Effects of Exercise and Cognitive Training on Executive Function in Parkinson's Disease
Phase: NA
Conditions: Parkinson's Disease
Sponsor: VA Office of Research and Development

Study Protocol and Statistical Analysis Plan 
Official Title:  Effects of Exercise and Cognitive Training on Executive Function in 
Parkinson's Disease (NCT 01156714) 
Document Date: 9/28/18 (date when document was most recently updated) 

Study Protocol: 
Screening Methods: 
Screening for participation in the study will be held in 1) Baltimore VAMC, and 2) UMPDC. 
Patients will go through initial evaluation (history, medical & neurological exams), mental exam, 
visual acuity exam, exercise fitness test and daily living questionnaire. Assessment will be done 
during the “ON period”, when antiparkinsonian medications are working optimally. Below is a 
description of each assessment tool: 
Informed Consent: Written consent for participation will be obtained from each participant at 
their first evaluation by trained study staff. Participants will undergo an Evaluation to Sign 
Consent. An assessment of patient understanding of the protocol is also required prior to study 
entry. 
Hoehn & Yahr: The Hoehn & Yahr scale (57) will be used to assess general staging of PD. 
Classification ranges from 1 to 5, with higher scores indicating greater disability. The cut-point 
in the present study is stages 1- 3 (1 = Unilateral involvement only, usually with minimal or no 
functional impairment, 2 = Bilateral or midline involvement, without impairment of balance, 3= 
First sign of impaired righting reflexes; patients are physically capable of leading independent 
lives, and their disability is mild to moderate). This assessment will be performed by a 
movement disorders specialist.  
UPDRS: The Motor subscale of the UPDRS (58) will be used to assess disease severity, with 
particular attention to items #28 (gait) and #30 (postural instability). To be included in this study, 
a subject must score between 1 and 3 on item #28, and 1 and 2 on item #30, indicating the some 
impairment of gait or balance but preserved ability to walk independently. On the motor UPDRS, 
scores each item ranges from 0-4 with a maximum of 108. Higher scores indicate greater disease 
severity. The motor UPDRS will be assessed by neurologists who specialize in movement 
disorders. 
OARS: The OARS (55) is comprised of 14 questions including 7 ADLs and 7 IADLs. ADLs are 
self-care activities (walking, eating bathing, dressing, grooming, transferring in/out of bed and 
using the toilet), IADLs are activities necessary to function independently in the environment 
(housework, shopping, travelling, preparing meals, using the telephone, managing medication 
and handling money). For each ADL and IADL, the patient is asked if they are able to perform 
the task independently. In the original version of the OARS each activity is scored with a 3-point 
scale (1=no difficulty, 2=needs some help, 3=unable to perform). We will use a modified version 
of the OARS previously reported by our research group for patients with PD (63). The modified 
version adds two intermediate responses: slower/with greater difficulty and needs moderate help. 
To be included in the proposed study, a subject must score between 1 and 3 in the gait section of 
the OARS. The total maximum score is 70 indicating the highest level of disability.  
Folstein Mini-Mental State: The Folstein Mini-Mental State (59) examination will be used to 
assess gross cognitive function and rule out dementia. The test will be administered by a trained 
research assistant.  

Montreal Cognitive Assessment: The Montreal Cognitive Assessment will be used to assess mild 
cognitive impairment.  
 
Corrected Visual Acuity: A corrected near visual acuity of  > 20/70 will be required to ensure 
subjects can participate in computer-based cognitive training protocols and neuropsychological 
testing. Visual acuity will be measured with a vision chart developed by Ferris et al… This chart 
conforms to the standards of acuity testing proposed by the National Academy of Science-
National Research Center Committee on Vision (NAS-NRC 1980). A force-testing procedure 
will be adopted, where the participant is required to guess even if the letters appear illegible until 
at least 4 of 5 letters on a row are named incorrectly. This test will be administered by a trained 
research assistant.  
 
