Efficacy of Adapted Tai Ji Quan to Slow Cognitive Decline in Older Adults
Phase: NA
Conditions: Mild Cognitive Impairment
Sponsor: Oregon Research Institute

1 
 
Trial Protocol* 
 
 
Last updated: September 12, 2024 
 
Note: the research protocol was approved by the IRB at the Oregon Research Institute, dated 9/12/2024 
 
Identifiers: NCT04070703 
Unique Protocol ID: AG059546 
 
Published in: Li F, Harmer P, Eckstrom E, Fitzgerald K, Winters-Stone K. Clinical effectiveness of 
cognitively enhanced tai ji quan training on global cognition and dual-task performance during walking in 
older adults with mild cognitive impairment or self-reported memory concerns: A randomized controlled 
trial. Ann Intern Med. 31 October 2023. [Epub ahead of print]. doi:10.7326/M23-1603 
 
*This study protocol has been developed and presented by the authors to provide readers with additional 
information about the trial reported in their article. The material was not copyedited. 
 
 
 
 
 
 

2 
 
Supplement 1: Trial Protocol 
Table of Contents 
 
Trial Protocol Synopsis ............................................................................................................................ 3-5 
Study Background and Rationale .............................................................................................................. 6 
Study Aims ................................................................................................................................................... 6 
Study Design and Methodologies - Original In-Person Protocol ....................................................... 6-20 
Statistical Analysis Plan ...................................................................................................................... 21-30 
Data Management ..................................................................................................................................... 31 
Timing of Statistical Analysis .................................................................................................................. 31 
Adverse Events Reporting ........................................................................................................................ 31 
Annual Progress Reports ......................................................................................................................... 31 
Dissemination Plan .................................................................................................................................... 31 
Trial Funding ............................................................................................................................................ 32 
Trial Approval by the Institute Review Board ....................................................................................... 32 
Study Design and Methodologies - Modified Online Protocol Due to COVID-19 
Background ............................................................................................................................................... 33 
Trial Modifications .............................................................................................................................. 33-34 
1. Modifications to subject recruitment .................................................................................................. 34 
2. Modifications to intervention setting ................................................................................................... 34 
3. Modifications to intervention ............................................................................................................... 34 
4. Modifications to outcome measures ............................................................................................... 34-35 
5. Modifications to the assessment protocol ....................................................................................... 35-36 
6. Modifications to data analysis ............................................................................................................. 36 
References Cited ................................................................................................................................... 37-38 
 
 
 
 
 
 
 
 
 

3 
 
Trial Protocol Synopsis 
Protocol title 
Cognitively enhanced tai ji quan training to improve global cognitive 
function and lower dual-task costs during walking in older adults with 
mild cognitive impairment: A randomized clinical trial 
Principal investigator 
Fuzhong Li, Ph.D. 
Oregon Research Institute 
3800 Sports Way 
Springfield, OR 97477 
E-mail: fuzhongl@ori.org 
Study design 
The design is a prospective, assessor-blinded, 3-arm parallel group, 
randomized clinical trial with a 1:1:1 allocation ratio 
Study duration 
5 years 
Conditions or focus of study 
Mild cognitive impairment  
Primary aim 
To determine whether a cognitively enhanced tai ji quan training 
intervention, in comparison to a standard tai ji quan intervention and 
an exercise stretching control, is more effective, at 24 weeks, in 
improving global cognitive function and dual-task walking 
performance among community-dwelling older adults with mild 
cognitive impairment (MCI). 
Secondary aim 
To determine whether the effect resulting from the acute intervention 
phase can be sustained 24 weeks after training stopped. 
Setting 
Community residential homes across the United States 
Population and eligibility 
criteria 
Population: community-dwelling older adults with MCI. 
Inclusion criteria: (a) being 65 years or older; (b) having a reported 
memory decline (by the participant and/or an informant); (c) having a 
diagnosis of MCI by a global score of ≤0.5 on the Clinical Dementia 
Rating (range: 0-3); (d) showing no diagnosis of dementia or 
significant cognitive impairment, as indicated by a score of ≥24 on the 
Mini Mental State Evaluation (MMSE, range: 0-30) 
Exclusion criteria: (a) having no medical clearance from a healthcare 
provider; (b) having participated in structured (class-based, instructor-
led) rigorous activities or muscle-strengthening activities (>2 times a 
week for >15 minutes per session) in the past 3 months; (c) showing 
clinically significant depression (>4 on the Geriatric Depression Scale; 
range: 0-15); (d) having any physical condition that would preclude 
participation in moderate-intensity exercise; and (e) being unwilling to 
commit to the duration of the intervention or accept group assignment. 
Intervention 
Cognitively enhanced tai ji quan: A tai ji quan intervention with 
explicitly integrated cognitive training exercises, conducted twice 
weekly, for 60 minutes per session for a total of 24 weeks. Tai ji quan 
training exercises include repeated practice of (a) symmetrical postural 
forms/movements synchronized with breathing, (b) controlled 
displacement (weight-shifting) of the body’s center of mass over the 
base of support, (c) dynamic eye-hand movements during whole-body 
motion, (d) multidirectional (anterior-posterior and medial-lateral) 
stepping, and (e) rotational ankle sway and self-induced reactive 
postural recovery actions. These dynamic exercises are superimposed, 
concomitantly, with a mix of interactive, cognitively stimulating, dual-
task practices that challenge attention control, working memory, 
verbalization, response inhibition, processing speed, dual tasking, task 

4 
 
switching/prioritization, and spatial orientation and postural 
awareness. 
 
Standard tai ji quan: A conventional tai ji quan intervention, 
conducted twice weekly, for 60 minutes per session for a total of 24 
weeks. Training exercises include practice of tai ji quan forms with 
synchronized breathing, supplemented by a set of mini-therapeutic 
exercises. Specifically, the training involves repeated practice of (a) 
symmetrical, coordinated, trunk-driven tai ji quan form movements, 
(b) controlled displacement (weight-shifting) of the body’s center of 
mass over varying sizes of the base of support, (c) dynamic eye-hand 
movements during whole-body motion, and (d) multidirectional 
(anterior-posterior and medial-lateral) stepping. As a balance-based 
training program, movement practices emphasize a dynamic interplay 
of stabilizing and self-induced destabilizing postural actions and 
balance exercises that target mobility, stability limits, and sensory 
integration. 
 
Stretching exercise: A stretching exercise intervention, conducted 
twice weekly, for 60 minutes per session for a total of 24 weeks. 
Exercises consist of breathing, stretching, and relaxation. The core 
exercises encompass a variety of light and static stretches for joints 
and muscles, performed in a seated or standing position, that involve 
the upper body (arms, neck, upper back, shoulder, back, and chest), 
lower extremities (quadriceps, hamstrings/calfs, and hips), and gentle 
and slow trunk rotations. Also included are intermittent light walking, 
deep abdominal breathing exercises that emphasize inhaling and 
exhaling to maximum capacity, and progressive relaxation of major 
muscle groups. 
Duration of intervention 
The intervention lasts 24 weeks 
Primary efficacy endpoints 
The trial has the following two a priori specified co-primary endpoints 
at 24 weeks post-randomization: 
1. change in the Montreal Cognitive Function measure (MoCA; 
score range: 0 to 30)  
2. change in dual-task cost (difference in walking speed 
[seconds] between performance conducted under single-task 
and dual-task conditions) 
Secondary outcomes 
The trial has the following secondary outcomes at 24 weeks post-
randomization: 
1. change in CDR Sum of Boxes scores (score range: 0 to 18) 
2. change in Trail Making Test B (seconds) 
3. change in Category Fluency for Animals (number of animal 
names recalled) 
4. change in Forward Digit Span (score range: 1 to 16) 
5. change in Backward Digit Span (score range: 1 to 16) 
6. change in Timed Up&Go test (seconds) 
7. change in 30-second chair stand test (number of times)  
8. change in 4-stage balance test (score range: 0 to 4) 
Tertiary outcomes 
The trial has the following tertiary outcomes at 24 weeks post-
randomization 

5 
 
1. change in Everyday Cognition (score range: 1 to 4) 
2. change in Geriatric Depression Scale score (score range: 0 to 
15) 
3. change in Pittsburgh Sleep Quality Index global score (score 
range: 0 to 21) 
4. change in EuroQol EQ-D5 utility score (score range: -1 to 1) 
Covariates 
There are no pre-specified covariates for the primary and secondary 
endpoints. 
Follow-up schedule 
16 weeks (mid point), 24 weeks (intervention termination), 48 weeks 
(post-intervention follow-up) 
Masking 
Outcome assessors, data analysts 
Number of subjects 
The target sample size is 315 participants to provide 80% power to 
detect a medium-size difference in mean MoCA change of 1.5 points 
between the cognitively enhanced tai ji quan and the standard tai ji 
quan groups and a large-size difference of 3 points between the 
cognitively enhanced tai ji quan and the stretching control groups at 24 
weeks. 
Statistical analysis 
The effect of the intervention on the primary endpoints will be 
evaluated using the intention-to-treat approach, in which participants 
are grouped according to randomization assignment. To compare 
change in outcome measures among the three intervention groups at 6 
months, we will analyze a 3 (Group) by 3 (Time) mixed-effects model 
with repeated measures on the second factor (i.e., outcome measures 
assessed at baseline, 4 months, and 6 months). In the presence of a 
Group by Time interaction effect, pre-specified follow-up pair-wise 
comparisons will be performed to determine between-group 
differences (indicated below). Secondary outcomes will be similarly 
analyzed. Results from primary analyses will be presented as the 
difference in mean MoCA and dual-task performance between the 
cognitively enhanced tai ji quan and standard tai ji quan groups and 
between the cognitively enhanced tai ji quan and the stretching 
exercise control, with a Bonferroni-adjusted 2-tailed significance level 
of .0125 for each of the two primary outcomes and a 98.75% 
confidence interval.  
Interim analysis 
No interim analyses for efficacy or futility. However, interim 
monitoring is performed with a focus on subject accrual, intervention 
fidelity, protocol adherence, data completeness and quality, and 
intervention safety and analysis. 
 
 

6 
 
Study Background and Rationale 
Mild cognitive impairment (MCI) is an intermediate stage between the common phenomenon of 
cognitive decline with aging and the more pronounced decline of dementia due to Alzheimer’s disease 
(AD).1,2 Approximately 16%-20% of adults over age 65 have MCI,3 exposing these individuals to a 
higher risk of developing AD. Estimates show that more than 30% of individuals with MCI progress to 
developing dementia related to AD within 5 years.4,5 These data call for an increased effort and demand to 
develop and test effective cognitive health care strategies that can prevent cognitive decline and slow the 
progression of MCI to AD.  
Exercise plays an important protective role in preserving cognitive function or mitigating the 
progression of cognitive impairment for older adults with MCI.6-8 Among various exercise modalities, tai 
ji quan represents one of the promising mind-body integrative therapeutics for promoting brain health.9  
However, studies examining the clinical impact of tai ji quan on influencing MCI remain insufficient to 
inform evidence-based recommendations due to (a) the limited number of rigorously designed studies and 
(b) the lack of explicit integration of a cognitive training component that could further boost its cognitive 
benefit. As a result, it is difficult to synthesize research findings and confirm the clinical merit or public 
health impact of tai ji quan in promoting and preserving cognitive function in people with cognitive 
impairment, including MCI.  
 
