Published online Feb 27, 2024.
https://doi.org/10.3349/ymj.2023.0119
Effect of Dietary Habits on Alzheimer’s Disease Progression
,1
Jee Hyang Jeong,2
Kyung Won Park,3
Eun-Joo Kim,4
Soo Jin Yoon,5
Bora Yoon,6
Jae-Won Jang,7
Yangki Minn,1
and Seong Hye Choi8
Abstract
Purpose
Research on the relationship between diet and dementia among Koreans are lacking. This study investigated the association between dietary habits and dementia progression over 3 years in patients with Alzheimer’s disease dementia (ADD).
Materials and Methods
This study included 705 patients with mild-to-moderate ADD. Dietary habits were assessed using the Mini Dietary Assessment Index, comprising 10 questions. Outcome measures included the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), and neuropsychological test battery (NTB) z-scores, which were evaluated annually over 3 years.
Results
In Q10 (eat all food evenly without being picky), the 3-year mean differences in CDR-SB (increases in scores represent worsening) compared to the “rarely” group were -1.86 [95% confidence interval (CI)=-3.64 – -0.09, p=0.039] for the “usually” group and -2.23 (95% CI=-4.40 – -0.06, p=0.044) for the “always” group. In Q7 (add salt or soy sauce to food when eating), the 3-year mean differences in CDR-SB compared to the “always” group were -2.47 (95% CI=-4.70 – -0.24, p=0.030) for the “usually” group and -3.16 (95% CI=-5.36 – -0.96, p=0.005) for the “rarely” group. The “rarely” and “usually” groups in Q7 showed significantly less decline in NTB z-score and CGA-NPI compared to the “always” group.
Conclusion
Eating a balanced diet and reducing salt intake were associated with a slower decline in dementia severity, cognition, and behavioral alterations in patients with ADD.
Graphical Abstract
INTRODUCTION
The global population of individuals with dementia is presently estimated at approximately 50 million, and this number is projected to increase to 152 million by the year 2050.1 Alzheimer’s disease (AD) is the most common cause of dementia, characterized by an insidious onset and a progressive decline in cognitive, functional, and behavioral abilities. In patients with AD, their final years are characterized by persistent severe disability. The societal costs associated with AD increase with the severity of dementia. Despite extensive research in the field of dementia, only few drugs, such as anti-amyloid-beta (Aβ) antibodies like aducanumab and lecanemab, have been reported to prevent AD progression. Currently, these are the only drugs available on the market that have received approval from the United Stated Food and Drug Administration. However, aducanumab has an annual cost of $56000 (range $33600–84000),2 rendering it not cost-effective, even when considering the social cost of dementia.3 Alternative therapies, including non-pharmacological approaches, are needed not only to prevent dementia but also to decelerate its advancement.
Potential modifiable risk factors for dementia include lack of education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, low social contact, excessive alcohol consumption, traumatic brain injury, and air pollution. Nutrition and diet have long been suggested as potential contributors to dementia risk. Observational studies have focused on individual components, including omega-3 polyunsaturated fatty acids, vitamin B complexes (vitamins B6, B12, and folate), antioxidants (vitamins A, C, and E), vitamin D, and selenium, as potential protective factors against dementia. However, there is limited evidence from well-sized randomized controlled trials (RCTs) that nutritional interventions can benefit cognition in later life. However, in the last few years, research has shifted from the investigation of single nutrients to the examination of dietary patterns, such as a Mediterranean diet (high consumption of vegetables, legumes, fruits, nuts, cereals, and olive oil, and low intake of saturated lipids and meat), along with similar patterns such as the Nordic diet.4, 5, 6 These dietary patterns consider the simultaneous intake of various macronutrients and micronutrients. It has been well-established that certain dietary patterns prevent the development of dementia in older adults.7 Nutritional interventions have been conducted as part of multidomain interventions (simultaneously targeting multiple lifestyle factors).8, 9 However, further evidence, especially from RCTs, is required to confirm or disprove these hypotheses.
