Aerobic Exercise and Cognitive Training in Older Adults
Phase: NA
Conditions: Sedentary Lifestyle
Sponsor: VA Office of Research and Development

 
 
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Protocol 
 
1. Aerobic Exercise and Cognitive Training in Older Adults 
 
(Short title: Nocera Exercise) 
 
Principal Investigator:  Joe Nocera, PhD 
 
Co-Investigators:  
Bruce Crosson, PhD 
 
 
 
Jeffrey Boatright, PhD 
 
 
 
Machelle Pardue, PhD 
 
 
2. Abstract: 
 
The purpose of this study is to examine the impact of a combined cognitive training and 
aerobic exercise intervention in sedentary older adults. It is hypothesized that the 
aerobic exercise will potentiate and increase the generalizability of the cognitive 
training. Importantly, this study will focus on older adults at-risk for mobility disability. 
This area is of particular importance considering a large percentage of adults are 
entering old age and therefore likely to suffer from age-related cognitive decline and 
mobility disability. 
 
To address our research question 60 adults (age 18-89) will be randomized to one of 
two 12 week intervention groups: 1) Cognitive Training alone (CT) or 2) Aerobic 
Exercise + Cognitive Training (AE+CT). The aerobic exercise arm of the study will 
follow the same format shown to improve a broad range of executive functions in older 
adults in previous research. The cognitive training arm will consists of a popular 
commercially-available brain fitness program that has demonstrated specific cognitive 
improvements and high adherence.  
 
Outcome measures will include changes in the battery of executive function tests which 
target verbal fluency, response inhibition, and working memory. Additionally, to 
strengthen our methodology, we will examine tasks that are not expected to change 
because of their higher reliance on peripheral memory systems or crystallized word 
knowledge.  We will also examine the effects of AE+CT versus CT alone on changes in 
the hemodynamic response during two fMRI tasks: verbal fluency and verbal working 
memory.  Finally, we will examine the effects of AE+CT versus CT alone on changes in 
mobility and physical function. To examine the effects of the interventions on mobility 
we will examine walking speed as our primary outcome. 
 
 
3. Introduction and Background: 
 
Significantly, declining mental health and mobility disability are primary components of 
the expected 25 percent growth in health care cost related to the aging crisis in America 

 
 
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[1]. Although, combining aerobic exercise and cognitive training may significantly ease 
these inevitable features of aging, these findings need to be objectively quantified. 
Interestingly, in 2002 Fabre and colleagues demonstrated that combining cognitive and 
exercise training seemed to result in greater effects on cognitive function than either 
technique alone [2]. However, the Fabre study did not focus on executive functions 
which are an excellent proxy for cognitive health in older adults [3]. Further, no study to 
date has examined the significant outcomes of the proposed study in sedentary older 
adults at risk for mobility disability. Considering that many older adults are sedentary 
and at risk for functional decline targeted interventions are desperately needed. In the 
following background sections, we will establish a case for combining aerobic exercise 
and cognitive training as a potential intervention for executive function impairments in 
older adults.  
 
Cognitive Impairment and Executive Functions. People over the age of 65 frequently 
have difficulty thinking abstractly as well as problems with planning, initiating, 
sequencing, monitoring and stopping complex behaviors. As such, the ability to carry 
out essential tasks of daily living are compromised. These difficulties are commonly 
attributed to executive dysfunction demonstrated in aging. In the context of this 
proposal, executive functions are frontally mediated cognitive functions which require 
conscious intentional control and include; verbal fluency, inhibition, and working 
memory. For example, generating words from a category (verbal fluency) requires an 
individual to initiate a search of words stores while inhibiting competing resources. 
Further, working memory requires temporarily storing and managing information 
required to carry out the fluency task.  
 
Cognitive Improvements as a Result of Exercise. Colcombe and colleagues [4] 
cross-sectionally studied the effects of cardiovascular fitness levels on cortical density in 
aging humans.  They examined the density of gray and white matter in adults ages 55-
79 and related those measures to the cardiovascular fitness levels of the participants. 
Results demonstrated that older adults with greater levels of cardiovascular fitness had 
significantly less atrophy of gray matter in the frontal cortex as well as significantly less 
loss of tissues in both the anterior and posterior white matter tracts.  
 
Evidence from animal models has demonstrated several possible mechanisms that may 
underlie the ameliorative effects of aerobic exercise on cortical structure in aging. For 
example, in rats exercise has been shown to increase brain neurotrophins such as 
brain-derived neurotrophic factor, [5] and nerve growth factor. Also, physical activity has 
been shown to have neuroprotective effects on the brain, leading to neurogenesis in the 
hippocampus, new cell growth  and protection from ischemic damage within the 
hippocampal formation. Additionally, chronic exercise is associated with growth of blood 
vessels (angiogenesis) and synaptogenesis in cortex [6]. Collectively, these 
transformations result in a brain that is more efficient and perhaps more receptive to 
neuroplastic changes resulting in increased performance and learning.  
 
As indicated, both the animal model and cross sectional humans studies of brain 
morphology suggested that aerobic activity positively influences cortical structure with 

 
 
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the greatest neuroprotective effects localized to the frontal and prefrontal areas of the 
human brain [4]. Significantly, several randomized-controlled clinical trials have 
produced findings consistent with these theorems. For example, research demonstrated 
that older adults who participated in 6 months of aerobic fitness training significantly 
increased brain volume in both gray and white matter.  Further, no such change was 
demonstrated for the older adults who participated in stretching or toning (non-aerobic) 
exercise [7]. These findings are meaningful because frontal areas typically demonstrate 
the greatest age-related decline. 
 
Equally important, the demonstrated enhancement in frontal integrity highly correlated 
with the behavioral research demonstrating that aerobic fitness has the greatest impact 
on frontally-mediated executive functions. For example, the seminal work by Kramer 
and colleagues demonstrated that 124 older adults randomly assigned to receive 
aerobic training experienced substantial improvement in performance tasks dependent 
on executive control processes and the integrity of the prefrontal and frontal cortex [8]. 
Similarly, neuroimaging studies showed that aerobically trained individuals increased 
functioning of key aspects of the attentional circuitry during cognitive tasks. More 
specially, individuals who participated in an aerobic exercise intervention showed 
greater attention on task-related activity in the prefrontal area (middle frontal gyrus and 
the superior frontal gyrus) of the cortex when compared to non-exercise controls [9].    
 
Although studies examining the effect of aerobic exercise on cognition have been 
remarkable, other studies have failed to observe such a relationship. The explanations 
for these differential findings may be described as followed. First, the manner in which 
cardiovascular fitness was assessed has differed between studies (e.g. resting heart 
rate versus the benchmark VO2 max). Secondly, the cognitive processes examined 
have differed between studies. For example, cognitive tasks have been evaluated that 
fall outside the capacity of the frontal cortex previously demonstrated to improve as a 
result of exercise. And lastly, the age, health, sex and fitness level of the participants 
have differed between studies. Despite these alternative findings, collectively research 
demonstrates the relationship between aerobic fitness and cognitive health is 
encouraging with three key findings.  To summarize, first, aerobic exercise can protect 
the brain from age-related atrophy. Secondly, aerobic interventions increase activity in 
frontal structures during tasks requiring executive control. Lastly, and equally important, 
these structural and functional improvements are consistent with behavioral studies 
demonstrating improvements in executive control processes reliant on the frontal cortex.  
 
Cognitive Training in Older Adults. A growing body of research demonstrates the 
beneficial effects of cognitive stimulation in later life to promote neural plasticity. 
Research from both the human and animal models demonstrates that environmental 
stimulation can enhance and maintain cognitive functioning. Similarly, cognitive 
remediation has been found to positively impact neural structure while limited education 
is a predictor of dementia. Importantly, there is a sizable body of research supporting 
various cognitive training paradigms that have demonstrated large and durable effects 
on cognitive functioning in older adults. For example, Ball and colleagues demonstrated 
cognitive interventions targeting memory, reasoning and speed of processing were 

 
 
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effective to the magnitude equivalent to the amount of decline expected in older persons 
without dementia over a 7-14 year interval.   
 
Unfortunately, despite these promising findings, the generalizability of cognitive training 
is limited. For example, Owens and colleagues recently examined cognitive training 
tasks designed to improve reasoning, memory, planning, visuospatial skills and 
attention in over 11,000 participants. Interestingly, the researchers found improvements 
in every one of the observed cognitive tasks trained, however, “no evidence was found 
for transfer effects to untrained tasks, even when the tasks were cognitively closely 
related” [10].   
 