Study Aims 
Primary Aim. The primary aim of this study is to determine the effectiveness of a cognitively 
enhanced tai ji quan exercise intervention, compared to a standard tai ji quan intervention and an exercise 
stretching control, in improving cognitive function and dual-task walking ability among community-
dwelling older adults with MCI. On the basis of preliminary results,10-12 the primary hypothesis is that 
during a 6-month intervention, participants receiving enhanced tai ji quan training, compared to 
participants receiving either a standard tai ji quan intervention or stretching exercise control, will show 
greater improvement in the primary outcome measures of global cognitive function and dual-task walking 
ability. Secondary outcomes include cognitive impairment and domain-specific cognitive function and 
physical performance measures. 
Secondary Aim. The secondary aim of this study is to evaluate how well the intervention effects in 
the cognitively enhanced tai ji quan intervention group will persist long-term. Specifically, we will 
examine whether group differences in primary and secondary outcomes will remain for 6 months after the 
end of the supervised interventions.  
 
Study Design and Methodologies  
Original In-Person Intervention Protocol (dated August 1, 2019) 
 
Study design and setting  
We plan to conduct a prospective, assessor-blinded, 3-arm randomized parallel trial (with a 1:1:1 
allocation ratio), in which the cognitively enhanced tai ji quan intervention will be evaluated against a 
standard tai ji quan intervention and a stretching exercise control. Enrolled participants will participate in 
a 60-minute exercise session, twice weekly for 24 weeks.  
The trial will be conducted in local community settings, including senior centers, community centers, 
churches, outpatient medical clinics, or non-profit organizations.  
The trial reporting will follow the general guidelines described in the Consolidated Standards of 
Reporting Trials (CONSORT). 
 
Trial registration 
ClinicalTrials.gov number: NCT04070703: Released August 28, 2019 
 
 
 

7 
 
Trial protocol approval 
The in-person trial protocol was fully reviewed and approved by the Institute Review Board 
(IRB) of Oregon Research Institute. The protocol also will receive an annual IRB review during each year 
of the project. A Safety Officer, approved by the National Institute on Aging (NIA), will review and 
approve the study protocol, oversee the safety and scientific integrity of the study, and receive annual 
updates on the progress made on the various aspects of the project activity. Informed consent will be 
obtained from all participants. 
 
Study population 
The study targets older adults (age 65 and older) with clinically diagnosed MCI per Petersen criteria 
and criteria established by the National Institute on Aging—Alzheimer Association workgroup.13,14 
Potential eligible participants will be drawn from community-living older adult residents living in the 
state of Oregon who meet the following eligibility inclusion and exclusion criteria:  
Inclusion: 
• 
having complaint about memory loss, reported by the participant and corroborated by an 
informant (spouse, partner, or caregiver) 
• 
having no or questionable dementia, i.e., scoring ≤0.5 on the Clinical Dementia Rating (CDR)15 
(confirmed via participant and informant interviews) 
• 
showing no major cognitive impairment, i.e., scoring ≥24 on Mini-Mental State Examination 
(MMSE)16 
• 
showing no major difficulties in performing activities of daily living 
Exclusion:  
• 
having medical conditions likely to compromise survival, such as metastatic cancer, or render the 
participant unable to engage in physical activity, such as severe cardiac failure 
• 
showing significant depression symptoms (scoring <4 on the Geriatric Depression Scale [GDS])17 
• 
participating in structured rigorous activities or muscle-strengthening activities (>2 times a week 
for >15 minutes per session) in the past 3 months 
• 
incapable of exercising safely, as determined by a healthcare provider  
• 
unwilling to be randomly assigned to an intervention condition and complete the 24-week 
intervention and 6-month follow-up 
• 
having no medical clearance to participate 
 
Criteria for premature withdrawal 
Enrolled participants will be informed in the study consent form that they are free to withdraw their 
participation from the study at any time without any consequences. Although all three exercise 
interventions involve minimal risk (per the federal regulations at §46.102(j))18 for injury or 
musculoskeletal pain or discomfort, we do not anticipate that there will be any requirement for a 
premature withdrawal. Our trial primary analysis will be intention-to-treat with all randomized 
participants who give full consent to the study.  
 
Recruitment sources and procedures 
Recruitment strategies to identify potential study participants include promotions at local 
senior/community centers, meal sites, offices of healthcare professionals and medical clinics, targeted 
mass mailings, organizational websites, and local newspaper advertisements. To reduce potential 
expectation bias, participants will be informed that the study compares three different exercises and that 
they will be assigned to one of these exercise groups at random.  
To ascertain eligibility, a research assistant will make an initial telephone contact with those who 
respond to the study promotion. This initial prescreen telephone contact will determine basic eligibility 
set forth under the recruitment inclusion and exclusion criteria. Potentially, individuals who meet initial 
inclusion criteria will be scheduled for a 2-hour in-office visit at our research office, where the remainder 

8 
 
of the screening work (i.e., CDR, MMSE) will be completed, along with baseline assessment if the 
participant is qualified.  
 
Randomization, allocation, concealment, and blinding 
Eligible participants will be randomized to 1 of the 3 intervention groups with an allocation of 1:1:1 
through a permuted block randomization with a block size of 3 or 6 to prevent anticipation of assignment 
to the study condition. Concealment of allocation will be implemented. The project data analyst will use 
computer software (nQuery) to generate a randomization schedule, which will be kept in a sealed 
envelope. On the day of the assignment, a research assistant will assign qualified individuals to 
intervention groups. The allocation sequence assigns individuals in the order that they were scheduled for 
baseline assessment. Randomization will occur after informed consent is obtained and baseline 
assessments have been completed. 
Project data analysts will be blinded to group allocation. All study assessors who collect study 
outcome measures will also be blinded to the main study design and group allocation. Blinding will be 
strictly maintained by emphasizing to assessors the importance of minimizing assessment bias and regular 
checking of the blinding status. Efforts will be also made to maintain separation between the study 
assessors and research assistants who deal with administrative activities and class safety monitoring, and 
between study assessors and class instructors who deliver the intervention classes. Because of the nature 
of the interventions, study participants and interventionists will not be masked to group allocation. 
Participants will be instructed not to reveal their group status to the assessment staff at any time during 
follow-up.  
 
Intervention 
The intervention for the trial consists of three exercise modalities: (a) cognitively enhanced tai ji 
quan, (b) standard tai ji quan, and (c) stretching exercise. Each is described below. The protocol, which is 
specified in detail via a teaching manual, requires that each intervention be implemented, by a qualified 
interventionist, twice weekly, for 60 minutes per session for a total of 24 weeks (6 months).  
 
Cognitively enhanced tai ji quan 
The basic exercise routine entailed in this intervention consists primarily of an 8-form tai chi quan 
routine, derived from the well-established Tai Ji Quan: Moving for Better Balance (TJQMBB) 
protocol.10,19 The training protocol includes preparatory (warm-up) exercises; an average of 50 minutes of 
core exercise that involves learning, practicing, and repeating the 8 forms (in the order listed below); and 
a brief cool down exercise that involves walking-the-forms and light breathing.  
 
• 
(1) “Move a Ball,” (2) “Part Wild Horse’s Mane,” (3) “Repulse Monkey,” (4) “Brush Knees,” (5) 
“Fair Lady Works the Shuttles,” (6) “Grasp Peacock’s Tail,” (7) “Single Whip,” and (8) “Waving 
Hands like Clouds.” 
 
The protocol involves two phases: (a) learning and practicing tai ji quan forms (weeks 1 through 15) 
and (b) exercising tai ji quan form movements concomitantly with integration of cognitively enhancing 
and stimulating tasks (weeks 16 through 24). During the learning phase, exercise focuses on practicing (a) 
symmetrical and coordinated postural movements synchronized with breathing, (b) controlled 
displacement (weight-shifting) of the body’s center of mass over the base of support, (c) dynamic eye-
head movements during motion, (d) multidirectional (anterior-posterior and medial-lateral) stepping, and 
(e) rotational ankle sway and self-induced reactive postural recovery actions. During the integrated 
exercise period, practices are superimposed by a set of interactive, cognitively stimulating, dual-task 
activities that exercise attention control, working memory, verbalization, response inhibition, processing 
speed, dual tasking, task switching/prioritization, and spatial orientation and postural awareness.  
The key principles of integration of tai ji quan and cognitive exercises in this intervention are 
summarized in the box shown below.   

9 
 
Targeted cognitive 
domains 
Concurrent tai ji quan and superimposed 
cognitive tasks 
Practice examples 
Attention control 
(selective attention, 
rapid attention 
switching, divided 
attention) 
Forms practiced with varied or differential 
instructional cueing or with a posturally-
challenging stance 
Practicing forms with visual cueing 
only or with verbal cueing only; 
practicing forms in a narrow stance 
(e.g., a semi-tandem stance); practicing 
in response to correct form instructions 
while ignoring incorrect (interfering) 
instructions or practicing rapid 
attention-switching between two out-
of-sequence forms 
Working memory 
Forms practiced with recall or retrieval of forms 
from either a sequenced or out-of-sequence 
order 
Recalling and performing a set of tai ji 
quan forms from the sequenced order 
(e.g., performing 2 or 3 forms 
BEFORE or AFTER Fair Lady Works 
the Shuttle) or out of sequence (e.g., 
Performing Brush Knee followed 
quickly by Single Whip and/or Part 
Wild Horse’s Mane) 
Verbalization 
Saying the form names and associated 
movement steps involved out loud 
Following the instructor, reciting step-
by-step movement instructions for a 
form or saying the name of each form 
being practiced 
Response inhibition  
Responding only to correct instructional cueing 
while ignoring other non-relevant verbal or 
visual instructional cueing 
Practicing “Simon Says” game by 
responding to correct form instructions 
for exercises (e.g., “Simon Says Brush 
Knees”) while suppressing interfering 
(non-Simon Says) instructional form 
(i.e., Brush Knees).  
Processing speed 
Responding to randomly called-out forms  
Performing tai ji quan forms called out 
randomly, by the instructor, from the 8-
form routine during walking/stepping 
Task switching 
Practicing deviations from pre-specified 
sequence order or format 
Forms practiced with (a) side-switching 
(i.e., alternating between lateral and 
bilateral sides), (b) switching between 
odd and even orders in the forms 
sequence (i.e., practicing forms 1, 3, 5, 
and 7 followed by forms 2, 4, 6, and 8), 
or (c) sequence direction switch (i.e., 
practicing the sequence forward as 
ordered and backward (in reverse 
order)) 
Dual tasking 
Practicing a form concurrently with a cognitive 
(verbal) task without task prioritization 
Practicing a form in synchronization 
with a word-spelling or number-
counting task 
Task prioritization 
Practicing a form concurrently with a cognitive 
task, with an emphasis on the performance of 
the form 
Practicing a form (primary task) while 
reciting numbers or phrases backward 
continuously (secondary task) 
Spatial orientation 
and postural 
awareness 
Practicing forms with change in direction and 
size of base of support 
Practicing a set of forms with (a) steps 
taken in multiple directions or (b) a 
narrow stance (e.g., feet close together) 
or semi-tandem stance 
A sample session (Week 15) of this training protocol is shown at the end of this Intervention section. 
Exercise intensity. Exercise intensity will be closely monitored throughout the intervention period. 
Specifically, during the 1st month, participants will be instructed to exercise physically at a level 

10 
 
characterized as being “Light” (equivalent to 2-3 on the Borg CR10® 1-10 scale [1 being “Very Light 
Activity” and 10 being “Maximum Effort Activity”]). In the 2nd month, participants will then proceed to 
a “Light to Moderate” level (equivalent to 3-4 on the scale). In the 4th-6th months, practice will be 
maintained at a “Moderate” level (equivalent to 4-6 on the scale). Exercise intensity will be evaluated on 
a weekly basis by the class instructor.  
 
