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© 2019 S. Karger AG, Basel
Research Article
Dement Geriatr Cogn Disord
Muscle Strength Is Independently
Related to Brain Atrophy in Patients
with Alzheimer’s Disease
Yeonsil Moon a Won-Jin Moon b Jin Ok Kim c Kyoung Ja Kwon d
Seol-Heui Han a, d
a Department of Neurology, Konkuk University Medical Center, Konkuk University School
of Medicine, Seoul, South Korea; b Department of Radiology, Konkuk University Medical
Center, Konkuk University School of Medicine, Seoul, South Korea; c Department of
Neurology, Daejeon Eulji University College of Medicine, Daejeon, South Korea; d Center for
Geriatric Neuroscience Research, Institute of Biomedical Science, Konkuk Medical Science
Research Center, Konkuk University School of Medicine, Seoul, South Korea
Keywords
Muscle strength · Muscle mass · Cognition · Alzheimer’s disease
Abstract
Background/Aims: Alzheimer’s disease (AD) is the most common cause of dementia world-
wide. Interestingly, muscle mass (MM) and muscle strength (MS) are related to AD. In addition
to the muscle profile, brain atrophy is also a prominent feature of AD. There is substantial
evidence showing an association between muscle profile and dementia, but the role of the
muscle profile and cerebral cortical atrophy within this association is less well understood. The
objective of this study was to determine if there is any association between muscle profile and
brain regional volume in AD. A secondary objective was to determine whether this relation-
ship continues as the clinical stage of AD progresses. Methods: We recruited 28 patients with
probable AD without weakness. We assessed the patients’ basic demographic characteristics,
Mini-Mental State Examination score, and brain magnetic resonance images. MM was mea-
sured using body dual-energy X-ray absorptiometry. MS was assessed in Nm/kg with an iso-
kinetic knee extensor using an isokinetic device at an angular velocity of 60°/s. An automatic
analysis program was used for brain regional volumetric measurements. Dementia was di-
vided into two stages: mild and moderate. Results: MS was related to left hippocampal vol-
ume ratio. After adjusting for age and cognitive status, the relationship remained. MS did not
demonstrate any relationship to any brain regional volume ratio in the mild stage; however,
in the moderate stage, it was positively related to both the right and the left hippocampal
Accepted: April 30, 2019
Published online: July 16, 2019
Seol-Heui Han
Center for Geriatric Neuroscience Research, Institute of Biom edical Science
Konkuk Medical Science Research Cente r, 120-1 Neungdong-ro, Gwang jin-gu
Seoul 05030 (South Korea)
E-Mail 20060246 @ kuh.ac.kr
www.karger.com/dem
DOI: 10.1159/000500718
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© 2019 S. Karger AG, BaselDOI: 10.1159/000500718
volume ratio. Conclusions: Our findings imply a shared underlying pathology relating MS and
brain volume and suggest cognitive functional declines through the muscle-brain axis. Further
longitudinal studies are needed to find possible and related causes of reduced MS and corti-
cal atrophy in patients with dementia. © 2019 S. Karger AG , Basel
Introduction
Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Interestingly,
muscle mass (MM) and muscle strength (MS) are related to AD, a neurodegenerative disease
characterized by cognitive decline. Although the mechanisms by which one’s muscle profile is
related to one’s brain functions are yet to be established, it is certain that MM by itself is not a
significant contributor to cognition [1, 2]. Indeed, MS seems more attributable to the neurode-
generative process than MM. MS was associated with global cognitive function in nondisabled
elderly men [3, 4], as well as in individuals with preclinical AD [5] and those with dementia
[6]. Infrequent physical activity and inadequate dietary intake, leading to loss of MM and/or
MS, may be one factor in the relationship between the muscle profile and cognition. Another
potential mechanism of muscle change shares several features with AD, namely, inflammation,
proinflammatory cytokines, oxidative stress, and myokines [2, 4, 7–11].