Entry TM Exercise Test: determines cardiopulmonary safety and neuromotor capacity to 
participate. To acclimate to the TM, subjects start at zero incline and 0.1 mph, increasing by 0.1 
mph increments to a self-selected pace (with physician rating of gait stability).(1) Following a 
15-minute rest, subjects perform a peak effort TM exercise test. The incline is gradually 
increased at the pre-selected constant velocity to assess cardiopulmonary response and safety of 
more strenuous exercise.(2) Patients minimize handrail support, gait safety belt is worn at all 
times, and tests are physician-supervised with continuous vital signs and ECG monitoring.  
 
Cardiovascular Fitness Test: is conducted with open circuit spirometry, using the subject's pre-
selected velocity at progressive inclines.(1-2) Since reliability of fitness testing is not established 
in PD, each subject performs 2 exercise tests, 1-2 weeks apart, to avoid confounding effects of 
fatigue. Highest of 2 values is accepted as V02 max or peak, if true max is not achieved. (3) Data 
are expressed as V02 ml/kg/min to account for any change in weight that may occur. Intra-class 
correlation coefficients will analyze reliability of repeated baseline tests. Peak ambulatory work 
load capacity (Mets) is estimated from exercise tests, as previously reported.(4) All tests are 
conducted in the VA Exercise & Robotics Center using velocity-calibrated TM's and 
Sensormedics Metabolic Systems.(2,5) 
 
Interventions: 
 
The intervention protocols will be implemented at VAMHCS sites. All 3 study interventions will 
be conducted by study personnel with the same training will continue for 3 months. When the 
intervention is completed, patients will receive two post-assessments within a week of the final 
training session.  
 
TAEX Protocol: The exercise protocol of the TAEX group has been successfully implemented in 
patients with PD. Subjects will exercise 3 times per week for 3 months. Treadmill walking will 
start conservatively at 15 minutes with target heart rate 40–50% of maximal heart rate reserve 
(HRR), by the formula of Karvonen (64). Subjects incapable of continuous treadmill walking 
will perform intermittent exercise until 20 minutes is achieved. Exercise intensity and duration 
will be increased by 5 minutes every two weeks, and 0.1 MPH increments as tolerated until 
reaching a target of 30 minutes at 70-80% HRR. Speed and/or hill will be increased as tolerated 
every week to maintain the 70-80% HRR. Vital signs will be taken prior, during and after 
exercise. Heart rate monitoring (Polar) will be used to monitor exercise intensity. Training will 

be discontinued for blood pressure drop > 20 mm Hg for medical evaluation. Logbooks will be 
used to document daily training parameters, complaints or concerns. All participants will be 
supported in a non-weight bearing fashion in a Biodex™ harness (Biodex Medical Systems, Inc 
Shirley, NY) to eliminate risk of falls. Health professionals credentialed in exercise training and 
cardiopulmonary resuscitation will monitor all training sessions at each intervention site 
(Baltimore VAMC and Parkinson & Movement Disorder Center). 
 
TCOG Protocol: Subjects in the TCOG group will perform cognitive training 3 times per week 
for 3 months. A commercially available computer-based program will be used (Insight Program 
by Posit Science, San Francisco, CA). This program was chosen for our study because it has 
been validated in studies of older adults (14, 15) and is readily available for use. Training will 
consist of five visual-based exercises designed to improve divided attention, working memory, 
visual information processing speed, and useful field of view. The program is set up so that the 
level of difficulty is continuously adjusted to user performance, to maintain a correct rate of 
about 85%. The program uses a Bayesian algorithm to estimate and then adjust to the 
individual’s performance on a trial-by-trial basis (66). Correct trials are rewarded with points and 
animations.  
 
Each training session will last 40 minutes, and subjects will be monitored to spend 10 minutes on 
each of the 4 exercises per session. Training will be performed in a quiet room with monitoring 
by a trained research assistant to assure the subject’s understanding of the tasks, the time spent 
on each exercise, and the level of motivation. Even though this could be executed by the subject 
alone, the presence of a trainer during cognitive exercises has been recommended in the 
literature (13). Adherence to the protocol will be monitored using electronic data upload to the 
Posit Science Research Database after each training session. Subject will complete cognitive 
remediation under an identification code. Data will be de-identified upon transmission. In 
addition, logbooks will be used daily to document subjects’ complaints or concerns. 
 