Standard tai ji quan 
The standard tai ji quan intervention serves as an active concurrent neuromuscular control in this 
study. As in the cognitively enhanced tai ji quan group, participants in this group will receive an adapted 
version of Tai Ji Quan: Moving for Better Balance (known as TJQMBB),10,19 which includes the identical 
8 forms of training. The training protocol requires that each session begin with a set of preparatory 
exercises, followed by approximately 50 minutes of core training involving learning and practicing, with 
repetition, single forms, or a series of pre-ordered forms. Each session ends with a simple set of walking-
the-forms and breathing exercises.  
The intervention follows a traditional tai ji quan training approach, where the instructor plays a 
dominant and leading role in teaching (with clear verbal and visual instructions) and practicing, without 
instructor-participant interaction during exercise. Accordingly, the training involves primarily teaching 
participants, via both verbal and visual cues, tai ji quan forms and movements through repeated practice. 
Specific tai ji quan training activities include controlled, self-initiated tai ji quan–based postural 
movements with synchronized breathing, including center-of-gravity displacement using a dynamic 
interplay of stabilizing and self-induced destabilizing postural actions involving unilateral weight-bearing 
and weight-shifting movements, trunk and pelvic rotation, ankle sway, multidirectional stepping, and 
coordinated eye-head-hand movements. The training is progressive, with learning and practicing taking 
place during the first 15 weeks and repeated practice with variations thereafter. The exercise is 
accompanied by sets of therapeutic and functional tai ji quan–based exercises involving ankle sway, sit-
to-stand, sensory compensation, turning, and stepping exercises that target mobility, stability limits, and 
sensory integration. 
A sample session (Week 15) of this training protocol is shown at the end of this Intervention section. 
Exercise intensity. Exercise intensity will be identical to that in the cognitively enhanced intervention 
and will be closely controlled and monitored throughout the intervention period by the class instructors. 
 
Stretching exercise 
The rationale for using stretching exercise is to provide participants with a low-intensity exercise 
program that contains identical social interaction, enjoyment, and physical activity (i.e., by traveling to 
and from the intervention locations), as well as changes in lifestyle secondary to study participation, that 
are inherent components in the other two tai ji quan-based exercise interventions, without providing 
comparable cognitive-physical exercise training benefits.  
The program consists of breathing, stretching, and relaxation, with the majority of activities 
performed in a seated position.10,20 Each session begins with a set of warm-up exercises (10 minutes) such 
as stretching the arms, neck, shoulder and back, hips, thighs, and legs; ankle and trunk rotation; and light 
walking. The core part of the training session consists of exercises that encompass a variety of combined 
stretches (seated and standing) involving the upper body (arms, neck, upper back, shoulder, back, and 
chest), lower extremities (quadriceps, hamstrings/calves, and hips), and gentle and slow trunk rotations. 
Also included are abdominal breathing exercises that emphasize inhaling and exhaling to maximum 
capacity, as well as progressive relaxation of major muscle groups.  
A sample session (Week 15) of this training protocol is shown at the end of this Intervention section. 
Exercise intensity. Exercise intensity in this group will be kept at a “Light” level (2-3 on the Borg 
CR10® scale) throughout the 24-week intervention period. 
 
 

11 
 
 
 

12 
 
 

13 
 
  
 

14 
 
Adverse events monitoring  
Throughout the study period, both intervention- and non-intervention-related adverse events will be 
closely monitored and recorded by research staff and adjudicated by the Principal Investigator of the 
study. We will classify adverse events in three categories: Mild, Moderate, and Serious. Similarly, for all 
events observed or reported in this study, we will further classify them into three categories in relation to 
the intervention: Unrelated, Possible, or Definite. The following section describes the classification and 
categorization of our study adverse events. Per our IRB protocol, any serious adverse events will be 
reported to the IRB and the project Safety Officer within 48 hours of the reported incident.  
 
Adverse Event and Serious Adverse Event Collection Process 
The project defines Adverse Events and Serious Adverse Events as follows: 
Definition of Adverse Events may include the following: 
• Any musculoskeletal pain or discomfort, including lower back pain, ankle/muscle soreness or 
pain, or a fall without needing medical attention 
• Any event that requires medical treatment but is not an immediate life-threatening condition (e.g., 
eye surgery or a medical procedure) 
 
Definition of Serious Adverse Events are undesirable experiences associated with the prescribed exercise 
interventions in this project. Serious Adverse Events may include the following: 
• Death 
• Falls that result in a serious injury that requires immediate medical attention  
• Prolonged hospitalization  
• Important medical or life-threatening events such as a heart attack that require treatment in an 
emergency room 
• Events that cause persistent or significant disability or incapacity 
 
Classification of Adverse Events 
This project will classify any adverse events observed during the 6-month active exercise intervention 
period into the following three categories: 
• Mild: events that require no medical treatment or are non-life threatening  
• Moderate: events that require medical treatment but are not immediate life-threatening conditions 
• Serious: events that result in death or are life threatening and require medical treatment, including 
prolonged hospitalization or significant disability/incapacity 
 
Relatedness 
For all events observed or reported, the project will further classify them into three categories in relation 
to the intervention:  
• Not related: an event that is reported but not directly related to participation in the intervention 
• Possibly related: an event that is observed during an exercise class that is considered likely to be 
associated with participation 
• Definitely related: an event that is observed or reported during an exercise class and is considered 
directly related to participation.  
 
Adverse Events and Serious Adverse Event (SAE) Reporting Process 
We will carefully monitor for unexpected adverse events, as well as the expected outcomes, that 
participants experience during each online exercise session and outcome assessment, whether or not the 
events or outcomes are directly related to the study intervention. All symptoms reported by the study 
participants will be tabulated in a checklist format and recorded by a designated research assistant. When 
an adverse event is identified, the staff member will report it directly to the Principal Investigator (PI). An 
Adverse Event Report Form will immediately be completed, filed, and reported to PI. 
 

15 
 
The PI will be directly responsible for monitoring and documentation of adverse events during the 
implementation of all prescribed exercise sessions across the three study conditions. Once the project is 
implemented, any activities (during a class session or during an assessment session) resulting in 
participant distress or discomfort, exercise-related side effects, injuries, or falls will be reported 
immediately to the PI, who will, upon consultation with other members of the team, take appropriate 
action. This will include consultation with the team’s medical expert. The PI will report such incidents 
immediately to the IRB Chair at ORI. Summary reports of adverse events, and any subsequent IRB action 
taken as a result of such events, will be routinely provided to the NIA PO and the NIA-appointed Safety 
Officer. 
 
For each event observed or reported, regardless of setting where the event takes place (i.e., at home or 
during exercise classes), a designated research assistant will contact the participant within 3 working 
days, via a telephone call, to ascertain detailed information related to the event. During this phone contact, 
information about date/time, location, nature of the event, symptoms experienced, and any measures 
taken for the event will be collected and documented. If necessary, the informant for the study participant 
will be contacted to verify the information provided by the participant. The recorded event, along with a 
detailed description, will be tabulated in a checklist format and entered into the project’s Adverse Event 
Log. It will be shared immediately with the PI, who will report, within 3 working days, to the IRB, NIA-
appointed Safety Officer, and Project Officer at NIA. 
 
The following summarizes the reporting procedure to be implemented in this project: 
• Expedited reporting: All SAEs (including expected and related or possibly related) observed 
during the active study period will be reported to local IRB and Safety Officer within 3 working days. 
• Routine reporting: All events will be included in routine reports. 
 
Fidelity of intervention delivery 
A standardized intervention protocol and a process evaluation checklist, developed via prior trials,10 
will be implemented. These measures focus primarily on intervention fidelity and involve issues such as 
(a) interventionist qualifications and training, (b) teaching quality of the individual forms/movements or 
routine in each session, (c) exercise intensity and consistency in training dosage across different sites, and 
(d) weekly class attendance checking and monitoring. The evaluation will be conducted monthly by either 
an authorized research team member or an instructor, per guidelines specified in an established fidelity 
checklist.10 In evaluating the item in (b), high intervention fidelity will be considered achieved if at least 
95% of the mandatory components (overall completion of pre-specified activities, quality of verbal and 
visual instructions, emphasis of core training points, session completion time) are fully or partially 
delivered in each session.  
 
Attention control across intervention groups 
Participants assigned to each of the three intervention groups will receive the same amount of contact 
time from class interventionists and research staff. Specifically, 48 exercise sessions are planned for each 
exercise program in the study. Assessment time at each assessment time point will be constant (i.e., 
around 2.5 hours per visit). Unless there are special circumstances (e.g., participants experience an 
adverse event or illness), there will be no additional contact time with the project instructors or staff.  
 
Trial interventionists 
The community exercise instructors who deliver all three exercise interventions will be trained per 
our previously established criteria.10 These trial interventionists will be trained by the Principal 
Investigator initially via an 8-hour training and orientation workshop, during which detailed instructions 
about the specifics of program delivery, practice safety, and teaching requirements will be provided. In-
service training will be provided on a monthly basis and when needed as determined by the investigators. 

16 
 
These trial interventionists will also be asked to maintain the confidentiality of the study participants in 
their classes.  
 
Trial outcome assessors 
All research outcome assessors will complete a computer-based training course through Oregon 
Research Institute, an educational requirement for all researchers who conduct or support research 
involving human subjects. This will be completed during the project start-up period before data 
collection. In addition, these assessors will complete an online training on the clinical administration of 
cognitive-based measures (i.e., CDR, MoCA) and receive training from the Principal Investigator on 
established assessment procedures related to all study outcome measures including self-reports and 
performance-based measures.  
 
Intervention adherence and attrition 
The overall intervention adherence (i.e., exercise class attendance) rate is defined as the sum of the 
total number of participants attending divided by the maximum number of 48 sessions planned, multiplied 
by 100, during the 6 months of active intervention. For the trial, we will strive for an adherence rate of 
≥75%. Accordingly, class attendance across the three study conditions will be closely monitored on a 
weekly basis. As an adherence procedure, participants who miss two consecutive sessions will be 
contacted by phone to ascertain the reason(s) for their absences and to encourage them to return.  
Unavoidable drop-outs, from causes such as death, onset of severe illness, changes in health 
conditions, or other medical complications, are anticipated during the course of our active intervention. 
Based on our prior trial records,10 we estimate a 15% intervention dropout rate for the overall study (i.e., 
15% of the total enrolled participants will withdraw from or stop attending assigned exercise classes).  
 
Study retention 
Study retention is defined as participants who voluntarily provide primary outcome data regardless of 
intervention participation status. For the trial study, we have planned an overall study retention rate of 
85%. To accomplish this goal, planned measures will be taken to ensure that as many participants as 
possible, including dropouts, attend each scheduled in-person assessment visit at our research facilities. 
Our proactive methods will include frequent telephone and e-mail contacts with subjects who miss 
scheduled data assessment appointments. 
 
