The Entorhinal Cortex and Aerobic Exercise in Aging
Phase: NA
Conditions: Aging
Sponsor: Boston University

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Protocol for: The Entorhinal Cortex and Aerobic Exercise in Aging 
 
 
NCT#: NCT02775760 
IRB Number: H-34579 
 
Sponsor: NIH/National Institute on Aging (NIA) 
 
Principal Investigator: Karin Schon, Ph.D. 
brainex@bu.edu 
72 East Concord St., L-1004 
Boston, MA 02118 
 
 August 17, 2020 
 
Statistical Plan: pages 17-18 

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Background 
Exercise has many health benefits. Some of these benefits are increased physical fitness and reduced 
risk of developing heart disease. Researchers currently do not know whether exercise also benefits the 
human brain. These benefits may include cognitive (thinking) processes, such as learning, memory, and 
navigating through unfamiliar environments. Exercise may be an effective and low-cost way to promote 
brain health and healthy aging. 
Aerobic exercise consistently appears as one of the most effective interventions to attenuate cognitive 
decline in Alzheimer’s disease (AD) (Burns et al., 2010; Burns et al., 2008), which is characterized by a 
profound hippocampal and entorhinal pathology (Braak and Braak, 1997). In humans, the 
neurophysiological mechanisms through which exercise improves cognition are unknown, with most 
studies focusing on prefrontal-mediated executive and memory functions (Colcombe et al., 2004), or 
hippocampal volume (Erickson et al., 2009; Erickson et al., 2011). Recent research from our laboratory 
illuminated a striking association between entorhinal cortical (EC) volume and aerobic fitness in young 
volunteers such that greater fitness was associated with a prominent increase in EC volume (Whiteman 
et al., 2015). Within the medial temporal lobes (MTL), the EC uniquely displayed this effect. The EC sits 
at the epicenter of inputs to the hippocampus (HC), serving as a gateway for cortical-hippocampal 
communications (Hoesen et al., 1975). The EC has direct projections to the dentate gyrus (DG) (Hoesen 
et al,. 1975; Witter et al., 1989) the neurogenic zone of the HC. EC and HC respond strongly to aerobic 
exercise in animal models by enhancing neurogenesis (van Praag et al., 1999; Pereira et al., 2007) and 
increasing spine density (Head et al., 2012), respectively, and in clinical trials and cross-sectional studies 
in humans by showing increased volume (Erickson et al 2011; Honea et al., 2009; Maass et al., 2014). 
Thus, it is plausible that aerobic exercise may improve memory formation by enhancing communication 
between the EC and the HC. Based on the strong response of patients with mild cognitive impairment 
and, to a lesser extent, of healthy seniors to aerobic exercise, we hypothesize that the EC-HC memory 
system in healthy seniors will respond well to exercise, but the response might vary depending on the 
degree of atrophy and functional impairment of the EC. For instance, participants with more severe EC 
atrophy or individuals with poorer EC function, such a poor allocentric spatial navigation, might exhibit a 
strong response to aerobic exercise. 
The goal of this proposal is to establish proof-of-principle and provide evidence that the EC and EC-HC 
communication are affected positively by aerobic exercise, and that those seniors with a smaller EC 
volume relative to brain size and those who perform more poorly on behavioral tests of EC function, will 
benefit most strongly. Interaction between the EC and the HC memory system is vital for allocentric 
spatial navigation and context-dependent memory formation. Critically, loss of function of the EC is a 
central factor in the pathophysiology of AD. Apparently healthy older adults show impaired allocentric 
navigation compared to young adults (Moffat et al., 2002; Moffat et al., 2009). Spatial navigation deficits 
may distinguish those at risk of developing AD from normal cognitive aging (Lithfous et al., 2013). We 
hypothesize that the EC and EC-hippocampal functional connectivity are important 
functional/anatomical targets of aerobic exercise. In this study, we will examine whether the EC and 
other MTL areas and EC-hippocampal functional connectivity are responsive to aerobic exercise. We will 
also investigate whether particular subsets of participants, such as those with poor performance on 
tests of spatial cognition or those with greater EC atrophy, might be more responsive to aerobic 
exercise. 

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Behavioral and fMRI Pilot Studies 
The purpose of the pilot studies is to develop the cognitive tasks for fMRI and adapt them for our aging 
sample. For fMRI we do not generally use existing, normed, tasks such as those neuropsychologists 
would use. Instead, we develop cognitive tasks such that they are optimized to answer our specific 
research question outlined above for Aims #1 and #2. The pilot studies will be optimized for the specific 
population studied (healthy older adults) while at the same time taking into account technical 
constraints of fMRI (e.g. low temporal resolution, responses most often restricted to button presses). 
Specifically, with the behavioral pilots we want to determine the timing of the events that happen 
during the task (e.g. for how long should we show an item to the participants that they later remember 
the items and/or have enough time to respond?). This is critical for studies in older adults, because 
reaction times are known to slow with aging. Once the cognitive tasks have been optimized through 
behavioral piloting, we also have to make sure they work in the fMRI scanner (e.g. does a task designed 
to depend on a certain brain area actually result in activation of this brain area with fMRI? Does the task 
timing work given the technical constraints of fMRI? Due to physiological changes associated with aging 
a task that works well in terms of activating brain areas in young adults may not work well in older 
adults. Behavioral and fMRI piloting therefore makes sure the cognitive tasks work for our group of 
participants (healthy older adults), before we recruit participants for the experiments described for Aims 
#1 and #2. 
There are two reasons why we propose pilot studies along with the main study: 
1) The need to fine-tune the project-specific tasks before launching the actual study (described in Aims 
#1 and #2). 
2) The pilot studies are specific to the funded project. They are not intended to generate pilot data for a 
future grant application. 
Project-specific task piloting is a standard procedure in cognitive neuroscience / neuroimaging studies. 
Since the task will be designed to be used as described in Aims #1 and #2, there will be no amendment 
necessary when the task pilots are completed. 
 
 
Study Summary 
We propose to examine the effects of exercise and cardiovascular fitness on cognitive processes utilizing 
a parallel design randomized clinical trial. Specifically, we will investigate if exercise improves brain 
function in a brain area known as the entorhinal cortex. Together with the hippocampus this brain area 
is important for memory formation and spatial navigation. Participation in this research study will take 
approximately 4 months. During this time, participants will make three initial study visits. The first visit is 
for informed consent and screening, the second visit is for baseline fitness testing, and the third visit is 
for cognitive testing and a functional MRI exam. Functional MRI is a brain imaging technique that uses a 
magnetic field to "take pictures" of the brain while a person performs a cognitive task. It will take up to 
approximately three weeks to complete these initial three study visits. Following the three initial study 
visits, the exercise-training program will begin. Participants will be randomized to one of two training 

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programs: a cardiovascular endurance-training program (aerobic exercise) and a strength, balance, and 
flexibility training program (non-aerobic exercise). The exercise training program will last 12 weeks. 
There will be three one-hour exercise sessions per week. After completion of the exercise-training 
program, participants will attend two follow-up study visits. The first follow-up visit is for fitness testing. 
The second follow-up visit is for cognitive testing and an MRI exam. 
 
