Evolving methods to combine cognitive and physical training for individuals with mild cognitive impairment: study protocol for a randomized controlled study
Lee et al. Trials
Evolving methods to combine cognitive and physical training for individuals with mild cognitive impairment: study protocol for a randomized controlled study
Ching-yi Wu 0 1
Ching-hung Teng 1
Poyu Chen 1
0 Healthy Ageing Research Center, Chang Gung University , Taoyuan , Taiwan
1 Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, College of Medicine, Chang Gung University , 259 Wenhua 1st Rd, Taoyuan 333 , Taiwan
Background: Nonpharmacologic interventions, such as cognitive training or physical exercise, are effective in improving cognitive functions for older adults with mild cognitive impairment (MCI). Some researchers have proposed that combining physical exercise with cognitive training may augment the benefits of cognition. However, strong evidence is lacking regarding whether a combined therapy is superior to a single type of training for older adults with MCI. Moreover, which combination approach - combining physical exercise with cognitive training sequentially or simultaneously - is more advantageous for cognitive improvement is not yet clear. This proposed study is designed to clarify these questions. Methods/design: This study is a single-blinded, multicenter, randomized controlled trial. Eighty individuals with MCI will be recruited and randomly assigned to cognitive training (COG), physical exercise training (PE), sequential training (SEQ), and dual-task training (DUAL) groups. The intervention programs will be 90 min/day, 2-3 days/week, for a total of 36 training sessions. The participants in the SEQ group will first perform 45 min of physical exercise followed by 45 min of cognitive training, whereas those in the DUAL group will perform physical exercise and cognitive training simultaneously. Participants will be assessed at baseline, after the intervention, and at 6-month follow-up. The primary cognitive outcome tests will include the Montreal Cognitive Assessment and the color-naming Stroop test. Other outcomes will include assessments that evaluate the cognitive, physical, and daily functions of older adults with MCI. Discussion: The results of this proposed study will provide important information regarding the feasibility and intervention effects of combining physical exercise and cognitive training for older individuals with MCI.
Mild cognitive impairment; Physical exercise; Cognitive training; Hybrid therapy
Mild cognitive impairment (MCI) or minor
neurocognitive disorder represents an intermediate stage
between cognitive intactness and clinically diagnosed
dementia [1, 2]. Although definite diagnostic criteria
are lacking, individuals with MCI are characterized by
self- or caregiver-reported memory and/or cognitive
complaints, objective cognitive impairment, but
independence in performing daily activities . People with
MCI can perform activities of daily living (ADLs)
without assistance, but they appear to have a greater risk of
falls and other adverse consequences .
Furthermore, MCI is a precursor of dementia or other
severe cognitive disorders. The progression rate from
MCI to dementia ranges from 10 to 15 % each year, and
severe cognitive impairment or dementia will develop in
more than 50 % of the MCI population within 5 years
. Therefore, providing early and appropriate
interventions to individuals who manifest MCI may reduce the
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risk of adverse events, prevent cognitive decline, and
ultimately, could decrease the burden of their caregivers
and related medical expenses.
Clinical pharmacologic trials that used drugs to treat
MCI have not been very successful [2, 4]. More
encouraging results have been reported from
nonpharmacologic treatments such as cognitive training or physical
exercise [5, 6]. Cognitive training could enhance brain
activation in the areas related to memory . A
systematic review has demonstrated that cognitive training
programs have some positive effects on cognitive
functions in older adults with and without MCI, especially
on the specific tasks being practiced . Physical
exercise, on the other hand, had neuroprotective effects and
lowered the risk of developing Alzheimer’s disease and
related cognitive disorders . A meta-analysis showed
that in addition to health-related physical fitness and
daily functions, physical exercise is favorable for
unspecific cognitive abilities in older individuals with and
without MCI . It is thus suggested that physical
exercise facilitates neuroplastic potential (e.g., neurogenesis)
and that cognitive training induces positive
neuroplastic changes for improving cognitive function .
