Journal of

Clinical Medicine

Article
Combined Intervention of Physical Activity, Aerobic
Exercise, and Cognitive Exercise Intervention to
Prevent Cognitive Decline for Patients with Mild
Cognitive Impairment: A Randomized Controlled
Clinical Study
Hyuntae Park 1,2 , Jong Hwan Park 3 , Hae Ri Na 4 , Shimada Hiroyuki 2 , Gwon Min Kim 1 ,
Min Ki Jung 1 , Woo Kyung Kim 5 and Kyung Won Park 5,6, *
1 Department of Health Care Science, Dong-A University, Busan 49315, Korea
2 Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology,
Obu 474-8511, Japan
3 Health Convergence Medicine Research Group, Biomedical Research Institute, Pusan National
University Hospital, Busan 49241, Korea
4 Department of Neurology, Seongnam Center of Senior Health and Bobath Memorial Hospital,
Gyeonggi-do 13552, Korea
5 Busan Metropolitan Dementia Center, Busan 49201, Korea
6 Department of Neurology, College of Medicine, Dong-A University, Busan 49201, Korea
* Correspondence: neuropark@dau.ac.kr; Tel.: +82-51-240-2966
!"#!$%&'(!
Received: 4 May 2019; Accepted: 26 June 2019; Published: 28 June 2019 !"#$%&'

Abstract: This study aimed to investigate the association between a dual-task intervention program
and cognitive and physical functions. In a randomized controlled trial, we enrolled 49 individuals with
MCI. The MCI diagnosis was based on medical evaluations through a clinical interview conducted
by a dementia specialist. Cognitive assessments were performed by neuropsychologists according
to standardized methods, including the MMSE and modified Alzheimer’s disease Assessment
Scale-Cognitive Subscale (ADAS-Cog), both at baseline and at 3 months follow-up. The program
comprised physical activity and behavior modification, aerobic exercise, and a cognitive and exercise
combined intervention program. Analysis of the subjects for group-time interactions revealed that
the exercise group exhibited a significantly improved ADAS-Cog, working memory, and executive
function. Total physical activity levels were associated with improvements in working memory
function and the modified ADAS-Cog score, and the associations were stronger for daily moderate
intensity activity than for daily step count. The 24-week combined intervention improved cognitive
function and physical function in patients with MCI relative to controls. Encouraging participants
to perform an additional 10 min of moderate physical activity under supervision, during ongoing
intervention, may be more beneficial to prevent cognitive decline and improve exercise adherence.

Keywords: dual-task; randomized controlled trial; dementia; older adults

1. Introduction
Mild cognitive impairment (MCI) is a state of declined cognitive function and developing
Alzheimer’s disease (AD), or it may be present in the preclinical stage of other types of dementia.
In this state, the ability to perform daily functional activities is retained, indicating that the patient is at
an intermediate stage between normal aging and dementia [1,2]. Therefore, early intervention at the
MCI stage can allow patients to retain and improve their cognitive function [3].

J. Clin. Med. 2019, 8, 940; doi:10.3390/jcm8070940 www.mdpi.com/journal/jcm

J. Clin. Med. 2019, 8, 940 2 of 12

Previous randomized controlled trials and meta-analyses have indicated that exercise is associated
with improvements in executive function, attention, and processing speed in older adults [4,5].
In addition, aerobic exercise has been shown to enhance brain volume [4,6] and improve functional
connectivity between regions of the posterior, frontal, and temporal lobes in healthy older adults [7].
However, a previous meta-analysis reported that a single-bout type of exercise did not improve
cognitive function in patients with MCI. Holtzer et al. [8] reported that dual-task exercise (e.g., walking
while talking), rather than single-bout exercise, is e↵ective in improving brain function. Previous
studies [9] have been limited to only focusing on the function of memory, and the e↵ects of
dual-task exercise on di↵erent domains of cognitive function, including attention, executive function,
and processing speed, remain unclear. Finally, most previous studies have been conducted in a
community-based setting, which may be limited by the lack of professionals to perform cognitive and
physical function assessments as in a clinical setting.
The present study aimed to investigate the association between a dual-task intervention program
and cognitive and physical functions. A single-blinded, randomized, controlled clinical trial was
performed to examine the e↵ect of exercise and cognitive combined intervention on the risk factors for
dementia in patients with MCI. It was hypothesized that dual-task intervention would have beneficial
associations in patients with MCI.