 
Design and Procedures 
Participants will be randomized into one of two groups: 1) an aerobic exercise intervention group and 2) 
a non-aerobic exercise control group (strength, balance, flexibility training). They will have a 50% chance 
to be randomized into one of the two groups. 
The PI will be responsible for the randomization, because the PI's role in participant recruitment and 
screening is minimal. The study staff members performing the recruiting, informed consent, and 
screening will not know which group each participant will be randomized to at the time of recruitment, 
informed consent, or screening. 
1) Study Visit 1: Informed Consent and Screening 
Duration of Study Visit 1: Approximately 2 hours. These numbers include informed consent, general 
screening, breaks and neuropsychological testing. The duration of the neuropsychological testing is 
approx. 60-80 minutes (including breaks). 
Location: Cognitive Neuroimaging Center or Cognitive Neuroimaging Laboratory at Boston University 
Charles River Campus 
Procedures: 
1. 
Informed consent (approx. duration: 40 min) 
After initial pre-screening over the phone (see attached phone and email pre-screening protocol) and/or 
email, we will invite potential participants for a study visit with a study staff member trained in human 
subject protection and consent procedures at the Cognitive Neuroimaging Center or Cognitive 
Neuroimaging Laboratory at Boston University Charles River Campus. During this visit, the study staff 
member will first allow the participant to read and review the consent form independently. If requested 
by the potential participant, the study staff member will go over any specific paragraph of the consent 
form with the potential participant. The study staff member will ensure that the potential participant 
understands the purpose of the study, how many visits will be required, and the approximate study 
duration and duration of each visit. In addition, the study staff member will ensure that the potential 
participant understands the purpose of each visit and what payments participants will receive for what 
part of the study and when. For each section of the consent form, the study staff member will ask the 
participant whether he or she has any questions. Once the participant and study staff member have 
signed and dated the consent form, the participants of Specific Aims #1 and #2 will undergo all screening 
procedures. Participants will be consented for all procedures (cardio-respiratory fitness and strength 
assessments, cognitive testing, functional and structural MRI) at the initial study visit, but will have the 
opportunity to receive a copy of the consent form before coming in for Study Visit 1 (by mail or email). 

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In general during the consenting process, the potential participant will be reassured that his or her 
participation is voluntary and that he or she can withdraw consent at any time, even after signing the 
consent form, as long as it is safe for the participant to do so (e.g., the 
participant may need to stay on the treadmill for a cool down). BREAK (if needed; approx. 5 min or less) 
2. 
Screening, part I: Interviews, questionnaires, and instruments (approx. duration: 45-60 min) 
In line with new guidelines from the American College of Sports Medicine (ACSM), we will exclude 
participants if they have any known cardiovascular, pulmonary, or renal disease. Those who do not have 
any signs or symptoms, nor diagnosis, will not require medical clearance. This is also in line with new 
regulations from ACSM based on studies finding low predictability of adverse event by CVD risk factors, 
coupled with high prevalence in older adults. Only those older adults interested in participating in the 
research study that have any signs or symptoms of cardiovascular, pulmonary, or renal disease or mild 
musculoskeletal issues (such as osteopenia, osteoporosis, or arthritis) will be required to submit a 
medical clearance form signed by his or her physician before participating in exercise testing or training 
(FitRec Personal Training Medical Waiver form). In addition, we will exclude participants if they have any 
contraindicator of MR imaging (e.g. non-removable ferromagnetic metal in or on the body), bioelectrical 
impedance analysis (BIA; e.g. pacemaker), or if they have any neurological or psychiatric conditions or 
disorders that are known to affect the brain and cognitive functions. In addition, participants will be 
excluded if they are physically active, or are not considered "sedentary": The American College of Sports 
Medicine defines a sedentary lifestyle as a lifestyle in which a person is not participating in at least 30 
minutes of moderate intensity physical activity on at least three days per week for at least three months 
(definition according to American College of Sports Medicine, Thompson et al., 2010). Finally, individuals 
will be excluded if they self-report susceptibility to severe motion sickness or claustrophobia, given that 
(1) the cognitive task performed in the MRI scanner may cause discomfort for individuals who are 
susceptible to motion sickness, and (2) being inside the MRI scanner may cause discomfort for 
individuals who are susceptible to claustrophobia. 
Screening includes a general health screening, neuropsychological testing, screening for exercise 
readiness, and screening for MR compatibility. Screening will also include measurements of weight, 
height, waist circumference, and hip circumference. In collaboration with Dr. Storer, Ph.D., the P.I. will 
oversee the screening to exclude adults with medical conditions that might affect the biochemical 
variables of interest and will ensure that the cardiovascular fitness and strength testing is appropriate 
for each participant, based upon their exercise assessments. If participants respond with “Yes” to any 
questions of the General Screening form in sections B, C or D (Health Screening for Exercise Readiness) 
or to any of the questions of the HHQ, the P.I. will consult Dr. Storer, Ph.D. Participants will be screened 
using the attached screening forms, standard neuropsychological and neuropsychiatric tests, and 
questionnaires (all neuropsychological tests are described in Strauss, E., Sherman, E. M. S., and Spreen, 
O. (2006) A Compendium of Neuropsychological Tests. Administration, Norms, and Commentary. Third 
edition. New York, NY: Oxford University Press). Participants will complete the CHAMPS questionnaire, 
which will provide the investigators with a picture of how physically active the participant has been over 
the past 4 weeks. This information will be used for future analyses, not for inclusion/exclusion. 
Participants will also complete a Computer Experience Questionnaire; this will not be used for 
inclusion/exclusion, but instead, will be used as a covariate in data analysis. Next, we will assess 