Facilitation and guidance of neuroplasticity are two
challenges of positive neuroplastic changes for cognitive
gains. To overcome these two challenges, some recent
studies have proposed that combining physical exercise
and cognitive training may augment the intervention
benefits on cognition for individuals with MCI [10, 11].
Animal studies have demonstrated that combining
physical exercise and cognitive training promoted neurogenesis
and angiogenesis, which resulted in greater cognitive
improvement than exercise alone [12, 13]. Studies of
community-dwelling older individuals without cognitive
complaints found that combining physical exercise with
cognitive training significantly improved memory and
general cognitive functions compared with no
intervention or a single type of training [10, 14].
Only a few studies have investigated the combined
effects of physical exercise and cognitive training in
people with MCI [15–18]. Barnes et al. recruited
inactive older adults with cognitive complaints and
found that the participants who received both aerobic
exercise and mental activity training showed
improvements in global cognitive function comparable to those
who received a single mode (aerobic exercise only or
mental activity only) of training . Another study by
Fiatarone Singh et al.  examined the sequential combination
effects of progressive resistance training and cognitive
training in older adults with MCI. Surprisingly and contrary to
their initial hypotheses, the participants who received
hybrid training improved less than those who participated in
progressive resistance training alone or cognitive training
Kounti et al.  and Suzuki et al.  designed
specific therapeutic programs that combined physical and
cognitive training in a dual-task format in which physical
exercise and a cognitive task were performed
simultaneously. Both studies found that the combined therapy
induced significantly greater improvements on various
cognitive functions in adults with MCI compared with
the control groups that received health education
programs [16, 17]. Another trial of dual-task training found
that group-based training for 26 weeks improved global
cognitive function in older adults with MCI compared
with an exercise-only group, which highlighted the
finding that group-based dual-task training enhanced global
cognitive function .
As can be observed from this brief review, the
treatment effects of combined physical exercise and cognitive
training have varied across studies. The diverse
treatment benefits could be attributed to different training
approaches as well as to different combination methods
– combining physical exercise and cognitive training
sequentially or simultaneously – that are used in the
studies. In addition, the control groups in those studies
were not always dose-matched, did not involve active
intervention, or were uneven (i.e., the study controlled
for the exercise component but not the cognitive
component). Hence, it is difficult to draw a consensus
regarding (1) whether combining physical exercise and
cognitive training is superior to a single mode of training
for older individuals with MCI, and (2) which
combination method (sequential versus simultaneous training)
might result in better treatment outcomes.
Sequential training combines physical exercise and
cognitive training sequentially. Studies conducted in
rats/mice and in cognitively intact individuals have
proposed that performing physical exercise before cognitive
training may increase arousal level and thus facilitate
cognitive task performance [20, 21]. Furthermore,
physical exercise before cognitive training may enhance
memory consolidation and influence the performance of
memory retrieval [22, 23]. Winter et al.  examined
the effects of a single bout of intense exercise on
vocabulary learning and memory. The participants who
engaged in intense exercise acquired the vocabularies
20 % faster than those who did not exercise or who
engaged in low-intensity exercise. More interestingly, the
intense exercise group also retained the vocabularies
better than the control groups 1 week after the training
. Neurophysiologic measures revealed that exercise
led to elevated levels of brain-derived neurotrophic
factor and increased the cortical activation level of the
prefrontal and occipital areas [20, 24], which are
important for subsequent cognitive training.
In dual-task training, physical exercise and cognitive
tasks are performed simultaneously. Dual tasking is one
executive function that is especially important for ADLs.
Recent studies revealed strong correlations between
performance of ADLs and executive function in older adults
. Using functional near-infrared spectroscopy, Doi et
al. found that increased prefrontal activation during dual
tasking was correlated with executive functions in older
adults with MCI . Imaging studies in cognitively
intact young and old adults also showed that behavioral
improvement after dual-task training was associated
with changes in prefrontal activation [27, 28]. The
evidence from these studies suggests that an intervention
using dual-task training could be a promising approach
for individuals with MCI.