While cognitive training does appear to impact specific trained cognitive functions 
strategies are needed to potentiate and increase generalizability of the outcomes. 
Interestingly, a recent article in the October 2010 edition of Gerontology [11] suggested 
the need to combine both exercise and cognitive-focused intervention to “enhance 
improvements in functional independence over and above the interventions being used 
separately.” While the cognitive benefits of cognitive training has been demonstrated, it 
cannot be assumed that aerobic exercise will potentiate the effect. Unfortunately, 
studies have yet to adequately investigate the effect of cognitive training used in 
conjunction with aerobic exercise in older adults. This proposal specifically 
addresses this gap in the literature.  
 
The Executive Function and Mobility Link. Traditionally, walking has been thought of 
as an automatic motor function with little higher mental input. However, walking and 
mobility are becoming increasing linked to cognitive functioning, specifically, executive 
functions. For example, gait impairment and executive function problems are common 
in aging and often coincide [12]. Further, having a gait disorder increases the chance of 
developing non-Alzheimer dementia threefold [13]. Lastly, older adults with poor 
executive functions walk slower, have increased gait variability, fall more often, and 
perform poorly on complex mobility tasks such as rising from a chair and dual tasking.  
 
Significantly, pharmacological and cognitive training that targets the executive functions 
have been demonstrated to improve gait [14]. For example, utilizing a randomized 
single-blind controlled design, Verghese and colleagues studied cognitive training to 
improve gait velocity in 24 sedentary older adults. The cognitive training utilized a 
computer-based program which focused on training attention, visual spatial skills and 
executive functions. Of significance, participants randomized to cognitive training 
improved their gait velocity from baseline during a normal walking condition and on a 
walking while talking condition. It was concluded that improvement in walking speed 
was due to the cognitive training modules that targeted tasks relevant to gait (e.g. 
executive functions) [13].  
 
Neuroimaging and Aerobic Exercise. To date the neural mechanisms underlying the 
improvements associated with cardiovascular fitness and aerobic exercise in aging 
adults has not been well studied in human populations [9]. However, recently Colcombe 
and colleagues demonstrated, both cross-sectionally and longitudinally following an 

 
 
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aerobic intervention, that increased cardiovascular fitness resulted in increased task-
related activation in the frontal attentional circuitry thought to be necessary for executive 
functions [9]. For example, after an aerobic exercise intervention older adults showed 
significantly greater level of activity in both the medial frontal gyrus and superior frontal 
gyrus during a version of the flanker task than non-exercising controls. Successful 
completion of this task requires participants to invoke selective spatial attention through 
the frontal circuitry, which in turn should bias regions of visual cortex to isolate the 
central (target) cue, and inhibit the peripheral flanking cues. This is one of the few 
studies that has attempted to identify specific improvements in the plasticity of the aging 
human brain following aerobic exercise.  
 
Work from the Co-PI’s lab has consistently demonstrated that during verbal fluency 
tasks, older adults show a bilateral pattern of recruitment in the frontal cortex when 
compared to the strongly left lateralized activity pattern of young adults. Consistent with 
our pilot data (see preliminary studies), we hypothesize that aerobic exercise will result 
in a “younger looking” pattern of lateralization in older adults during a verbal fluency 
task. 
 
 
4. Objectives: 
 
Cognitive decline is a significant health concern among older adults, with limited 
treatment options [15]. Cognitive decline greatly hinders quality of life as it often 
coincides with mobility disability [16]. Despite growing fiscal resources, cognitive decline 
and mobility disability rates continue to rise in older adults. As such, interventions that 
can target these vital aspects of independence are desperately needed. Recent studies 
have shown that computer-based cognitive training strategies may improve 
performance on cognitive measures but the generalizability of the benefit is lacking [10]. 
Interestingly previous research demonstrates that aerobic exercise can improve 
cognitive performance in older adults in an array of age-susceptible frontally-mediated 
cognitive-executive functions [4]. Importantly, these outcomes are in addition to the 
robust, well documented benefits of physical activity. While it is plausible that aerobic 
exercise can potentiate and increase generalizability of cognitive training while 
concurrently benefiting mobility, this intervention approach has not been adequately 
studied in sedentary older adults at-risk for mobility disability.   
 
Therefore, the short term objective of this proposal is to take the next logical step and 
identify the combined/synergists effects of cognitive training in conjunction with aerobic 
exercise on executive functions and mobility in older adults at risk for mobility disability. 
To address this research question 60 adults (age 18-89) will be randomized to one of 
two 12 week intervention groups: 1) Cognitive Training alone (CT) or 2) Aerobic 
Exercise + Cognitive Training (AE+CT). The aerobic exercise arm of the study will 
follow the same format shown to improve a broad range of executive functions in older 
adults in previous research [7, 17]. The cognitive training arm will consists of a popular 
commercially-available brain fitness program that has demonstrated specific cognitive 

 
 
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improvements and high adherence [18, 19]. Groups will be equalized for contact and 
monitoring. The following specific aims and hypotheses are proposed:  
 
1. To assess the relative effect of the interventions on frontally-mediated executive 
function tasks.  
Consistent with the demonstrated executive function improvement following 
aerobic exercise we hypothesize that compared to CT alone, those randomized 
to AE+CT will demonstrate greater improvements on frontally-mediated 
cognitive tasks.  
 
2. To assess the relative effect of the interventions on changes in brain activity 
(assessed through functional MRI) and blood derived neurotrophic factor (BDNF)..  
Consistent with our pilot data, we hypothesize more unilateral (left) pattern of 
frontal recruitment in the AE+CT group, suggesting a more efficient recruitment 
of the frontal cortex. Additionally we hypothesize an increase in BDNF in the 
AE+CT group. 
 
3. To assess the relative effect of the interventions on changes in mobility (walking 
speed) and perceived health status (self-reported physical function and quality of 
life).  
We hypothesize that compared to CT alone, those randomized to AE+CT will 
demonstrate greater improvements on mobility and physical function. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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5. Study design and methods: 
 
The study will enroll between 60 and 80 
older, sedentary adults. Participants will be 
randomly assigned to one of two 12-week 
interventions conditions: AE+CT or CT 
alone.  
 
Specific Aim 1: To assess the relative 
effect of the interventions on frontally-
mediated executive function tasks. 
 
The primary outcome will be changes in the 
battery of executive function tests which 
target verbal fluency, response inhibition, 
and working memory. Additionally, to 
strengthen our methodology, we will 
examine tasks that are not expected to 
change because of their higher reliance on 
peripheral memory systems or crystallized 
word knowledge. The following experimental 
measures will be given in the standard 
manner, using different stimuli when 
possible in each of the conditions (i.e. pre, 
post-intervention, 12 week follow-up). The 
order of stimulus lists will be 
counterbalanced across participants. We 
will also look at retention of benefits as all 
participants will be followed-up 12 weeks after completion of the interventions.  
 
Measures for Specific Aim 1. 
 
Verbal Fluency 
1. Letter Verbal Fluency: Participants produce as many words (F, A, S, or P, R, W) as 
they can that begin with that letter in 60 seconds. Clinical findings are in line with 
numerous functional magnetic resonance imaging studies, demonstrating that letter 
verbal fluency is associated with extensive activation in the left frontal cortex. 
Further, age-related decline in letter fluency have been demonstrated . 
 
2. Semantic Verbal Fluency: Participants produce as many words as they can that fit a 
particular category (animals or fruits/vegetables) in 60 seconds. This is generally 
considered a measure of a verbal component of executive function and has been 
demonstrated to decline with age. 
 
3. Switching Verbal Fluency: The switching condition evaluates the examinee's ability 
to generate exemplars while alternating between two different semantic categories 
Week 3-15 
Week 1 
Sedentary 
older veterans 
Informed Consent 
Screening  
Cognitive  
Evaluation 
Physical 
Evaluation 
Counter balanced 
Aerobic 
Exercise 
+ 
Cognitive
  12 weeks 
Cognitive 
 Evaluation 
Physical 
Evaluation 
Week 2 
Week 16 
12 weeks 
Cognitive 
Evaluation 
Physical 
Evaluation 
Week 28 
fMRI/Blood Draw 
fMRI/ Blood Draw 
Cognitive 
Training 

 
 
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(i.e. fruits and furniture) in 60 seconds. Switching requires the ability to engage in 
strategic search processes such as initiation, cognitive flexibility and mental set 
shifting. Because it is related to fronto-executive functioning, impaired performance 
is seen among patients with frontal lobe lesions and older adults.  
 
Response Inhibition 
1. Color-word Interference Test: Participants say the color in which another color word 
is printed in (e.g., for BLUE printed in red ink, the answer is ‘red’). This is a 
commonly-used executive function task. Additionally, the interference effect, caused 
by difficulty inhibiting over-learned word reading, is often more pronounced in older 
adults. 
 