2. Materials and Methods

2.1. Participants
We recruited 126 patients with MCI who attended a memory and dementia clinic at a university
hospital because of memory disturbance or a decline in cognitive function. Seventy-seven were
excluded for not meeting the inclusion criteria and 49 agreed to join the intervention program.
The MCI diagnosis [10] was based on medical evaluations through a clinical interview by a dementia
specialist. The diagnosis was also based on neurological examinations, blood test, brain computed
tomography or magnetic resonance imaging, and detailed neuropsychological assessments. In this
study, seventy-four participants were excluded from the data analysis, although their feedback was still
evaluated because they had a history of stroke or were undergoing treatment for stroke or epilepsy; they
were suspected of having other degenerative diseases or mental illnesses based on their medical history;
they were depressed or abusing drugs; or they had head injuries, thyroid malfunction, or other medical
abnormalities that could impair cognitive function. Non-amnestic MCI was also excluded from the
subtypes of MCI classified by the Petersen criteria. A total forty-nine patients with amnestic MCI were
enrolled [1]. The patients in a healthy group were >60 years old, could provide information regarding
their daily function, and were cognitively normal. After obtaining informed consent from the patients
and/or family care providers of the participants, patients were randomly divided into control (n = 24)
or exercise (n = 25) groups (Figure 1). However, two patients dropped-out of each group. The present
study was performed in accordance with the International Harmonization Conference guidelines on
Good Clinical Practice and was approved by the Dong-A University Hospital Institutional Review
Board (IRB No. 14-214) and the IRBs of each center prior to commencement of the study. Prior to
participation in the study, all participants or their legally authorized representatives provided written
informed consent to participate in the study. This study was registered in the University Hospital
Medical Information Network (UMIN) Clinical Trials Registry (No. UMIN000018933).
J. Clin. Med. 2019, 8, 940 3 of 12

J. Clin. Med. 2019, 8, 940 3 of 12

Figure 1. Subject flow diagram from initial contact through to study completion.
Figure 1.Assessment
2.2. Neuropsychological Subject flow diagram from initial contact through to study completion.

General cognitiveAssessment
2.2. Neuropsychological assessments were performed by neuropsychologists according to standardized
methods, including the Korean Mini-Mental State Examination (KMMSE) [11] and modified the
General cognitive assessments were performed by neuropsychologists according to standardized
Alzheimer’s Disease (AD) Assessment Scale-Cognitive Subscale (ADAS-Cog, range 0–89), both before
methods, including the Korean Mini-Mental State Examination (KMMSE) [11] and modified the
the intervention and at the 3 months follow-up [12,13]. Symptoms of depression were assessed using the
Alzheimer’s Disease (AD) Assessment Scale-Cognitive Subscale (ADAS-Cog, range 0–89), both before
15 item Korean Version of the Geriatric Depression Scale (SGDS-K) [14,15]. Verbal function was assessed
the intervention and at the 3 months follow-up [12,13]. Symptoms of depression were assessed using
using word fluency tests (category and letter fluency tests) [16]. Detailed neurocognitive function
the 15 item Korean Version of the Geriatric Depression Scale (SGDS-K) [14,15]. Verbal function was
was evaluated using the Seoul Neuropsychological Screening Battery-Dementia version [17,18], which
assessed using word fluency tests (category and letter fluency tests) [16]. Detailed neurocognitive
includes assessments of attention, frontal lobe executive function, and verbal functions. Attention was
function was evaluated using the Seoul Neuropsychological Screening Battery-Dementia version
assessed with the digit span test (forward and backward) [19]. Frontal lobe executive function was
[17,18], which includes assessments of attention, frontal lobe executive function, and verbal functions.
assessed with the Korean color-word Stroop test [17,18].
Attention was assessed with the digit span test (forward and backward) [19]. Frontal lobe executive
2.3. Physical
function wasFunction
assessedAssessment
with the Korean color-word Stroop test [17,18].