Study Outcome Measures and Procedures  
Assessment schedule 
The primary measures of global cognitive function and dual-task gait performance ability and other 
specified secondary and tertiary outcome measures will be assessed at baseline (before randomization), 4 
months (midpoint), and 6 months (intervention termination). The repeated data collection will be 
performed by outcome assessors who have gone through a training process to familiarize themselves with 
the assessment protocol. All assessors will be blinded to group allocation. 
 
 
 

17 
 
Primary endpoints 
Primary efficacy endpoints for the trial are changes in global cognitive function and cost of dual-task 
gait performance at 6 months from baseline.  
Global cognitive function will be assessed by the Montreal Cognitive Assessment (MoCA),21 which 
measures cognitive function of multiple domains (attention/concentration, executive functions, short-term 
memory, language, visuospatial abilities, orientation to time and place). The MoCA will be administered 
to the study participants by trained study assessors at baseline, 4 months, and 6 months. MoCA has a total 
score that ranges from 0 to 30, with higher scores representing better cognitive functioning. One point is 
added to the total scores for participants who received less than 12 years of education. To avoid potential 
practice effect associated with the repeated measures, we will use a different version at each of the three 
assessment time points (Note: Version 8.1 at baseline, Version 8.2 at 4 months, Version 8.3 at 6 months 
[Version 8.1 is repeated at 12 months]). 
Dual-task cost will be assessed via an Instrumental Timed Up&Go (iTUG) gait performance (APDM, 
Inc.) in which the participant is asked to stand up from a chair, walk a 6-m walkway at normal pace (3 m 
toward a line, turn, and 3 m toward the chair), turn around, and sit down on the chair, with no cognitive 
task (single-task walking). The participant is then asked to perform the same procedure with a concurrent 
cognitive task (counting backward by 3s, starting with an odd number, e.g., 81).12 The total walking 
duration (in seconds) during both 6-meter walks, at normal pace, will be recorded. These tests will be 
administered by trained study assessors at baseline, 4 months, and 6 months. Using the score ascertained 
from each walk, a dual-task cost measure is estimated using the following formula: 
(1) Dual-task walking costbaseline = (dual-task walking – single-task walking) / single-task walking x 100 
(2) Dual-task walking cost6_months = (dual-task walking – single-task walking) / single-task walking x 100  
(3) Change (Δ) in dual-task walking cost = dual-task walking cost6_months – dual-task walking costbaseline  
Scores derived from formula 3 above will be used for efficacy, for which positive values indicate 
deteriorated performance in dual-task walking (i.e., dual-task walking cost), whereas negative values 
represent an improvement in dual-task walking performance with respect to single-task walking 
performance (i.e., dual-task walking benefit). 
 
Secondary outcomes 
Our key secondary outcome is change in cognitive impairment. Other secondary outcome measures 
include changes in domain-specific cognitive function and physical performance, from baseline. The 
operationalization of each outcome is described below. 
Clinical Dementia Rating 
The Clinical Dementia Rating (CDR) scale15 uses a semi-structured interview with both the 
participant and a reliable informant (usually a spouse or adult child) to rate six domains of cognitive and 
functional performance: memory, orientation, judgment and problem solving, community affairs, home 
and hobbies, and personal care. Each domain is rated according to one of five levels of impairment: 0 = 
none, 0.5 = questionable, 1 = mild, 2 = moderate, and 3 = severe (Note: the personal care item is scored 
on a 4-point scale without a 0.5 rating available). A global CDR score is then assigned according to 
published rules to indicate the presence or absence of dementia, and, when present, its severity. A CDR 
test score of 0 indicates no dementia and scores of 0.5, 1, 2, and 3 indicate very mild, mild, moderate, and 
severe dementia, respectively. This measure will be administered by the outcome assessors who have 
received training on CDR administration (https://knightadrc.wustl.edu/cdr/cdr.htm).  
As a key secondary outcome in this trial, a CDR sum of box (CDR-SB) score, a validated outcome 
measure used in clinical trials of Alzheimer’s disease,22 will be obtained by summing each of the domain 
box scores, with scores ranging from 0 to 18 (higher scores indicating great impairment in cognition and 
function). 
 
Paper-and-pencil cognitive battery tests 
This set of tests includes cognitive domains of attention, processing speed, visuospatial ability, 
executive function, verbal fluency, and memory. Each is described below.  

18 
 
Trail Making Test (TMT) (Parts A and B) (attention, executive function). The TMT consists of two 
parts (A and B).23 Part A, which has little executive input, requires the participant to use a pencil to 
connect a series of numbered circles arrayed randomly on a sheet of paper. In part B, which tests 
cognitive flexibility and stresses central executive processes of task-set inhibition, the participant 
connects numbers and letters in an alternating progressive sequence, 1 to A, 2 to B, 3 to C, and so on. For 
parts A and B, scoring is expressed in terms of the time (in seconds) to completion. In order to measure 
central executive functioning, the difference in time taken to complete Part B versus Part A is calculated, 
with smaller difference scores indicating better executive function. 
Stroop Color and Word Test. The Stroop Color and Word Test24 will be used to assess the executive 
aspects of attention control, information processing speed, selective attention, cognitive flexibility, and 
executive function in terms of the ability to inhibit a usual response in favor of an unusual response. The 
test consists of speeded trials of Word Reading, Color Naming, and Color-Word Interference and assigns 
a score for each trial based on the number of words read or colors named in 45 seconds. Upon completion 
of the test, the number of items correctly named in 45 seconds in each condition is calculated (i.e., W, C, 
CW), and this is followed by calculating the predicted CW score (Pcw) using the following formula: 
Pcw = 45/{((45 × W) + (45 × C))/(W × C)} 
Or equivalent to: 
Pcw = (W × C)/(W  + C) 
The Pcw value is subtracted from the actual number of items correctly named in the incongruous 
condition (CW) (i.e., IG = CW − Pcw). This procedure results in an interference score (IG) based on the 
performance on both W and C conditions. Thus, a negative IG value represents a pathological ability to 
inhibit cognitive interference, whereas a lower score represents greater difficulty in inhibiting cognitive 
interference. 
Category Fluency for Animals. This is a test that assesses verbal fluency and executive function.25 
The participant is asked to generate the names of as many animals as possible in 60 seconds. 
Block Design Test. As a subset of the Wechsler Adult Intelligence Scale (WAIS-IV),26 the Block 
Design Test provides a measure of visuospatial ability. The participant is asked to use his/her hand to 
arrange blocks that have various color patterns on different sides to match a pattern according to a 
presented model as accurately and quickly as possible. Though the items in the test can be scored both by 
accuracy in matching the pattern and by speed in completing each item, in this study we will score the test 
by speed measured in seconds. 
Digit Symbol Coding. As another subset of WAIS-IV,26 Digit Symbol Coding measures processing 
speed. The participant is given a piece of paper with nine symbols (on the bottom line) corresponding to 9 
digits (on the top line) and 27 digits on the next seven lines. Next, on the same piece of paper are eight 
rows of digits with empty spaces below them. The participant is asked to fill in as many corresponding 
symbols as possible in 120 seconds. The total score is the number of correctly drawn symbols (possible 
scores, 0-135) within the time limit allocated, with higher scores indicating better processing speed.  
Digit Span (Forward and Backward) Test. As a third subset of WAIS-IV,26 this test involves 
evaluation of two main components: attention span and working memory. The participant is verbally 
presented with a series of digits (e.g., 6, 2, 9, 7) at a rate of one digit per second and is required to repeat 
them verbatim. If the participant succeeds, he/she is given a longer list (e.g., 5, 3, 8, 1, 6). The number of 
digits increases by one until the participant consecutively fails two trials of the same digit span length. 
The length of the longest list a person can remember is that person’s digit span. This test contains two 
separate tasks. In the “Forward Digit-Span,” the participant is asked to repeat the digits in the given called 
order. In the “Backward Digit-Span,” the participant is required to repeat the digits in reverse. The 
participant receives 1 point for each correct answer. The maximum number of points in the entire test is 
32. To minimize a learning effect, different lists of numbers are given to the participants in each of the 
four testing occasions. 
 
 
 

19 
 
Computerized cognitive battery tests 
To augment our paper-and-pencil measures, we will also employ Cogstate (cogstate.com), a set of 
customized, computerized tasks taxing verbal learning, including (a) International Shopping List Task 
plus a recall (the number of correct responses is used as the unit of measurement); (b) attention 
(Identification [speed of performance]); (c) working memory (One Back Task [speed of performance]); 
(d) visual recognition memory/attention (One Card Learning Task [accuracy of performance]); and (e) 
executive function (Groton Maze Learning Task [accuracy of performance]). These assessments are 
performed on a desktop computer and administered according to guidelines. The test session takes about 
45 minutes to complete, with a practice before every task. Similar to the paper-and-pencil tests, a 
composite cognitive score will be calculated from these computerized cognitive tests.  
 
Physical Performance 
Functional Reach. In an upright standing position, this measure (measured in inches) assesses the 
maximal distance the participant can reach forward, beyond arm’s length, while maintaining a fixed based 
of support in the standing position.27  
Short Physical Performance Battery (SPPB). This measure includes (1) increasingly challenging 
standing balance tasks (side-by-side stand, semi-tandem stance, tandem stance), (2) a 4-meter walk (gait 
velocity) at normal pace, and (3) repeated chair stands (leg strength).28 A single SPPB measure is used, 
with the scale score ranging from 0 points (worst physical function) to 12 points (best physical function).  
Timed Up&Go (TUG) test. The TUG measure29 is recorded in seconds (the time taken by an 
individual to stand up from a standard armless chair, walk a distance of 3 meters, turn, walk back to the 
chair, and sit down). 
 
Covariates 
There are no pre-specified covariates in this study. 
 
Tertiary measures  
These measures include the (a) Everyday Cognition scale,30 (b) Pittsburgh Sleep Quality Index,31 (c) 
Geriatric Depression Scale,17 and (d) EuroQol EQ-5D for health-related quality of life.32 These measures, 
described below, are included in a paper survey completed by participants.  
Everyday Cognition. This is assessed using the brief version of the informant-based Everyday 
Cognition questionnaire,30 which will be completed by the informant of the participant. In people with 
MCI, the measure assesses a participant’s ability to perform everyday tasks in the following areas: 
memory, language, visuospatial abilities, planning, organization, and divided attention. The average will 
be derived from the mean average of all responses (range from 1 to 4), with higher scores indicating 
greater impairment in everyday functional cognitive ability. 
Pittsburgh Sleep Quality Index (PSQI). The PSQI31 includes seven indices: subjective quality, latency 
(i.e., time needed to fall asleep), duration (i.e., number of hours of actual sleep per night), efficiency (i.e., 
total sleep time divided by time in bed, converted to a score of 0-3), sleep disturbances (e.g., waking up in 
the middle of the night and the like), use of sleeping medication, and daytime dysfunction (e.g., having 
difficulty staying awake during the day). Each of the component scores ranges from 0 to 3, with the PSQI 
global score ranging from 0 to 21 points, with higher scores indicating poorer sleep quality.  
Geriatric Depression Scale. The 15-item version of the scale17 will be used to assess depressive 
symptoms. The score for the measure ranges from 0 to 15. A score of 0 to 4 is considered to be within the 
normal range, 5 to 9 indicates mild depression, and a score of 10 or more indicates moderate to severe 
depression.  
EuroQol EQ-5D. The EQ-5D32 assesses health status in five domains: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each domain is measured at three levels: no problems 
(coded as 1), some problems (2), and extreme problems (3). An EQ-5D utility score at baseline and 6 
months for each participant will be calculated based on the U.S. population-based (preference-weighted) 

20 
 
health index scores on a scale ranging from less than 0 (worst health state) to 1.0 (best or perfect health 
state).33 
 
Assessment of intervention adherence 
Intervention classes will be closely monitored by research staff throughout the study period. Session-
by-session attendance of the study participants will be recorded by research staff, regardless of 
participants’ participation status, and this information on exercise adherence rate will be used as an 
indicator of intervention adherence across the three intervention groups. For each intervention group, 
there will be a total of 48 exercise classes to be completed over the 24-week intervention period. 
Accordingly, the average intervention adherence rate will be calculated as follows: number of 
intervention sessions attended during the 24 weeks divided by total number of sessions prescribed for the 
study, reported as a percentage.  
 