Working Memory  
1. N-back task: Both the verbal and visual working memory tasks will be evaluated in 
the versions of the n-back task.  Versions of n-back tasks have been shown to be 
sensitive to working memory. During the n-back tasks, verbal or visual stimuli are 
shown one at a time using a laptop computer.  For each stimulus, participants click 
the left mouse button of the computer if the stimulus is a target and the right mouse 
button if the stimulus is a non-target. Targets are stimuli that occur n stimuli 
previously (i.e., n stimuli back).  For each task, 1-back, 2-back, and 3-back runs are 
given.  Each run has 100 stimulus presentations, with 20 targets and 80 non-targets. 
Stimuli are presented for 500 ms with inter-stimulus intervals of 3000 ms.  A 60 sec 
break occurs after the first 50 stimuli of each run.  Both accuracy and latency of 
response are recorded. Verbal and visual stimuli are as follows:  (1) Verbal stimuli 
are common, highly imageable English words 4 to 6 letters in length.  3 stimuli are 
chosen from each of 3 categories (animals, tools, vehicles).  Targets are trials in 
which an animal name is presented when an animal name is presented n stimuli 
back (e.g., in the following 3-back sequence, the target is in bold: “dog, horse, 
hammer, cat, car”).  (2) The visual task are 9 non-sense shapes.  Targets are any 
trial on which a shape is presented when the identical shape is presented n stimuli 
back.  
 
2. Digit Span forward/backward: Participants must recall increasingly long strings of 
digits in order (forward) or reverse order (backwards) of presentation. Central 
executive component of working memory has been demonstrated to play a key role 
in digit backward span performance and age-related decline has been reported. 
 
3. Hopkins Verbal Learning Test- Assess verbal learning and memory (immediate 
recall, delayed recall, delayed recognition). 
 
4. Digit Symbol-Coding- a neuropsychological test sensitive to brain damage, 
dementia, age and depression. It consists of digit-symbol pairs followed by a list of 
digits. Under each digit the subject should write down the corresponding symbol as 
fast as possible. The number of correct symbols within the allowed time (e.g. 90 or 
120 sec) is measured. 

 
 
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Non-Verbal Executive Function 
1. Sorting Test: Participant must sort cards on one of three possible dimensions, 
examines problem solving and spatial concept formation.  
 
2. Trail Making Test A and B: Easily administered tests measure attention, visual 
searching, mental processing speed, and the ability to mentally control simultaneous 
stimulus patterns. 
 
 
Further, to measure if the AE+CT group demonstrated greater generalizability than the 
CT alone group we will utilize the cognitive evaluation that is part of the MindFit 
software. The MindFit will be utilize for the cognitive training arm of this study and is 
further described in the “Interventions” section of the methods. The Mindfit cognitive 
evaluation was designed to evaluate cognitive functioning in older adults and describe 
progress rates of participants utilizing the software. It is anticipated that the CT training 
group will only improve on measures specific to the MindFit cognitive evaluation. In 
contrast, those randomized to the AE+CT will have improvements on executive function 
tests not specific to the MindFit cognitive training program. Test within the MindFit 
cognitive evaluation include (as described in the software):  
 
1. Naming: This is a naming task that involves visual information processing and 
matching objects, words, and letters in a fast-response condition. The software 
measures accuracy percentage of correct responses and response time. 
 
2. Psychomotor skills (i.e., tracking): In this test, the user is asked to track a moving 
ball with the computer mouse cursor. This task requires eye-hand coordination, 
spatial perception, and focused attention. The software measures the accuracy of 
the tracking—the percentage of time that the computer cursor is in the middle of the 
ball. 
 
3. Sustained attention in tasks involving allocated attention to a target—with and 
without distractor: In this test, the user is asked to click on a ball appearing in 
different locations on the screen. When a (distracting) yellow hoop also appears, the 
user is instructed to ignore the hoop and continue clicking on the ball. The software 
measures the accuracy—percentage of correct clicks and response time. 
 
4. Time estimation, both auditory and visual: In this test, pictures are presented, 
sounds are turned on, and the task is to estimate the length of each stimulus 
presentation. The software measures deviation (under- and overestimation of time). 
 
5. Maze test—planning is tested in a maze task: In this test, the users must make their 
way through three mazes, one after another. The level of complexity increases with 
each subsequent maze. The software measures the number of errors made per 
maze and execution time (the time to complete each maze). 
 

 
 
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All cognitive testing will take place in the primary laboratory of the PI/Co-PI at the 
Atlanta VA Medical Center. All evaluations will be done by the PI or appropriate study 
staff. Additionally to evaluate efficacy of interventions participants will self report on:  
 
1. Mac-Q- 6 item questionnaire to asking participants to describe their ability to 
perform memory task as compared to when they were in high school.  
2. Behavior Rating Inventory of Executive Function (BRIEF)- Assesses self reported 
impairment of executive function task related to activities of daily living.  
3. Self Efficacy for exercise scale - a 13-item instrument that measures self-efficacy 
barriers to exercise,  
4. Epworth Sleepiness Scale- self report used to determine the level of daytime 
sleepiness. 
5. Apathy Index (MAI)- 14 item self report instrument that measures overall apathy 
and participants interest in new things.   
6. Pittsburgh Sleep Quality Index- 10 item questionnaire examining participants 
sleep habits over the past month.  
The final neurocognitive assessment test is the the Visual Paired Comparison [VPC] 
task. This task was developed at Emory and has already been used for studies 
approved through the Emory IRB (IRB#00001272). This testing will take place at 
Wesley Woods, where previous testing with the VPC task has taken place, on the same 
day that subjects undergo their MRI. Thus, subjects will not have to undergo a separate 
visit to complete this testing. 
 
Task: The VPC task does not require any significant computer skills, thus the task 
should not pose operational problems for patient groups or the control subjects. Eye-
tracking data will be gathered concurrently with the administration of the behavioral 
task. The eye-tracking apparatus and procedures are described below.  
The VPC Task:  Subjects view a new picture and a recently presented picture side-by-
side on the computer monitor and the subject’s spontaneous tendency to look at the 
new picture is measured. Eye movements will be recorded while subjects view pairs of 
black and white images.  Each trial of this task consists of two phases, a familiarization 
phase and a test phase. Familiarization phase. In this phase the subject is presented 
with two identical black and white line drawings, side by side on the computer screen. 
After a delay interval (2 sec, or 2 min) during which the screen is blank, the test phase 
begins. Test phase. After the delay, subjects are presented with a picture of the old 
stimulus and a picture of the novel stimulus, side by side.  This task requires about 30 
minutes. 

 
 
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Specific Aim 2: To assess the relative effect of the interventions on changes in brain 
activity (assessed through functional MRI), visual outcomes, and blood derived 
neurotrophic factor (BDNF). 
 
Research Design: Our overarching goal for aim 2 is to examine the effects of AE+CT 
versus CT alone on changes in the hemodynamic response during two fMRI tasks: 
verbal fluency and verbal working memory.  
 
MRI. Structural images using T-1 weighted and diffusion imaging (DTI) sequences will be 
acquired while the participant is at rest within the scanner. During this time (15 minutes) 
participants are given the option to view a movie to alleviate potential boredom.  
 
FMRI Tasks. For the verbal fluency task in the scanner, participants will see different 
categories at the center of a video screen while in the scanner. The participant’s task will 
be to generate different exemplars of the respective category (semantic) or as many 
words that begin with a particular letter (phonemic). The fMRI fluency task will consists of 
two blocked conditions of category or phonemic generation, which will alternate with a 
control condition (reading the word “rest” aloud). A baseline condition will be used to 
control for activity associated with (a) basic visual processing, (b) articulation and, (c) 
hearing of the subject's own voice. A total of 4 blocks for each condition will be collected 
(i.e., 40 trials for category and phonemic fluency).  
 
For the verbal working memory task, both memory and control trials will be presented in 
a pseudorandom order across five runs, each containing 14 trials. This will produced 35 
memory trials and 35 control trials over the course of the experiment. For a memory 
trial, the first slide will depict a single lexical target. Participants will be instructed to read 
and remember this “target word” with the knowledge that sometime later they will be 
shown a second word, referred to here as the “decision word”. Upon seeing the decision 
word, participants will initiate a button press indicating whether the target and decision 
words are semantically related. The time in-between presentation of the target and 
decision words will be filled with additional slides, referred to here as “distractor slides”. 
Each distractor slide will present two words. Participants will be asked to make a 
semantic relatedness judgment for each of these distractor word pairs. A single memory 
trial is depicted in the diagram below. The timing parameters will be identical for both 
the memory and control trials. Specifically, slides 1-4 will present for 2 seconds each, 
and slide 5 will be shown for 4 seconds. These parameters were established through 
pilot testing in the lab of a colleague (Dr. Anna Moore) of the Primary Mentor and were 
chosen to allow sufficient time for the button-press response and to elicit satisfactory 
task performance. A 10-second blank screen inter-trial interval will used to allow 
hemodynamic response recovery. 
 