TAEX + TCOG Protocol: Subjects in the combined intervention (TAEX + TCOG) group will 
perform both treadmill exercise and cognitive training 3 times per week for 3 months. The order 
of exercise will be TAEX followed by TCOG. This order was chosen to take advantage of the 
immediate effects of TAEX on learning, which might augment the cognitive performance during 
TCOG training (16-18). The treadmill portion of the combined intervention will follow the same 
protocol as the TAEX group, and the cognitive portion of the combined intervention will follow 
the same protocol as the TCOG group. The overall time for the combined intervention will be 1 
hour and 30 minutes. Two health professionals credentialed in exercise training and 
cardiopulmonary resuscitation will monitor the TAEX portion of the intervention and a research 
assistant will monitor the TCOG portion of the intervention.  
 
Outcomes Testing: 
 
Pre-tests and post-tests will be conducted at the Baltimore VAMC. All measurements will be 
performed by trained professionals (exercise physiologists, neuropsychologists and research 
assistants) blinded to the subject group. Below is a description of the outcome measures 
categorized into cognitive, cardiorespiratory function, behavioral, dual task, and daily activity  
measures.  

 
Outcome Measures specific to Aim 1: Compare the efficacy of TAEX versus TCOG versus 
TAEX + TCOG to improve EF in PD. 
 
Cognitive Measures:  
 
Neuropsychological assessment will consist of both paper-and-pencil and computer-based tests 
of EF. Subtests from the ANAM test system were selected since: 1) our previous work validated 
these tests in PD (see preliminary data section a) 2) tests were required that are free of floor or 
ceiling effects, since a wide range of cognitive ability is expected in our sample, 3) tests must 
isolate the effects of the disease on cognition from the biasing effects of age-related cognitive 
decline, since older subjects with PD will participate in the study. Our selected test battery meets 
these qualifications.  Following is a description of each selected test:  
 
a. ANAM tests:  
The ANAM was developed by the Department of Defense (DoD) as a computerized performance 
battery sensitive to cognitive change (67). It is administered via computer, uses a mouse interface 
and requires approximately 30 minutes of administration time. Seven subtests shown to be 
sensitive to cognitive change in PD a) will be administered, including Simple Reaction Time, 
Two-Choice Reaction Time, Procedural Reaction Time, Delayed Matching to Sample, Sternberg 
Memory Search, Running Memory Continuous Performance and the Tower Test. The battery 
utilizes a pseudo-randomization procedure to generate stimulus items such that each test session 
(pre-test and post-test) includes a different combination of items in order to minimize practice 
effects. Ratings of speed, accuracy, and general cognitive efficiency are generated for each 
subtest. Below is a brief description of each subtest. 
 
Simple Reaction Time:  
The test consists of pressing a specified response key each time a stimulus is presented on the 
computer screen. The test provides a measure of pure reaction time as well as a means to parse 
out the effects of motor response from cognitive processing time. 
 
Two-Choice Reaction Time: 
This test measures patients’ ability to shift mental set. One of two stimuli are presented on the 
screen (e.g. + or *). Subjects press a specified response button on the keyboard corresponding to 
the presented stimulus. In order to obtain a measure of cognitive processing time, the Simple 
Reaction Time scores are subtracted from the Two-Choice Reaction Time scores.  
 
Procedural Reaction Time:  
This test measures processing speed and decision making speed. Subjects differentiate between 
two sets of characters. The test presents a stimulus on the screen (e.g. the number 2, 3, 4, or 5). 
Subjects are required to press the left mouse key if a 2 or 3 is presented, or the right mouse key if 
a 4 or 5 is presented. As for the previous test, in order to obtain a measure of cognitive 
processing time, the Simple Reaction Time scores are subtracted from the Procedural Reaction 
Time scores. 
Delayed Matching to Sample: 
This test assesses visual working memory. Subjects view a 4X4 red and white block design. 