Physical
2.3. Physical and anthropometric
Function Assessment variables were measured at before the intervention and after 12 weeks
in both groups. Body weight and height were measured to the nearest 0.1 kg and 0.1 cm, respectively,
usingPhysical and anthropometric
a body composition analyzer variables
(N20, AIIA were measured at Inc.,
Communication, before the intervention
Korea). and after
Body mass index (BMI)12
weeks in both groups. Body weight and height were
was calculated as weight (kg) divided by height squared (m ). 2
measured to the nearest 0.1 kg and 0.1 cm,
respectively,
Arterial using
blood apressure
body composition
was measuredanalyzer
using a(N20, AIIAsphygmomanometer
mercury Communication, Inc., Korea).
after Body mass
the participants
index (BMI) was calculated as weight (kg) divided by height squared (m 2).
were seated at rest for 10 min. Two measurements were taken at each time point, and the mean was
Arterial
calculated blood
and usedpressure was measured using a mercury sphygmomanometer after the participants
for analysis.
were Grip
seated at rest for 10 min.
strength was measured Two measurements
using an isometricwere taken at each
dynamometer time point,
(TKK-5401, andJapan)
Tokyo, the mean was
for the
calculated
dominant arm.and used for analysis.
The time up and go was measured based on the time required to stand from a standard
armchair, walk 2.44 m, turn, walkusing
Grip strength was measured backan isometric
2.44 m, and dynamometer
sit down again(TKK-5401, Tokyo,
at the fastest Japan)
speed. for the
Walking
dominant
speed wasarm. The time
measured at 5up and go was
m walking measured
time, based
except for 1.5 mon the in
each time required to
acceleration stand
and from a standard
deceleration zones,
respectively. To assess balance and sit-to-stand (short physical performance battery), existing test
guidelines for each procedure were followed.
J. Clin. Med. 2019, 8, 940 4 of 12

2.4. Dual-Task Exercise Program

The combined activity program involved 24 weekly 110 min sessions focused on physical and
cognitive activities. Between five and six individuals participated in each session conducted by two
geriatric exercise specialists and one nurse or occupational therapist. The program combined the
physical activity promotion and behavior modification, aerobic exercise, and cognitive and exercise
dual-task training program. In the dual-task training, participants conducted cognitive tasks such as
word games, performed fast simple numerical calculations, and played a simple memory span game
while performing aerobic exercises, what we called “cognicise” [20]. Each session featured, in order,
a warm-up for 10 min, stretching training for 10 min, aerobic exercise for 20 min, balance exercise for
10 min, aerobic and cognitive dual-task training for 30 min, rest with feedback and promoting daily
physical activity education for 20 min, and cooling down for 10 min. The aerobic exercises included
stair stepping, endurance walking and stair climbing, and walking on an agility ladder. The target
heart rate zone for aerobic exercise during the intervention was at 55%–80% of maximum heart rate
(HR), consistent with previous studies. The HR was self-assessed immediately following aerobic
exercise based on pulse rate using the Polar S410s heart rate monitor (Polar Electro Oy, Kempele,
Finland). The maximum HR was estimated as follows: 207 0.7 ⇥ age.
To promote physical activity and healthy behaviors, an exercise specialist provided feedback and
encouraged the participants as to how exercise a↵ects dementia, monitored daily physical activities,
and advised on how to improve their daily activity with self-directed activity goals.

2.5. Physical Activity Measurements

Details of the procedure have been described previously [20–25]. In brief, an accelerometer
(modified Kenz Lifecorder, Suzuken Co., Ltd., Nagoya, Aichi, Japan) was attached to a waist belt
on either the left or right side of the body. This device measured the number of steps counts and
the intensity of physical activity every 4 s throughout each day for 24 weeks. The intensities were
categorized into 11 levels, based on the pattern of the accelerometer signal; the output was expressed
in metabolic equivalents (METs) [21]. This recording instrument received detailed appraisals from
several groups of investigators [21–23]; step counts were determined with an intra-model reliability
of 0.998 and an accuracy within ±3% of the actual number of steps taken. Following inspection for
inappropriate data recording, the total step counts and intensity categories were calculated over each
24 h period between midnight and the following midnight. The parameters calculated were the average
daily period of exercise at an intensity judged as higher than moderate for a typical elderly person
(>3 METs). On the basis of individual interviews, we confirmed that the physical activity patterns of
our subjects had relatively remained.