Diagram of the experimental task, showing a single memory trial and a single control 
trial. Each trial will last 12 seconds for both task conditions (control & memory) and will 
be separated from the subsequent trial by a 10-second blank screen. Color-coding 
indicates the phases delineated for the functional task activation analysis. 

 
 
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The fMRI acquisition for semantic will follow protocols currently utilized in the 
investigators’ laboratory and therefore will employ a sparse-temporal sampling design in 
which the response is assessed in the scanner during an off-phase, and the 
hemodynamic response is acquired after a short time delay; thereby movement artifacts 
due to the articulation process are avoided. Since the working memory task involves no 
overt speech, a continuous sampling acquisition will be used to allow for temporal 
resolution of the different phases of the working memory task. A T2*-weighted Fast-
Field Echo, Echo-Planer-Imaging (FFE-EPI) sequence utilizing a parallel imaging 
technique will be used. Prior to the first scan, a training session outside of the scanner 
will be performed to familiarize the participants with experimental tasks. Participants will 
be scanned prior to and following the 12 week intervention but not at 12 week follow-up. 
Additionally, for fluency both semantic and phonemic stimulus presentation will be 
different but equalized for difficulty from pre to post.  
 
The MRI/FMRI will be conducted at Emory University’s Center for Systems Imaging 
(CSI). The CSI houses a 3 T Siemens Trio scanner with the total imaging matrix (TIM) 
suite.  The scanner is equipped with a 32-channel Siemens head coil, which allows for 
rapid acquisition of high-resolution functional images (e.g., 2 X 2 X 2 mm voxels with a 
whole brain acquisition every second). It has the latest Siemens VB17 software and has 
a number of advanced Siemens product sequences including Blood Oxygenation Level 
Dependent (BOLD) imaging and in-line analysis suite with 3D PACE realtime motion 
correction.   
 
Blood Draws and Biomarker Evaluation 
Whole blood will be collected, by a certified phlebotomist, via venipuncture or peripheral 
venous line into standard plasma tubes or serum separator tubes (~40 ml per visit). 
Following collection, tubes will be transferred in accordance with blood borne pathogens 
training standards to the  Molecular Core facility (for which Dr. Boatright is Director) of 
the Atlanta VAMC. Serum and plasma aliquots will be analyzed for biomarkers (e.g., 
BDNF) by ELISA, western immunoblotting, and other standard molecular biology 
assays. 
 
The procedure below describes the blood collection timeline during the 12-week 
intervention period and follow up:  

 
 
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Baseline: 4 measurements over 1 hour, taken every 15 minutes, to demonstrate 
reliability of the measures.  
 
Week 1: Taken immediately prior to exercise, immediately post, 15 min post, 30 
min post. These time points will be mimicked in the non-exercised CT group.  
 
Week 4: Taken immediately prior to exercise, immediately post, 15 min post, 30 
min post. These time points will be mimicked in the non-exercised CT group.  
 
Week 8: Taken immediately prior to exercise, immediately post, 15 min post, 30 
min post.  
These time points will be mimicked in the non-exercised CT group. 
 
Week 12: Taken immediately prior to exercise, immediately post, 15 min post, 30 
min post.  
These time points will be mimicked in the non-exercised CT group.   
 
Follow-up: 1 measurement taken at 12-week follow-up.  
 
All blood draws will be conducted at the Atlanta VA Medical Center. Tubes will be coded 
and thus have no identifiable patient information. It is expected that all blood sample 
processing and storing will be conducted at the Atlanta VAMC in the Molecular Core 
facility. However, in the event that equipment or other resources are needed for 
completing sample analysis, samples will be analyzed at Dr. Boatright’s laboratory at 
Emory University (5th Floor, Emory Eye Center, Clinic Building B, 1365-B Clifton Road, 
Atlanta, GA). Sample labels will be de-identified by having only Subject #, Visit #, Draw 
#. The master code list will be maintained in a locked file cabinet in the Atlanta VAMC 
office of the PI or Co-investigator. Deidentified sample remainders will be kept at the 
Atlanta VA Core facility or, if needed, the Emory facility, while the study remains open. 
 
Visual Assessment 
Visual assessment will include retinal function (electroretinogram; ERG), retinal 
morphology (scanning laser ophthalmoscope/spectral domain-optical coherence 
tomography; SLO/SD-OCT), and other selected measures of visual function. All 
methods are currently routinely conducted in the laboratories of the investigators [5, 15]. 
 
ERG:  Following 30 minutes of dark-adaptation, a DTL fiber electrode (0.5% 
proparacaine hydrochloride in the eye receiving the DTL fiber) will be connected to the 
subject with a cup electrode attached to the temple serving as a reference for the DTL 
fiber. A dim flash (-1.43 cd s/m2 or 1.5 Td•s) is then presented (10 flashes with 10 
second interstimulus interval, sampling interval of 256 seconds, filter settings of 0.3 to 
300 Hz). Analysis of ERG waveforms will include amplitude and implicit times of a- and 
b-waves and filtered OPs. Following dark-adaptation, the subject will be light-adapted 
for 10 minutes and 28 Hz flicker will be presented (average of 25 flashes at 3.0 cd s/m2 
or 128 Td•s). Amplitude and implicit time of the flicker waveform will be analyzed.  
Analysis of the response from the different subject cohorts will consist of two-way 

 
 
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repeated ANOVA for each ERG parameter with Holm-Sidak post-hoc comparisons to 
evaluate differences between subjects groups across time for each flash stimulus. 
 
SLO/SD-OCT:  Following placement of dilating drops (2.5% 
phenylephrinehydrochloride,1% tropicamide), the subject is asked to place their head in 
a chin rest in front of a SLO/SD-OCT instrument.  The subject looks at a fixation light 
and the back of the eye is non-invasively imaged using a laser.  This is a clinically-
approved instrument that requires no contact with the patient's eye.  The imaging will 
take no longer than 10 minutes. Dilation of the pupils lasts for 3-5 hours.  Subjects will 
be instructed to bring sunglasses to testing to wear after the exam when leaving the 
building. 
 
Visual Function:  
Contrast sensitivity (CS) will be determined using the CSV1000E Contrast Chart and/or 
the Pelli-Robson Contrast Sensitivity Chart [27]. For the CSV1000E Contrast Chart, the 
subject will view the self-illuminated (85 cd/m2) screen monocularly while wearing their 
normal correction while a drifting grating is presented. CS thresholds will be assessed 
for both eyes individually. The Pelli-Robson chart  is viewed at a distance of 1 m.  
Subjects will be encouraged to give a response for each letter until 2 of 3 letters in a 
triplet are incorrectly answered. 
 
Visual acuity (VA) is measured using the Early Treatment of Diabetic Retinopathy Study 
(ETDRS) chart [28] and the Smith-Kettlewell Institute Low Luminance (SKILL) [29] 
chart.  For the ETDRS chart, subjects will be placed at a distance of 3 m, if at least the 
top line can be read correctly, and encouraged to give a response for each letter until 5 
successive incorrect answers are recorded.  This test will take 10 minutes to complete. 
The SKILL test is designed to assess vision under conditions of low contrast and 
lighting, through a test performed under standard office lighting. The SKILL card has a 
standard high-contrast near acuity chart on one side, and a chart of gray letters on a 
dark background on the other. The low reflectance of the dark side of the card 
effectively simulates testing in a dim environment.  The SKILL score is the acuity loss 
(number of letters) between the light and dark sides.  This test will take 12 minutes to 
complete. 
 
Visual field (VF) is measured by the Humphrey Visual Field Analyzer (HVFA). The 
subject will look into a half-dome and fixate on a light in the middle while the perimetry 
targets are flashed onto the dome at predetermined points within a pattern (3-zone 
screening protocol) to determine the threshold light sensitivity at each point in the 
pattern.  The two eyes are tested separately.  This test will take 30 minutes to complete. 
 
Comparisons across subject groups will be performed using two-way repeated ANOVA 
with Holm Sidak post hoc comparisons to evaluate differences in CS and VA between 
subject groups across time.  
 
Specific Aim 3: To assess the relative effect of the interventions on changes on 
mobility and physical function. 