After a delay they are shown two designs from which they must select the original design. 
 
Sternberg Memory Search: 
This test assesses working memory and sustained attention. Subjects learn a 6-letter set then 
determine if individually presented letters were part of the set. 
 
Running Memory Continuous Performance:  
This test assesses working memory and sustained attention. Subjects determine if a letter 
appearing on the screen is the same or different from the letter immediately preceding it in a 
sequence.  
 
The Tower Test: 
This test assesses planning, problem solving and adherence to rules. Subjects are presented with 
a display of blocks situated on a “tower.” Their goal is to move blocks from a random position to 
create a replica of the display tower in the fewest number of moves possible while adhering to 
stated rules. 
 
b. Paper-and-Pencil Cognitive Tests: 
 
Stroop Test:  
The Stroop Color and Word Test (68) is a measure of selective attention and cognitive flexibility 
in which the subject must inhibit a preponderant response. Subjects are asked to complete three 
parts under timed conditions: (1) reading words describing colors that are written in black-and-
white, (2) naming those colors when printed as Xs, and (3) naming the color ink when words 
describing the colors are mismatched with the colors (suppressing the verbal content). The scores 
for this test are the number of items completed correctly in 45 seconds. 
 
Delis-Kaplan EF System (D-KEFS): 
The D-KEFS sorting subtest (69) is a measure of problem-solving, concept-formation, and 
cognitive flexibility. Subjects are asked to sort six cards into two groups according to as many 
rules as possible. The outcome measure for this test is the number of correct sorts within 4 
minutes. The ability to recognize the correct sorting rules is also assessed. 
 
The North American Adult Reading Test (NAART): 
The NAART provides an estimate of intelligence by assessing the ability to read 61 non-phonetic 
words (70). 
 
Action Fluency: 
Action Fluency is a measure of executive function in which the examinee is asked to 
spontaneously produce as many action words (i.e., verbs) as possible in one minute (71). 
Previous research has found this test to be particularly sensitive to cognitive decline in patients 
with PD (72). The total score is the number of different verbs produced in one minute. 
 
 
Cardiorespiratory Function Measures:  
 

a. Cardiorespiratory fitness test: 
A cardiorespiratory fitness test with open circuit spirometry will be conducted in all study 
subjects (54, 65, 73). For detailed description see section 1.4.7. Data will be expressed as V02 in 
ml/kg/min to account for variation in body weight. Peak ambulatory work load capacity (METs) 
will also be estimated from exercise tests, as previously reported (54, 73). This test will be 
conducted in the VAMC Exercise Physiology Lab using non-rebreather masks (Hans Rudolph), 
velocity-calibrated treadmills and Sensormedics Metabolic Systems (54, 64, 73). 
 
b. Six-minute walking test: 
The six-minute walking test will be used as an additional measure of cardiopulmonary 
performance and gait performance. This test was originally developed for patients with 
pulmonary disease but has also been used in neurologic populations including stroke (74) and PD 
(75). The test consists of walking on a track for 6 minutes at a comfortable walking speed. The 
distance covered in 6 minutes is the outcome measure.  
 
c. Submaximal Effort Treadmill Economy of Gait: Economy of gait is measured using open 
circuit spirometry during two standard constant load submaximal effort treadmill walking tasks 
at pre-established gait velocities (1mph and 2mph). The mean rate of VO2 is calculated based on 
the final 2.5 minutes of both 5-minute walks under steady state oxygen consumption conditions, 
as previously described. Patients not achieving a plateau in VO2 are re-tested at a lower velocity 
on a different date to eliminate potential confounding effects of fatigue on testing. These tests 
will be performed on the same day, in order to prevent fatigue becoming an issue, between each 
5 minute test, the participant will have a 10 minute rest period. 
 