Dietary patterns reflect a nation’s culture and are difficult to alter artificially. Even within the same culture, both healthy and unhealthy eating habits coexist. Some people in Mediterranean cultures consume salty or greasy foods. In Korea, many older adults rarely eat dairy products, olive oil, cereals, and wines, which are common in Western diets. This makes it difficult to adopt a Mediterranean diet in daily Korean life. Instead, traditional Korean foods, such as kimchi and fermented soybean paste, offer potential health benefits. However, these fermented foods can also contribute to elevated sodium intake due to the salt added during the fermentation process.
Although numerous studies have explored the relationship between diet and prevention of dementia and cognitive impairment, none have definitely correlated specific dietary habits to disease progression.10 In addition, the effects of such dietary habits on the progression of symptoms, including cognitive impairment, impaired activities of daily living (ADL), and behavioral and psychological symptoms of dementia, remain poorly understood in patients with dementia.11
The present study aimed to investigate the dietary habits associated with the progression of dementia over 3 years in patients with Alzheimer’s disease dementia (ADD) enrolled in the Clinical Research Center for Dementia of South Korea (CREDOS). This was a hospital-based multicenter registry project, which took place from November 2005 to January 2015.12
MATERIALS AND METHODS
Participants
We selected 705 patients with mild-to-moderate ADD based on a Clinical Dementia Rating scale (CDR) of ≤2. We included patients with probable ADD using the criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association in 1984,13 and the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders.14 Patients were selected, in the time period from 2008 to 2013, based on the results of the Mini Dietary Assessment Index (MDA) for Koreans, a questionnaire survey used to assess their eating habits.15 We included patients with reliable caregivers and those who had completed the MDA at baseline. We excluded patients with any of the following: 1) an altered laboratory test, such as an abnormal thyroid function test, a deficiency in vitamin B12 or folate, or a positive syphilis test; 2) mental illness, such as major depressive disorder, psychosis, or intellectual developmental disorders; 3) a history of a brain disease, such as a brain tumor, encephalitic or metabolic encephalopathy, traumatic intracranial hemorrhage or subarachnoid hemorrhage, or head trauma with loss of consciousness lasting longer than 1 h; 4) medical conditions, such as an active gastric ulcer, uncontrolled diabetes mellitus (DM), sick sinus syndrome, a second or third degree atrioventricular block, severe pulmonary, hepatic, or renal disease, or an untreated malignancy;16 5) a severe periventricular and deep white matter hyperintensities, determined by a score of 3 on the Fazekas ischemic scale;17 and 6) other types of dementia, such as dementia with Lewy bodies, progressive supranuclear palsy, or frontotemporal lobar degeneration.16
All patients and their legal guardians who participated in this study provided their written informed consent. This study complied with the International Harmonization Conference Guidelines on Good Clinical Practice. The study was approved by the Institutional Review Boards of each center prior to its commencement (INHAUH-2020-10-014).
Clinical assessment
All participants underwent detailed physical and neurological examinations performed by a neurologist. The interview focused on the participants’ cognition, behavioral alterations, ADL, demographic characteristics, vascular risk factors, current medication, and the presence of other comorbidities. The participants underwent extensive standardized neuropsychological testing using the Seoul Neuropsychological Screening Battery (SNSB),18 the Mini-Mental State Examination (MMSE),19 Geriatric Depression Scale-15 items (GDS-15),20 CDR,21 Caregiver-Administered Psychiatry Inventory (CGA-NPI),22 and Seoul Instrumental ADL (S-IADL).23
To rule out other causes of dementia, we carried out brain MRI and laboratory tests, including thyroid function, hemoglobin A1c, fasting blood glucose, blood urea nitrogen, creatinine, liver function test, lipid panel, complete blood count, vitamin B12 level, folate level, and venereal disease research laboratory tests. Hypertension was considered as a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥90 mm Hg, and as antihypertensive medications intake.24 DM was defined based on current insulin use or oral hypoglycemic medication intake, and an 8-h fasting plasma glucose ≥126 mg/dL or HbA1c ≥6.5%.25 Dyslipidemia was defined as total cholesterol ≥200 mg/dL, low-density lipoprotein cholesterol ≥130 mg/dL, high-density lipoprotein cholesterol <40 mg/dL, serum triglycerides level ≥150 mg/dL, or the intake of lipid-lowering drugs.26 Participants’ weight and height were measured while wearing light clothing. Body mass index (BMI) was calculated as weight in kilograms (kg) divided by the square of height in meters (m2).