 
 
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Research Design. Our overarching goal for aim 3 is to examine the effects of AE+CT 
versus CT alone on changes in mobility and physical function. To examine the effects of 
the interventions on mobility we will examine walking speed as our primary outcome. 
We chose walking speed as it has been demonstrated to highly represent overall health 
status in older persons [18]. Additionally, to strengthen the relationship with the 
interventions and activities of daily living we will include a dual-task measure of gait 
speed (walking while talking) as well as measures of upper extremity function and 
measures of visual and spatial cognition.  Self reported falls as well as physical function 
and quality of life will be evaluated as secondary endpoints. All measures for Aim 3 will 
be done at pre, post and at 12 week follow-up. Significantly, the Godin Leisure-Time 
Exercise Questionnaire will be used to monitor the participant’s physical activity levels 
during the 12-week follow-up period. 
 
Measures for Specific Aim 3. 
 
1. 400 Meter Walk. Participants will be asked to walk at their usual pace, without 
over-exerting. They can stop for up to 1 min for fatigue or other symptoms.  A 
time limit of 15 minutes to perform the test has been established based on the 
following considerations. First, individuals who complete the walk in >15 minutes 
have an extremely slow pace (<0.44 m/sec), which would make their walking 
capacity of little utility in daily life. Second, selecting a higher cut-point, such as 
30 or 60 minutes makes the objective assessment impractical and does not add 
to the clinical significance of the outcome. Participants will be allowed to use a 
cane, but not a walker, to complete the 400 m walk. Procedurally, we will first 
request that participants attempt the walk without the use of a cane. Those who 
feel unsafe will be allowed to attempt the walk with their cane.  
 
2. Walking and Walking While Talking. Participants will be asked to walk across an 
electronic walk way which captures walking speed and foot placement in a quiet 
well-lit hallway wearing comfortable footwear. Start and stop points 10 meters 
apart will be marked by lines on the floor and include 3 feet from the walkway 
edge for initial acceleration and terminal deceleration. Eight  walking trials will be 
randomly conducted; 4 single task walking only trials and 4 dual-task walking 
while talking trials. For the walking while talking trials participants will be asked to 
recite alternating letters of the alphabet. The order of the initial letter will 
randomly vary between “A” and “B” to minimize practice effects and/or count 
backwards by 3’s. [64].  
 
3. Short Physical Performance Battery (SPPB). The SPPB is based on a timed 
short distance walk, repeated chair stands and a balance test (as described by 
Guralnik et al.[17]). The battery will be administered by a trained and certified 
examiner. 
 
4. Tinetti Balance Test. This test measures balance and gait while performing 
typical daily activities. The activities are graded as normal, adaptive, or abnormal 

 
 
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to determine the severity of balance impairment. 
 
5. The Activities-specific Balance Confidence (ABC) Scale- indicates self report of 
participants’ level of confidence in doing daily activity without losing their balance 
or becoming unsteady. Self-Report Function Questionnaire. We will use a 
modified version of the disability instrument that was used in LIFE-P, now called 
the Pepper Assessment Tool for Disability (PAT-D) [19].  The questionnaire, 
inquires about perceived difficulties in general activities of daily living during the 
last month. For each item, the response categories include: 1) no difficulty, 2) a 
little difficulty, 3) some difficulty, 4) a lot of difficulty, or 5) unable to do.  Answers 
are averaged across the items, in order to better assess the overall perceived 
disability burden by a person. The questionnaire consists of 5 subscales: 
mobility, transferring, upper extremity, instrumental and basic ADLs. In addition 
to being a valid measure, the disability questionnaire has been shown to be 
responsive to change in previous exercise intervention studies among various 
disease populations [20].  
 
6. Weekly Fall Diary. All participants will track falls over the course of each week 
while in the intervention at up until the final 12 week follow-up. In addition to the 
fall date and time, events surrounding the fall will be described. 
 
7. Purdue Peg Board Task: The Purdue Pegboard measures unimanual motor 
dexterity. The test consists of two parts: 1) placing pins in a column of holes and 
2) an assembly task using three components (pin, washer, collar). The 
participant is asked to place as many items as possible in 30 or 60 seconds, 
respectively.  
 
8. Nine Hole Peg Board Task: A standard dexterity assessment, this task ask 
participants to place and remove pegs on a nine-hole pegboard as quickly as 
possible. 
 
9. Pinch and Grip Strength: FDI and hand strength will be assessed using standard 
dynamometer (JAMAR) squeeze tests. 
 
10. Coin rotation task: Another dexterity assessment, this task asks participants to 
rotate a coin (U.S. nickel) as quickly as possible for 20 rotations. 
 
11. Halstead finger tapping: The Halstead finger tapping test is a standard test for 
testing psychomotor speed.  The participant is asked to press a lever attached to 
a counter as many times as possible in 10 second trials. 
 
12. Target force matching: The target force matching task is similar to 
the anisometric FDI muscle training used in the behavioral intervention. A 
computer presents a target force marker and the participant’s task is to match the 
cued lift load target and hold for a set period of time. EMG is of the FDI taken 
during this assessment. 

 
 
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13. Motor tracking: The motor tracking task is a computer based presentation of a 
stimulus (vertical bar) moving laterally. The participant is instructed to track the 
movement of the stimulus using a computer cursor controlled by a touchpad 
input device.  
 
14. Sleep Profiler: These monitors will provide pre and post-intervention objective 
data on sleep quality, patterns, and continuity that will supplement the Pittsburg 
Sleep Quality Index, Epworth Sleepiness Scale. They are non-invasive wearable 
recorders with 3 EEG electrodes housed with a headband placed just below the 
hairline that provide study-validated information including total sleep time, REM 
sleep, sleep efficiency, snoring intensity and frequency, and arousal. Participants 
will be provided a brief orientation and instruction on how to properly wear the 
device. The device requires minimum setup, and the wearable headband is 
similar to a headband that might be worn at the gym. It is battery powered, with 
up to 16 hours of recording between charges, and data is stored and easily 
downloaded via USB from the device.  
 
 
Additional Measures of Physical Function for Aim 3.  
To confirm the cardiovascular effect of the aerobic training participants will also perform 
a sub-maximal exercise test on a cycle ergometer before and after the intervention. This 
test called the VO2 sub-maximal fitness assessment will be supervised by the Principal 
Investigator, Dr. Joe Nocera in the Movement Studies Laboratory of the Rehabilitation 
Research & Development Center in the Atlanta VA. During this test we will measure 
ventilation and oxygen and carbon dioxide concentration of the inhaled and exhaled air. 
We will adhere to the YMCA sub-maximal test protocol. This sub-maximal test will be 
used to estimate the participant’s maximal oxygen uptake (VO2max) prior to, after and 
12 weeks following the interventions. VO2max is the most appropriate test as it 
accounts for initial fitness level of the participant. This test uses and “extrapolation” 
method in which heart rate workload values are obtained at 2-4 points and extrapolated 
to predict workload at the estimated maximum heart rate (MHR) (e.g. 220-age). VO2max 
is then calculated from the predicted maximum workload.  Participants will be asked to 
ride a stationary bicycle for 4 three-minute stages (Table 3). The first stage will be a 
warm-up at 50 revolutions per minute (RPM) at a power level of 25 watts. During all 
testing stages, heart rate will be continuously monitored and will not exceed 85% of 
age-predicted maximum heart rate.  For the analysis, average heart rate during the final 
30 seconds of the 2nd and 3rd minutes will be plotted against workload. Three minute 
trial workloads, shown in Table 4 below will be chosen based on the participants’ heart 
rate at the end of the warm-up period. The fourth 3-minute stage will be a cool down 
period added to the end of the test. Participants will be allowed to stop the test at 
anytime if they feel faint, dizzy, short of breath, or for any other reason. Heart rate will 
be monitored using the Polar Tracker heart rate monitor. This will also be used to 
monitor heart rate during the exercise sessions. 
 