Behavioral and neurophysiologic evidence suggests
that combining physical exercise and cognitive training
sequentially or simultaneously has benefits on cognitive
functions. However, strong evidence is lacking
regarding which combination approach is more feasible,
acceptable, and advantageous for older adults with
MCI. This proposed randomized controlled trial is
designed to address three specific aims: (1) to determine
whether combined therapy, sequentially or simultaneously,
is a feasible approach to train older adults with MCI, (2) to
determine whether combined therapy can induce superior
treatment outcomes compared with a single mode of
intervention, and (3) to compare which combination
approach – sequential or simultaneous – is more
advantageous for improving cognitive functions, physical
fitness, ADLs, and quality of life in adults with MCI.
We anticipate recruiting 80 participants from
community facilities, day care centers, and nursing homes. The
inclusion criteria are (1) men and women aged 60 years
or older, (2) the ability to follow instructions, (3)
objective cognitive impairment as measured by a Montreal
Cognitive Assessment (MoCA) score < 26, (4) having
self- or informant-reported memory or cognitive
complaints, (5) the ability to perform ADLs, and (6) no
diagnosed dementia . Participants who have other
neurologic disorders or an unstable medical condition
(e.g., heart failure) that prevents them from performing
physical exercise or cognitive training will be excluded.
The participants will be randomly assigned to four
groups: cognitive training (COG), physical exercise
training (PE), sequential training (SEQ), and dual-task
training (DUAL) groups. We specifically include the
COG and PE groups as the “active control” groups to
ensure that all participants can benefit from the study.
Sample size estimation
No published study to date has compared the treatment
effects of cognitive training, physical exercise training,
sequential training, and dual-task training in older
adults with MCI. Therefore, we estimated the sample
size for the current study from the studies that
compared sequential training or dual-task training with
control intervention(s) in older adults with cognitive
complaints [15–17]. Because our primary outcomes will
include global cognitive function and executive
function, we calculated the sample sizes on the outcomes
that involve these cognitive aspects. Kounti et al. 
found significant benefits of dual-task training on
global cognitive function, as measured by the Mini-Mental
State Examination (MMSE), in participants with MCI.
Compared with the control intervention, the calculated
effect size (Cohen’s d) was 0.63 for dual-task training
. Using G*Power software  with a power of 0.80
and a two-sided type I error of 0.05, the calculated total
sample size for the current study will be 20 participants
(i.e., 5 participants in each group). The study conducted
by Suzuki et al. showed that compared with the control
group, the multicomponent dual-task training group
had greater improvement in MMSE after intervention
. Based on the calculated effect size for the MMSE
(Cohen’s d = 0.45), we estimated the sample size for the
current study will be 12 participants in each group.
Barnes et al. investigated the treatment effects of a
sequential combination of physical exercise and mental
activity training and found significant benefits on the
Useful Field of View (UFoV), a measure of executive
function, in older adults with cognitive complaints .
We used the calculated effect size for the UFoV from
Barnes’ study (Cohen’s d = 0.21)  to estimate a
sample size of 32 participants in each group.
Similar to the study design conducted by Barnes et al.
, we employ the active control groups (i.e., COG and
PE groups) instead of a no-treatment or passive control
group. On the other hand, the primary outcome
measures used in the current study are closer to those used
by Kounti et al.  and Suzuki et al. . Hence, a
mean value from the estimated sample sizes of the three
studies was calculated, and we anticipated that recruiting
16 participants for each group should be sufficient for
this proposed study.
The dropout rate in our pilot trial was approximately
20 % during the intervention period; hence, we plan to
recruit 20 participants for each group resulting in a total
sample size of 80 patients for four groups.
Study design and procedures
This proposed study is a randomized controlled trial
with pretest, posttest, and 6-month follow-up
assessments (Fig. 1). The study protocol is approved by the
Chang Gung University Institutional Review Board.
Intervention therapists will screen for potential
participants and obtain signed informed consents from the
Fig. 1 Flow diagram of the study
eligible individuals before they participate in the study.