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handedness with the Edinburgh Handedness Inventory. While we will not use this test for screening; 
knowledge of handedness will aid in interpreting the fMRI data. 
Participants will be required to fill out the questionnaires and instruments either on paper or 
electronically (e.g. using REDCap software). The general screening form will be filled out by a study staff 
member and administered in interview format. 
List of Questionnaires and Instruments (administration time: approx. 45 min): 
1) 
General health screening: General_ScreeningForm_R21 
2) 
General health screening for pilot studies: General_ScreeningForm_R21_short 
3) 
Exercise readiness: Health History Questionnaire (appended HHQ_R21) 
4) 
Exercise questionnaires: CHAMPS 
5) 
MR compatibility: CNC_ScreenForm 
6) 
Computer Experience Questionnaire: Computer Experience Questionnaire 
7) 
FitRec Medical Clearance: PersonalTrainingMedicalWaiver (if applicable) 
8) 
Handedness: EdinburghHandednessInventory 
9) 
Anthropometric Measures and Vital Signs 
Note that none of the questionnaires and instruments listed above are used routinely for standard 
clinical care. We noted sources on the forms when available. 
BREAK (10-15 min): Once the participant has completed this part of the screening, we will offer him or 
her a brief break before continuing with the neuropsychological and neuropsychiatric assessment. 
3. Screening, part II: Neuropsychological assessment (Exp. 2; total duration: 40-50 minutes) Cognitive 
domains assessed and screening for older adults includes general dementia screening, assessment of 
attention, processing speed, and executive functions, and assessment of motor function. Note that we 
selected the following tests and questionnaires from published standard tests/questionnaires (Strauss, 
Sherman, and Spreen, 2006). Neuropsychological assessment with older adults is necessary to screen for 
potential dementia and age-related cognitive deficits. 
Psychiatric functioning: 
1) 
Depression: Geriatric Depression Scale (Brink et al., 1982; Yesavage et al., 1983; administration 
time: 5-10 min) 
2) 
Anxiety: Beck Anxiety Inventory (Beck and Steer, 1990; administration time: 5 min) 
3) 
Stress: Perceived Stress Scale (Cohen et al., 1983; administration time: 5 min) 
Estimated IQ / cognitive functioning: 
1) 
General dementia screening: Dementia Rating Scale-2 (DRS-2; available at parinc.com; 
administration time: approx. 15-30 min). Note this standard test has not been attached here; it will be 

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purchased. The DRS-2 has five subscales, which provide additional information on specific abilities, 
include Attention, Initiation/ Perseveration, Construction, Conceptualization, and Memory. 
2) 
Attention, processing speed, and executive functions: Trail-Making Test Versions A and B 
(Strauss, Sherman, Spreen, 2006; administration time: 5-10 minutes); Stroop Test, Victoria version 
(Strauss, Sherman, Spreen, 2006; administration time: approx. 5 min) 
3) 
Motor function: Grip Strength test using the Smedley Dynamometer (available online from 
various healthcare retailers), see GripStrengthTest_Instructions (Strauss, Sherman, Spreen, 2006; 
administration time: less than 5 min) 
Note that the neuropsychiatric and neuropsychological instruments listed above are routinely used for 
clinical diagnosis of neuropsychological impairments. All assessments are as stated in the Human Subject 
Protection pages of the attached parent NIH R21 grant. 
4. Physical activity and exercise diary (instruction time: 5 min or less) 
At the end of Study Visit #1, we will give the participant an exercise diary to take home with him or her. 
We will ask the participant to use this diary to report the type of physical activity performed each day, if 
any, and to provide information about duration and intensity of the physical activity. We will ask him or 
her to fill out the physical activity log daily for the duration of the study. For sedentary individuals, filling 
out this log should only take a few minutes each day. Participants will be asked to include the exercise 
sessions of the intervention on the physical activity diary. 
2) Study Visit 2: Baseline fitness testing and body composition exam 
Duration: Approx. 2-2.5 hours 
Location: BU Fitness and Recreation Center 
Procedures: 
1. 
Explanation of procedures and measurement of vital signs at rest (approx. duration: 10 min) 
These measurements will include blood pressure, pulse and/or heart rate. We will ask participants to 
change into clothing appropriate for exercise. 
2. 
Performance of the Mnemonic Similarity Task (approx. duration: 15 minutes) 
While we are waiting for the participants heart rate and blood pressure to reach resting levels, the 
participants will use the computer to perform the Mnemonic Similarity Task (MST). The task consists of 
assessing recognition memory performance for objects using not only the traditional targets and 
unrelated foils, but also using similar lures (that intentionally vary along several different dimensions). 
2. Body composition analysis using the InBody Test (approx. duration: less than 15 min) The InBody Test 
uses safe, low-level currents sent through the body via hand and foot electrodes. (The participant 
contacts these electrodes by standing on the device, which resembles a scale, and holding the cylindrical 
hand-held electrodes.) The impedance that the currents encounter are measured, and from there, body 
composition is derived. The amount of this current is slight enough that the participant cannot feel it. 
The InBody Test will provide an estimate of total body water, dry lean mass, body fat mass, weight, 
skeletal muscle mass, body mass index, and percent body fat. These estimates are printed out on the 

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InBody Results Sheet, which has been included with this protocol (InBody_E_Book.pdf). Each participant 
will be offered a copy of his or her results to compare body composition from before and after the 
exercise intervention. Outcome measures for the purposes of this study include weight, body mass 
index, and percent body fat. 
3. 
Cardio-respiratory fitness tests (incremental work rate test) (approx. duration: 30-40 min) We 
will use standard submaximal clinical exercise testing procedures, including that of a submaximal, 
incremental work rate test, designed to ensure participant safety and measurement accuracy (Cooper 
and Storer, 2001; Thompson et al., 2010). We will follow the guidelines established by the American 
College of Sports Medicine for submaximal clinical exercise testing (ACSM; Thompson et al., 2010). 
We will use a modified Balke treadmill protocol that uses a fixed walking speed and increasing 
increments in grade. We will choose the speeds and grades used for each participant (Cooper and 
Storer, 2001) so that all participants walk at a relatively comfortable pace with the grade increments 
calculated to provide a total test duration of 8-12 minutes (Buchfuhrer, 1983). The test will be continued 
until the participant reaches 85% of his or her age-predicted maximum heart rate (HRmax = 206.9 - (0.67 
× age)) or 70% of heart rate reserve (HRreserve = HRmax –HRrest). While this test does not allow direct 
measurement of maximum oxygen uptake (VO2max), 
the results of this test allow us to predict VO2max based on the known linear relationship between 
heart rate and VO2max. VO2max is a secondary outcome measure. Notably, participants will warm up 
for 3 to 4 minutes and cool down for 7 to 10 minutes before and after the test, respectively. 
For this test, participants will wear a chest strap to measure heart rate and a blood pressure cuff to 
measure blood pressure (BP). During the test, heart rate will be continuously monitored and recorded 
and BP will be measured at multiple points before, during, and after the test. We will take the 
participant's BP at standing rest on the treadmill, at the end of the 3-minute warm-up, and after 
completing the first 3 minutes of the test. If the participant demonstrates any adverse response to the 
exercise (e.g., demonstrating a BP over 220/110), we will continue to measure BP every 3 minutes 
during the test. If not, we will take BP immediately after the participant reaches 85% of his or her age- 
predicted maximal heart rate while treadmill speed and grade are quickly returned to low warm-up 
levels. 
At regular intervals while performing the test, we will also ask the participant to rate how hard he or she 
believes he or she is exercising (using the standard 15-grade scale for ratings of perceived exertion; 
Borg, 1982, Table 1; see attached RPE scale). If the participant fails to conform to the exercise testing 
protocol, experiences adverse signs or symptoms, requests to stop, or experiences an emergency 
situation, we will terminate the test. Symptoms such as unusual shortness of breath or leg, back, or 
chest discomfort will be investigated, and the test will be stopped for participant safety. We will instruct 
the participant to inform the technician about any discomfort he or she experiences during the test, 
such as dizziness, nausea, extreme shortness of breath, and/or extreme leg fatigue. Participants may ask 
to stop the test at any time. Trained medical staff will be available or on call for each test. 
Finally, following completion of testing, there will be a recovery time including a cool-down walk on the 
treadmill and sitting in a chair. Throughout the duration of the recovery time, heart rate and BP will be 
monitored until the participant's heart rate and BP have approximately returned to pre-exercise 