 
Table 3. YMCA Sub-maximal Cycling Protocol 

 
 
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18 
 
< 80 bpm* 
80-90 bpm* 
90-100 bpm* 
> 100 bpm* 
Stage 1 
125 watts 
100 watts 
75 watts 
50 watts 
Stage 2 
150 watts 
125 watts 
100 watts 
75 watts 
* beats per minute 
 
 
 
 
Participants will not undergo exercise stress testing. This decision may be 
perceived as a potential weakness of the proposed study. We considered adding an 
exercise stress test prior to randomization. An advantage of this would be that it would 
provide an additional opportunity to detect severe cardiac disease that might increase 
the risk of an acute event during our aerobic exercise intervention. After extensive 
deliberations, our research team decided with unanimous vote that including an 
exercise stress was not necessary and would not add additional information for the 
study or protection to the human subjects. This decision was based on the following 
considerations:  
 
• The recommendations published in JAMA by Gill et al. [21] advised that a screening 
protocol based on a simple cardiovascular reserve test, similar to the one described 
above is more suitable for screening older adults than a protocol based on stress 
exercise testing. 
• The American Heart Association (AHA) and the American College Sports Medicine 
(ACSM) joint position statement advised that “apparently healthy persons of all ages 
and asymptomatic persons at increased risk may participate in moderate-intensity 
exercise without first undergoing a medical examination or a medically supervised, 
symptom-limited exercise test” [22].  
• The majority of older persons (>75%) are unable to satisfactorily complete a 
treadmill exercise test, [23] which makes its utility as a screening tool in the elderly 
population questionable. 
• Older persons have a high prevalence of ECG abnormalities, which diminish the 
diagnostic accuracy of treadmill exercise testing [24].  
• Participants with potential cardiac contraindications to the proposed exercise 
program will be identified and excluded by means of the screening process. 
• Exercise of will be conducted in a supervised environment as described below in 
interventions section.  
• We have found that a maximal or near maximal exercise test on a treadmill is an 
unpleasant, if not frightening experience, for sedentary and unfit adults. Requiring an 
exercise stress test may deter older persons from participating in the trial as 
assessed in the LIFE-P ancillary study on maximal exercise testing conducted at the 
Cooper Field Center.  
• Regular exercise and physical activity may actually reduce the overall risk of 
myocardial infarction and death among older persons, possibly through 
improvements in cardiac risk factors and overall fitness; ACSM joint position 
statement advised [22].  
 
 
In summary, we concluded that exercise stress testing would provide little additional 
information, was not necessary to protect the safety of participants, and that it is disliked 

 
 
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by sedentary and unfit participants. Our protocol for the aerobic exercise intervention 
also requires that the sessions carefully monitored for cardiac and other signs and 
symptoms by trained staff. 
 
Interventions.  
 
Aerobic Exercise + Cognitive Training Group. For this arm of intervention, 
randomized participants will attend both exercise training sessions and cognitive 
training sessions demonstrated to facilitate physiological changes. For the aerobic 
exercise component of this group, participants will follow the guidelines provided by 
the American College of Sports Medicine for optimizing cardiovascular fitness. Thus, 
participants will exercise 3 times a week on a stationary ergometer. Exercise intensity 
will begin at low levels (50% of maximal heart rate reserve) calculated utilizing the 
Karvonen method. Briefly, target exercise HR is calculated by subtracting the persons 
age from 220.  Resting heart rate is then subtracted from this number. The answer is 
then multiplied by the target percent (50% for example) and the product is added back 
to resting heart rate to provide the target exercise session heart rate. Intensity will be 
increased by 5% every week (as tolerated by the participant) to a maximum of 90% of 
maximal heart rate. Exercise time will progress from an initial 20 minutes per session to 
a maximum of 60 minutes by increasing 5 minutes each week. Each session will be 
monitored by a certified CPR and fitness specialist. Further, the intervention site is 
located in the Atlanta VA Health Care System and portable defibrillators are available at 
the intervention site.  
 
The cognitive training component for this group will take place immediately after the 
exercise session (15 minutes following the exercise cool down). This time frame allows 
for the cognitive training to be done within the 15-60 minute window in which the 
neurotrophic exercise mediated response is elevated. The commercially available 
Mindfit program will be utilized for the cognitive training. The Mindfit was selected based 
on its mainstream popularity and its demonstrated effectiveness and adherence (99.2%) 
in previous studies [14]. Each training session includes a mixture of 21 visual, auditory 
and cross modality tasks aimed at attention and executive functions as well as other 
cognitive processes. Each training session lasts 20 minutes and can progress on three 
levels of difficulty- easy, moderate and hard. These levels can be further adjusted 
according to the participant’s progress.  
 
Cognitive Training Only Group. For this arm of the intervention, randomized 
participants will follow the same guidelines as the cognitive component of the AE+CT 
group but will not partake in aerobic exercise. To equalize contact/monitoring of the 
groups this group will meet for the same total duration time as the AE+CT group; 
however, instead of aerobic exercise, progressive whole body stretching and toning 
exercises designed for individuals 65 and older will be done prior to their cognitive 
training. “Stretching” controls groups have been utilized in previous studies examining 
cognition and aerobic exercise and have not been shown to result in improvements in 
cognitive function [8].  
 

 
 
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Age-Related Macular Degeneration Group. Participants who are at least 70 years old 
with a diagnosis of AMD will complete 6 months of the aerobic exercise program or 6 
months of the stretching and toning exercises. These participants will complete the 
cognitive assessments described above. This group will complete the following visual 
assessments: 
 
-Contrast Sensitivity-Visual Acuity, Amsler grid:  Participants will look at an 
illuminated screen and/or chart, one eye at a time while wearing their normal 
eyeglasses/contacts.  We will test how pale of a target they can see, how small a 
target they can see, and the appearance of a grid pattern. These tests will take 
about 1 1/2 hours. 
-Low Luminance Questionnaire: Participants will be asked to complete a Low 
Luminance Questionnaire that asks several questions about their ability to see in 
various lighting conditions.  
-Dark Adaptometry: Dark adaptation or night vision is known to be affected with 
increasing stages of age-related macular degeneration (AMD). This test will probe 
the ability of the eye to dark adapt, and it will require for the pupils to be dilated. 
They will be asked to place their head in a chin rest in front of the machine. Each 
eye will be tested individually, and the opposing eye will be covered with an eye 
patch. After dilation, while fixating on a light at the back of the machine, a bright 
flash will be presented to bleach the photoreceptors in the eye and then you will be 
presented a series of dimmer circular spots that you will be asked to identify 
whether you saw or not by pushing a response button. The duration of the test is 
about 5 minutes per eye. Corrective lenses may be put in the machine in front of 
the eye to correct for blur if necessary. 
-Eye Photography:  A series of photographs will be taken of the eyes. For this test, 
the pupils will be already dilated from the previous exam. They will be asked to 
place their head in a chin rest in front of a special camera called a scanning laser 
ophthalmoscope/optical coherence tomography machine (SLO/OCT). They will look 
at a point of light and the back of their eye will be imaged.  The SLO/OCT is used 
routinely in eye doctor’s offices and vision clinics.  It is safe and requires no contact 
with the eye. The imaging will take no longer than 30 minutes.   
The AMD group will also complete the Physical Function Assessments. Those who are 
able will complete a Maximal Treadmill Exercise Test to determine peak oxygen uptake 
(VO2 max). They will wear a breathing apparatus to measure their oxygen, carbon 
dioxide, and ventilation. A registered nurse will be present for the entire test and 
manually monitor blood pressure at baseline and during each stage of exercise, as well 
as monitor continuous EKG recordings. Those who are unable to complete the maximal 
treadmill test will complete the submaximal test described above. 
 

 
 
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21 
This group will complete blood draws at three time points: at the start of the exercise 
intervention, at 3 months, and 6 months.  
 
 
 
Exercise Lab Space: The exercise classes and cognitive training will be held in the 
Movement Studies Laboratory in the Atlanta VA Rehab R&D Center. The Movement 
Studies Laboratory is a 41 X 34 ft work out area that will serve as the venue for the 
group exercise. The cognitive training arm of the study, which must be done within 15 
minutes of completion of the aerobic exercise in the AE+CT group, will take place in a 
nearby lab space. Interventionists will have offices located on site with access to 
computers and phones for monitoring adherence of participants. Because the lab space 
is housed in the Atlanta VAMC, emergency procedures are done in accordance with 
emergency preparedness plans. A phone is located in the facility which can be used to 
contact emergency services (911) in the event of a medical emergency. CPR and the 
AED will be utilized if needed until Emergency Services assumes responsibility. All staff 
are certified in basic life support and first aid and the facility houses AED devices.   
 
Risks/Discomforts 
 
Cognitive Testing. Patients may experience some frustration if they have trouble with 
cognitive testing.  Researchers will be trained on how to handle frustration by taking 
breaks, allowing patients to express frustration, and offering encouragement.  As noted 
above, we will also include items that the participants can answer correctly to minimize 
frustration.  In the vast majority of patients, these techniques are adequate to deal with 
frustrations.   
 