The enrolled participants will be randomly assigned into
the COG, PE, SEQ, or DUAL group with the allocation
ratio of 1:1:1:1 . Random tables based on the type of
recruitment site (day care centers versus nursing homes
versus community) will be generated by an independent
research assistant using the web-based Research
Randomizer tool (freely available at http://www.randomizer.org/)
. The research assistant will use the random table to
decide the group allocation of a newly enrolled participant
and will inform the relevant therapist to carry out the
respective intervention. The intervention therapist will not
know the group allocation until the pretest measurement
is completed. Each intervention group will consist of three
to five participants and will be guided by a trained
therapist. The participants will engage in 90 min of training, two
to three times a week, for a total of 36 training sessions.
Outcome measures, including cognitive functions,
physical functions, ADLs, quality of life, and social
participation, will be assessed before the treatment
(pretest), after 36 training sessions (posttest), and 6 months
after treatment (follow-up test). All outcome measures
will be evaluated by independent evaluators who will be
blinded to the group allocation of the participants. The
evaluators will be trained by the principal investigator
and senior therapists before the study begins to ensure
that the measures will be conducted consistently. The
assessments will be completed within 1 week before
and after the intervention.
The first participant who adhered to the current study
protocol was recruited in August 2015, although we
piloted the study procedures in March 2015. We
anticipate continuing to recruit until the sample size of 80
participants is reached.
The intervention therapists will be qualified
occupational therapists or physical therapists, and will be
trained by the principle investigator and the senior
therapists to ensure standardized administration of the
intervention protocols. The therapists will be required
to complete a competency examination before
providing the interventions. During the intervention period,
the therapists will keep a daily log to record the
progress and responses of each participant.
BrainHQ (Posit Science Inc., San Francisco, CA, USA)
will be used to train different cognitive functions of the
participants in the COG group. BrainHQ is a game-based
computer program specifically designed to train various
cognitive functions. This cerebral neuroplasticity-based
computerized cognitive training program has been
demonstrated to have significant benefits on various cognitive
functions in community-dwelling older adults [33, 34].
During the training sessions, laptops with touchscreens
will be provided to the participants so that they can
play the computer-based games without having to
manipulate a mouse. The BrainHQ games that involve
cognitive functions of visuospatial processing, attention,
memory, language, and logical thinking will be chosen
for the participants to practice.
The participants will practice two to three games in 90
min, and the difficulty of the tasks will be adjusted to
each individual's ability. The participants will not
compete against each other but will play the games based on
their own capability. The task will become more
challenging as a participant improves. The intervention will
contain 10 min of warm-up (explaining the rules), 70
min of cognitive training, and 10 min of cool-down
(asking participants to recall and provide feedback to the
activities). Each participant’s performance will be recorded
in the daily log.
Previous studies suggested that a multimodal exercise
program (aerobic with balance and strength training)
may induce greater effects than a single mode of
exercise [10, 35]. Therefore, we incorporate a
multicomponent exercise program that includes balance training,
strength training, and upper and lower limb aerobic
exercise. The 90-min training session will be divided into
two parts. In the first 45-min session, the participants
will engage in aerobic exercise. The target intensity of
the aerobic training will be 40 to 70 % of the maximal
heart rate. Our pilot testing revealed that heart-related
problems in some older people may prohibit them from
achieving an aerobic level of exercise if measured by
maximal heart rate. Thus, we will also adopt a Borg
rating of perceived exertion (RPE) score of 12 to 14 as
an indicator of achieving the aerobic level . The
therapists will adjust the aerobic level according to the
capability of each participant, and the participants can rest
In the second 45-min session, the participants will
engage in balance training and muscle strengthening.