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baseline and/or until BP is below 140/90. (Notably, as per the expertise of our study exercise 
physiologist, exercise induced hypertension up to 220/110 during exercise is normal. 
Thus, monitoring BP to a point where it is below 140/90 ensures that the participant's cardiovascular 
system is returning to normal levels.) 
4. 
Strength Assessment (duration: approx. 30 min) 
Following cool-down and a brief break, participants’ strength of major muscle groups in the upper body 
will be assessed using a chest press and a latissimus dorsi pulldown. Secondly, lower body strength will 
be evaluated using a leg press. 
The total fitness evaluation session (Study Visit 2) will take approximately 2-2.5 hours (including review 
of exercise-related screening results, instructions, body composition analysis, setup, exercise tests, 
recovery periods, etc.). 
3) Study Visit 3: Baseline MRI exam 
Duration: Approx. 4 hours 
Location: Cognitive Neuroimaging Center at Boston University Charles River Campus 
Procedures: 
1. 
Task Instruction and Practice (approx. duration: 30 min) 
Before going into the MRI scanner, participants will be instructed in how to perform the cognitive tasks. 
2. 
MRI procedures and cognitive testing (approx. duration: 100 min) Overview 
We will give each participant an MRI (Magnetic Resonance Imaging) exam of his or her brain while he or 
she performs cognitive tasks in the MR scanner using structural and functional MRI (fMRI). During fMRI 
scanning, we may monitor the participant’s heart rate, breathing rate, and 
/or pulse. For all MRI procedures, we will use a Siemens 3.0T magnet at the Cognitive Neuroimaging 
Center at Boston University Charles River Campus. 
Description of functional MRI procedures 
Before the MRI, we will ask the participant about any metal in or on his or her body. The participant will 
be asked to remove all metal objects, regardless of whether they are ferromagnetic (e.g. hearing aids, 
dentures, jewelry, watches, hairpins, and makeup with metallic specs or shimmer) from his or her body. 
The participant will be asked to change into scrubs for the MRI scan. During the screening visit, we will 
ask the participant to prepare by wearing metal- free clothing/undergraments on the day of the MRI 
exam. 
Before entering the MRI scanning room, we may take vital sign measurement, and the participant will 
receive task instructions. At this time, the participant will practice each task. Then, immediately before 
entering the MRI, we will ask the participants to wear earplugs to reduce the scanner noise. 
During the MRI, the participant will be required to lie still on the MRI table. The participant will be able 
to hear and speak to the research staff at all times during the MRI procedures, but we will ask him or her 

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not to speak during any scans unless there is an emergency (for example, if he or she feels 
claustrophobic or sick) or he or she is prompted to speak. The researcher and/or the MR technologist 
will remain in contact with the participant throughout the scans, and the participant may terminate his 
or her participation in the study at any time (even during a scan). We can stop the procedure at any 
time, if necessary. 
When the participant is in the MRI scanner, we will begin by taking several structural brain images. Soon 
after, the cognitive tasks will begin. We will instruct the participant to look at virtual environments, 
pictures, words and/or objects while he or she is inside the MRI scanner. He or she may be asked to 
listen to words and/or sounds through a headset while in the scanner. He or she may be moved 
passively through a virtual environment or be asked to move actively through a virtual environment 
using a joystick or button-box. While in the scanner, the participant may be asked to make decisions 
about the presented stimuli, scenes, or environments, and to indicate responses on handheld response 
keys or with a joystick. Between each set of stimuli, there will be a short break. We will remind the 
participant to keep his or her head as still as possible during task performance and the breaks in 
between. 
We may take measurements of blood pressure, heart rate, and/or pulse immediately before entering 
and immediately after exiting the MRI scanner room. During scanning, we may use pulse oximetry. 
Additionally, after the scan, we may ask the participant to fill out a brief questionnaire to assess motion 
sickness symptoms. (Motion Sickness Questionnaire: Nausea_profile). This questionnaire will be used as 
a covariate in our statistical analyses, not as inclusion/exclusion, given that we address susceptibility to 
motion sickness in our general screening procedures. 
3. 
Post-MRI cognitive testing (approx. duration: 60-90 min) 
After the scanning session, we will ask the participant to complete additional cognitive tasks at the 
Cognitive Neuroimaging Center. These tasks include: 
1. 
Spatial reasoning Assessment: Triangle Completion Task104 (approx. duration: 20 min) and 
Virtual Y-Maze task106 (approx. duration: 5 min ) (note these tasks were developed by co- investigator 
Scott Moffat for use with geriatric adults). 
2. 
Spatial Cognition: Santa Barbara Sense of Direction Scale126 (approx. duration: 8 
min), Rey-Osterrieth Complex Figure Test, copy condition121 (alternate version used for post- testing, 
counter-balanced; approx. duration: 5 min) 
3. 
Verbal Memory: Rey Auditory Verbal Learning Test (RAVLT)121 (alternate version used for post- 
testing, counter-balanced; approx. duration: 10-15 min) 
4. 
Visual-Spatial Memory: Rey-Osterrieth Complex Figure Test, delay condition121 (alternate 
version used for post-testing; counter-balanced; approx. duration: 5 min) 
All assessments are as stated in the Human Subject Protection pages of the attached parent NIH R21 
grant. Note that numbers refer to references in the Bibliography & References Cited section of the NIH 
R21 grant. 
4) Study Visits 4-39: Exercise Training 