2.6. Statistical Analysis

The Shapiro–Wilk test was used to determine the normality of data distribution. The student’s t-test
was used to assess di↵erences in the baseline (beginning of the intervention) variables. We used the
intention-to-treat approach, and between-group comparisons of continuous variables were conducted
using linear mixed models after adjusted for the premeasurement covariates for primary and secondary
endpoint outcome. Time was treated as a categorical variable, and the models included group, time,
and group-by-time interaction as fixed e↵ects, and participants as random e↵ect. For each group, data
were expressed as change from baseline (admission) to discharge, determined by the time coefficients
(95% CI) of the model. The primary conclusions about e↵ectiveness of the combined intervention were
based on between-group comparisons of change in global and prefrontal cognitive function (working
memory, processing, and executive function) from baseline to 24 weeks after, as assessed with the
ADAS-Cog, KMMSE, digit span test (DST), trail making test-A (TMT), and digit symbol substitution
test (DSST) determined by the time-by-group interaction coefficients of the model. All comparisons
were two-sided, with an alpha level of 0.05, where the Bonferroni–Holm multiple test adjustment was
intervention were based on between-group comparisons of change in global and prefrontal cognitive
function (working memory, processing, and executive function) from baseline to 24 weeks after, as
assessed with the ADAS-Cog, KMMSE, digit span test (DST), trail making test-A (TMT), and digit
symbol substitution test (DSST) determined by the time-by-group interaction coefficients of the model.
J. Clin. Med. 2019, 8, 940 5 of 12
All comparisons were two-sided, with an alpha level of 0.05, where the Bonferroni–Holm multiple test
adjustment was applied. All statistical analyses were made with SPSS, version 20 (IBM Corp) and R,
applied.3.2.2
version All(Rstatistical analyses
Foundation) were made
software. with
All data SPSS,
were versionusing
analyzed 20 (IBM
the Corp)
IBM SPSSand Statistics
R, versionversion
3.2.2
(R Foundation)
25.0 software packagesoftware.
for All data were
Windows analyzed
(SPSS using the
Inc., Chicago, IL,IBM SPSS
USA) Statistics
and version software
SAS statistical 25.0 software
(SAS
package 1996).
Institute, for Windows (SPSS Inc., Chicago, IL, USA) and SAS statistical software (SAS Institute, 1996).

3.3.Results
Results

3.1.Primary
3.1. PrimaryOutcomes
Outcomes(Global
(GlobalCognitive
CognitiveFunction)
Function)
Analysisof
Analysis of subjects
subjects for
for group-time
group-time interactions
interactions revealed
revealed that
that the
the exercise
exercise group
groupexhibited
exhibitedaa
significantly improved modified ADAS-cog score (range 0–89), working memory (DST), andexecutive
significantly improved modified ADAS-cog score (range 0–89), working memory (DST), and executive
function (DSST) scores (Figure 2 and Table 1). The KMMSE score was slightly improved ininthe
function (DSST) scores (Figure 2 and Table 1). The KMMSE score was slightly improved the
interventiongroup,
intervention group,but
butnot
not in
in the
the control
control group;
group; however,
however, this
this did
did not
notreach
reachstatistical
statisticalsignificance,
significance,
andthere
and therewas
wasnonodifference
di↵erencein inthe
theprocessing
processingspeed
speed among
among the
the two
two groups.
groups.

Figure
Figure2.2.Change
Changeinincognitive
cognitiveperformance
performance during the 24
during the 24 week
week intervention.
intervention. Mean
Meanchange
changeininmodified
modified
the Alzheimer’s Disease Assessment Scale-Cognitive Subscale ADAS-Cog score from baseline
the Alzheimer’s Disease Assessment Scale-Cognitive Subscale ADAS-Cog score from baseline (negative (negative
differences
di↵erencescorrespond
correspondtotolower
lowerscores,
scores,indicating
indicatingperformance
performanceimprovement).
improvement).Error Errorbars
barsareareSEM;
SEM;p-
value (p <(p0.05)
p-value from
< 0.05) mixed-model
from repeated
mixed-model measure
repeated analysis,
measure group
analysis, × time
group interaction.
⇥ time * p <* p0.05.
interaction. < 0.05.
J. Clin. Med. 2019, 8, 940 6 of 12

Table 1. Adjusted comparisons of change in measurements from baseline and 24 in intervention group
and control group.