The participants were assessed annually using the same clinical and neuropsychological protocols employed during the baseline examination. Specifically, 584 patients were reevaluated 1 year after baseline assessment, 247 underwent reevaluation 2 years after baseline, and 57 were reevaluated 3 years after the baseline assessment.
Dietary assessment
The caregivers of the participants conducted dietary pattern assessment using the MDA questionnaire.15 A 10-component system was devised based on the dietary guidelines and the Korean National Health and Nutritional Examination Survey.15 This system comprised four food elements that participants were encouraged to consume, which included milk, meat, vegetables, and fruits. Additionally, there were three food elements that participants were advised to limit, which included fat, salt, and sugar. Dietary regulations and variety were also assessed. Since the question inquired about eating habits, respondents were not asked to specify a particular time period, and their responses generally reflected their current eating patterns.15 Participants were instructed to indicate “always,” “usually,” or “rarely” in their responses, corresponding to scores of 5, 3, or 1 (where 5 indicates a good habit and 1 signifies a bad habit). The total possible maximum index score was 50 (Supplementary Table 1, only online).
Outcome measures
We used four indices to assess dementia progression: CDR-Sum of Boxes (CDR-SB), CGA-NPI, neuropsychological test battery (NTB) z-score, and S-IADL. The NTB z-score was estimated by averaging the z-scores from the following assessments: Digit Span Forward and Backward tests, Boston Naming test, copying, immediate and 20-min delayed recalls, and recognition tests of the Rey—Osterrieth Complex Figure, Seoul Verbal Learning test, category fluency test, Controlled Oral Word Association test, and Stroop Color Word test in the SNSB.18 These scores were based on the mean and standard deviation of each measure in the age- and education-matched normal Korean population. Further details of the other tests are provided in a previous publication.16 Increases in scores represent worsening for the CDR-SB, CGA-NPI, and S-IADL, and improvement in NTB z-score.16 We measured these four indices annually for up to 3 years in the patients.
Statistical analyses
For the unadjusted analysis, we used a linear mixed model with a random subject effect to analyze the relationship between each question score as an explanatory variable and the four clinical outcomes. The fixed effects included each question, time (baseline, 1, 2, and 3 years), and question-by-time interaction. We used the first order autoregressive covariance structure in the mixed model, which was selected using the Akaike information criterion of the model.27 In the analysis of each question, we used a group with a score of 1 as the reference. It was considered meaningful when at least one of the four clinical outcomes improved in the group with a score of 3 or 5 compared to the group with a score of 1.
To assess the heterogeneity of age, education, BMI, and GDS-15 and MMSE scores across the score levels of each question, which were found to be significant in the unadjusted analysis, we conducted one-way analysis of variance and Tukey’s post hoc test. For categorical variables, namely sex, hypertension, DM, dyslipidemia, current smoking habit, and current drinking habit, we calculated the frequencies and compared their differences across the score levels of the questions using the χ2 test.
In the multivariate analysis, we evaluated the relationship between the four clinical outcomes and each of the following questions (Q): Q2. Eat foods made of meat, fish, eggs, beans, or tofu at least 3–4 times daily; Q7. Add salt or soy sauce to food when eating; and Q10. Eat all food evenly without being picky. These questions were found to be significant in the unadjusted analysis. We used linear mixed models that included a random subject effect and incorporated baseline age, sex, education, baseline BMI, current drinking and smoking at baseline, baseline GDS-15 score, baseline MMSE score, each score of Q2, Q7, and Q10 at baseline, time, and each question-by-time interaction as fixed effects. We included well-known dementia risk factors that exhibited significant differences in the univariate analyses between the corresponding score groups (scores 1, 3, and 5) in Q2, Q7, and Q10 as fixed effects in the linear mixed models.
Statistical analyses were performed using SPSS 26.0 (IBM Corp., Armonk, NY, USA). p<0.05 was considered statistically significant.