Baseline measures 
At baseline, demographic and other information about age, sex, ethnicity/race, income, education, 
living arrangements, medical conditions, health status, habitual physical activity,34 and residence location 
will be collected via a survey questionnaire. Body weight, assessed by a medical scale, and height, 
measured by with a ruler fixed on a wall, will also be ascertained. These data will be used to describe 
study population characteristics at baseline.  
 
 
 

21 
 
Statistical Analysis Plan (SAP) 
 
Study aims 
The study has the following primary and secondary aims. 
 
Primary aim 
To determine whether a cognitively enhanced tai ji quan intervention, in comparison to a standard tai 
ji quan intervention and an exercise stretching control, is more effective in improving global cognitive 
function and dual-task walking performance among community-dwelling older adults with MCI. 
 
Primary hypothesis: We hypothesize that, at 6 months, cognitively enhanced tai ji quan training will 
result in greater gains in the primary outcomes of global cognition and dual-task gait performance than 
either standard tai ji quan or stretching control. 
 
Secondary aim 
To determine whether the effect resulting from the acute intervention phase can be sustained 24 
weeks after training stopped. 
 
Secondary hypothesis: We hypothesize that compared with standard tai ji quan or stretching control, 
participants in the cognitively enhanced tai ji quan training will retain their intervention gains in the 
primary outcomes of global cognition and dual-task gait performance at 12 months (post-intervention) 
follow-up. We also hypothesize that cognitively enhanced tai ji quan training will continue to be superior 
to either standard tai ji quan or stretching control, at 12-month follow-up, in terms of sustaining the 
training effect on slowing disease progression to dementia, as indexed by the continued improvement in 
the mean CDR-SB score from baseline. 
 
Study design 
This study is designed as a prospective, assessor-blinded, 3-arm parallel group, randomized clinical 
trial with a 1:1:1 allocation ratio. The primary co-outcome measures are global cognition function and 
dual-task walking costs. The target sample size is 315 participants, enrolled from local communities. The 
goal is to detect, with 80% power, 1.5 points in MoCA between the cognitively enhanced tai ji quan and 
the standard tai ji quan groups and 3 points between the cognitively enhanced tai ji quan and the 
stretching control groups at 24 weeks. The study will consist of a 6-month acute intervention phase 
(designed for addressing the primary aim) followed a 6-month maintenance phase (for addressing the 
secondary aim).  
 
Outcomes 
Table 1 below describes the study’s primary, secondary, and tertiary outcomes, source of data, and 
follow-up schedule. 
 
 
Measure 
Data source 
Follow-up schedule 
Primary outcome 
 
 
 
Global cognition 
Montreal Cognitive Function 
measure  
(MoCA; score range: 0 to 30) 
Assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Dual-task walking costs 
Difference between single- 
and dual-task gait speed  
(expressed in percentage)  
Assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Secondary outcome 
 
 
 

22 
 
Cognition and function 
Clinical Dementia Rating 
Sum of Boxes score  
(range: 0 to 18)  
Interviews with 
participants and 
informants 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Executive function 
Trail Making Test (B) 
(measured in seconds) 
Cognitive 
assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Attention and memory 
Category Fluency  
(number of animal names 
recalled)  
Cognitive 
assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Attention 
Forward Digit Span  
(range: 1 to 16) 
Cognitive 
assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Memory  
Backward Digit Span  
(range: 1 to 16)  
Cognitive 
assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Mobility  
Timed Up&Go  
(measured in seconds) 
Physical 
assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Lower-extremity strength 
30-second chair stand test 
(number of times) 
Physical 
assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Static balance 
4-stage balance test  
(range: 0 to 4) 
Physical 
assessment 
conducted by 
assessors 
4 months, 6 months, 
and 12 months 
Tertiary outcome 
 
 
 
Everyday cognitive 
function 
Everyday Cognition Scale 
(range: 1 to 4) 
Informant-rated 
questionnaire 
4 months, 6 months, 
and 12 months 
Depressive symptoms  
Geriatric Depression Scale 
(range: 0 to 15) 
Survey completed 
by participants 
4 months, 6 months, 
and 12 months 
Sleep quality  
Pittsburgh Sleep Quality 
Index (range: 0 to 21) 
Survey completed 
by participants 
4 months, 6 months, 
and 12 months 
Quality of life 
EuroQol EQ-5D  
(range: -1 to 1) 
Survey completed 
by participants 
4 months, 6 months, 
and 12 months 
 
Randomization 
Method of randomization 
Eligible participants will be randomized to one of the three intervention groups with an allocation of 
1:1:1 through a permuted block randomization method with a block size of 3 or 6 to prevent anticipation 
of assignment to the study group. The project data analyst, who will not be involved in the recruitment of 
participants, will use computer software (nQuery, version 4.0, Statistical Solutions Ltd) to generate a 
randomization schedule, which will be kept in a sealed envelope. No one else on the project will be 

23 
 
involved in generating the randomization. The schedule will be released by the data team to a research 
assistant before each wave of recruitment is scheduled. On the day of the assignment, the research 
assistant will assign qualified individuals to the intervention groups. The allocation sequence assigns 
individuals in the order that they were scheduled for baseline assessment. Randomization will occur after 
informed consent is obtained and baseline assessments have been completed. 
Allocation concealment 
To control for selection bias, all study assessors who collect study outcome measures will be blinded 
to the main study design and group allocation. Blinding will be strictly maintained by emphasizing to 
assessors the importance of minimizing assessment bias and by random checking of the blinding status. 
Efforts will be also made to maintain separation between the study assessors and research assistants who 
deal with administrative activities and class safety monitoring, and between study assessors and class 
instructors who deliver the intervention classes. Because of the nature of the interventions, study 
participants and interventionists will not be masked to group allocation. Participants will be instructed not 
to reveal their group status to the assessment staff at any time during follow-up. 
 
Statistical interim analyses and stopping guidance 
None. However, annual data and safety information related to the project will be presented to the 
project Safety Officer appointed by the funding agency. The Safety Officer will determine whether any 
interim statistical analyses will be necessary and whether data collection continues on the basis of the 
project progression on subject recruitment, study assessment, or intervention adherence.  
 
The following describes our pre-specified data analysis plan. Data will be coded to maintain group 
allocation blinding during analysis.  
 
Descriptive analyses 
• Trial flow. Information on the number of individuals screened, excluded, and qualified per the 
study eligibility criteria and assigned to the intervention, as well as the follow-up status, at each 
assessment time point will be presented in a figure in accordance with the CONSORT guidelines. 
• Comparability of intervention groups  
▪ 
Baseline characteristics of the study population will be summarized by intervention group 
using summary statistics (e.g., mean, standard deviation, range, frequencies, or percentages) 
for continuous variables and frequency or percentages for categorical variables. Median IQRs 
will be calculated for variables that are not normally distributed.  
▪ 
Participants’ characteristics ascertained at baseline will be compared across intervention 
groups using independent samples or Wilcoxon rank sum tests, as appropriate, for continuous 
variables and a chi-square or Fisher’s exact tests, as appropriate, for categorical variables. 
Although no significant differences are expected due to the randomized intervention 
assignment and the relatively large sample size, any variables found to be significantly 
different will be noted and accounted for, by controlling for them as covariates in supplements 
to the main analyses.  
• Time-specific and change scores. Scores at each follow-up and change in mean scores from 
baseline at 24 weeks, by intervention group, for all outcome measures will be calculated and 
presented.  
• Intervention adherence, attrition, and retention. Class attendance data will be calculated as the 
average number of scheduled intervention sessions (48 total) attended by participants across 
intervention groups. Study attrition and retention rates will also be calculated and reported, by 
intervention group, as the number of participants who completed the 24-week intervention and 
those who completed all scheduled study follow-up assessments.  
 
 
 

24 
 
Analysis populations 
Efficacy analyses. The effect of intervention on the co-primary study outcomes will be evaluated 
using an intention-to-treat approach in which participants will be analyzed according to randomization 
assignment. A modified intention-to-treat analysis will be conducted that includes all participants who 
have undergone randomization and have completed all study follow-up assessments, regardless of their 
participation adherence status. Finally, a per-protocol analysis will include participants in the intention-to-
treat population who have an overall class attendance rate of ≥75% (out of the total planned 48 
intervention class sessions) of their assigned exercise intervention.10  
 
Co-primary endpoint analyses 
To test the Primary hypothesis, we plan to use a generalized linear mixed model with random 
intercepts and fixed treatment effects for the primary outcomes. Specifically, we will determine the 
intervention effect through an analysis of a 3 (Group) by 3 (Time) mixed-effects model with repeated 
measures (follow-up time point) on the second factor (i.e., outcome measures assessed at baseline, 4 
months [mid-point], and 6 months [intervention termination]).  
In the presence of a Group by Time interaction effect, follow-up pair-wise comparisons, using 
independent t tests, will be performed to identify a priori specified between-group differences. 
Specifically, we will determine the intervention effect of cognitively enhanced tai ji quan for change in 
MoCA and costs of dual task in gait performance from baseline to 24 weeks by making a comparison 
between cognitively enhanced tai ji quan and standard tai ji quan and between cognitively enhanced tai ji 
quan and stretching exercise.  
Level of statistical significance and confidence intervals. Our primary outcome analyses will be 2-
sided with an adjusted significance level of <0.0125 (0.05 / 4 comparisons) and a 98.75% confidence 
interval (CI). For each group, both estimated means and their corresponding standard error of estimates at 
each assessment point will be presented. In presenting between-group differences, mean differences with 
CIs will be presented. SPSS “MIXED” function will be used in analyzing our primary outcomes.  
 
Secondary and tertiary outcome analyses 
A similar analytic approach will also be applied to all secondary and tertiary (continuous) outcome 
variables described in Table 1. All study outcomes are expected to follow a normal distribution. In the 
case of deviation from normality, generalized estimating equations will be used to assess the effect of 
intervention over time. No Bonferroni correction will be made to account for multiple comparisons.  
Level of statistical significance and confidence intervals. All tests and CIs will be 2-sided, and 
statistical significance will be defined as a P value of <0.05. For each group, we will report both estimated 
means and their corresponding standard error of estimates at each assessment point. In presenting 
between-group differences at 24 weeks, estimated mean differences with CIs will be presented.  
 