Static and dynamic balance training will be carried out
under sitting and standing positions. Thera-Bands and
weights will be used for the muscle-strengthening
programs of the upper and lower limb muscles. The order
of balance training and muscle strengthening will be
intermixed. Each 45-min training session will contain 5
min of warm-up, 35 min of physical exercise, and 5 min
of cool-down. The exercises will be performed without
The participants in the SEQ group will first perform 45
min of physical exercise, followed by 45 min of cognitive
training. During the physical exercise session, the
participants will engage in 5 min of warm-up, 35 min of
physical exercise, and 5 min of cool-down. The physical
exercise programs will involve 15 to 17 min of aerobic
exercise and 18 to 20 min of balance training and
muscle strengthening. During the cognitive training
session, the intervention therapists will spend 5 min
explaining the rules of the tasks. Then, the participants
will engage in 35 min of cognitive training with the
BrainHQ games, as described in the COG group. The
participants will be given one or two games to practice
during the training session. The session will end with 5
min of cool-down activities such as proving feedback
and asking the participants to recall the activities.
Participants in the DUAL group will be instructed to
perform physical exercise and cognitive tasks
simultaneously. Because dual-task training is a more challenging
approach for participants with MCI, we have used
PowerPoint presentations to design simpler versions of
the BrainHQ games to make sure that the participants
will be able to follow the instructions and engage in the
games (Fig. 2). Similar to the COG and SEQ groups, the
difficulty of the cognitive tasks will be adjusted as the
participants improve in their performance. The physical
exercises involved in this group will be carefully chosen
to ensure that our participants can effectively perform
the exercises while focusing on the cognitive tasks. The
exercise programs will also include the components of
aerobic exercise (e.g., stepping in place), balance training
(e.g., static standing or walking), and muscle
strengthening (e.g., using Thera-Band or weights). Examples of the
dual-task training programs include practicing math
calculations while stepping and search for a different bird
on the screen (Fig. 2a) while strengthening the hip
muscles with a Thera-Band.
During the 90-min dual-task training session, the
participants will engage in two combinations of physical
activity and cognitive training program. For each
combination, the intervention therapists will spend 10 min
explaining the cognitive task and the method to
perform the physical activity, followed by 35 min of
Sociodemographic variables, including age, gender,
education level, comorbidity, smoking, alcohol intake, and
depressive symptoms, will be recorded during the initial
evaluation. This study will assess the participants before,
immediately after, and 6 months after the intervention
programs. The outcome measures will include several
domains: cognitive functions, physical functions, ADLs,
quality of life, and social participation.
Primary outcome measures
The MoCA will be used to assess general cognitive
function. The MoCA examines visuospatial processing,
naming, verbal fluency, abstract concept, short-term memory,
digit forward and backward span, counting, and
orientation. The total score for the MoCA is 30, with a higher
number indicating a more intact cognitive function. The
MoCA has been shown to be a valid and promising tool
to detect MCI and early Alzheimer’s disease .
The color-naming Stroop test will be used to assess
the abilities of inhibition, set-shifting, and selective
attention . The participants will be tested under
congruent and incongruent conditions. In the congruent
condition, the ink color of a word is consistent with the
Fig. 2 Examples of the PowerPoint versions of BrainHQ games. a Hawk eye: search for a different bird and determine the location of that bird.
b Divided attention: determine whether the two figures have the same color, shape, or number
written color name; however, the ink color differs from
the written color name under the incongruent condition.
The participants will be required to read out the ink
color of the word (but not the word itself ) as accurately
and as soon as possible. The time to complete the task
will be calculated for each condition [38, 39].
Secondary outcome measures
Cognitive functions Subtests of the Wechsler Adult
Intelligence Scale (WAIS) and the Wechsler Memory
Scale (WMS) will be used to measure memory and
cognitive functions. The subtests of WAIS will include digit
symbol-coding (total score = 133) and matrix reasoning
(total scale = 26). The WMS subtests will consist of facial
recognition (total scale = 48), verbal paired associates
(total scale = 32), word lists (total scale = 48), and spatial
span (total scale = 32). The WAIS and the WMS have
high reliability and validity and are often used to
differentiate individuals with memory or cognitive deficits
from those who are cognitively intact. The WAIS and
the WMS can also be used to assess cognitive
improvements after a specific intervention .