RESULTS
From the CREDOS study, 705 patients with mild-to-moderate AD, who had completed the MDA questionnaire at baseline, were included in this study. Table 1 shows the baseline characteristics of the study participants. In the unadjusted linear mixed models, Q2 (eat foods made of meat, fish, eggs, beans, or tofu at least 3–4 times daily), Q7 (add salt or soy sauce to foods when eating), and Q10 (eat all foods evenly without being picky) evidenced a positive effect on some clinical outcomes (Table 2). In Q2, the “always” (score 5) group exhibited a significantly lower decline in the CGA-NPI over 3 years compared to the “rarely” (score 1) group. In Q7, the “usually” (score 3) and “rarely” (score 5) groups evidenced significantly lower deterioration in the CDR-SB, NTB z-score, and CGA-NPI over 3 years compared to the “always” (score 1) group. In Q10, the “usually” (score 3) group exhibited a significantly lower decline in CDR-SB compared to the “rarely” (score 1) group.
Table 1
Baseline Characteristics of Study Participants (n=705)
Table 2
Unadjusted Mean Differences for Each Outcome between Different Score Groups for Each Question on the Mini Dietary Assessment Index Over 3 Years
Table 3 lists the differences in well-known dementia risk factors for each score group (scores 1, 3, and 5) for Q2, Q7, and Q10. There were significant differences in sex, education, current smoking habit, current drinking habit, GDS-15 scores, and MMSE scores within the different score groups in Q2; significant differences in sex, education, current smoking habit, and current drinking habit within the different score groups for Q7; and significant differences in age, sex, education, current drinking habit, BMI, GDS-15 scores, and MMSE scores within the different score groups in Q10. Finally, baseline age, sex, education, current smoking habit, current drinking habit, BMI, and GDS-15 and MMSE scores were used as confounding variables in the multivariate analyses.
Table 3
Univariate Analysis of the Relationship between Potential Confounders and Questions 2, 7, and 10 of the Mini Dietary Assessment Index
Table 4 summarizes the adjusted mean differences for each outcome between the different score groups for Q2, Q7, and Q10 on the MDA over 3 years. In Q7 (add salt or soy sauce to foods when eating), the 3-year mean differences in CDR-SB compared to the “always” (score 1) group were -2.47 [95% confidence interval (CI)=-4.70 – -0.24, p=0.030] in the “usually” (score 3) group and -3.16 (95% CI=-5.36 – -0.96, p=0.005) in the “rarely” (score 5) group (Fig. 1). In Q7, the 3-year mean differences in NTB z-score compared to the “always” (score 1) group were 1.48 (95% CI=0.45–2.51, p=0.005) for the “usually” (score 3) group and 1.22 (95% CI=0.18–2.27, p=0.021) for the “rarely” (score 5) group. In Q7, the 3-year mean differences in CGA-NPI compared to the “always” (score 1) group were -29.64 (95% CI=-45.25 – -14.02, p<0.001) in the “usually” (score 3) group and -32.64 (95% CI=-48.08 – -17.21, p<0.001) in the “rarely” (score 5) group. In Q10 (eat all foods evenly without being picky), the 3-year mean differences in CDR-SB compared to the “rarely” (score 1) group were -1.86 (95% CI=-3.64 – -0.09, p=0.039) for the “usually” (score 3) group and -2.23 (95% CI=-4.40 – -0.06, p=0.044) for the “always” (score 5) group (Fig. 2).
Fig. 1
Adjusted mean scores of clinical outcomes according to the score groups of Q7 (add salt or soy sauce to food when eating) on the Mini Dietary Assessment Index in participants with Alzheimer’s disease dementia for 3 years. Increases in scores represent worsening of the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living (S-IADL), and Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), and improvement in neuropsychological test battery (NTB) z-score. Scores in Q7 correspond to “1=always, 3=usually, and 5=rarely.” The adjusted means of clinical outcomes were calculated by a linear mixed model including age, sex, education, baseline body mass index, current drinking and smoking at baseline, score of Geriatric Depression Scale-15 items at baseline, baseline Mini-Mental State Examination score, each score of Q2, Q7, and Q10 at baseline, time, and question-by-time as fixed effects.