Analyses on examining intervention durability at 48-week follow-up  
We will use the same analytic strategy outlined in our primary and secondary outcome analyses, with 
the exception of CDR-SB (described in detail below), to examine whether the intervention effects will 
persist 24 weeks after the end of the 24-week supervised interventions (Secondary hypothesis).  
With the longitudinal data, we will test the hypothesis that the rate of improvement over time in the 
mean CDR-SB score, at 24-week post-intervention follow-up, will be greater in the cognitively enhanced 
tai ji quan group compared with the other two exercise groups. To test this hypothesis, we will use the 
latent growth curve modeling approach,35 with maximum-likelihood estimation, analyzing the rate of 
change in the mean CDR-SB score defined by the four measurement time points: baseline, 16 weeks (mid 
intervention assessment), 24 weeks (end of intervention assessment), and 48 weeks (24 weeks post 
intervention follow-up).  
Accordingly, we will operationalize our basic growth curve model with two latent growth factors: 
Intercept (defining the initial level of CDR-SB – baseline) and Slope (defining the rate of change over the 
course of the 48-week study period), with each factor being defined by the four time-specific CDR-SB 

25 
 
measures. A schematic representation of the planned latent growth model to be evaluated for each 
intervention group is shown in Figure 1. The factor loadings for the Intercept factor will be fixed with a 
constant value of 1 for all measurement points whereas the loadings for the Slope factor, defining the rate 
of change over time, will be fixed at 0 for CDR-SB at baseline, 1 for CDR-SB at 16 weeks, 2 for CDR-
SB at 24 weeks, and * for CDR-SB at 48 weeks (where * indicating an undefined, free estimate at 48 
weeks). All other model parameters to be estimated include latent Intercept mean and its variance, latent 
Slope mean and its variance, the correlation between Intercept and Slope (covariance), and error variance 
for each of the four time-specific measurements (shown as E’s). The model estimation will include all 
available data derived from the trial, hence, an intent-to-treat approach.  
The model estimation of change in CDR-SB will involve two steps. First, we will estimate an 
unconditional latent growth model (i.e., without the group predictor [e.g., cognitively enhanced tai ji quan 
group vs standard tai ji quan group]). This unconditional growth curve model allows us to examine the 
overall pattern of change in the CDR-SB score over time. Next, a group predictor (as a binary variable 
[1=cognitively enhanced tai ji quan group and 2=standard tai ji quan group]) is added to the model 
parameterization. By regressing the Slope factor on to the predictor of the group variable, this model will 
examine the pre-specified intervention effect of the cognitively enhanced tai ji quan training, compared 
with each of other two active groups, individually, on the rate of change in cognitive functioning 
trajectories. The schematic representation of this second latent growth model with the group, as a 
predictor, is shown Figure 2 (next page). For reporting purposes, we will present (a) latent slope mean for 
each group and (b) the regression coefficient relating group and the latent slope (with 95% CI). A 
negative slope mean for CDR-SB will indicate an improvement in cognitive functioning and, therefore, a 
lowering of the disease progression, whereas a positive mean slope will indicate deterioration in cognitive 
functioning.  
 
A statistically significant regression coefficient indicates the difference in the rate of CDR-SB 
progression. All tests and CIs will be 2-sided, and statistical significance will be defined as a P value of 
<0.05. The planned statistical analyses on change in CDR-SB will be performed in Mplus statistical 
software version 8.2 (Muthén & Muthén).  
 

26 
 
 
 
 
 
 
 
 
 
 

27 
 
Post-hoc exploratory analyses 
No pre-specified post-hoc exploratory analyses are planned.  
 
Subgroup analyses 
In light of the findings reported in prior studies,36,37 we also plan to conduct a series of subgroup 
analyses. Specifically, using a three-way interaction model that involves factors of Group, Time, and 
Subgroup, we will examine whether the expected between-group differences in the two primary outcomes 
are associated with pre-specified subgroups that include sex (1 = men, 2 = women), age (1 = 65-74, 2 = 
75-84, 3 = 85+ years old), and level of education (1 = high school diploma or lower, 2 = college degree or 
higher). We are aware of the fact that these subgroup analyses are not powered statistically, and we will 
therefore interpret any statistically significant results with caution. All subgroup analyses are based on an 
alpha level of <0.05. 
 
Power estimation for primary outcomes 
This study is powered to detect a mean difference in change in the primary outcomes of MoCA and 
motor-cognitive dual-task gait performance between (a) the cognitively enhanced tai ji quan intervention 
and a standard tai ji quan intervention operationalized by TJQMBB,10 and (b) the cognitively enhanced tai 
ji quan intervention and a non-tai ji quan control condition – stretching – at 6 months, among older adults 
with MCI. We estimated the magnitude of the effect size (difference score divided by its pooled standard 
deviation) that is detectable with at least 80% power using a 2-sided 0.05-level test. We expect that 
participants in the cognitively enhanced tai ji quan intervention would experience a clinically meaningful 
improvement of at least 1 score unit in MoCA and a 10% reduction in dual-task costs on gait performance 
speed between the enhanced tai ji quan intervention and each of the two comparison arms. The following 
details the parameters used and results of our power analyses for each of the two primary outcomes. 
MoCA. Assuming two (pre and post) repeated measurements and a between-level correlation of 0.7, 
the planned sample size of 267 participants would provide >80% power to detect a medium-size 
difference (Cohen d = 0.4) in mean MoCA change of 1.5 points (SD = 3.5) between the cognitively 
enhanced tai ji quan and the standard tai ji quan groups and a large-size difference (Cohen d = 0.8) of 3 
points (SD = 3.5) between the cognitively enhanced tai ji quan and the stretching control groups at 6 
months. No minimal clinically important difference (MCID) in MoCA has been established in the 
physical exercise literature, but our target estimate is close to that of 1.22 points established for the stroke 
patient population.38  
Dual-task gait performance. Using the same assumptions, at 6 months, we estimated a 10% reduction 
in dual-task walking costs between the cognitively enhanced tai ji quan and standard tai ji quan 
interventions and a 20% reduction between cognitively enhanced tai ji quan and stretching interventions. 
At the time of developing this research proposal, no MCID for reduction in costs in dual-task 
performance in gait is available. The target estimates calculated in this trial were inferred from our prior 
completed studies.10,12 
Taking into account a conservative 15% loss during the 6-month active intervention period, a total of 
315 participants was planned for the study.  
 
Treatment of noncompliance and missing data 
All enrolled study participants will be followed until the trial period ends, whether or not the 
participant is still receiving or complying with the intervention. Primary endpoint analyses will be 
conducted according to the original randomization scheme in an intention-to-treat approach. We will use 
a multiple imputation data method for missing data. We plan to perform 10 sets of imputations. Variables 
without missing data to be used for prediction of imputed values on the study variables will include 
baseline measures of age, sex, level of education, MMSE, number of chronic conditions, and depression. 
The imputed data will be submitted to the same analytic model (i.e., linear mixed model) as the non-
imputed observed data, and the results of each analytic model will be pooled across the 10 imputed data 

28 
 
sets. The secondary outcome analyses will also be conducted using the multiple imputation method 
described above. Tertiary outcome analysis will be conducted with observed data without imputation.  
 
Interim analysis 
We do not plan to perform any interim analyses for efficacy or futility. Instead, we will conduct 
interim monitoring performance with a focus on subject accrual, protocol adherence, intervention fidelity, 
data completeness and quality control, and intervention safety and analysis. Each is described below.  
 
Subject accrual  
We plan to conduct 10 staggered recruitment and enrollment waves, with approximately 35 
participants planned at each wave, over 3.5 years of the 5-year project life. Each recruitment wave will be 
closely monitored at monthly staff meetings, with presentation of recruitment charts, to ensure we achieve 
our enrollment target. The accrual rate will be reviewed annually by research staff and will be reported to 
ORI IRB and the project Safety Officer appointed by NIA.  
 
Protocol adherence 
The overall intervention adherence (i.e., exercise class attendance) rate is defined as the sum of the 
total number of participants attending divided by the maximum number of 48 sessions planned, multiplied 
by 100, during the 6 months of active intervention. For the trial, the target adherence rate is ≥75%. Class 
attendance across the three study conditions will be closely monitored on a weekly basis by research staff 
and reviewed on a monthly basis by key personnel of the project. Participants who miss two consecutive 
sessions will be contacted by phone to ascertain the reason(s) for their absences and to encourage them to 
return. 
 
Intervention fidelity 
Intervention fidelity will focus primarily on issues such as (a) interventionist qualifications and 
training, (b) teaching quality of the individual forms/movements or routine in each session, (c) exercise 
intensity and consistency in training dosage across different sites, and (d) weekly class attendance 
checking and monitoring. The evaluation will be conducted monthly by either an authorized research 
team member or an instructor, per guidelines specified in an established fidelity checklist.10 In evaluating 
the item in (b), high intervention fidelity will be considered achieved if at least 95% of the mandatory 
components (overall completion of pre-specified activities, quality of verbal and visual instructions, 
emphasis of core training points, session completion time) are fully or partially delivered in each session. 
Deviations related to intervention delivery protocol will be captured on a protocol deviation form and be 
entered into a project database for evaluation by the research staff and Principal Investigator. Prompt 
action will be taken by the Principal Investigator to remedy any problems and deviations identified.  
 
Data completeness and quality control 
Data completion refers to the study measurement ascertainment status from all enrolled study 
participants. The project strives to collect study outcome measures on every participant at each scheduled 
time point (baseline, 4 months, 6 months, and 12 months), regardless of his/her intervention participation 
status. As specified in the protocol for the study, we have planned an overall study retention rate of 85% 
(i.e., having primary and secondary outcome measures available on 85% of the enrolled participants and 
their informants). To accomplish this goal, planned measures will be taken to ensure that as many 
participants as possible, including dropouts, attend each scheduled in-person assessment visit at our 
research facilities. Our proactive methods will include frequent telephone and e-mail contacts with 
subjects who miss scheduled data assessment appointments. The planned completion of data 
ascertainment at each follow-up time point is described in the Table 2 below.  
Table 2. Projected completion of data ascertainment on study outcome measures at each measurement 
time point 
 

29 
 
Measure\Time point 
4 months 
6 months 
12 months 
Primary 
95% 
90% 
85% 
Secondary 
95% 
90% 
85% 
Tertiary  
95% 
90% 
85% 
 
Outcome measures ascertained will be closely checked and verified for accuracy and completeness 
via a rigorous data checking and reviewing process implemented by the trial analyst(s) who will be 
blinded to group allocation. Specifically, data quality and accuracy will be assured via the following 
steps. 
• 
All assessment data (i.e., surveys, semi-interviews, observational assessments) will be double 
checked for errors (e.g., out-of-range data, missing data, and accuracy) by research assistants 
before they are entered into a database.  
• 
Raw data will be entered twice via an existing data entry module. 
• 
All entered data will be subject to a process that checks for accuracy and consistency and will be 
verified by the project statistician. In the event that data entry errors are discovered, additional 
charts will be randomly selected for internal review. 
• 
Raw data entry, cleaning, coding, manipulation, verification, and merging from all four time 
points (baseline, 4 months, 6 months, and 12 months) of assessment will be completed within 5 
days after each follow-up. 
• 
Charts and plots will be presented to the study’s statistician and Principal Investigator every three 
months for quality assurance. 
 