Useful Field of View (UFoV) is the visual area over
which useful information can be obtained at a quick
glance without eye or head movements. This UFoV will
be assessed with the Double Decision game in the
BrainHQ program. The participants will be asked to
select a particular symbol shape located at the center while
remembering the position of another image presented
on the screen. The UFoV requires the abilities of
visuomotor processing, divided attention, and selective
Dual-task tests will be used to assess an individual’s
ability to perform two tasks simultaneously. The
dualtask test could reflect the attentional limitation, central
executive ability, and automatic processing ability of the
participant [42, 43]. The dual-task performance will be
evaluated while the individual performs the 10-m Walk
Test and the Box and Block Test (BBT). For the 10-m
Walk Test, the participants will be asked to walk 10 m
at their comfortable walking speed. The walking time
and number of steps will be recorded. The BBT will be
assessed with a wooden box containing two equally sized
compartments. Cubes will be placed in one
compartment, and the participants will be instructed to use
their dominant hand to move the cubes to the other
compartment one-by-one at their fastest speed. The
number of cubes moved within 60 s will be recorded.
The secondary cognitive task that will be performed
during the 10-m Walk Test or BBT will be the counting
task and the response time task. For the math
calculation, the participants will be required to count
backward by 7 from a given number (e.g., 100 or 200); for
the response time task, the participants will be required
to listen to a series of sounds and respond to a high- or
low-pitch tone as fast as possible. The results of the
dual-task tests will provide information about whether
the two tasks compete for the same class of neural
resources or one of the tasks can be carried out
Physical functions The Timed Up and Go (TUG) test
will be used to assess mobility and dynamic balance
ability. The participants will be required to stand up from a
chair, walk 3 m at their comfortable speed, turn around,
then walk back to the chair and sit down. The time to
complete the TUG test has been shown to be a good
indicator to detect potential people who are likely to fall
and frail older people . The test-retest reliability of
the TUG on individuals with cognitive impairment is
The 30-s Chair-Stand Test (CST) will be assessed to
indicate the strength and endurance of the lower
extremities. The participants are asked to stand up from a
standardized chair and then sit down as many times as
possible within 30 s. The feasibility and reliability of
using the CST in people with cognitive impairment have
been established to be good .
The Chinese version of the International Physical
Activity Questionnaires (IPAQ) is an international
measure for health-related physical activity. This study will
use a short form of the IPAQ to assess changes in
physical activity before and after the intervention. The
reliability and validity of the IPAQ has been established
across 12 countries .
ActiGraph GX3 accelerometers (ActiGraph, Shalimar,
FL, USA) will be used to measure physical activity
outside the laboratory settings [48, 49]. The participants will
be asked to wear the actigraphy on both wrists all day
for three consecutive weekdays before and after the
intervention. The number and average counts of
movement per minute for the participants will be recorded
and calculated by the accelerometer. Data recorded by
the actigraphy will be analyzed using MAHUFFE
software (http://www.mrc-epid.cam.ac.uk/). The use of
actigraphy to measure arm use and physical activity has
been established for older people .
Decreased muscle mass, muscle strength, and
movement quality are related to the aging process that will
affect physical activities in older adults . Therefore,
muscle strength will also be recorded on both sides for
knee extension, knee flexion, and grip strength using a
handheld dynamometer (Commander Power Track
Muscle Dynamometer Manual Muscle Tester, JTECH
Medical) and a Jamar Handgrip Dynamometer.
ADLs, quality of life, and social participation The
ADLs will be assessed with the Chinese version of the
Disability Assessment for Dementia (DAD), a
questionnaire for evaluating the basic ADLs and instrumental
ADLs in participants in the early stages of dementia.
The DAD subtests include hygiene, dressing,
continence, eating, meal preparation, telephoning, going on
an outing, finance and correspondence, medications,
and leisure and housework. The DAD assesses an
individual’s performance from the perspectives of initiation,
planning and organization, and effective performance .