In addition to the muscle profile, brain atrophy is also a prominent feature of AD. AD is
characterized by cerebral cortical atrophy and loss of neurons, often presented with a
decrease in the size of the brain. Brain atrophy is assessed by structural magnetic resonance
imaging (MRI), with atrophy predominantly affecting the temporal and parietal lobes, which
have been demonstrated to be valid markers of AD on postmortem histology. Among the core
biomarkers of AD, hippocampal atrophy is the most established, with widespread agreement
on its clinical significance and appropriate accuracy in its measurement [12].
There is substantial evidence showing an association between muscle profile and
dementia, but the role of the muscle profile and cerebral cortical atrophy within this associ-
ation is less well understood. Several studies have investigated the relationship between
muscle structure and cerebral cortical atrophy [11]. Indeed, there is evidence that muscle
structure and brain structure are related, and some studies have suggested a muscle-brain
axis theory, which posits that a change to the muscle profile affects dementia through cortical
atrophy. However, there are few studies investigating the cortical atrophy within each region,
and the vast majority of the existing studies have included gait speed to assess muscle function,
rather than the muscle itself. There is also a dearth of studies on the role of this relationship
as AD dementia progresses.
The objective of this study, therefore, was to determine if there is any association between
muscle profile (MM and MS) and brain regional volume in AD. A secondary objective was to
determine whether this relationship continues as the clinical stage of AD progresses.
Subjects and Methods
Participants
We reviewed the medical records of patients with dementia from the Konkuk dementia registry between
November 2014 and September 2015. The data included all available information such as basic demographic
characteristics which were assessed based on self-reporting, global cognitive assessment (Mini-Mental State
Examination [MMSE] and Clinical Dementia Rating scale [CDR]), brain imaging, and the muscle profile.
In the present study, patients with probable AD without weakness were included. Weakness was defined
as a score below Medical Research Council grade 5 on the manual muscle test. The diagnoses of dementia and
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Dement Geriatr Cogn Disord
Moon et al.: Muscle Strength and Brain Atrophy in AD
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© 2019 S. Karger AG, Basel
DOI: 10.1159/000500718
AD were based on the National Institute of Neurological and Communicative Disorders and Stroke and the
Alzheimer’s Disease and Related Disorders Association [13].
We excluded subjects with seizures, Parkinson’s disease, multiple sclerosis, cerebral palsy, Hunting-
ton’s disease, encephalitis, vascular surgery of the brain, cancer diagnosed within the previous 3 years
excluding skin cancer, kidney dialysis, liver disease, hospitalization for mental or emotional reasons within
the previous 5 years, drug abuse within the previous 5 years, episode(s) of unconsciousness exceeding 1 h,
illness including stroke resulting in a permanent decrease in memory or other mental functioning, visional
impairment that would prevent reading ordinary print (even with glasses), and significant gait/mobility
difficulties.
From the registry, 93 patients with probable AD were included. Of these patients, 65 were excluded
on whom an inappropriate MRI protocol for volumetric cortical measurement had been executed. Finally,
28 patients with appropriate MRI data for imaging analysis were included in the final analyses. Dementia
was divided into two stages according to the CDR score: mild (CDR score = 0.5) and moderate (CDR
score = 1).
MR Image Acquisition and Analysis
MRI was performed at the Konkuk University Medical Center using a Signa HDx 3.0-T unit (GE Healthcare,
Milwaukee, WI, USA) with an 8-channel high-resolution head coil. The routine MRI protocol included the
following sequences: (1) axial and sagittal T1-weighted inversion recovery (TR/TE/TI, 2,468/12/920 ms;
section thickness, 5 mm; matrix, 512 × 224); (2) axial T2-weighted fast spin-echo acquisition (TR/effective
TE, 4,000/106 ms; section thickness, 5 mm; matrix, 384 × 384); (3) axial fluid-attenuated inversion recovery
acquisition (TR/TE/TI, 11,000/105/2,600 ms; section thickness, 5 mm; matrix, 384 × 224); and (4) axial
T2-weighted gradient-echo acquisition (TR/TE, 550/17 ms; section thickness, 5 mm; matrix, 384 × 224; flip
angle, 15°). To analyze the cortical volumes, we obtained additional T1-weighted volumetric spoiled gradient
recalled-echo images (TR/TE, 7.3/2.7 ms; section thickness, 1.5 mm; matrix, 256 × 256; flip angle, 13°). The
field of view was 230 × 230 mm.
