, PHQ-9, GAD-7, SF-36 PCS and MCS) as the outcome variables, group, time and interactions 
between group and time as independent variables while adjusting for stratification variables and other 
baseline covariates that may be different among the four groups. Significant interactions between group 
and time in these models would indicate differences in changes of functional outcomes, depressive 
symptoms, and anxiety levels or quality of life over time among the four groups. Post-hoc analyses will 
also be conducted following significant interactions in the mixed effects models to compare the 
combined training group to the other three groups and to determine how early a group difference can 
be detected and whether the effect extends beyond the training period. 
 
Exploratory Aim 1: Changes in the serum levels of CRP, IL-1, IL-6, IL-8, TNF- α, S-100β, GFAP, BDNF, 
VEGF, and IGF-1 will be calculated and used as the dependent variables in ANCOVA models with group 
as the independent variable and adjusting for stratification variables and baseline covariates that are 

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found to be different among the groups in univariate comparisons. Post-hoc comparisons will be used 
following a significant group effect to compare biomarker levels in the combined training group to the 
other three groups. 
 
Missing Data: Two types of missing data are anticipated in this trial. The first is due to death during 
follow-up. Our previous studies on ICU survivors have shown that most post-ICU deaths happen within 
the first 30 days of discharge. We do not expect rates of death to differ among the four randomized 
groups. The second type of missing data comes from participant withdrawal during follow-up. There 
may be a potential for higher rate of withdrawal in those enrolled in the intervention groups than in the 
control group. The mixed effects model approach we propose to use is robust under the missing at 
random assumption, i.e. the probability of missing is unrelated to the missing observations. We will 
compare baseline characteristics of subjects with missing outcomes due to death or dropout during 
follow-up to detect potential violation to the missing at random assumption. Intention to treat analysis 
will be used in all models. Further sensitivity analyses will be performed using various methods of 
imputation or a full parametric likelihood approach assuming various patterns of missing data.131  
 
Sample Size and Power: Cognitive training had been found to have a moderate effect size of 
approximately 0.5 SD and the combined training was found to have a larger effect size of 0.9 SD when 
comparing to the control group in healthy elderly subjects.102,103,132 Assuming effect sizes of 0.4 SD in the 
cognitive training only group and the exercise only groups at 3 and 6 month post baseline compared to 
the attention control group and effect size of 0.8 SD in the combined training group at 3 and 6 month 
post baseline compared to the attention group, a sample size of 60 patients in each group will yield 83% 
power at detecting a significant group by time interaction in a mixed effect model adjusting for 
correlations of 0.2 for outcomes measured 3 month apart and correlations of 0.1 for outcomes 
measured 6 month apart at α=0.05. The power estimation was conducted using the GLMPower 
procedure in SAS. To further assume that 30% patients may miss some post-baseline assessments, we 
will need to enroll a total of 344 patients into the study (86 patients per group). Outcomes in Secondary 
Aim 1 will also have 83% power to detect effect sizes similar to those described for the Primary Aim. For 
Secondary Aim 2, we will have 81.7% power to detect an overall treatment effect in changes in 
biomarkers with effect sizes of 0.31 SD in the cognitive training only and the exercise only groups and 
0.62 SD in the combined training groups at α=0.05 using one-way ANOVA and the Power procedure in 
SAS. 
 
9. Outcome Measures 
 
[During COVID-19 health crisis, outcomes assessments will be completed via phone; abbreviated 
measures of cognition, and no measures of physical function will be obtained due to the limitations of 
phone administration. Blood samples will not be collected.] 
 
Cognitive Outcome Measures: The Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS)27 total index score will provide the primary outcome for the trial. Secondary outcomes will be 
assessed using individual neuropsychological tests of processing speed, executive control, and new 
learning ability as follows: Trail Making Test Parts A and B (seconds to complete),120 and Stroop Color 
and Word Test (interference trial).121 These measures sample major domains of cognition affected in ICU 
survivors.10 
 

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Physical Performance and Cardiovascular fitness: Physical training effects on balance and strength will 
be assessed via the Short Physical Performance Battery (SPPB),28 a validated objective assessment. The 
SPPB yields a performance score of 0-12 (0-4 poor, 5-7 intermediate, 8-12 good). A difference of 1 point 
indicates a significant change in function. Physical training effects on cardiovascular fitness will be 
assessed via the 2-minute step test.29 We have selected the 2-minute step test for cardiovascular fitness 
because it is a validated measure of aerobic capacity, does not require equipment, and can be used in 
the home setting.29 Grip strength with dominant hand will also be measured. 
 