Fig. 2
Adjusted mean scores of clinical outcomes according to the score groups of Q10 (eat all food evenly without being picky) on the Mini Dietary Assessment Index in participants with Alzheimer’s disease dementia for 3 years. Increases in scores represent worsening of the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living (S-IADL), and Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), and improvement in neuropsychological test battery (NTB) z-score. Scores in Q10 correspond to “1=rarely, 3=usually, and 5=always.” The adjusted means of clinical outcomes were calculated by a linear mixed model including age, sex, education, baseline body mass index, current drinking and smoking at baseline, score of Geriatric Depression Scale-15 items at baseline, baseline Mini-Mental State Examination score, each score of Q2, Q7, and Q10 at baseline, time, and question-by-time as fixed effects.
Table 4
Adjusted Mean Differences for Each Outcome between Different Score Groups for Each Question on the Mini Dietary Assessment Index Over 3 Years
DISCUSSION
In this study, eating all food evenly without being picky was associated with a slow progression of dementia severity as measured by the CDR-SB in patients with ADD over 3 years. The dietary habit of always adding salt or soy sauce to food when eating food was also associated with a relatively rapid progression in dementia severity as measured by the CDR-SB, a rapid decline in cognitive function as measured by the NTB z-score, and a greater increase in behavioral alterations as measured by the CGA-NPI in these patients over 3 years.
In previous studies, the Mediterranean diet has demonstrated the potential to slow the development of dementia in people without prior dementia diagnosis.28, 29 Some authors have suggested that this effect may be attributed to the anti-inflammatory effects of the Mediterranean diet.30 However, dietary patterns and ingredients are unique to local cultures and are thus difficult to change. We analyzed the effects of dietary habits on patients with dementia, taking into account their own diets and ingredients.
Understanding the nutritional status of a population is essential for promoting public health. The MDA was developed to easily investigate eating habits when implementing community-based health promotion projects in public health centers. Some studies have evaluated dietary patterns and cognitive decline using a dietary index.31, 32 However, cross-sectional studies have failed to yield consistent results. While higher Mediterranean diet scores were associated with slower rates of cognitive decline, similar associations have not been observed for the Healthy Eating Index-2005 (HEI-2005) scores.32 In our study, we did not find a significant positive or negative effect of the total MDA score on dementia progression (data not shown). We analyzed the effect of each item on cognitive function rather than developing a composite score.
It is also possible that eating habits are not directly involved in the deterioration of dementia and may act indirectly through other risk factors. In general, people who are well educated have healthier eating habits.33 Studies conducted in both Korea and the United States have indicated that highly educated people consume more vegetables, fruits, and whole grains.33, 34 In our study results, people with good eating habits often had fewer risk factors for dementia (Table 3). After adjusting for all these factors in the analysis, we found that good eating habits, such as eating evenly throughout the day, and having low salt intake can slow the progression of dementia.
Most clinical studies compared groups with similar baseline characteristics through random assignment before intervention began.9 In studies of dietary patterns or habits of the participants, dietary habits were a factor applicable long before the start of the study.28 Therefore, in a study that investigated dietary patterns or habits, to match the condition of the participant, at least at the beginning of the study, the study was not conducted on patients with dementia but on healthy people.9, 28, 29 The endpoint was the development of dementia. However, this study design could not establish the effect of eating habits on dementia progression. Dementia is expected to aggravate linearly over time, and our study revealed this linear deterioration in dementia. In studies involving participants without dementia and with dementia occurrence as the dependent variable, it is easier to interpret the effect of factors through survival analysis, such as Cox analysis. In a study involving patients with dementia, the heterogeneity of participants at the start of the study presents a challenge. To address this, we did not compare the differences in the outcome measure tests (CDR-SB, CGA-NPI, NTB z-score, and S-IADL) in the third year, but instead used a mixed model for the longitudinal analysis of repeatedly measured data. We considered that if the good dietary habits group (score 3 or 5) had more favorable estimated means (lower CDR-SB, CGA-NPI, S-IADL scores, or higher NTB z-score) at one of the outcome measures than the group with bad dietary habits (score 1), then good dietary habits could delay the progression of dementia. Patients with dementia experience a functional decline, behavioral alterations, and cognitive dysfunction. In our study, we found that eating all food evenly without being picky and avoiding the addition of salt or soy sauce to food were associated with less deterioration not only in CDR-SB but also in NTB z-score and CGA-NPI.