Coronal T1-weighted volumetric images were used for analysis with the automated tool. Each brain was
segmented into 11 regions – hippocampus, amygdala, caudate, putamen, pallidum, thalamus, forebrain
parenchyma, cortical gray matter, cerebellum, lateral ventricles, and inferior lateral ventricles – and each
region consisted of the left and right counterparts, resulting in 22 regions. An automatic MRI assessment
method called NeuroQuant® (CorTechs Labs, San Diego, CA, USA) was used for reliable volumetric
measurement.
The intracranial volume was calculated to correct for differences in head size. The images were resam-
pled to 1.0-mm3 isovoxels and spatially realigned based on the axis of the anterior commissure-posterior
commissure line. After individual segmentation of the gray matter, white matter, and cerebrospinal fluid
volumes, the segmented subtotals were summed [14]. This process was also automatically calculated by
NeuroQuant®. Each brain regional volume is presented in relation to the total intracranial volume, the result
being expressed as a percentage. The detailed mechanism of automatic volumetric analysis is described else-
where [15, 16].
Measurement of the Muscle Profile
Appendicular skeletal muscle mass (ASM) was measured using body dual-energy X-ray absorptiometry,
which is currently considered the standard [17–20], and was calculated as the sum of the lean soft tissue
mass in the arms and legs. The parameters derived by dual-energy X-ray absorptiometry were used to
quantify the total body skeletal MM, and the MM was calculated by the ASM divided by height squared (ASM/
height2 in kg/m2) [21]. MS was assessed by isokinetic knee extensor MS using an isokinetic device at an
angular velocity of 60°/s in Nm/kg [19, 22].
Statistical Analysis
Normality of the data was tested before performing parametric analysis with the Kolmogorov-Smirnov
test. Descriptive statistics comparing those with a CDR score of 0.5 with those with a CDR score of 1 were
calculated by t test. Spearman correlations were used to assess the relationship between regional brain
volume and muscle profile or cognition. Thereafter, partial correlation analyses were used to exclude the
effect of age or MMSE score. SPSS (v.17.0; SPSS Inc., Chicago, IL, USA) was used for the statistical analyses,
and a p value < 0.05 was considered the threshold of significance.
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© 2019 S. Karger AG, BaselDOI: 10.1159/000500718
Results
Demographic Characteristics, Muscle Profile, and Brain Regional Volume Ratio
The sample was composed of mostly females (89.3%) and the mean age was 76.9 ± 7.6
years. The mean MM and MS were 5.49 ± 0.73 kg/m2 and 0.56 ± 0.27 Nm/kg, respectively,
which are low values, given that the cutoff points for an insufficient MM and for weak MS were
5.27 kg/m2 and 0.79 Nm/kg, respectively. These cutoff points were generated from sarco-
penia study data on Korean adults [23]. All brain regional volumes in the current study were
smaller than those reported in other studies without dementia patients [15, 16].
In all, 16 patients were in the mild stage of AD (CDR score = 0.5) and 12 patients were in
the moderate stage (CDR score = 1). When divided by stage, the patients in the moderate-
stage group were older, had less MM, and had lower MMSE scores. The left-side forebrain
parenchyma and bilateral amygdalae were smaller in the moderate-stage group than in the
mild-stage group (see Table 1 for a summary of the demographic characteristics, muscle
profiles, and brain regional volumes).