Self-reported Mood and Anxiety symptoms: We will use the Patient Health Questionnaire–9 (PHQ-
9)30,31 and Generalized Anxiety Disorder Scale (GAD-7)32,33 to determine the impact of the intervention 
on ICU’s survivors’ mood and anxiety. The PHQ-9 is a nine-item depression scale with a total score from 
0 to 27 and the GAD-7 is a seven-item anxiety scale with a total score from 0 to 21. Both of these scales 
are derived from the Patient Health Questionnaire, have good internal consistency, and test–retest 
reliability as well as convergent, construct, criterion, procedural and factorial validity for the diagnosis of 
major depression and general anxiety disorder.30-33 
 
Self-reported quality of life outcomes: ICU survivors’ health–related quality of life will be assessed using 
the Medical Outcome Study Short Form (SF-36).34-36 This scale has eight components (physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and 
mental health) that are aggregated into a Physical Component Summary (PCS) and a Mental Component 
Summary (MCS).34-36  We will use both the PCS and the MCS as the quality of life outcomes. Changes that 
differ between groups by 2 or more points on a scale of 0 to 100 have been shown to be clinically or 
socially meaningful.36   
 
Collection of Biological samples: The blood will be collected and stored according to biological samples 
protocol to maximize sample quality and decrease sample variability due to sample collection and 
processing techniques. Blood samples will be collected at baseline and at 3 months. The 3-month time-
point is chosen because this marks the immediate post-training assessment phase, a point where we 
expect to see the maximum effect of interventions, improvements in the neurobiology and concomitant 
biomarker profile. Two tubes (one lavender- and one red- top) will be used to collect 20 ml of blood 
from each patient. These tubes will then be labeled with pre–printed labels with a de-identified code. To 
avoid biomarker degradation and platelet activation, these samples will be centrifuged immediately at 
3000 x g. The supernatants will be removed and stored in aliquots so that multiple episodes of freezing 
and thawing will be unnecessary during assay procedures. An additional 4ml fresh blood will be 
collected at Baseline and/or 3 months for DNA extraction. The tubes will be placed on dry ice for 
transport. Once at the storage facility, the aliquots will be placed in pre-labeled boxes and the boxes 
stored at -80 o C.  
 
Biomarkers: The conceptual model holds that the cognitive benefit of combined physical exercise and 
cognitive training is achieved through modulation of physiologic process (Secondary specific aim 2). As a 
result, we will measure circulating levels of the pro-inflammatory cytokines (IL-1, 6, 8, TNF-α); the acute-
phase reactant (CRP); neurotrophic factors (IGF-1, VEGF, BDNF); and markers of glial dysfunction and 
astrocyte activation (S-100β, GFAP). Serum marker quantifications will be performed in duplicates using 
pre-validated commercially available assay kits. Each kit employs 1-2 positive control(s) of known 
concentration and a negative control in every run. We will follow manufacturer provided established 
protocols for these assays.  
 

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APOE Collection and Assay: Genomic DNA will be extracted from blood samples using the DNeasy Blood 
& Tissue Kit (Qiagen, Inc., Valencia, CA) according to the manufacturer's protocol. Approximately 50ng 
of genomic DNA will be used for amplification. APOE genotypes will be determined by restriction 
enzyme digestion of amplified DNA.123  
 
Plasma amyloid-β Aβ42/Aβ40: As number of recent studies have reported that a low ratio of plasma 
amyloid-β Aβ42 over Aβ40 is associated with increased Alzheimer’s disease risk and greater cognitive 
decline,124,125 we will explore the effect of a low ratio on our intervention. Samples will be analyzed using 
standard analysis techniques.124  
 
Acute Health Care Utilization: In addition to patient reported emergency department and hospital 
admission data, we will use the local data-warehouse to capture all of the data needed to determine 
utilization. Furthermore, we will also use the data from the Indiana Network for Patient Care (INPC) to 
complement any data use outside of our health system. INPC is the primary health information 
exchange in the state of Indiana and it provides data for acute care services from all of the health care 
systems within the state of Indiana. We will determine the number of emergency department visits and 
the number of re-hospitalizations during follow-up as well as the diagnoses associated with each 
utilization episode. 
 
Other data collection: At hospital discharge and baseline we will measure subject’s age, race, gender, 
years of education, visual acuity, height, weight, body mass index, heart rate, blood pressure, Charlson 
Comorbidity Index,126 APACHE II score,127 activities and instrumental activities of daily living (ADL/IADL) 
prior to ICU admission through Katz and Lawton scales,128,129 cognitive status prior to admission through 
IQCODE,130 cognitive and physical activity levels prior to admission, admission and discharge diagnoses, 
duration of mechanical ventilation, duration of delirium, ICU/hospital length of stay, and ICU and in-
home medications. These measures will be used to describe the ICU survivors characteristics and as 
potential confounders.  
 
Study team will request physical therapy, occupational therapy, and speech therapy records from rehab 
facilities to identify physical and cognitive training received between ICU discharge and study 
intervention for subjects discharged to a facility.  
 
 
10. Privacy/Confidentiality Issues 
 
Loss of confidentiality is a risk in this type of data collection. Our data management and quality 
assurance techniques have proven effective in past trials in maintaining confidentiality and all study 
personnel have completed training in Human Subjects Research and HIPAA standards. 
 
11. Follow-up and Record Retention 
 
This is a five-year study and study documents will be destroyed seven years after the end date of the 
study. 
 

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