In addition, deviations related to outcome assessment and data ascertainment protocols will be 
captured on a protocol deviation form and be entered into a project database for review and evaluation by 
the research team and Principal Investigator during quality assurance meetings, which will be held on 
either a monthly or quarterly basis. Prompt action will be taken by the Principal Investigator and team’s 
statistician to remedy any problems and deviations identified, and they will perform follow-up evaluations 
of actions taken, if necessary.  
 
Intervention safety and analysis 
Throughout the study period, both intervention- and non-intervention-related adverse events will be 
closely monitored and recorded by research staff and adjudicated by the Principal Investigator. We will 
classify adverse events in three categories: Mild (i.e., events that require no medical treatment or are not 
life threatening), Moderate (i.e., events that require medical treatment but are not immediate life-
threatening conditions), and Serious (i.e., events that result in death or are life threatening and require 
medical treatment, including hospitalization, or significant disability/incapacity). For all events observed 
or reported, we will further classify them into three categories in relation to the intervention: Unrelated 
(an event that is reported but not directly related to participation in the intervention), Possible (an event 
that is observed during a class and that is considered likely to be associated with participation), or 
Definite (an event that is observed or reported during a class and is considered directly related to 
participation).  
Per our IRB protocol, any serious adverse events that we have collected during the entire course of 
intervention will be reported to the IRB and the project Safety Officer within 48 hours of the reported 
incident. This will also include unanticipated issues such as prolonged hospitalizations and deaths. Safety 
analysis will involve tabulating the occurrence of adverse events, including Serious adverse events 
(deaths and hospitalizations) and unanticipated problems/issues among the three groups. Given the low 
risk of the trial, no inferential statistical tests are planned for safety.  
 
 
 
 

30 
 
Statistical software 
Statistical analyses will be performed with the use of Stata software (version 17, Stata Corp), SPSS 
software (version 25, SPSS), and Mplus software (version 8.4, Muthén & Muthén).  
 
Programming plan 
All statistical programs used to generate the study results and unidentifiable data will made available 
upon reasonable request to the PI of this project.  
 

31 
 
Data Management 
All data collected (self-reports, interviews, recorded study outcome performance ratings or scores) 
from the project will first be stored in locked filing cabinets in a designated area inside the ORI office 
building and, after review for completeness and accuracy, will be entered into a secure, password-
protected ORI computer network database to be established by the data team staff. Only authorized 
project staff conducting this project will have full access to the data collected. Participants and 
informants’ responses to the project surveys, interviews, and other forms of data will be coded with a 
unique numeric identification code. Only designated project staff will have the key to the file cabinets or 
password to the database and will have access to the data only for status checking or data verification 
purposes. An Excel data system will be created to track the subjects’ status related to recruitment, 
enrollment, intervention participation, and follow-up assessment. For all raw data, a system file will be 
created, using the SPSS statistical software, that merges various subsets of data for final analyses. A 
periodic security check on the data files will be conducted under the supervision of project’s statistician. 
Only the designated data analyst, project biostatistician, and PI will have access to the raw data and 
analyses. 
 
Timing of Statistical Analysis 
To address the primary aim of the study, preliminary and main statistical analyses and evaluation of 
the trial primary and secondary outcome measures specified in this protocol will begin immediately upon 
completing the last study participant follow-up at 6 months. To address the secondary aim of the study, 
analyses and evaluation of trial data will begin immediately upon completing the last study participant 
follow-up at 12 months. 
 
Adverse Events Reporting 
The following summarizes the procedures that will be followed by the investigative team when a 
participant experiences an adverse event (during the entire course of the study project): 
1. The participant will be encouraged to call ORI’s research staff at 541-484-2123 or 855-434-
1548 (toll free). 
2. ORI’s staff will file an incident report and immediately report the event to the Principal 
Investigator (Fuzhong Li, Ph.D.). 
3. The Principal Investigator will inform ORI’s IRB administrator (Kathryn@ori.org) and 
project Safety Officer appointed by NIA of the incident within 48 hours. 
4. The incident report will be sent to the Project Officer at NIA and filed in the project database. 
5. An ORI staff member will conduct a follow-up contact with the participant within 5 working 
days to reassess the situation and report back to the Principal Investigator. 
 
Annual Progress Reports 
Annual review and progress reports of this trial will be submitted to (a) the Institute Review Board of 
the Oregon Research Institute and (b) the Safety Officer approved by the NIA. The report will include the 
following information on data and safety monitoring:  
1. Overall summary of the project progress 
2. Recruitment and enrollment status 
3. Intervention participation status 
4. Data ascertainment status 
5. Participant safety, including detailed information on intervention and non-intervention-
related adverse events 
 
Dissemination Plan 
In compliance with the funding agency’s (National Institutes of Health, NIH) policy on the 
dissemination of NIH-funded clinical trial information, we will publish our research findings in scientific 
journals. Trial participants will be provided with a summary of our findings in the form of a newsletter.  

32 
 
Trial Funding 
This trial is funded by the National Institute on Aging (R01AG059546), National Institutes of Health.   
 
Trial Protocol Approval by the Institute Review Board 
The original in-person trial protocol was approved on January 23, 2019, by the Institute Review 
Board of Oregon Research Institute (IRB Registration No. 00000278). The protocol also received (or will 
receive) an annual review during each project year. A Data Safety Monitoring Officer, approved by the 
National Institute on Aging, reviewed and approved the study protocol, will oversee the study, and 
received (or will receive) annual updates.  
 

33 
 
Modified Study Protocol due to the COVID-19 pandemic (dated March 20, 2022) 
 
Background 
On March 15, 2020, due to the widespread nature of the COVID-19 pandemic and for the safety and 
wellbeing of trial participants and project staff, the in-person study trial protocol (see above), approved by 
ORI’s IRB and with notification given to the funding agency, was completely suspended. At the time of 
the suspension, we had a total of 28 participants who were 3 months into the active intervention.  
Upon IRB approval, on March 30, 2020, all research activities were resumed by moving the trial 
activities online, delivered at home through Zoom videoconferencing. The decision to switch from in-
person to online delivery was made by the investigative team based on (a) the need to adapt to the 
COVID-19 pandemic situation in order to continue the project, (b) pilot data on the safety of conducting 
the project through home-based online classes, and (c) the feasibility of ascertaining study outcome 
measures via videoconferencing.  
 
Trial Modifications 
To move the trial forward using an online telehealth approach, it was necessary for the investigative 
team to make important modifications to our original study protocol outlined previously. These 
modifications included the following six areas:  
1. subject recruitment 
2. setting  
3. interventions 
4. outcome measures 
5. assessment  
6. data analysis  
These modifications, which are described in detail below and are reported in accordance with the 
current guidelines for completed trials modified due to the COVID-19 pandemic and other extenuating 
cirumstances,39 were approved by ORI’s IRB on April 2020 and were fully pilot evaluated for feasibility 
and safety, with results shown in two published studies, one in 202140 and one in 2022.41 No alternations 
were made to the trial timeline, trial design, or target population (including eligibility criteria and sample 
size).  
 
1. Modifications made to subject recruitment  
Between March and June 2020, due to COVID-19-related restrictions on in-person contacts, all 
activities related to recruitment were moved online via telephone and Zoom (HIPAA-compliant) 
videoconferencing. (Note: All modified recruitment activities remained HIPAA compliant). Specific 
modifications made to study recruitment are described below. 
 
Study promotion to identify participants. Our modified recruitment methods involved mainly (a) 
mass mailing, (b) social media, (c) word of mouth (by telephone or e-mail communications), and (d) 
digital advisement. Because the online delivery platform of our intervention was no longer constrained by 
geographic region, we expanded our study sampling area from the originally planned recruitment area in 
the state of Oregon to include other cities and towns throughout the continental United States (U.S.), as 
described below.  
 
Study recruitment areas. For the purpose of enhancing generalizability, we purposely focused our 
recruitment efforts on four geographic regions (Northeast, Midwest, South, and West) in the U.S. and 
included states that had a high proportion of the population aged 65 years and older (i.e., Maine, Florida, 
West Virginia, Vermont, Montana). Following the identification of our recruitment regions, special 
attention was given to targeting counties and cities within each state that, per the US Census Bureau, had 
the highest index scores on Racial and Ethnic Diversity (www.census.gov/library/stories/state-by-
state.html).  

34 
 
Study recruitment procedure. The modified subject contact procedure involved the following:   
1. The study recruiter made a return phone call to those who responded to our study promotions. 
During these calls, a prescreening was conducted with respect to eligibility related to age and 
memory. 
2. Those potential participants who met the initial entry criteria were further screened, via Zoom 
conferencing, for eligibility, including CDR (both participants and informants) and MMSE. 
3. Those who met all eligibility criteria were immediately scheduled for a baseline assessment 
via Zoom. The assessment was completed by an outcome assessor who was blinded to group 
allocation. 
4. Each participant received an e-mail with a secure (password-protected) ORI Zoom link on the 
assessment day. 
5. On the assessment day, the assessor: 
a. initiated a phone call 
b. described the assessment protocols 
c. visually checked the home environment 
d. conducted the assessment per the protocol 
The assessment was completed by an outcome assessor who was blinded to group allocation. 
6. Those who met the study eligibility criteria, signed the study consent form, and completed 
baseline assessment were randomized into one of the three interventions. 
 
2. Modifications made to intervention setting 
The originally planned community-based intervention delivery approach was replaced by hosting the 
intervention classes online via videoconferencing using Zoom. This switch from in-person class delivery 
mode to a home-based online delivery mode allowed us to both effectively and efficiently resume our 
intervention while maintaining the interactive features of in-person, instructor-led training in a face-to-
face social context.  
 
3. Modifications made to interventions  
Prior to resuming the intervention classes, appropriate modifications were made to fit the online 
videoconferencing delivery method. While the original in-person exercise protocol was used for each 
intervention group, some minor practical modifications were made to fit the interventions in a home 
situation. The home-based videoconferencing protocol included the following: 
1. Participants received an ORI-initiated Zoom link sent via e-mail, and the exercises were done at 
home. 
2. Instructors delivered the exercise classes from our ORI research facility. 
3. Virtual class sessions were delivered twice per week, as originally planned. 
4. Each exercise class session was closely supervised and monitored by the project staff for safety 
and compliance.  
 