While the Mediterranean diet has been shown to be beneficial for controlling the development of dementia, in non-Mediterranean regions, individuals who adhere to such diets tend to have higher socioeconomic statuses. Higher socioeconomic status often translates to better healthcare access and more years of education.33 A previous longitudinal study found no strong association between the development of cognitive dysfunction and any of the dietary patterns investigated in the same dietary culture.31 However, this study was also conducted on people without dementia.
In a Chinese cohort study, excessive dietary salt aggravated cognitive impairment progression and increased dementia risk in older adults independently of known risk factors, including hypertension and apolipoprotein E genotype.35 In a previous study, a salt-rich diet caused brain endothelial dysfunction, cerebral hypoperfusion, and hyperphosphorylation of tau, which subsequently led to cognitive dysfunction in mice.36 These findings may suggest a causal relationship between dietary salt and Alzheimer’s disease. These previous results support our findings that the dietary habit of always adding salt or soy sauce to food when eating food was associated with rapid progression in dementia severity and dementia symptoms, including cognitive impairment and abnormal behaviors, in patients with ADD.
In a Japanese cohort study, eating a variety of foods was associated with prevention of dementia among middle-aged and older adults.37 Dietary diversity was also associated with the prevention of hippocampal atrophy in middle-aged and older adults.38 These studies support our findings that eating all food evenly without being picky was associated with a slower progression of dementia in patients with ADD. Rather than a single food or nutrient, a nutritionally balanced diet that integrates a variety of foods and nutrients contributes to the maintenance of brain function and may be effective in preventing dementia.
A major limitation of our study is that dietary habits were assessed only at the beginning of the research. As dementia progresses, patients’ preferences change and interest in meals decreases. Due to the loss of appetite, patients tend to experience nutritional deterioration as their dementia progresses.39, 40 The patient is gradually unable to eat alone and requires a helper. In contrast, caregivers may actively intervene in the patients’ eating habits. Second, although our sample represents the natural history of a real-world population visiting memory clinics with a starting size of 705 patients with ADD, the results should be interpreted with caution due to the small final sample. People who experience a faster decline may drop out of the study at an earlier time. Third, although we adjusted for MMSE scores in the multivariate analysis, we cannot rule out the possibility that patients in the early stages of dementia had good dietary habits, which may have influenced our results. Fourth, eating habits were not quantified and were only investigated through questionnaires. Fifth, we did not adjust for the influence of exercise or social activity as factors that may be related to the progression of dementia.
In conclusion, good dietary habits, especially low salt intake and eating without being selective, have positive effects on dementia, even after adjusting for the associated major risk factors. It is important not only to find and consume special foods that potentially slow the progression of dementia but also to reduce salt intake and eat foods evenly in a given environment, as these practices can contribute to the management of dementia.
SUPPLEMENTARY MATERIAL
Mini Dietary Assessment IndexSupplementary Table 1
This study was presented at CTAD 2022 in San Francisco (Nov 29, 2022–Dec 2, 2022).
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS:
Conceptualization: Yangki Minn and Seong Hye Choi.
Data curation: Kyung Won Park, Eun-Joo Kim, Soo Jin Yoon, Bora Yoon, Jae-Won Jang, and Seong Hye Choi.
Formal analysis: So Hyun Ahn, Yangki Minn, and Seong Hye Choi.
Funding acquisition: Seong Hye Choi.
Investigation: Jee Hyang Jeong, Kyung Won Park, Eun-Joo Kim, Soo Jin Yoon, Bora Yoon, Jae-Won Jang, and Seong Hye Choi.
Methodology: So Hyun Ahn, Yangki Minn, and Seong Hye Choi.
Project administration: Yangki Minn and Seong Hye Choi.
Resources: Jee Hyang Jeong, Kyung Won Park, Eun-Joo Kim, Soo Jin Yoon, Bora Yoon, and Jae-Won Jang.
Software: Yangki Minn and Seong Hye Choi.
Supervision: Yangki Minn and Seong Hye Choi.
Validation: Yangki Minn and Seong Hye Choi.
Visualization: So Hyun Ahn and Yangki Minn.
Writing—original draft: So Hyun Ahn and Yangki Minn.
Writing—review & editing: Seong Hye Choi and Yangki Minn.
Approval of final manuscript: all authors.
ACKNOWLEDGEMENTS
This research was supported by a grant from Inha University.
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