Table 1. Demographics, muscle profile, and brain structure volumes in relation to total intracranial volume
in percent, as well as p values for between-diagnostic-group differences
Category CDR score 0.5 (n = 16) CDR score 1 (n = 12) p value
Age, years 74.0 (7.7) 80.7 (5.9) 0.020
Female sex, n (%) 14 (87.5) 11 (91.7) 0.729
MMSE score 21.0 (4.32) 14.5 (3.87) <0.001
MM (ASM), kg/m25.74 (0.74) 5.14 (0.58) 0.030
MS, Nm/kg 0.62 (0.29) 0.49 (0.22) 0.235
Hippocampus_R 0.20 (0.02) 0.18 (0.03) 0.124
Hippocampus_L 0.20 (0.01) 0.17 (0.03) 0.061
Amygdala_R 0.09 (0.00) 0.07 (0.01) 0.002
Amygdala_L 0.09 (0.01) 0.07 (0.01) 0.001
Caudate_R 0.22 (0.02) 0.23 (0.04) 0.547
Caudate_L 0.22 (0.03) 0.21 (0.04) 0.687
Putamen_R 0.34 (0.03) 0.37 (0.05) 0.075
Putamen_L 0.37 (0.03) 0.39 (0.05) 0.332
Pallidum_R 0.02 (0.01) 0.02 (0.00) 0.188
Pallidum_L 0.03 (0.01) 0.02 (0.00) 0.252
Thalamus_R 0.51 (0.04) 0.50 (0.05) 0.537
Thalamus_L 0.53 (0.04) 0.51 (0.05) 0.357
Forebrain parenchyma_R 30.41 (7.29) 30.79 (1.83) 0.863
Forebrain parenchyma_L 32.41 (1.78) 30.43 (1.70) 0.007
Cortical gray matter_R 15.08 (1.38) 14.16 (2.01) 0.165
Cortical gray matter_L 15.29 (1.24) 14.01 (2.07) 0.053
Cerebellum_R 4.07 (0.39) 4.05 (0.28) 0.917
Cerebellum_L 4.04 (0.39) 4.01 (0.25) 0.789
Superior lateral ventricle_R 1.70 (0.59) 1.91 (0.64) 0.382
Superior lateral ventricle_L 1.74 (0.72) 1.94 (0.68) 0.453
Inferior lateral ventricle_R 0.14 (0.08) 0.15 (0.06) 0.855
Inferior lateral ventricle_L 0.12 (0.06) 0.14 (0.07) 0.385
The values represent the mean (SD) or n (%). MMSE, Mini-Mental State Examination; CDR, Clinical
Dementia Rating; MM, muscle mass; ASM, appendicular skeletal muscle mass; MS, muscle strength.
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© 2019 S. Karger AG, Basel
DOI: 10.1159/000500718
Relationship of Muscle Profile to Brain Regional Volume Ratio
The MM and MS scores were not related to each other (rs = 0.210, p = 0.314). MM was
related to neither age (rs = –0.292, p = 0.131) nor MMSE score (rs = 0.255, p = 0.190), whereas
MS was related to age (rs = –0.453, p = 0.023) but not to MMSE score (rs = 0.181, p = 0.387).
Age was related to MMSE score (rs = –0.480, p = 0.010).
No relationship was observed between MM and any brain regional volume ratio; however,
MS was related to left hippocampal volume ratio (LHV) (Table 2). After adjusting for age and
MMSE score, the relationship between MS and LHV still remained (Table 3).
The relationship between muscle profile and brain regional volume ratio was different
according to stage. MM was not related to any brain regional volume ratio in either the mild
or the moderate stage. Similarly, MS did not demonstrate a relationship to any brain regional
volume ratio in the mild stage. However, in the moderate stage, MS was positively related to
both right hippocampal volume ratio (RHV) and LHV. The partial correlation analysis demon-
strated a significant correlation between MS and LHV after adjusting for age and MMSE score
in those in the moderate stage (Table 3).
Discussion
Our results demonstrated a relationship between reduced MS and hippocampal atrophy,
independent of age and MMSE score, and that the relationship becomes more evident as the
disease progresses. However, MM was not related to any brain regional volume.