Intervention Group Control Group Between-Group p Value

Variables (Follow- Di↵erence between
(Before) (Follow-up) (Before) (95% CI) Groups
up)
Primary outcome
Modified ADAS-Cog 26.2 ± 2.9 24.6 ± 3.3 25.7 ± 3.1 26.1 ± 2.7 1.9 ( 0.9 to 2.3) <0.01
MMSE 24.6 ± 2.6 24.8 ± 3.7 24.4 ± 3.1 24.2 ± 3.0 0.3 ( 0.2 to 0.9) 0.06
Secondary outcome
Working memory (Digit
2.7 ± 0.2 2.4 ± 0.2 2.6 ± 0.3 2.9 ± 0.2 0.6 ( 0.3 to 1.6) 0.02
Span Scores)
Processing speed (TMT-A) 25.3 ± 7.1 23.1 ± 6.3 24.7 ± 6.2 24.1 ± 6.7 0.4 (0.2 to 1.0) 0.1
Exucutive function (SDST) 30.7 ± 8.0 36.3 ± 8.7 34.2 ± 10 34.7 ± 8.1 6.3 ( 4.2 to 8.4) <0.01
GDS 2.6 ± 1.1 2.5 ± 1.0 2.5 ± 0.9 2.7 ± 1.2 0.6 ( 0.1 to 1.2) 0.02
Gait speed (m/s) 1.06 ± 0.3 1.11 ± 0.4 1.08 ± 0.3 1.05 ± 0.3 0.4 (0.0 to 0.9) 0.02
Grip strength (kg) 27.8 ± 6.2 28.6 ± 5.4 26.7 ± 7.1 29.0 ± 6.8 0.5 ( 0.7 to 1.6) 0.132
Timed up and go (s) 10.1 ± 3.1 8.9 ± 3.4 9.7 ± 4.1 9.5 ± 3.9 0.8 ( 0.4 to 1.4) <0.01
Sit to standing time (s) 18.0 ± 5.2 16.9 ± 4.5 17.3 ± 4.7 17.7 ± 4.8 0.9 (0.4 to 1.7) <0.01
MVPA (min/day) 12.2 ± 7.7 22.3 ± 9.3 11.9 ± 6.3 10.7 ± 6.5 10.6 (7.3 to 20.1) <0.01
Step counts (steps/day) 4876 ± 867 7893 ± 1001 4794 ± 763 4210 ± 861 2996 (1307 to 3816) <0.01
Abbreviations: ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cog; MVPA, moderate and vigorous physical
activity; GDS, Geriatric Depression Scale; TMT, train making tese, SDST, Symbol–Digit Substitution Test: MVPA,
Moderate to vigorous physical activity, Values are given as means± SD. P < 0.5 was considered significant.

3.2. Secondary Outcomes

At baseline, there were no significant di↵erences in physical characteristics among the two groups
(Table 2). The within-group analyses showed that body mass did not di↵er significantly in either group
after 12 weeks, nor did BMI. The within-group analyses showed that the waist–hip ratio did not di↵er
significantly from the baseline values in either the exercise or control groups after 12 weeks. However,
the within-group analyses showed that appendicular skeletal muscle index (ASMI) was significantly
higher than at baseline in the exercise group after 12 weeks.

Table 2. Baseline characteristics of socio-demographic, physical characteristics, daily physical activity,

mental and cognitive function.

Variables Exercise Group (n = 25) Control Group (n = 24) p value

Socio-demographic
Age (years) 70.55 ± 6.46 72.76 ± 5.37 0.239
Male, n (years) 8 (40.0%) 7 (33.3%) -
Education level (years) 7.15 ± 2.94 7.05 ± 3.28 0.971
Job, n (%) 2 (10.0%) 3 (14.3%) 0.95
Smoking (yes), n (%) 3 (15.0%) 1 (4.8%) 0.281
Alcohol consumption (yes), n (%) 5 (25.0%) 1 (4.8%) 0.077
Physical Characteristics
Height (m) 1.55 ± 0.09 1.56 ± 0.07 0.689
Weight (kg) 55.17 ± 5.46 57.50 ± 6.51 0.224
Body Mass Index (kg/m2 ) 23.05 ± 2.29 23.70 ± 2.07 0.342
Waist hip ratio 0.87 ± 0.05 0.87 ± 0.05 0.329
Fat (%) 29.86 ± 9.99 30.22 ± 9.99 0.886
ASMI (kg/m2 ) 7.24 ± 1.60 7.33 ± 1.27 0.839