In addition, the Chinese versions of the Barthel Index
(BI) and the Lawton Instrumental Activities of Daily
Living Scale (Lawton IADL) will be assessed. These
questionnaires measure the performance of feeding,
grooming, bathing, toileting, transferring, and tool
using, among others. The BI and the Lawton IADL are
both commonly used to evaluate older adults with
cognitive impairment .
The treatment effects on quality of life will be
assessed with the Chinese versions of the Quality of
Life in Alzheimer’s Disease Instrument (QoLAD), the
Caregiver Burden Inventory (CBI), and the short form
of the Geriatric Depression Scale (GDS). The Chinese
versions of these assessments have good reliability and
Finally, social participation will be assessed with the
Community Integration Questionnaire (CIQ), which
measures items relevant to home integration, social
integration, and productive activities . The reliability and
validity of the CIQ have been established in patients
with traumatic brain injuries and stroke [56, 57].
We will use analysis of variance (ANOVA) and χ2 to
analyze differences in baseline characteristics and baseline
outcome measures among the groups. Any differences
among the groups in the baseline sociodemographic
variables will become covariates in the subsequent statistical
analysis. Repeated measures ANOVA will be used to
determine the intervention effects for the four groups. A
significant statistical level will be set at 0.05 for all
comparisons. Besides p values, effect size η2 will also be
calculated to determine the group difference for each outcome
measure. An η2 greater than 0.138 is considered to be a
large effect, an η2 between 0.138 and 0.059 is a moderate
effect, and an η2 between 0.01 and 0.059 is a small effect
. Intention-to-treat will be used for missing data. Data
analysis will be performed with PASW Statistics 18.0
software (IBM Corp., Armonk, NY, USA).
Data management and monitoring
Outcome measures will be recorded with pen-and-paper
during assessment. A trained research assistant will
manually enter the data into an electronic database. A
second research assistant independent from this study
will check the quality and accuracy. The paper data
collection sheets and signed informed consents will be
stored in a locked cabinet, and the electronic database
will be password-protected. Any unanticipated adverse
events that occur during the course of data collection
will be reported to the Institutional Review Board in
accordance with the procedures of Chang Gung University,
Taoyuan, Taiwan. For any revised study procedure, the
modification will be submitted to the Chang Gung
University Institutional Review Board for approval and
to ClinicalTrials.gov. The data will be kept confidential
with only limited access to research investigators and
related research assistants and graduate students.
Potential adverse events
One potential adverse event that may occur during the
intervention is an increased risk of falls when physical
exercises are performed in the standing position. To
minimize the risks of falls, the intervention therapists
will ensure that group exercises are performed while
sitting. When the participants are required to stand up
or walk around to enhance their balance abilities,
oneon-one therapy will be conducted to ensure the
The goals of this proposed study are to first determine
whether the combined therapy – joint physical exercise
and cognitive training – is a feasible approach for
training older people with MCI and, second, to investigate
whether the combined therapy will result in superior
cognitive, physical, ADLs, and quality of life outcomes
compared with exercise or cognitive training alone.
Some studies have used combined therapy to train
adults with MCI, but the results were inconsistent.
Although some studies found that the combined therapy
is more advantageous for cognitive functions than a
single mode of training, some reported no superior
benefits . Fiatarone Singh et al. (2014) even
observed that the participants who received combined
intervention showed less improvement in cognitive
functions than those who had received exercise training
alone or cognitive training alone. This result generated
the hypothesis that the combined approach may cause
excessive mental and physical stress to the participants,
leading to less favorable outcomes . Because most
adults with MCI are at an older age, with possibly
several chronic disorders (e.g., hypertension, diabetes,
etc.), probing the feasibility and acceptability of the
combined therapy is necessary and important.
This proposed project aims to move the field forward
by comparing the intervention effects of different
combination approaches – combining physical exercise and
cognitive training sequentially or simultaneously – with
a single type of training. Both combination approaches
have been investigated, but which hybrid method could
result in superior outcomes is not yet clear. Some have
suggested that performing physical exercise before
cognitive training could increase the arousal level for
subsequent cognitive tasks [20, 21] and enhance memory
consolidation and retrieval [22, 23]. These cognitive
benefits were associated with elevated levels of
brainderived neurotrophic factor  and increased cortical
activation level of the prefrontal and occipital areas
. Dual-task training also activated the prefrontal
areas in older adults with MCI , and the changes in
prefrontal activation were associated with
improvements in executive functions [27, 28]. It has been
postulated that cerebellar activation would be stronger
when individuals perform two tasks simultaneously and
could, therefore, lead to greater training benefits for the
learned task .