Magnetic Resonance Imaging (MRI). More than 150 million diagnostic magnetic 
resonance studies have been performed worldwide.  The vast majority of these 
procedures were completed with no sign of patient injury [25].  There is a high degree of 
patient safety with an fMRI because of the miniscule value of magnetic susceptibility 
and lack of ferromagnetic components of human tissue.  Studies have ranged in 
magnetic field intensities from 1.5 to 8T.  No negative cardiac, physiological, or 
cognitive effects were noted [26].  Therefore, long-term effects on human health from 
magnetic resonance imaging are unlikely.  Those at risk for injury include those with 
indwelling ferromagnetic material (e.g. foreign object in eye, surgical implant) or an 
implanted bioengineering device (e.g. pacemaker, infusion pump), due to the possible 
interaction with a magnetic field.  Subjects identified as at risk from the screening 
checklist will be excluded from the study. 
 
Another potential hazardous effect is related to the high level of noise produced by the 
machinery during imaging.  Unprotected, patients can experience hearing loss.  For this 
reason, individuals will be given foam earplugs to wear to minimize this risk.   
 
Additionally, some individuals are perceptible to experiencing distress during the fMRI 
process.  The small, closed-in space may trigger anxiety.  Participants will be screened 

 
 
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22 
for claustrophobia, generalized anxiety disorder, post-traumatic stress disorder, or 
obsessive-compulsive disorder.   
 
Further, persons who are pregnant (or could be pregnant) or those with a seizure 
disorder should not undergo magnetic resonance imaging, and will be excluded.   
 
Subjects may have early stages of disease, not previously diagnosed, detected through 
the use of MRI. A trained neuroradiologist is available to the investigators to evaluate 
the findings and determine if there is pathology present or a normal variant should the 
investigators suspect that the imaging shows abnormalities.  If pathology is present or 
suspected, subjects will be counseled about what the findings are and what should be 
the next steps for clarification of ambiguous findings or seeking help with pathological 
findings.  This is not a risk in the conventional sense of physical harm or disease, but 
does pose a potential psychological risk to the patient. 
 
Participants ages 70 years and older with Age-Related Macular Degeneration will not 
complete the fMRI. 
 
Blood Draw. The risks of drawing blood from a vein include discomfort at the site of 
injection; possible bruising and swelling around the injection site; rarely an infection; 
and, uncommonly fainting from the procedure.  A trained phlebotomist will collect all 
blood samples following standard protocol. 
 
Visual Assessments.   
 
Physical function and Exercise Intervention. While the risk of a cardiac emergency is 
increased when a person is exercising, these events are rare and usually occur during 
high-intensity activities. The cardiovascular benefits of exercise have been consistently 
shown to outweigh the acute cardiovascular risk during the act of exercising. Moreover, 
a person beginning a moderately intense exercise program is actually at a lower overall 
risk of sudden death than their sedentary peer.  Neither an ECG nor a stress 
electrocardiogram will be included in the screening process due to the lack of evidence 
to support their usage in detecting those who will have an adverse exercise outcome. 
 
Some participants will experience exercise-related injuries and possibly muscle 
soreness and fatigue as a result of the testing and the intervention. There is a small risk 
for loss of balance and injury from a fall while walking and during balance 
measurements.  However, walking and balance measurements will only be a few 
minutes at a time and research personnel will be with the participant at all times. Most 
injuries will be self-limited, though it is possible for permanent injuries to occur, including 
broken bones or joint problems. There are minor risks of musculoskeletal problems 
associated with the performance evaluation measures of the study. The potential risks 
of loss of confidentiality will be minimized through assigning all data collection 
instruments a unique code without individual identifying information. All HIPAA 
regulations pertaining to protection of participants and eliminating identification will be 
followed.  
 

 
 
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23 
 
 
 
Potential Benefits 
 
There are substantial potential benefits of participation in this study.  All participants 
may benefit from the pre intervention evaluation, which may detect unknown or 
inadequately treated medical problems. Potential benefits for adults who exercise 
include: 
 
• improvement of physiologic indicators of health (e.g., balance, blood pressure); 
• full or partial elimination of impairments in ability to do daily activities; 
• improvement in mental and/or social health status; 
• reduction of risk of falls and fall-related injuries; 
• reduction in risk of mortality; and 
• reduction in medical care costs. 
 
Potential benefits for adults who participate in the exercise testing include: 
 
• improved awareness of their cardiovascular fitness level; 
• greater confidence in the knowledge of their cardiovascular fitness level; 
• greater knowledge of their fitness changes and the relationship between those 
measures and their ADLs. 
• improvement in mental and/or social health status; 
• reduction of risk of falls and fall-related injuries; 
• reduction in risk of mortality; and 
• reduction in medical care costs 
 
Participants may be compensated ($200) for their participation in the study. The AMD 
group may be compensated up to $150 for their participation in the study. 
 
 
 
6. Participant selection: 
 
The study will enroll between 60 and 80 older, sedentary adults. Participants will be 
randomly assigned to one of two 12-week interventions conditions: AE+CT or CT alone. 
The pre and post evaluations will be conducted over 3 days during a 1-week period. For 
example, Monday-Cognitive Evaluation, Wednesday-fMRI, Friday-Physical Evaluation.  
Each day will last no more than 2 hours.  The investigators expect a dropout rate of 
anywhere from 10-15% of participants.  To ensure completion of study by 60 
participants, as many as 80 subjects may be enrolled. Importantly, all participants will 
be evaluated on  
 
Inclusion/Exclusion Criteria. We will complete a Health Screening for Exercise with all 
potential participants. If the participant answers no to all the screening questions, study 

 
 
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24 
staff will proceed with scheduling the participant for enrollment. If a participant answers 
yes to any question, the study staff must receive a physician’s written medical approval 
for participation in the fitness assessment and/or exercise intervention.  We will provide 
the physician a letter to sign if the participant is cleared explaining the study protocol. 
The key inclusion criteria and final participant pool will consist of right handed English 
speaking individuals aged 18 to 89. Participants will be sedentary as defined by < 120 
min/week of aerobic exercise over prior 3 months and a summary score on the SPPB 
between 7 – 10 [17]. Additionally, participants will be non-demented (MMSE ≥ 24) and 
will have no cognitive-executive function deficit (MoCA ≥  26). Further, those with 
severe diabetes requiring insulin will also be excluded. However, those with less severe, 
controlled diabetes that meet our physical and cognitive function inclusion criteria will be 
allowed to participant. Additionally, those with early staged Parkinson’s disease (H&Y 1-
3) will be allowed to participate.   
 
Recruitment. Individuals will be recruited from the Atlanta VA Rehab R&D Subject 
Registry (IRB00000159) based on the inclusion and exclusion criteria. The Subject 
Registry study staff will query the data base of all patients meeting the inclusion and 
exclusion criteria who have consented to be contacted for research purposes and will 
print out their contact information. The Principal Investigator, or his research colleagues, 
will contact these individuals and will summarize the study procedures. If the potential 
participant is interested we will mail them a copy of the informed consent and will 
schedule an orientation session that describes the study goals and provides an 
opportunity to go over the informed consent.  
 
Healthy subjects will also be recruited via the Emory University Alzheimer Disease 
Research Center (ADRC) Registry.  Written permission from all patients is recorded on 
a signed informed consent form before inclusion in the ADRC Registry. This consent 
requires that the patients be willing to complete detailed histories, undergo 
comprehensive neurological and neuropsychological evaluations on an annual basis; 
submit blood for ascertainment of genetic information and establishment of 
lymphoblastoid cell lines; and agree to be contacted regarding participation in research 
projects of Emory investigators.   
 
The PI and the Research Coordinator(s) will be added to the ADRC Registry protocol 
(IRB #133-98). Following this, the ADRC request form will be filled out in order to 
identify an appropriate list of potential participants.   
 
The VA Data Manager will query medical records within the VISN 7 Corporate Data 
Warehouse to identify potentially eligible patients with upcoming appointments at the VA 
Medical Center. Once patients are identified, the Research Coordinator will discuss the 
patients and the study with the providers. Those patients determined to be appropriate 
for the study will be introduced to the study team by the provider. 
We propose to use the VA Informatics and Computing Infrastructure (VINCI) databases 
to identify patients at the Atlanta VA Medical Center who may be eligible for 
participation in the research study.  We will ask the VINCI data managers to pull 

 
 
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25 
requested data from the Corporate Data Warehouse (CDW).  The data requested 
includes patient names, dates of birth, phone numbers, addresses, social security 
numbers, visit and hospital information, laboratory tests, medication use, eye exams, 
and smoking history. 
This identified data will be directly transferred electronically from the VINCI environment 
to the secured research server VHAATGFPC10 located in the OIT server room at the 
facility.  This will be done by Christine Jasien, Atlanta VAMC data manager.  The 
servers are managed by the Atlanta and Region 3 OIT offices and security is managed 
by the Information Security Officers at that facility.  The server room has appropriate 
security controls in place (including a locked room, password protection, and 
encryption), and the drive that the data will reside at will be controlled so that only the 
research team has access to the data.  Once the data has been transferred to the 
secured research server Antonio Laracuente, Director, Atlanta VAMC Research 
Operations will create a folder specific to the study under said secure drive. Only 
approved individuals listed on eIRB for the study will be granted permission and access 
to this folder. 
 Medical records housed in VINCI will be used to ensure that patients who are not 
eligible for participation are not approached.  Patients approved for contact will be sent 
an IRB approved letter with a brief summary of the research and study contact 
information.  The study team will discuss the study with interested patients by 
telephone, providing further information about the study. 
Additionally, participants may be recruited from word of mouth.  
 