There were significant improvements in SGDS-K values and habitual physical activity (moderate
to vigorous physical activity (MVPA) and step counts compared with scores in the control group at
24 weeks. Compared with the control group, lower-limb physical function such as gait speed, timed up
and go test, and sit to stand time showed significant improvement after the intervention. Total physical
 ASMI (kg/m2) 7.24 ± 1.60 7.33 ± 1.27 0.839

There were significant improvements in SGDS-K values and habitual physical activity (moderate
to vigorous physical activity (MVPA) and step counts compared with scores in the control group at 24
weeks. Compared
J. Clin. Med. with the control group, lower-limb physical function such as gait speed, timed
2019, 8, 940 7 of up
12
and go test, and sit to stand time showed significant improvement after the intervention. Total physical
activity levels were associated with improvements in working memory function and the modified
activity levels
ADAS-cog score,were
and associated with were
the associations improvements
stronger for indaily
working memory
duration function
of activity and the modified
of moderate intensity
ADAS-cog score, and the associations were stronger for daily duration of activity of
than for daily step count. The MVPA during the study duration (i.e., 12 weeks) was 10.1 ± 6.5 min/week moderate intensity
inthan for dailygroup
the control step count. The±MVPA
and 22.3 during the
9.3 min/week study
in the duration
exercise (i.e., Compared
group. 12 weeks) waswith10.1 6.5 min/week
the±control group,
in the control group and 22.3 ± 9.3 min/week in the exercise group. Compared
MVPA durations were longer in the intervention group, even after adjusting for covariates. In the with the control group,
MVPA durations
intervention period,werethe longer in the intervention group,
daily accelerometer-assessed timeeven after adjusting
in MVPA increasedfor covariates. In
exponentially to the
the
intervention
threshold period,
required for the daily accelerometer-assessed
improving function ~22 min/day (150 timemin/week),
in MVPA increased
with the exponentially to the
control group values
threshold
being required
slightly decreasedfor improving
(Figure 3).function ~22 to
Adherence min/day (150 min/week),
the combined programwith wasthe
95.3control group
± 2.3 in values
the exercise
being Heart
group. slightly decreased
rate (Figure
(HR) during the3). Adherence
exercise to the
program wascombined program
128.1 ± 5.8 was 95.3
beats/min. 2.3 in the exercise
This±corresponded to an
group. Heart rate (HR) during the exercise program
exercise intensity of 70% ± 4% of the age-predicted maximum HR. was 128.1 ± 5.8 beats/min. This corresponded to
an exercise intensity of 70% ± 4% of the age-predicted maximum HR.

Figure 3. Changes in averaged daily moderate to vigorous physical activity during the intervention
period. Black and gray lines show curve-fitting in both linear and exponential fit and 95% confidence
band. 3.
Figure Both groupsinwore
Changes waist-mounted
averaged accelerometers
daily moderate during
to vigorous the intervention
physical period.
activity during the intervention
period. Black and gray lines show curve-fitting in both linear and exponential fit and 95% confidence
4. Discussion
band. Both groups wore waist-mounted accelerometers during the intervention period.
The present study investigated the e↵ects of a 24 week multicomponent intervention on the
4.cognitive
Discussion
function and physical function of individuals diagnosed with MCI. In keeping with our initial
hypothesis, following
The present study adjustments
investigatedfor
thephysical
effects and/or
of a 24lifestyle-related factors, the
week multicomponent multicomponent
intervention on the
intervention
cognitive in patients
function with function
and physical MCI hadofa individuals
significant positive
diagnosed e↵ect
withon both
MCI. Incognitive andour
keeping with physical
initial
function. Additionally,
hypothesis, time interaction
following adjustments had aand/or
for physical significant e↵ect on the
lifestyle-related primary
factors, the outcome (global
multicomponent
cognition), main
intervention secondary
in patients withoutcome
MCI had (executive function,
a significant immediate
positive memory),
effect on and other
both cognitive secondary
and physical
outcomesAdditionally,
function. (gait speed, 5 time
chair standing time,
interaction haddaily MVPA), buteffect
a significant no significant e↵ect on processing
on the primary speed
outcome (global
or grip strength. There were positive e↵ects on global cognitive function, immediate memory and
executive function, and lower limb physical function.
The above results, in conjunction with our previously published findings in community-dwelling
subjects, may indicate that exercise intervention has positive e↵ects on physical and cognitive function
in individuals with MCI [20,26].
A previous systematic review suggested that the evidence of physical exercise on domain-specific
cognitive function and psychological outcomes remains unclear, that additional trials with rigorous
study design are required to provide further evidence [27], and that the limited evidence for the
J. Clin. Med. 2019, 8, 940 8 of 12