4. Modifications made to outcome measures 
Removal of planned outcome measures. To accommodate the online assessment environment, we had 
to remove a number of the secondary measures that were planned via the in-person assessment protocol. 
Removal of the following measures from the assessment protocol were approved by ORI’s IRB (dated 
May 5, 2020):  
(a) all computerized cognitive measures (One Card Learning, Block Design, Identification, 
International Shipping List, and One Back)  
(b)  Stroop test 
(c)  Digit Symbol coding 
(d)  the lab-based iTUG (6-meter walk) test involving walking under single-task and dual-task 
conditions 
 

35 
 
Modifications to other outcome measures. To accommodate the outcome assessment conducted in a 
virtual (home) environment, modifications were made to some of the other cognitive and physical 
performance measures. Details for each are described below. Modifications to the measures were 
approved by ORI’s IRB. These modified measures were pilot evaluated, and results from these 
evaluations have been published.40,41  
Montreal Cognitive Assessment (MoCA). In the Visuospatial/Executive section of the MoCA, 
participants were asked to verbally connect each letter to the corresponding number for the Trail Making 
task and draw both the object (e.g., cube) and clock on a piece of paper. After they completed the task, 
participants were asked to show the drawing to the assessor for evaluation. In completing the “Read list of 
letters” task in the Attention section, the letter-tapping task was replaced by asking participants to count 
the number of A’s in the list.  
Trail-Making B (TMT-B). Due to remote operation, this measure was administered verbally. 
Specifically, the hand-drawing task was replaced by asking participants to verbally recite numbers of 
letters out loud, alternating between numbers and letters (i.e., 1-A-2-B-3-C, etc.). The study assessor 
recorded the time needed to complete the task.  
Timed Up&Go (TUG). Before each walk, participants were asked to measure or estimate a 10-foot (3-
meter) distance away from a table or device (PC or iPad) (see the detail below). The remaining test 
procedure followed the in-person assessment protocol, that is, participants were asked to (a) stand up 
from a chair, (b) walk (10 feet forward) at a normal pace to an imaginary straight line on the floor, (c) 
turn, (d) walk back (10 feet) to the chair, and (e) sit down. The same protocol was applied for the walk 
under a dual-task condition, where participants were asked to walk while performing an arithmetic task 
(i.e., starting at the number 81 and sequentially subtracting 3 from the resulting number). No specific 
verbal instructions were given for prioritization of one of the walking tasks during the dual-task walking 
trial.  
Instructions. Prior to each of the scheduled assessments, participants were informed, by an e-mail, to 
prepare the following for the upcoming TUG assessment:  
a. a measuring tape 
b. a piece of paper 
c. a standard height chair (without wheels) 
d. an open home space of at least 12 feet in length (of which 10 feet will be measured on the 
floor for the walk test) 
e. regular footwear 
On the day of the assessment, participants were asked to (a) confirm the 10-foot walkway, (b) place 
the chair at the end of the walkway (away from the viewing device) and the piece of paper on the floor at 
the other end of walkway (near the viewing device), and (c) leave 2 extra feet to allow a safe turn around 
the piece of paper.  
The total duration (in seconds) during the 20-feet walk (10 feet away from the chair and 10 feet 
toward the chair), at normal pace, was recorded for both walking conditions. The dual-task costs, 
measured in percentage, at each time point were calculated as follows: (dual-task gait speed – single-task 
gait speed) / single-task gait speed x 100). The final dual-task costs on gait speed were estimated by 
taking the difference between dual-task costs at baseline and at 6 months, with negative values indicating 
deteriorated performance in dual-task walking speed (i.e., dual-task cost), whereas positive values 
represent an improvement in dual-task walking speed with respect to single-task (i.e., dual-task benefit). 
 
5. Modifications made to the assessment protocol  
Modified assessment procedure. We modified our follow-up assessment protocol (involving both 
cognitive and physical performance measures) to accommodate the switch from in-person to online 
assessment conducted via Zoom. Modifications included the following: 

36 
 
1. The study assessor made a phone call or sent an e-mail reminder to the study participant, 
notifying the participant of the follow-up assessment and requesting that it be scheduled. 
2. Prior to the scheduled assessment date, the participant received an e-mail with a secure ORI 
Zoom link. 
3. On the assessment day, the assessor: 
a. admitted the participant into the Zoom session  
b. described the assessment activities 
c. visually checked the home environment 
d. conducted the assessment per the protocol. 
Special note: Because there was no in-person assessment, information about each participant’s 
weight, height, and blood pressure was collected via a self-report during the online assessment. 
 
Modified survey completion procedure. We established a secure online site to allow participants to 
complete their study surveys online via Qualtrics (Qualtrics.com) if they chose to. Participants could still 
choose to submit their surveys via regular U.S. mail, as planned in the original protocol.  
 
6. Modifications made to data analysis 
No major modifications were made from the original SAP. However, in order to examine whether the 
intervention effects were impacted by shifting from in-person (before COVID-19 restrictions) to virtual 
delivery, we conducted post hoc sensitivity analyses on the two primary outcomes by excluding those 
who participated in our COVID-19-induced hybrid protocol. 
 
 
 

37 
 
References Cited 
1. Alzheimer’s Association. 2019 Alzheimer’s Disease Facts and Figures. Available at: 
https://www.alz.org/media/Documents/alzheimers-facts-and-figures-2019-r.pdf. Accessed May 30, 
2022.  
2. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: 
clinical characterization and outcome. Arch Neurol 1999;56:303–8. 
3. Roberts R, Knopman DS. Classification and epidemiology of MCI. Clin Geriatr Med 
2013;29(4):753-72.  
4. Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia: meta-
analysis of 41 robust inception cohort studies. Acta Psychiatr Scand 2009;119:252-65. 
5. Ward A, Tardiff S, Dye C, Arrighi HM. Rate of conversion from prodromal Alzheimer’s disease to 
Alzheimer’s dementia: a systematic review of the literature. Dement Geriatr Cogn Dis Extra 
2013;3:320-32 
6. Northey JM, Cherbuin N, Pumpa KL, Smee DJ, Rattray B. Exercise interventions for cognitive 
function in adults older than 50: a systematic review with meta-analysis. Br J Sports Med 2017;0:1–9. 
7. Panza GA, Taylor BA, MacDonald HV, et al. Can exercise improve cognitive symptoms of 
Alzheimer's disease? J Am Geriatr Soc 2018;66(3):487-495. 
8. Gheysen F, Poppe L, DeSmet A, et al. Physical activity to improve cognition in older adults: can 
physical activity programs enriched with cognitive challenges enhance the effects? A systematic 
review and meta-analysis. Int J Behav Nutr Phy Act 2018;15:63.  
9. Wayne PM, Walsh JN, Taylor-Piliae RE, et al. The impact of Tai Chi on cognitive performance in 
older adults: A systematic review and meta-analysis. J Am Geriatr Soc 2014;62(1):25-39. 
10. Li F, Harmer P, Fitzgerald K, et al. Effectiveness of a therapeutic Tai Ji Quan intervention vs a 
multimodal exercise intervention to prevent falls among older adults at high risk of falling. JAMA 
Intern Med 2018(10):1301-1310.  
11. Li F, Harmer P. Liu P. Tai Ji Quan and global cognitive function in older adults with mild cognitive 
impairment: a pilot study. Arch Gerontol Geriatr 2014;58:434–439.  
12. Li F, Harmer P, Chou L-S. Dual-task walking capacity mediates Tai Ji impact on physical and 
cognitive function. Med Sci Sports Exer 2019;51(11):2318-2324. 
13. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Int Med 2004;256:183-194. 
14. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild 
cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute of 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. 
Alzheimer Dement 2011;7(3):270-279. 
15. Hues C, Berg L, Danziger W, Coben L, Martin R. A new clinical scale for the staging of dementia. Br 
J Psychi 1982;140:566-572. 
16. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”. A practical method for grading the 
cognitive state of patients for the clinician. J Psychiatric Res 1975:12:189-198. 
17. Almeida OP, Almeida SA. Short versions of the geriatric depression scale: a study of their validity for 
the diagnosis of a major depressive episode according to ICD-10 and DSM-IV. Int J Geriatr 
Psychiatry 1999;14(10):858-865. 
18. National Archives. Code of Federal Regulations. Available at: https://www.ecfr.gov/on/2018-07-
19/title-45/subtitle-A/subchapter-A/part-46#46.102. Accessed June 1, 2019. 
19. Li F. Transforming traditional Tai Ji Quan techniques into integrative movement therapy – Tai Ji 
Quan: Moving for Better Balance. J Sport Health Sci 2012;3:9-15. 
20. Li, F, Harmer P, Fisher KJ, McAuley E, Chaumeton N, Eckstrom E, Wilson NL. Tai Chi and fall 
reductions in older adults: A randomized controlled trial. J Gerontol: Med Sci 2005;60A:66-74. 
21. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, 
Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive 
impairment. J Am Geriatr Soc. 2005;53(4):695-9. 

38 
 
22. van Dyck, CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med 
2023;388;9-21. 
23. Corrigan JD, Hinkeldey MS. Relationships between Parts A and B of the Trail Making Test. J Clin 
Psychol 1987;43:402–9. 
24. Golden CJ, Freshwater SM. Stroop Color and Word Test Adult Version: A Manual for Clinical and 
Experimental Uses. Wood Dale, Illinois: Skoelting; 2002. 
25. Sager MA, Hermann BP, LaRue A, Woodard JL. Screening for Dementia in community-based 
memory clinics. Wisconsin Medical Journal 2006;105(7):25-29. 
26. Wechsler D. Wechsler Adult Intelligence Scale – IV. Pearson: Bloomington, MN: Psychological 
Corporation; 1980.  
27. Duncan PW, Weiner DK, Chandler J, Studenski S. Functional reach: a new clinical measure of 
balance. J Gerontol 1990;45(6):M192-M197.  
28. Guralnik JM, Simonsick EM, Ferrucci L, et al. A short physical performance battery assessing lower 
extremity function: association with self-reported disability and prediction of mortality and nursing 
home admission. J Gerontol. 1994;49(2):M85-M94. 
29. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly 
persons. J Am Geriatr Soc 1991;39(2):142-148. 
30. Farias ST, Mungas D, Harvey DJ, Simmons A, Reed BR, DeCarli C. The measurement of Everyday 
Cognition (ECog): Development and validation of a short form. Alzheimers Dement 2011;7(6):593-
601. 
31. Buysse DJ, Reynolds CF III, Monk TH, et al. The Pittsburgh Sleep Quality Index: A new instrument 
for psychiatric practice and research. Psychiatry Res 1989;28:193-213. 
32. The EuroQol Group: The EuroQol – a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16:199–208. doi:10.1016/0168-8510(90)90421-9 
33. Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing 
of the D1 valuation model. Med Care 2005;43:203–220. 
34. Craig CL, et al. International physical activity questionnaire: 12-country reliability and validity. Med 
Sci Sports Exerc 2003;35:1381-95. 
35. Li F, Duncan TE, McAuley E, Harmer P, Smolkowski K. A didactic example of latent curve analysis 
applicable to the study of aging. J Aging Health 2000;12(3):388-425. 
36. Baker LD, Frank LL, Foster-Schubert K, et al. Effects of aerobic exercise on mild cognitive 
impairment: a controlled trial. Arch Neurol 2010;67(1):71-79. 
37. Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older 
adults at risk for Alzheimer disease: a randomized trial. JAMA 2008;300(9):1027-37. 
38. Wu CY, Hung SJ, Lin KC, et al. Responsiveness, minimal clinically important difference, and 
validity of the MoCA in stroke rehabilitation. Occup Ther Int 2019;2019:2517658. 
39. Orkin AM, Gill PJ, Ghersi D, et al. Guidelines for Reporting Trial Protocols and Completed Trials 
Modified Due to the COVID-19 Pandemic and Other Extenuating Circumstances: The CONSERVE 
2021 Statement. JAMA 2021;326(3):257–265.  
40. Li F, Harmer P, Voit J, Chou LS. Implementing an online virtual falls prevention intervention during 
a public health pandemic for older adults with mild cognitive impairment: A feasibility trial. Clin 
Interv Aging 2021;16:973-983. 
41. Li F, Harmer P, Fitzgerald K, Winters-Stone K. A cognitively enhanced, virtual exercise intervention 
for older adults with mild cognitive impairment: A feasibility trial. BMC Geriatrics 2022;22:76.