d. Over-ground Gait Economy: Over-ground gait economy will be measured using a portable 
metabolic monitoring system, K4b2 (Cosmed; Rome, Italy) during a 6 minute walk, with 
subjects walking at their comfortable self-selected walking speed while open circuit spirometry 
collects break-by-break data. The K4b2 consists of a small battery pack and portable gas 
analyzer (weighing less than 1 kg) that participants wear on their chest. Attached to the portable 
system is a flexible rubber facemask with flowmeter used for breath-by-breath analysis. The 
mean rate of VO2 will be calculated based on the final 3 minutes of a 6-minute walk under 
steady state oxygen consumption conditions. A 6 minute walk is a distance most representative 
of community-based ambulatory capacity and is a sensitive outcome measure in exercise studies 
in chronic stroke subjects. Prior to performing the 6 minute walk, subjects will undergo a period 
of acclimatization so subjects can feel comfortable wearing the rubber facemask described 
above. Following this familiarization period, subjects will be seated for a 10 minute rest period 
prior to performing the 6 minute walk. Subjects will use the same assistive device and/or 
orthoses typically used and will be instructed to cover as much distance as they can over a flat 
100-foot walking surface demarcated by traffic cones. 
 
Behavioral Measures: 
 
Psychiatric and behavioral features may interfere with cognitive performance (76, 77). We will 
control for the potential confounding effects of depression, apathy, fatigue, and self-efficacy on 
cognitive performance of our patients by assessing the following measures:  
 

a. Beck Depression Inventory: 
Depression will be assessed with the Beck Depression Inventory (BDI) (78). This measure has 
been shown to be valid for screening and diagnosis of depression in patients with PD (79).The 
BDI is a self-rating questionnaire that consists of 21 statements describing how you feel over the 
past week. The highest score on each item is 3 and for the full test (63), indicating extreme 
depression.  
 
b. Apathy Evaluation Scale: 
Apathy will be assessed with the Apathy Evaluation Scale (AES). The AES has been used to 
investigate apathy in many diseases including PD (77). The scale has 3 versions (clinician, 
informant and self-rated). We will use the self-rated version (AES-S) for this study. The scale is 
composed of 18 items, with a 4-point response format. Subjects are asked to base their answers 
on the past 4 weeks. Items are rated as follows: Not at all true=1, slightly true=2, somewhat 
true=3, Very true=4. Some items have positive and some have negative syntax. Higher scores 
reflect greater apathy.  
 
c. Fatigue Severity Scale: 
Fatigue will be assessed with the Fatigue Severity Scale (FSS). The FSS has been used to 
investigate fatigue in PD and has been shown to be independent of severity (80). The FSS is a 
self-rating questionnaire composed of 9 items. Each item is a statement on fatigue (e.g. “my 
motivation is lower when I am fatigued) and is rated from 1, “completely disagree” to 7, 
“completely agree”. Scoring is the sum of responses divided by 9, where the maximum score is 7 
indicating severe fatigue.  
 
d. Self-Efficacy Scale:  
Self-efficacy, the sense of personal competence to deal efficiently with stressful situations, will 
be assessed with the Loring Self Efficacy Scale (SES) (81). The SES is a self-rating 
questionnaire that evaluates 8 domains of self-efficacy (total of 26 items), including confidence 
in 1) obtaining medical information (1 item), 2) obtaining help (4 items), 3) communicating with 
physicians (3 items), 4) managing disease (5 items), 5) doing chores (3 items), 6) doing social 
activities (2 items), 7) managing symptoms (5 items), and 8) exercising (3 items). The original 
Loring scale has a 10 point response set, which has been found to be burdensome for PD patients 
in our clinic, so responses have been modified to a 3-point scale (ranging from 1=less confident 
to 3=very confident). The total score is a sum of the score on all items.  
 
Outcome Measures specific to Aim 2: Compare the efficacy of TAEX versus TCOG versus 
TAEX + TCOG to improve DT performance in PD. 
 
Dual Task Measures: 
Dual Tasking (DT) assessment will use a “walking while talking” paradigm. Dual tasking will be 
measured under 3 conditions: 
 
1) Single task Talking- generating words that start with the letter “s” for 60 sec while 
comfortably seated, subjects will be tape recorded during word generation to ensure that timing 
of words is captured for analysis. 
 