Table 2. Relationship of MM and MS to brain regional volume ratio
Category MM (ASM) MS
ρp value ρp value
Hippocampus_R 0.066 0.739 0.389 0.055
Hippocampus_L 0.211 0.281 0.504* 0.010*
Amygdala_R 0.195 0.320 0.195 0.350
Amygdala_L 0.316 0.102 0.283 0.171
Caudate_R –0.318 0.099 0.101 0.631
Caudate_L –0.282 0.146 –0.189 0.366
Putamen_R –0.350 0.068 –0.228 0.274
Putamen_L –0.181 0.355 0.017 0.934
Pallidum_R –0.118 0.550 –0.242 0.244
Pallidum_L –0.026 0.896 –0.081 0.700
Thalamus_R –0.110 0.578 0.227 0.274
Thalamus_L 0.053 0.789 0.136 0.518
Forebrain parenchyma_R –0.034 0.864 0.243 0.242
Forebrain parenchyma_L 0.025 0.901 0.235 0.257
Cortical gray matter_R 0.013 0.946 0.217 0.298
Cortical gray matter_L 0.024 0.903 0.131 0.533
Cerebellum_R 0.237 0.225 0.199 0.340
Cerebellum_L 0.123 0.534 0.305 0.138
Superior lateral ventricle_R –0.115 0.558 –0.121 0.565
Superior lateral ventricle_L –0.273 0.161 –0.305 0.138
Inferior lateral ventricle_R –0.110 0.576 –0.253 0.222
Inferior lateral ventricle_L –0.255 0.190 –0.316 0.124
MM, muscle mass; ASM, appendicular skeletal muscle mass; MS, muscle strength; ρ, Spearman’s correlation
coefficient. * p < 0.05.
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Moon et al.: Muscle Strength and Brain Atrophy in AD
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© 2019 S. Karger AG, BaselDOI: 10.1159/000500718
A few studies have investigated the relationship between brain regional volume and MS.
According to a systematic review by Kilgour et al. [11], a few papers from the PATH through
Life Project, the Cardiovascular Health Study, and the Lothian Birth Cohort 1936 study looked
at the relationship between handgrip and brain structure; however, the results were incon-
clusive.
There are few studies relating the muscle profile to brain atrophy; otherwise, many
studies reported a relationship of gait to brain atrophy. The hippocampus has been most
consistently associated with measures indicating slower and unstable gait patterns [11,
25–27]. Hippocampal atrophy showed significant associations with gait measures in cross-
sectional studies [26] and was associated with declines in gait speed in one longitudinal study
[27]. As the hippocampus is involved in sensorimotor integration, atrophy of the hippo-
campus may reflect the decline in MS through failure to control and integrate the sensory and
motor systems [27, 28].
The current results are similar to those of a study of gait and brain regional volume,
because we measured MS using maximal isometric knee extension, which is more relevant to
functional mobility and gait than handgrip. Handgrip strength is simpler for measures of MS,
but MS of the lower extremities is highly correlated to gait and balance [3, 29] and can
therefore be used as a standard indicator of overall MS [2].
Although the present study did not look into possible and related causes of reduced MS
and cortical atrophy, there are a few possible hypotheses postulating common underlying
processes between change in muscle profile and brain atrophy in AD [11]. Potential under-
lying mechanisms of reduced MS, including proinflammatory cytokines, lowered insulin-like
growth factor 1 (IGF-1), glucocorticoids, vitamin D, and oxidative stress [10, 11], may also
play a role as factors provoking brain atrophy in neurodegenerative diseases such as AD.
Patients with AD have lower serum levels of IGF-1, which are associated with cognition [9].
Decreased levels of IGF-1 in AD have been shown to not only attenuate the plasticity and
neuronal survival of the brain [4], but also to decrease knee extensor and flexor strength [8].
Inflammatory markers such as C-reactive protein, interleukin-6, and interleukin-1RA were
significantly correlated with physical performance and gait [2, 7] in addition to brain atrophy
[24].
CDR score 0.5 CDR score 1 Total
Model 1
RHV (%) –0.002 (0.994) 0.734 (0.010)* 0.389 (0.055)
LHV (%) 0.214 (0.463) 0.785 (0.004)* 0.504 (0.010)*
Model 2
RHV (%) –0.153 (0.572) 0.581 (0.078) 0.282 (0.182)
LHV (%) 0.219 (0.146) 0.677 (0.031)* 0.467 (0.022)*
Model 3
RHV (%) 0.021 (0.945) 0.509 (0.133) 0.302 (0.152)
LHV (%) 0.319 (0.287) 0.681 (0.030)* 0.483 (0.017)*
The values present r (p value). Model 1: simple correlation analysis.
Model 2: partial correlation analysis adjusting for age. Model 3: partial
correlation analysis adjusting for MMSE score. MS, muscle strength;
CDR, Clinical Dementia Rating; R/LHV, right/left hippocampal volume
ratio; r, Pearson correlation coefficient; MMSE, Mini-Mental State
Examination. * p < 0.05.