prevention of cognitive decline or dementia was insufficient [28]. However, another review found that
cognitive training had moderate to large benefits in terms of memory-related outcomes [29]. A recent
large cohort study reported that a physical activity promotion program, compared with a health
education program, did not result in improvements in global or domain-specific cognitive function in
sedentary older adults [30]. The results from this study indicate that there appears to be merit in a
multicomponent composite approach involving physical activity modification, aerobic exercise, and
cognitive exercises for improving cognitive and physical function in older patients with MCI, possibly
o↵ering more benefit than a single-bout intervention approach.
Increasing evidence indicates that acute aerobic exercise, defined as a single bout of exercise,
is associated with improved cognitive function, particularly prefrontal cortex-dependent cognition.
However, the e↵ects of a single session of exercise on cognitive functioning are generally small.
Therefore, besides the type, frequency, and duration over time, even the intensity is a parameter to be
significantly considered when evaluating intervention e↵ects.
The multidomain supervised intervention used in the present study was feasible and safe.
The dropout rates were low and adherence to the intervention domains was high. To the best of our
knowledge, this is the first randomized control trial to investigate the impact of a combination of
physical activity, aerobic exercise, and cognitive training (not only on cognitive function but also
on physical function) and objectively monitored physical activity during the intervention period for
motivating and dose adjustment of exercise in patients with MCI. The training was relatively intensive
and performed 2 days per week, under supervision. Epidemiological studies have suggested the
possibility that unsupervised moderate-intensity aerobic activity, consistent with American College
of Sports Medicine recommendations, or subject-choice physical or cognitive activities, may also
be beneficial in reducing age-related cognitive decline. However, evidence was not available when
the study investigating the direct e↵ects of a combined physical and cognitive training in patients
with MCI commenced. Therefore, it was considered important to provide supervised, reproducible
activities. In addition to this, the presence of daily activity supervision and feedback contributed to
high compliance in the training performed by subjects. The fact that training activities were inspired
by habitual activities made it possible for each participant to identify matching daily activities.
Numerous longitudinal studies have reported a reduced risk of cognitive decline in physically
active older adults [31,32] and protected cognition in patients with MCI with higher levels of physical
activity [33,34]. A previous study [33] suggested beneficial e↵ects on global cognition and cognitive
domains, which are highly relevant for everyday activities. Similarly, regular physical activity can
reduce this risk and provide other physical and possibly mental health benefits. However, the
dose–response relationship between physical activity and cognition is yet to be fully elucidated and
the majority of adults are not active at the recommended levels. In our intervention, it appeared
that professional advice and supervised guidance with continued support can encourage individuals
to be more physically active in daily life. A notable finding of our study was that the habitual
moderate to vigorous physical activity increased by approximately 10 min per day in the intervention
group, whereas it remained constant or decreased slightly in the control group during the course of
the study. This increase in daily activities in the intervention group resulted in increased physical
and cognitive function. Therefore, intervention studies should obtain information on the activity
levels of an individual, activity began, intervention duration, and baseline activity. Our combined
intervention program enhanced daily activity levels in patients with MCI, and the results suggest that
these protective e↵ects and the exercise intervention promoting an additional 10 min daily MVPA,
may be beneficial to prevent cognitive and physical decline. Of note, the activity of the participants
improved sufficiently to meet the minimum physical activity guidelines [35,36]. Therefore, it is possible
that these additional activities may have a↵ected the findings.
In the pre-dementia stage, converted patients showed lower global cognitive function and greater
semantic memory impairment (verbal fluency and vocabulary) than non-converted patients [37].
From a clinical perspective, working memory assessment is important. For example, working
J. Clin. Med. 2019, 8, 940 9 of 12