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Duration: Three 1-hour session per week for a period of 12 weeks Location: Boston University Fitness 
and Recreation Center 
Procedures: 
The study will use a randomized controlled trial. We will assign each participant by chance to one of two 
study groups. One group will participate in a cardiovascular endurance training program and the other 
group will participate in a strength, balance, and flexibility training program. We will assign participants 
randomly to the two training programs (50% chance). Participants will not be informed about group 
assignment until the first training session at the exercise facility. 
Trained and experienced exercise trainers will supervise the exercise training sessions at the BU Fitness 
and Recreation Center. (Note: all trainers will undergo CITI training for Human Subject Protection 
training and HIPAA as in our previously completed clinical trial, H-32635. Trainers will then be added to 
the IRB protocol prior to any exercise training). The research staff, after consultation of co-investigator 
Dr. Thomas Storer, will monitor training progress and adherence to the exercise training program. Each 
exercise training group will be composed of approximately 3 to 6 participants. Morning, daytime, and/or 
evening hours will be available for the participant to choose from, but will depend on the number of 
other participants enrolled and the collective group members' availabilties. 
The 12-week intervention will consist of 3 weekly, trainer-supervised exercise sessions that will 
gradually increase in intensity and duration. Heart rate and ratings of perceived exertion90 will be 
monitored and recorded for all participants. Dr. Storer will develop individualized exercise prescriptions. 
Note that all exercise interventions will be identical to those of our previously completed, IRB-approved 
clinical trial, H-32635. 
1) 
Cardiovascular endurance training group 
The aerobic exercise program will consist of three weekly 1-hour aerobic exercise sessions over a 12- 
week period. The participant will be required to wear a standard heart rate monitor and/or chest 
transmitter during each exercise session. We will provide the heart rate monitor and/or chest 
transmitter to the participant for use during the exercise session. Each session will include light 
cardiovascular warm-up exercise, such as slow walking, stretching exercises, heart-rate based aerobic 
exercise training on the treadmill (walking with grade adjusted depending on the participant’s ability 
level). Each exercise session will finish with a cool-down, and stretching and 
/or relaxation exercises. We will tailor exercise intensity for each participant’s fitness level based on the 
results of the cardio-respiratory fitness evaluation during the fitness testing session (Study Visit 2). Dr. 
Thomas Storer will design the individualized exercise training programs. 
Exercise intensity will increase gradually over the 12-week period of the aerobic exercise training 
program. The trainer will monitor and record intensity level, each participant’s perceived level of 
physical exertion (using the RPE scale), heart rate, and type and duration of the exercise in an exercise 
diary/log. 
2) 
Strength, balance, and flexibility training group 
The strength, balance, and flexibility exercise program will consist of three weekly 1-hour exercise 
sessions over a 12-week period. The participants will perform strength training exercises 

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that target all major muscle groups. In addition, the participants may perform exercises that are 
designed to improve balance and flexibility. The participants will be required to wear a standard heart 
rate monitor and/or chest transmitter during all exercise sessions. We will provide a heart rate monitor 
and/or chest transmitter to the participants for use during the exercise session. This will allow us to 
monitor heart-rate. Strength training exercises will use progressively greater resistance over the 12- 
week program. We will tailor the training program to each participant’s fitness level as determined 
during the fitness testing session (Study Visit 2). As in 
the cardiovascular endurance training, Dr. Thomas Storer will design the individualized exercise training 
programs. The trainer will instruct each participant in proper technique in order to prevent injury. With 
proper instruction, injury rates in strength training are very low in the general population. 
Participants will be encouraged to attend as many exercise sessions as possible by providing a 75-dollar 
finishing bonus and by visiting participants regularly during the exercise training program. Participants 
must have attended at least 30 of the 36 exercise training sessions and 
they must not have missed more than 1 exercise session per week to receive the finishing bonus. In the 
case that a participant anticipates being unable to attend one or more of the exercise training sessions, 
the participant will have the opportunity to work out on his or her own if he or she informs the trainer 
ahead of time. The trainer will then provide the participant with "homework" and a training log. The 
homework will describe the exercise the participant should do while away. The participant will be 
reminded that he or she will need access to exercise training equipment. The trainer will instruct the 
participant in how to fill out the training log. We may ask the participant to wear a heart rate monitor or 
activity monitor or similar device during the exercise. We will provide this device to them. A study staff 
member may call them about their training progress while they are away. Participants will be expected 
to return the training log to the trainer after their return. Participants will not have the opportunity to 
receive homework during the first four weeks of the exercise training program. This is for the safety of 
the participants, given that the trainers will monitor their progress and instruct them in proper 
technique during the first four weeks. If a participant anticipates being unable to participate during this 
time, we may exclude him or her from participating in this study or place him or her on a waiting list. A 
participant will not necessarily be excluded if he or she is not available for the duration of the study, 
unless the participant anticipates that he or she will miss any of the study visits (study visits 1, 2, 3, 40, 
41) and/or if he or she anticipates missing three exercise sessions in a row without fulfilling the 
homework and training log requirements. Make-up sessions during the same week will also be available. 
Exercise diary/log. We will ask the participants to continue using the exercise diary/log until the study is 
completed. We will go over the exercise diary with the participant on approximately a weekly basis. 
5) 
Study Visit 40: Follow-up fitness testing and body composition exam 
Duration: Approx. 2-2.5 hours 
Location: BU Fitness and Recreation Center 
Procedures: Procedures are identical to Study Visit 2. 
6) 
Study Visit 41: Follow-up MRI exam 
Duration: Approx. 4 hours 

13 
 
Location: Cognitive Neuroimaging Center at Boston University Charles River Campus 
Procedures: Procedures are identical to Study Visit 3. However, we will also include the following two 
neuropsychological exams, which were included at the Informed Consent and Screening Visit (Visit 1) 
rather than the Baseline MRI Visit (Visit 3). 
Visuospatial Attention: Trail-Making Test A and B121 (baseline testing to take place during screening 
visit; approx. duration: 5 min) 
Executive Functions: Stroop test, Victoria version121 (baseline testing during screening visit) 
Procedures for Re-Screening: 
Any participant who was determined eligible over three months before the exercise training program 
start date will need to be rescreened. The proposed timeline for eligibility and re- screening is as follows: 
Eligibility timeline: 
Eligibility determined at or less than 3 months before projected training start date: valid. Eligibility 
determined over 3 months but at or less than 12 months before projected training start date: requires 
phone re-screening,that will be valid for the following 3 months, detailed below. 
Eligibility determined more than 12 months before projected training start date: requires a full visit 
Study Visit 1b (Procedures are identical to Study Visit 1) to re-assess eligibility, the will be valid for the 
following year. 
The re-screening protocol will include a phone re-screening that consists of direct questions regarding all 
of the inclusion/exclusion criteria that are subject to change within 12 months or less (see attached 
Phone Re-Screening protocol). 
After re-screening, the principal investigator and study staff member will discuss the participant’s 
responses, and the investigator will determine whether or not the participant is still eligible for 
participation. 
Inclusion/exclusion criteria that will NOT be directly re-screened include the following: 
1. 
Fluent in English (must have attended elementary school and higher in English) (Inclusion 
Criterion #4): this cannot change from the time of initial screening to re- screening. 
2. 
Dementia Rating Scale performance (Exclusion Criterion #4): we do not expect the participant’s 
score to change by more than one point within the proposed 3-12-month timeline for re-screening. 
However, participants who originally scored a 9 on the AMSS or AEMSS at their Visit 1 will be required to 
come in for a full re-screening (Visit 1b) to confirm that cognitive decline has not occurred since Visit 1. 
3. 
Impaired participant performance on the Trail Making Test or Stroop Test (Exclusio n Criterion 
#5): this will not be re-assessed. Other re-screening questions will be used to inform the study staff of 
any changes to brain structure/function (i.e., any recent diagnoses regarding 
neurological/psychological/psychiatric conditions). If the investigator is concerned that the participant 
may not perform at normative levels on neuropsychological testing, the participant will be invited in for 
a full re-screening (Visit 1b). 