Table 3. Relationship between
MS and hippocampal volume
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Dement Geriatr Cogn Disord
Moon et al.: Muscle Strength and Brain Atrophy in AD
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© 2019 S. Karger AG, Basel
DOI: 10.1159/000500718
The majority of studies have not assessed the laterality of the hippocampal association
with MS. In a few studies analyzing the laterality of the hippocampus in cognitively healthy
elderly and MCI subjects, the RHV was more strongly related to MS than was the LHV.
Conversely, the current study found that only LHV was associated with MS. This may be
because our participants were diagnosed with AD and were, therefore, characterized by
atrophy of the LHV, which is more strongly associated with memory. It is also important to
consider that this discrepancy between findings may be due to statistical error because of the
small number of participants in each group.
MS was more strongly related to LHV atrophy in patients in the moderate stage than in
those in the mild stage of AD. This suggests a shared underlying pathology that progresses as
the disease progresses, thus causing the relationship between MS and LHV to become stronger.
Another study reported a mirrored change in cognition and grip strength, with the associ-
ation between cognition and grip strength being stronger just before death than earlier in life
[30]. As cognition has also a robust correlation with brain atrophy, we posit that this finding
implies a common underlying pathology in the brain and muscles. However, it could also
indicate that moderately demented patients may simply be less motivated to be active or less
able to activate themselves with maximal effort.
We report that MM is not related to brain regional volume in AD. This finding is fully in
accordance with those of prior studies reporting the existence of an independent role for
reduced MS, but not MM, in brain atrophy.
This study is limited due to its cross-sectional nature, and therefore we could not
determine the directional nature of the relationship between MS and brain atrophy, suggesting
a complex interplay between brain and muscle [1]. A further well-designed longitudinal study
would help in clarifying causation. The lack of information on the physical activity or the diet
of the patients also limits the study; however, whether physical activity or diet affects the
muscle profile or not, it may be concluded nonetheless that this study was able to confirm an
effect of MS on brain volume. Of course, physical activity or diet may also affect MS or brain
volume; therefore, further investigation is needed. The relatively small number of partici-
pants, the paucity of ethnic diversity, and the lack of data on ethnic differences in body compo-
sition are further shortcomings; however, we have taken an initial step forward in advancing
our understanding of the relationship between muscle profile and brain volume through this
controlled study. Although the lack of age- and education-matched elderly controls is one of
the limitations of this study, the objective was to evaluate the relationship of muscle profile
to brain volume in patients with AD, and we therefore did not include controls.
Conclusions
In patients with AD dementia, LHV atrophy is related to lower-extremity MS, but not to
MM. A longitudinal study is needed to find possible and related causes of reduced MS and
cortical atrophy in patients with dementia.
Acknowledgements
The authors thank Hui Jin Ryu, MA, and Min Young Kim, MA, for their support and guidance in the neuro-
psychological evaluation of the patients. Most importantly, the authors thank all those who participated in
the study for their dedication to helping research in dementia. The contents of this work are solely the
responsibility of the authors.
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Statement of Ethics
All the patients provided their written informed consent to using the data obtained in this study, and
the study was approved by the Institutional Review Board of Konkuk University Medical Center, Seoul, South
Korea.
Disclosure Statement
The authors have no conflicts of interest to disclose.
Funding Sources
This research was supported by a 2018 grant from the Konkuk University Medical Center. No funding
bodies were involved in the design, collection, analysis, interpretation, or writing of the manuscript. The
views expressed are those of the authors and not necessarily those of the Konkuk University Medical Center.
Author Contributions
Every author has made a substantive intellectual contribution to the submitted paper. Y.M. conceptu-
alized the study, recruited the patients, analyzed and interpreted the data, and drafted and revised the manu-
script. J.O.K. and K.J.K. contributed to the conceptualization of the study and acquisition of the data. S.-H.H.
designed and supervised the study and revised the manuscript.
The principal author, Y.M., takes full responsibility for the accuracy of the data analysis and the conduct
of the research. Y.M. has full access to all the data and the right to publish any and all data, separately and
apart from the guidance of any sponsor.
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