2) Single task gait- subjects will walk 50 feet at a comfortable speed, on the 24 foot Gaitrite mat, 
turning twice to complete 50 feet total 
 
3) Dual task- generating words that start with letter “f” while walking 50 feet on Gaitrite, 
subjects will be tape recorded during task performance so that rate of word production relative to 
walking speed can be analyzed. Start of tape recorder will be synched to start of walking.  
 
Walking spatial-temporal parameters will be measured using the Gaitrite 24 foot gait mat with 
existing hardware and software for analysis.  
 
Outcome Measures specific to Aim 3: Investigate whether improvement in DT performance 
translates into improved function in IADLs. 
 
Daily activity Measures: 
 
a. OARS: 
A detailed description of the OARS was provided in section 1.4.4. Validity and reliability for the 
OARS has been reported in the geriatric population (83). As described previously, the OARS is 
composed of ADL and IADL. Higher scores represent greater disability. For the purposes of this 
study (Aim III), we will focus our analysis on the IADL component of the scale. One limitation 
of this scale is that there may be a floor effect, due to the categorical nature of the scale (see 
preliminary data section f). This limitation is addressed by adding a second IADL measure: the 
Timed IADL test. 
 
b. Timed IADLs: 
Reliability and validity of Timed IADLs has been reported in older adults(56). We have selected 
this testing for the following reasons: 1) it generates continuous data (time in seconds), and 
therefore is free of ceiling or floor effects, and 2) it has been shown to be a sensitive measure to 
assess improvement in speed of processing following a cognitive training intervention in older 
adults84. The Timed IADL involves the timing of performance of 5 tasks that resemble everyday 
instrumental activities of daily living: 1) finding a telephone number for a given person in the 
telephone directory, 2) finding and counting out correct change from a group of coins, 3) finding 
and reading the ingredients on a food can label, 4) finding two food items in an array of food 
items on a shelf and 5) searching for and then reading the directions on a medicine container. For 
each task there is a 2 minute time limit, with the exception of the telephone number task which 
has a limit of 3 minutes. If the participant does not complete the task within the time limit, the 
task is terminated. The following error codes are assigned for each task: (1) completed without 
error and within the time limit; (2) completed with minor errors, or (3) not completed within the 
time limit or completed with major errors. For the tasks completed with minor errors, a time 
penalty is added to the completion time. This added time penalty is equal to 1 SD, based upon 
the data from the participants who completed the same item without error. The times for each of 
the tasks are transformed into Z scores which are then summed to form a composite (84). Higher 
scores mean worse performance.  
 
c. Activity Monitor:  
A microprocessor-linked step activity monitor (SAM) (Cyma Corporation; Mountlake Terrace, 

Washington) will be used to assess home ambulatory function. Previous research by our group 
has validated this device for patients with PD and has shown that step count as measured by this 
device is highly correlated with disease severity in PD (85). Subjects will wear the SAM at home 
over 48 hours while performing their usual daily routines (removing it during bathing and sleep). 
Recording will be done on the days that immediately precede or follow the on-site clinical 
testing of the other outcome measures. Placement of the SAM will be taught to the subject on 
site during their first testing session. Individual calibration will be done based on each subject’s 
height and gait (e.g. subjects will perform a 30-foot walk while an examiner records time and 
number of steps without the SAM). Two variables will be measured: mean step count per day 
and maximal number of steps per hour.  
 