14 
 
4. 
Grip strength test performance (Exclusion Criterion #6): this will not be re-assessed. Other re- 
screening questions will be used to inform the study staff of any changes to brain structure/function 
(i.e., any recent diagnoses regarding neurological/psychological 
/psychiatric conditions) or musculoskeletal health (i.e., any recent diagnoses of musculoskeletal 
impairments). 
Additionally, the obesity criterion (Exclusion Criterion #8) will be assessed based on the anthropometric 
measure obtained from the participant in his or her initial Visit 1: 
a. 
Participants with BMI < 30: for a participant, whose BMI is below 30, we will ask during the re- 
screening if he or she has gained weight since the initial study visit. If the answer is yes, the previously 
measured height of the participant and the self-reported current weight of the participant will be used 
to calculate BMI. If the participant still falls below a BMI of 35 with his or her new weight, then he or she 
will still be considered eligible for the study. If the participant falls at or above a BMI of 35, he or she will 
be invited in for a full re-screening (Visit 1b). This is due to the fact that a BMI of 35 or greater is one of 
the exclusion criteria to be considered in the obesity criterion (exclusion criterion #8). 
b. 
Participants with BMI ≥ 30: these participants will be invited in for a full re-screening (Visit 1b). 
Procedures for Pilot studies: 
For pilot studies involving only fMRI and/or cognitive testing (no neuropsychological assessment, fitness 
testing, or exercise training), participants will already come in for their initial study visit tentatively 
scheduled for behavioral testing and/or fMRI on the same day and/or on a day in the near future. 
However, the study staff will confirm the visit based on 1) whether they are still interested after 
explanation of the procedures and 2) whether they are eligible to participate based on screening. 
Cognitive pilot: 
The cognitive pilot requires two visits, which may be combined into a single visit. During the first visit, 
the investigator will review the consent form with the understanding that their choice to participate is 
completely voluntary. Following informed consent, the participant will undergo further screening 
questionnaires to determine eligibility. Visit 1 will last approximately 1 to 1.5 hours. Once fully deemed 
eligible, the second visit is for cognitive testing. The participant will perform the cognitive tasks on a 
computer screen. Breaks will be given in between runs as necessary and requested. Visit 2 will last 
approximately 1 to 2.5 hours. 
fMRI pilot: 
The fMRI pilot requires two visits, which may be combined into a single visit. During the first visit, the 
investigator will review the consent form with the participant to convey the understanding that his or 
her choice to participate is completely voluntary. Following informed consent, the participant will 
undergo further screening questionnaires to determine eligibility. This will include the CNC Screen Form 
(item 6, above), which will determine MRI safety for that subject. Visit 1 will last approximately 1 to 1.5 
hours. Once fully deemed eligible, the second visit is for fMRI scanning. The participant will perform the 
cognitive tasks in the scanner. Breaks will be given in between runs as necessary and requested. Visit 2 
will last approximately 1 to 2.5 hours. The same MRI procedures as described in study visit 3. 

15 
 
Screening for participants of pilot studies 
Participants recruited for pilot studies (behavioral pilot/pilot of cognitive tasks only; fMRI pilot 
/pilot of cognitive tasks in fMRI scanner; no neuropsychological testing, no cardio-respiratory fitness 
evaluation or exercise training) will be asked to fill out the short version of the General Screening Form 
(item 2, above) and the Edinburgh Handedness Inventory (item 8, above). 
Participants recruited for fMRI piloting will additionally be asked to fill out the CNC Screen Form (item 6, 
above). 
Description of functional MRI procedures for fMRI pilot 
Before the MRI, we will ask the participant about any metal in or on his or her body. The participant will 
be asked to remove all metal objects, regardless of whether they are ferromagnetic (e.g. hearing aids, 
dentures, jewelry, watches, hairpins, and makeup with metallic specs) from his or her body. If the 
participant’s clothing contains non-removable metals, such as metal zippers or buttons, especially near 
the head (e.g. on t-shirts or sweatshirts), the participant may be asked to put on a hospital gown instead 
(the MR technologist in charge of the scans will be consulted). During the screening visit we will ask the 
participant to prepare by wearing metal-free clothing on the day of the MRI exam. 
Before entering the MRI scanning room, we may take vital sign measurement and the participant will 
receive task instructions. At this time, the participant will practice each task. Then, immediately before 
entering the MRI, we will ask the participants to wear earplugs to reduce the scanner noise. 
During the MRI, the participant will be required to lie still on the MRI table. The participant will be able 
to hear and speak to the research staff at all times during the MRI procedures, but we will ask him or her 
not to speak during any scans unless there is an emergency (for example, if he or she feels 
claustrophobic or sick) or he or she is prompted to speak. The researcher and/or the MR technologist 
will remain in contact with the participant throughout the study, and the participant may terminate his 
or her participation in the study at any time (even during a scan). We can stop the procedure at any 
time, if necessary. 
When the participant is in the MRI scanner we will begin by taking several structural brain images. Soon 
after this, the cognitive tasks will begin. We will instruct the participant to look at virtual environments, 
pictures, words and/or objects while he or she is inside the MRI scanner. S 
/he may be asked to listen to words and/or sounds through a headset while s/he is in the scanner. S/he 
may be moved passively through a virtual environment or s/he may be asked to move actively through a 
virtual environment using a joystick or button-box. While in the scanner 
 
 
s/he may be asked to make decisions about the presented stimuli, scenes, or environments, and to 
indicate responses on handheld response keys or with a joystick. Between each set of stimuli there will 
be a short break. We will remind the participant to keep his or her head as still as possible during task 
performance and the breaks in between. 
We may take measurements of blood pressure, heart rate and/or pulse immediately before entering 
and immediately after exiting the fMRI scanner room. During fMRI scanning we may use pulse oximetry. 