memory performance has predictive value in patients with MCI with respect to the development of
dementia [38,39]. Although episodic deficits during disease progression have been widely investigated
and are the benchmark of a probable diagnosis of AD, more recent research has investigated working
memory and executive function decline during MCI, also referred to as the preclinical stage of AD.
Monitoring the performance on working memory and executive function tasks to track cognitive
function may signal progression from normal cognition to MCI to AD. A previous study reported the
progression of MCI toward AD in the intervention group consisted of disintegration of the compensatory
networks observed by under activation of the lateral PFC, precuneus and posterior parietal regions,
which are all involved in executive function, compared with non-impaired age-matched controls [40].
In the present study, the physical and cognitive combined intervention program improved
physical fitness, physical activity, executive function test scores, and working memory scores in older
patients with MCI than in the control group. This intervention enhanced prefrontal cognitive function
gains in patients with MCI. Brain volume shrinks 0.5%–1% annually after the age of 65 years, and
hippocampal volume shrinks by 1%–2% annually in older adults without dementia, increasing the risk
of cognitive impairment [41]. Despite this mechanism, the underlying beneficial e↵ects of exercise to
reduce the risk of AD remains unclear. A recent study [42] found that exercise boosted hippocampal
neurogenesis, reduced amyloid- levels, increased the levels of brain-derived neurotrophic factor, and
improved memory in an AD mouse model. The ablation of neurogenesis prevented the beneficial
e↵ects of exercise in this model. In the human study, a clinical trial of exercise training was e↵ective at
reversing hippocampal volume loss, cognitive decline, and cardiovascular physical performance in
late adulthood with moderate-intensity exercise [43].
Another possible explanation for the impact of exercise on cognition is that AD is marked by
changes in cerebral blood flow (CBF); patients with AD show a 40% decrease in global blood flow
compared with healthy controls [44]. The decrease in CBF occurs in individuals with MCI prior to its
transition to AD [45]. In healthy individuals, cardiorespiratory fitness mediates the age-related gray
matter CBF [46]. Therefore, increasing physical fitness by aerobic exercise assists in the prevention or
slowing of pathological cognitive decline by an increase in CBF.
The strengths of this randomized controlled trial include a clinical research design designed
to clarify the possibility to maximize cognitive benefits using the components of cognitive training
combined with the promotion of physical activity. The findings of this trial can be generalized or
applied to hospital clinics or regional dementia centers with trained instructors. In the previous study,
the long-term exercise and cognitive-composite program improved the cognitive function for 1 year or
6 month. However, in the present study, the 6 month well-supervised exercise intervention increased
cognitive function and physical function.
The present study had several limitations. The sample size was small and replication with a larger
group of adults with MCI would be beneficial. Other limitations include unknown group di↵erences
in the risk factors for cognitive decline and AD, including apolipoprotein E "4 genotypes [47] and
inflammation [48], although there were no significant di↵erences between the groups in hypertension,
diabetes mellitus, medications, physical performance or depressive moods. In addition, it is possible
that the improvement in the exercise group resulted from the social contact received by the intervention
group. This possibility is unavoidable and should be addressed in future studies.

5. Conclusions
As more is learned regarding the underlying mechanisms and the nuanced e↵ects exposed
by analyzing larger samples, the designing and tailoring of interventions can be more e↵ective.
The 24 week combined intervention improved cognitive function and physical function in patients
with MCI relative to controls. Encouraging participants to perform an additional 10 min of moderate
physical activity under supervision, during ongoing intervention, may be more beneficial to prevent
cognitive decline and improve exercise adherence.
J. Clin. Med. 2019, 8, 940 10 of 12

Author Contributions: H.P.: Study concept and review of the planned analysis and the manuscript, and guidance
for the statistical analysis. K.W.P. and S.H.: Study concept, interpretation of the data and review of the manuscript.
H.R.N. and J.H.P.: Acquisition of the data, and review of the manuscript. M.K.J., G.M.K., W.K.K.: Acquisition of
the data and interpretation of the data.
Funding: This research was funded by the Dong-A University research grant.
Acknowledgments: We thank the patients for participating, the Busan Metropolitan Dementia Center (BMDC),
Seongnam Centeral Hospital for help with participant recruitment, and the occupational speech therapists and
radiological technologists of the BMDC, Dong-A hospital, and Seongnam Senior Health Center. We also thank ST
Ngeema for assistance with writing and J Ryu and J Kim for assistance with intervention and investigation.
Conflicts of Interest: The authors declare that no conflict of interest exist.

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