Statistical Analysis Plan (SAP):  
 
The data from the study will be entered into a dataset and validated by the investigators. 
Descriptive statistics will be calculated for all variables using SAS version 9.1 (SAS institute, 
Cary, N.C.). Exploratory data analyzes will be performed to check the data for extreme values 
and to test for normality (Kolmogorov-Smirnov test). If our data is not normally distributed, we 
will try conventional normalizing and/or variance stabilizing transformations to obtain something 
close enough to a Gaussian distribution to enable the use of parametric statistics. A two-tailed 
p<0.05 will be considered indicative of a significant result. Below is a description of the 
statistical analyses to test each hypothesis of this study: 
 
Hypothesis I: The combined intervention TAEX + TCOG group will show greater improvement 
in EF than either group alone. 
EF performance will be stratified into domains and standardized as composite scores using z-
score transformation. In addition, an overall composite variable will be derived from the ANAM 
battery, representing an Index of Cognitive Efficiency (ICE). The ICE will be derived by 
weighting throughput scores from the individual ANAM tests and then combining them into a 
single score reflecting overall performance on the test battery. The weighting will be done so that 
each score contributes equally to the overall index with higher scores indicative of better test 
performance. This method has been used in previous studies to combine data in an efficient 
manner to look at cognitive performance over time (86). Our dependent variables are: 1) a total 
z-score for each EF domain and 2) the ICE.  
 
Each dependent variable will be evaluated with a parametric Mixed Models Repeated Measures 
Analysis of Variance (ANOVA), with Group as the between factor (TAEX, TCOG, 
TAEX+TCOG) and Time as the within factor (pre-test, post-test). Therefore, each intervention 
group will be compared against each other, and against the baseline phase (i.e. those undergoing 
delayed entry). We will adjust for potential confounding variables such as age, educational level, 
and behavioral variables (depression, fatigue, apathy and self-efficacy) by including these in the 
analysis as covariates. Post-hoc pair-wise comparisons will be done using Tukey’s Honestly 
Significant Difference with an alpha=0.05 as the experiment-wise error rate. An intention-to-
treat analysis paradigm will be used to account for missing data (e.g. subjects from whom we 
have obtained data at baseline, but who later drop out). The data collected from these subjects 
along with those who completed the study will be combined using multiple imputation. These 
analyses will be performed using the SAS procedures PROC MI and PROC MIANALYZE and 

will provide insight into the effectiveness of our interventions. 
 
Hypothesis II: The combined intervention TAEX + TCOG group will show greater improvement 
in DT than either group alone. 
Our dependent variables on DT performance are: 1) the number of words generated per second, 
2) spatiotemporal gait parameters including walking speed, stride length, cycle time, and 
variability of cycle time, 3) Cognitive Cost and 4) Gait Cost. Each dependent variable will be 
evaluated with a parametric Mixed Models Repeated Measures Analysis of Variance (ANOVA), 
with Group as the between factor (TAEX, TCOG, TAEX+TCOG) and Time as the within factor 
(pre-test, post-test). Therefore, each intervention group will be compared against each other, and 
against the delayed entry phase. Similar to the analysis described under Hypothesis I, we will 
adjust for potential confounding variables, run a Tukey’s Honestly Significant Difference post-
hoc test, and perform an intention-to-treat analysis for Hypothesis II. 
 
Hypothesis III: Improvement in DT performance will be associated with improvement in IADLs 
function. 
Our IADL measures are: 1) OARS IADLs, 2) Timed IADLs and 3) daily activity as measured by 
the SAM. To test Hypothesis III, these measures will be converted into change scores. Therefore 
our dependent measures are: 1) OARS change scores (post-test – pretest), 2) Timed IADLs 
(post-test – pretest), 3) SAM change scores (post-test – pretest). These measures will be 
correlated with DT performance measures, also represented as change scores. 
Correlations between OARS IADLs change scores and DT change scores will be calculated 
using non-parametric statistics, Spearman Correlation Analysis, because OARS produces rank-
ordered data. Correlations between Timed IADLs change and DT change, as well as correlations 
between SAM change and DT change will be calculated using parametric statistics: Pearson 
Product Moment Correlation Analysis.  
 
Secondary analyses: 
In order to investigate whether EF improvements are associated with cardiopulmonary fitness 
improvements, we will run Pearson Product Moment Correlations. Correlated variables will be: 
1) change in EF performance (z-scores and ICE) where change is calculated as pre-test – post-
test, and 2) change in cardiopulmonary fitness measures (Peak VO2 max, METs, 6 min walk test 
time) where change is calculated as pre-test – post-test.