16 
 
Outcomes 
Describe anticipated primary outcome and any secondary outcomes and how they will be measured: 
Primary Outcomes for Specific Aim #1: 
1) 
Better cognitive task performance post-exercise training compared to baseline (measurements: 
reaction times, accuracy, etc.); effect expected to be greater for aerobic exercise training than control 
(strength, balance and flexibility training) 
Measurements: reaction times, accuracy, and other cognitive task derived scores 
2) 
Increased activation in and functional connectivity between brain areas associated with task 
performance, effect expected to be greater following aerobic exercise training than control. 
Measurements: blood-oxygen level dependent fMRI scans 
Primary Outcomes for Specific Aim #2: 
1) 
Better cognitive task performance post-exercise training compared to baseline (measurements: 
reaction times, accuracy, path length, spatial reasoning test scores, etc.); effect expected to be greater 
for aerobic exercise training than control (strength, balance, and flexibility training) 
Measurements: reaction times, accuracy, path length, and other cognitive task derived scores 
2) 
Increased activation in and functional connectivity between brain areas associated with task 
performance, effect expected to be greater for aerobic exercise training than control; this effect of 
aerobic exercise training will be greater for subjects with 1) smaller compared to larger relative 
entorhinal cortex volume, and 2) below-median compared to above median path integration skills 
Measurements: blood-oxygen level dependent fMRI scans 
Secondary outcomes for all aims: 
1) 
Increased aerobic capacity for aerobic exercise group participants 
Measurements: VO2max (estimated from submaximal incremental work rate test) 
2) 
Increased strength for control group participants 
Measurements: upper body strength in lbs or kg (based on chest press and latissimus dorsi pulldown), 
lower body strength in lbs or kg (based on leg press) 
3) 
Increased lean body mass 
Measurements: Percent lean body mass from BIA (and/or skinfold measures) 
4) 
Neuropsychological test performance: improved performance scores on tests of spatial 
cognition, verbal memory, visuo-spatial memory, visuo-spatial attention, and executive functions post- 
exercise training compared to baseline and compared to controls 
Measurements: neuropsychological test scores 

17 
 
Data Analysis 
Provide a description of your plan for data analysis. State the types of comparisons you plan (e.g. 
comparison of means, comparison of proportions, regressions, analysis of variance). Which is the 
PRIMARY comparison/analysis? How will the analyses proposed relate to the primary purposes of your 
study? If you are doing qualitative research please state how comparisons will be made. 
Specific Aim #1: 
Behavioral and Fitness Data Analysis. The primary measures for the primary cognitive task (Sternberg 
memory load task) are % correct and reaction times, and for fitness are estimated VO 2 max. The 
primary statistical analyses will be repeated-measures ANOVAs with the factors group (aerobic vs. 
control) and time (pre vs. post) to examine group x time interactions on the outcome measures. Post- 
hoc tests (e.g. Tukey tests) will examine if a significant group x time interaction is due to a greater 
improvement post-intervention in the aerobic exercise group compared to controls. Dependent 
measures will be tested for normality and skewed data log-transformed. We will use an alpha of 0.05, 
corrected for multiple comparisons. 
Univariate fMRI and Functional Connectivity Analyses. We will use SPM8 and related software for 
statistical analysis of fMRI data. We will estimate voxel-based Statistical Parametric Maps (SPMs) 
and compare them between and within groups with mixed-design ANOVAs. We will use baseline fitness 
as a covariate. Because the entorhinal cortex and the hippocampus are our primary brain regions of 
interest, we will use a seed-based functional connectivity approach. We will compare task-related 
functional connectivity: 1) pre versus post intervention, and 2) aerobic exercise versus control. We will 
use the psycho-physiological interaction (PPI) approach91 using the Generalized PPI Toolbox92 for 
SPM8. The time course from a seed region constitutes the physiological variable, and the contrast of 
interest (e.g. high memory load > low memory load) constitutes the psychological variable in the PPI 
model. Our search space will be restricted to the medial temporal lobe region. We will determine the 
PPI variable by calculating the voxel-wise product between the physiological and the psychological 
variables. We will also correlate SPMs and functional connectivity strength with cognitive test scores. 
Analyses will include nuisance regressors (e.g. head motion). 
Specific Aim #2: 
Data Analysis. See Aim #1. The behavioral outcome variables of the primary cognitive task (allocentric 
navigation task) are distance traveled and movement speed. Addicional outcome variables are 
neuropsychological test scores and spatial reasoning test scores. Analyses will be as described for 
Specific Aim #1. In addition, we will compare two groups that differ in relative EC volume or path 
integration ability (by median split) using descriptive statistics (means, confidence intervals) due to the 
exploratory nature/ small sample size. 
Sample Size 
Sample Size Justification 
Approximately 94 participants will be recruited total for the study: For the exercise training program 

18 
 
/study intervention, approximately 84 participants will be recruited with the aim to enroll 42 
participants, 21 per group; for the cognitive and fMRI pilot studies, an additional 10 participants will be 
recruited with the aim to enroll 5 participants in the cognitive pilot and 5 participants in the fMRI pilot. 
Thus, this totals 94 participants (84 + 5 + 5 = 94) required to complete the cognitive pilot, fMRI pilot, and 
exercise training program/study intervention. 
For the exercise training program/study intervention, the sample size for enrollment was determined 
from simulation-based power predictions for fMRI (Desmond & Glover, 2002), and based on a meta- 
analysis on exercise training effects on cognition in older adults (Colcombe and Kramer, 2003). 1) fMRI: 
Given an estimated mean difference of 0.5% signal change, a between-subject variance of 0.5%, and a 
statistical power of 0.80, a sample size of 11-12 subject per group would be needed for α = 0.05 and N = 
21 per group for α = 0.002. 2) Cognition: we performed sample size calculations with G*Power 3.1.7 
based on effect sizes reported in the literature. Effect sizes were f = 0.26 for a short-duration exercise 
intervention, f = 0.30 for session durations of 45 min, f = 0.20 for cardiovascular training only, f = 0.21 
for the visuospatial domain, and f = 0.35 for participants aged 65+ years. Based on an average f of 0.26, 
a statistical power of 0.80, and alpha = 0.05, a total N = 32 subjects will be needed. Oversampling to 42 
Risks and Benefits 
Risks associated with the cardiovascular fitness and strength tests 
The exercise test will require a gradual increase of exercise intensity. Because it is very strenuous to 
reach maximum oxygen uptake even after rest it may pose a health risk for some participants. Risks and 
discomforts include the possibility of adverse changes during the test, including abnormal blood 
pressure, fainting, dizziness, severe fatigue, body aches, heart rhythm abnormalities, stroke, and very 
rare instances of heart attack. 
Risks and discomforts associated with the strength tests include feeling tired and experiencing muscle 
cramps. Other, less common, risks and discomforts include muscle tear, spraining a ligament (connective 
tissue) and lightheadedness. 
Risks associated with bioelectrical impedance analysis (BIA) 
The bioelectric impedance analysis (BIA) uses a very small electrical current, which passes between 
electrodes placed on the hands and/or feet. The amount of this current is slight enough that the 
participants will not be able to feel it and poses no risk to humans. However, there is a slight risk that 
this low current could disrupt an artificial pacemaker or defibrillator. 
Risks associated with exercise 
Walking and moderate-intensity physical activities are associated with a very low risk of musculoskeletal 
complications, but jogging and running are associated with increased risk of injury to the muscles, bones 
or joints. Acute heart attacks and sudden cardiac death can be triggered by unaccustomed vigorous 
physical exertion, particularly in sedentary men and women who have signs or symptoms of heart 
disease. 
MRI risks 