This study is distinctive for comparing the treatment
effects of various dose-matched interventions in older
adults with MCI. Schaefer and Schumacher
emphasized the importance of equal treatment time when
designing a randomized controlled trial for older
individuals with MCI . This study has, therefore,
designed a comprehensive assessment and intervention
protocol to investigate the treatment effects of
different combined therapies in people with MCI.
One big challenge that we may encounter for the study
is the difficulty in recruiting participants and another is
the ability to maintain those participants. Recruiting
older adults who have some cognitive impairment, but
do not have other neurologic or psychological disorders,
could be very challenging. Those older individuals
typically stay in their home community and maintain a fairly
active life before they become too old to carry out
household tasks. To address this problem, we will target
older adults who are sent to community day care centers
and some nursing homes that admit older individuals
without caregivers. Furthermore, the older adults who
agree to participate in the study may decide to
discontinue from the program during the 36 training sessions.
Dropping out of the intervention program may be due
to personal reasons (e.g., falls, diseases, or low
motivation) or family issues (e.g., moving, need to take care of
their partner, or change in caregivers) that may prohibit
them from continuing the study. We accounted for the
dropout rate in the sample size estimation to ensure that
we could reach sufficient power for the study.
The overall goal of this study is to compare the
treatment effects of different combinations of physical
exercise and cognitive training. The results of this study will
be important for clinicians as well as family caregivers to
select the most efficient and effective training approach
to improve cognitive, physical, and daily functions in
older individuals with MCI. Most importantly, the
ultimate goal of these interventions is to enhance their ability
to live independently and to improve their quality of life.
The trial has currently recruited 39 patients since August
2015, and 12 participants have completed the 6-month
follow-up test. We will continue to recruit until the
sample size of 80 participants is reached.
ADLs: Activities of daily living; BBT: Box and Block Test; CBI: Caregiver Burden
Inventory; CIQ: Community Integration Questionnaire; CST: Chair-stand Test;
DAD: Disability Assessment for Dementia; GDS: Geriatric Depression Scale;
IPAQ: International Physical Activity Questionnaires; Lawton IADL: Lawton
Instrumental Activities of Daily Living Scale; MCI: Mild cognitive impairment;
QoLAD: the Quality of Life in Alzheimer’s Disease Instrument; TUG: Timed Up
and Go; UFoV: Useful Field of View; WAIS: Wechsler Adult Intelligence Scale;
WMS: Wechsler Memory Scale
This study is funded by the Healthy Ageing Research Center at Chang Gung
University (EMRPD1E1711, EMRPD1F0321) and the Ministry of Science and
Technology (MOST 105-2314-B-182A-011-MY3), Taiwan. We would like to
thank the community centers, day care centers, and nursing homes for their
support in participant recruitment.
YL, CW, and PC conceived and designed the study protocol and developed
the intervention programs. YL, CW, and CT drafted and finalized the manuscript.
WH and KC contribute to the concept formation and study design. All authors
have approved the final manuscript.
Ethics approval and consent to participate
This proposed study has been reviewed and approved by the Institutional
Review Board (IRB number: 105-0115C) of Chang Gung University, Taoyuan,
Taiwan. Any amendment or revision of the study procedure will be submitted
to the Chang Gung University IRB for approval. The study is registered at
ClinicalTrials.gov (Identifier: NCT02512627). Participation in the study is
completely voluntary, and participants can withdraw from the study any
time. Withdrawal from the study will not affect any medical or treatment
services required by the participants. The study conforms to the principles
of the Declaration of Helsinki and Good Clinical Practice guidelines.
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