Individuals will be provided a copy of the informed consent and will be scheduled for an 
orientation session that describes the study goals and provides an opportunity to go 
over the informed consent. The PI/Co-PI or their trained and qualified colleagues will go 
over and describe the consent in a private office of the PI/Co-PI.  
 
 
 
 
7.  Statistical Analysis: 
 
Statistical Analysis for Specific Aim 1. We will model each of the outcome measures 
in Aim 1 (verbal fluency, non-verbal executive function and crystallized word knowledge, 
as well as the MindFit cognitive evaluation) jointly using a mixed linear model to 
determine whether the mean responses of the groups are significantly different across 
the time points. We expect that modeling the outcomes jointly, using subject as a 
random factor, will allow for some gains in power. Our fixed factors will be time, 
treatment group and their interaction. This model will enable us to estimate the overall 

 
 
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effects of time and treatment, and most importantly, how the effects of treatment differ 
with time.  
 
Statistical Analysis for Specific Aim 2. For each of the outcome measures in Aim 2 
(changes in fMRI activity during verbal fluency and verbal working memory as well as 
changes in BDNF) we will use a mixed linear model to determine whether the mean 
responses of the groups are significantly different across the time points. Our fixed 
factors will be time, treatment group and their interaction. This model will enable us to 
estimate the overall effects of time and treatment, and most importantly, how the effects 
of treatment differ with time.  
 
Statistical Analysis for Specific Aim 3. For each of the outcome measures in Aim 3 
we will use a mixed linear model to determine whether the mean responses of the 
groups are significantly different across the time points. Our fixed factors will be time, 
treatment group and their interaction. This model will enable us to estimate the overall 
effects of time and treatment, and most importantly, how the effects of treatment differ 
with time.  
 
Power Analysis and Sample Size. We powered this study on the executive function 
task of verbal fluency because of the high importance of word retrieval for everyday 
function and quality of life. For example, people over the age of 65 frequently have 
difficulty recalling words they wish to use to describe objects, actions, and concepts 
thus rendering them unable to effectively communicate. In aging, difficulties with fluency 
may result from a deterioration of frontal substrates that underlie the ability to access 
and/or retrieve word forms. Importantly, the cortical areas required for fluency are 
precisely those affected by aerobic exercise. While there currently is little understanding 
of the effects of exercise plus cognitive training on verbal fluency in older adults, data 
from our ongoing CDA-1 pilot study has shown an average improvement pre to post in 
an exercise-alone group (n=10) of 7 words.  In our non-exercise control group (n=2), the 
average improvement was 1 word. While this data does not provide enough information 
to enable us to estimate a required sample size under the mixed model that will be used 
in the final analysis, we can conservatively estimate the sample size assuming a two-
sample t-test would be performed on the post-pre differences for each group.  Under 
this simpler model, a sample size of 30 per group will give us approximately 80% power 
to detect a true difference between groups of 4.5 words, and 90% power to detect a 
difference of 5.2 words. While these effect sizes are relatively large (0.75 and 0.87, 
respectively), we will have more power under the mixed model that we actually will use 
to analyze the data. Importantly, we feel these improvements are clinically relevant as 
longitudinal research from a sample of cognitively normal adults (n=96; avg. age 75) 
followed for 2.3 to 5.9 years demonstrated an average rate of change -0.4 ± 1.6 
annually. 
 
The research staff will use REDCap issued through the Atlanta Veterans Health Care 
System. Only deidentified data will be entered into REDCap by VA credentialed 
research personnel to run data analysis. 
 

 
 
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8. Adverse event reporting: 
 
In the case of a reportable event, the Principal Investigator will complete the form 
“Reportable Protocol Event Form for VA sites,” attach supporting documentation, and 
provide it to the VA Science Information Office.  The SIO will then route the report to the 
Emory IRB.  The Emory IRB will be notified within five days of any adverse event 
occurring. 
 
9. Data and safety monitoring plan (DSMP) 
 
This is a minimal risk protocol and therefore data will not be reviewed by a Data Safety 
Monitoring Board (DSMB) or Data Monitoring Committee (DMC).  
 
This study will only recruit healthy older adults. Prior to beginning any portion of this 
study we must receive a physician’s written medical approval for participation in 
physical activity. We will contact the physician and inform him/her of their patient’s 
interest in participating in this study and explain the study criteria for participation 
detailing the intervention and testing procedures. Additionally, the pre/post testing 
carries minimal risks due to the sub-maximal nature of the fitness testing.  As per the 
YMCA protocol, “physician supervision is not necessary with sub-maximal testing in low 
to moderate risk adults.” (ACSM’s Health Related Physical Assessment Manual, 2007). 
Although any exercise program carries with some possibility of exercise-induced 
cardiovascular events, we will minimize this by including those who have been cleared 
by a health care professional. While the risk of a cardiac emergency is increased when 
a person is exercising, these events are rare and usually occur during high-intensity 
activities. This study will utilize a moderately intense exercise regiment for all 
participants. The cardiovascular benefits of exercise have been consistently shown to 
outweigh the acute cardiovascular risk during the act of exercising. Moreover, a person 
beginning a moderately intense exercise program is actually at a lower overall risk of 
sudden death than their sedentary peer. 
 
Protection Against Risk 
 
Several precautions will be made to reduce the risk of exercise-related injuries: 
 
• The exercises are carefully designed with warm-up, stretching and cooling down 
components to minimize injuries; 
• Written instructions highlighting some fundamental guidelines all study 
participants should do to ensure that they are exercising safely will be provided to 
all study participants; 
• For those individuals who are extremely de-conditioned, frequent rest periods 
and exercise from a sitting position will be offered at the beginning of the training 
period; 
• At each exercise session, participants will be questioned about the presence of 
musculoskeletal symptoms; 

 
 
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• If a participant experiences a significant illness requiring mobility restriction, 
surgery or hospitalization, the project coordinator will contact the participant’s 
primary physician for clearance to return to the intervention classes.  
• If adverse symptoms develop a 1-week hiatus from the exercise session will be 
enforced, and during this time the participant will perform static stretching 
exercises.  A slow reintroduction of the exercise program will follow all hiatuses; 
• The instructors/evaluators will be instructed to be alert for the emergence of 
symptoms of angina and shortness of breath. Participants will be instructed to 
discontinue exercise if there is significant pain, weakness, or joint swelling after 
exercise.  
• We will ensure that that the site has immediate access to a phone and that 
provision of interventions and evaluations are undertaken in the immediate 
vicinity of a phone. All trainers and evaluators will also be encouraged to carry 
cell phones; 
• All activities will occur inside an air-conditioned facility because environmental 
extremes are poorly tolerated; 
• Every precaution will be taken to provide fluids, rest and other measures to 
insure each participant is comfortable, safe and secure in the testing 
environment. 
 
Confidentiality of data is maintained by using research identification numbers that 
uniquely identify each individual. Safeguards are established to ensure the security and 
privacy of participants’ study records. The information collected from participants in this 
study has a low potential for abuse, since the data do not address sensitive issues. 
Nevertheless, appropriate measures are taken to prevent unauthorized use of study 
information. The research ID number is used. The research records are kept in a locked 
cabinet in the locked office of the PI. The files matching participants' names and 
demographic information with research ID numbers are kept in a separate locked room 
and are stored in a locked file that uses a different key from that of all other files. Only 
study personnel have access to these files. Electronic data will be stored in a password-
protected file on a secure network. After the study is completed, procedures for long-
term storage of VA data will be followed.  
 
FMRI data will be stored in a secure electronic environment in a locked office (6205 
A&B) at the Woodruff Memorial Research Building, 1639 Pierce Dr. Atlanta, GA 30322, 
without identifiers.   
 
10. Pharmaceutical, biologic, and device information: 
 
N/A 
 
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