19 
 
The MRI uses a strong magnet. The magnet may affect pacemakers, artificial limbs, and other medical 
devices that contain iron. The magnet will stop a watch that is close to the magnet. Any loose metal 
object has the risk of causing damage or injury if it is pulled toward the strong magnet. The loud acoustic 
noise from the MRI machine may cause hearing damage. Participants may also experience 
claustrophobia (fear of small spaces) or anxiety while in the magnet, because the top and sides of the 
machine will be very close to the body. There is a chance that the person performing the MRI may 
notice an incidental finding. It is possible that participants will be unnecessarily worried about the 
incidental findings. 
Risks of completing tasks 
Participants may get tired during the cognitive tasks. 
Questionnaire risks 
Participants may feel emotional or upset when answering some of the questions. 
Loss of confidentiality 
The main risk of using and storing identifiable information for research is a potential loss of 
confidentiality. 
How risks will be 
Risks associated with the cardiovascular fitness and strength tests 
Because it is very strenuous to reach maximum oxygen uptake even after rest, and thus, may pose a 
health risk for some participants, we will estimate, rather than measure, the level of maximum oxygen 
uptake. Therefore, participants will perform a submaximal, incremental fitness test. This test will follow 
established standards of the American College of Sports Medicine (ACSM). We will instruct participants 
to let the technician know about any discomfort, such as dizziness, nausea, extreme shortness of breath, 
and extreme leg fatigue. Participants may ask to stop the test at any time. The staff members who will 
perform the fitness testing have current certification in cardiopulmonary resuscitation (CPR). We will ask 
participants not to engage in strenuous physical activity for 24 hours prior to the test. Participants are 
advised not to participate in the fitness assessment if they have any heart or lung conditions or 
symptoms, or if they have any physical impairment that would preclude them from performing the test 
safely. We will screen them for these conditions and symptoms prior to testing. During the tests we will 
monitor heart rate, blood pressure and perceived exertion. Only well-trained personnel (technicians, 
physiologists, nurses or physicians) will conduct the exercise test. 
To reduce the risks associated with strength testing, participants will perform wrap-up exercises, and 
trained individuals will instruct them in proper technique. Participants will be able to take breaks as 
Risks associated with bioelectrical impedance analysis (BIA) 
We will exclude participants with pacemakers and defibrillators from participating in this study. 
Risks associated with exercise 
To reduce the risk of musculoskeletal injury and complications associated with exercise, the exercise 
training program will be tailored to each participant’s ability level and supervised by an experienced 

20 
 
trainer. The trainer will instruct each participant in proper technique. To reduce injury risk, each exercise 
session will include a light cardiovascular warm-up, cool-down and stretching, and the amount and 
intensity of the exercise will gradually increase over the 12 weeks of the exercise training program. 
MRI risks 
Participants will be excluded if they have any metal in or on their body, regardless of whether the metal 
is ferromagnetic, if the metal cannot be removed. This includes implanted devices, such as pacemakers 
and defibrillators. Participants will be screened for claustrophobia (fear of small spaces). If participants 
feel anxious during the procedure, they can ask us to stop the MRI at any time. The MR technologist of 
the Cognitive Neuroimaging Center, who is trained in magnet safety, will prepare the participants for 
MR imaging and will perform the scans.To prevent potential hearing damage participants will be 
required to wear earplugs. The MR technologist and the study staff are trained in magnet safety and 
will communicate with the participant during the MRI session. 
It is explained to the participants that the MRI scan being done is designed to answer research questions 
only and does not serve as a medical scan. However, if we believe that we have found a medical 
problem (or serious medical problem) in the MRI scan, we will consult the director of the Cognitive 
Neuroimaging Center, Dr. Chantal Stern, D. Phil., and/or the center’s MRI technologist, if needed. If Dr. 
Stern, D.Phil., and/or the MRI technologist thinks that there may be an abnormality, we will contact the 
participant and will help them get medical follow-up for the problem. The MRI scan will not be reviewed 
by a clinically-trained physician as a part of this research study. With the participant's permission, we 
may contact their primary care physician. 
Risks of completing tasks 
The testing procedures include breaks and the participants can rest at any time, except during timed 
tasks. For tasks performed in the fMRI scanner, we will split the tasks into several runs with brief breaks 
between runs. 
Questionnaire risks 
Participants will be instructed to let the interviewer know at any time if they want to take a break or 
stop the interview. Participants are not required to answer any questions that make them feel 
uncomfortable. However, they may be excluded if it cannot be established whether or not the 
participant meets the inclusion and/or exclusion criteria. 
Loss of confidentiality 
We will protect each participant’s confidentiality by labeling identifiable information with a code and 
keeping the key to the code separately from the research data either in a password-protected computer 
or as a paper file in a locked file cabinet. The master code is limited to BUMC investigators and we will 
not release it to anyone outside the institution. Dr. Storer will have access to the names and birthdates 
of participants in addition to the research data. Information will be stored on secure servers using 
REDcap or similar software. If it is necessary to use a laptop’s hard drive for storage of identifiable 
information this laptop’s hard drive will be encrypted with Truecrypt or similar disk encryption software 
prior to storing this information. All research staff will receive training in human subject protection and 
the HIPAA rule. 

21 
 
Potential Benefits 
Benefits to subjects 
Participants may or may not benefit from taking part in this study. Possible benefits to subjects include 
improved cardiovascular health, physical fitness and/or strength, and weight loss from participating 
regularly in the exercise training program. 
Benefits to society 
Others may benefit in the future from the information that is learned in this study. These potential 
benefits may include improved brain function through exercise and knowledge about how exercise 
affects the brain and cognitive (thinking) processes. 
Risk to Benefit Ratio 
Assessment of Risk/Benefit Ratio 
Even though the exercise interventions, exercise testing and MRI procedures performed are solely done 
to answer research questions, the risks are very reasonable in relation to anticipated benefits. This is so, 
because the risks associated with the research study are only minimal, while the anticipated benefits to 
subjects are expected to be more than minimal due to the well-known health-related benefits 
associated with regular exercise. 
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