
==== Front
Eur J Phys Rehabil Med
Eur J Phys Rehabil Med
EJPRM
European Journal of Physical and Rehabilitation Medicine
1973-9087
1973-9095
Edizioni Minerva Medica

38814196
8015
10.23736/S1973-9087.24.08015-8
Article
A randomized controlled trial on the effects of traditional Thai mind-body exercise (Ruesi Dadton) on biomarkers in mild cognitive impairment
KHANTHONG Phaksachiphon 1 2
SRIYAKUL Kusuma 1
DECHAKHAMPHU Ananya 2
KRAJARNG Aungkana 1
KAMALASHIRAN Chuntida 1
JAYATHAVAJ Vadhana 3
TUNGSUKRUTHAI Parunkul 1 *
1Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, Thailand; 2Faculty of Thai Traditional Medicine and Alternative Medicine, Ubon Ratchathani Rajabhat University, Ubon Ratchathani, Thailand; 3Faculty of Allied Health Sciences, Pathumthani University, Pathum Thani, Thailand
* Corresponding author: Parunkul Tungsukruthai, Chulabhorn International College of Medicine, Thammasat University, 12120, Pathum Thani, Thailand. E-mail: parunkul@hotmail.com
Authors’ contributions: Phaksachiphon Khanthong, Parunkul Tungsukruthai have given substantial contributions to the conception of the manuscript: Phaksachiphon Khanthong and Vadhana Jayathavaj analyzed and interpreted the data; Parunkul Tungsukruthai and Kusuma Sriyakul supervised the study; Ananya Dechakhamphu contributed to laboratory analysis. All authors have read and approved the final version of the manuscript.

30 5 2024
8 2024
60 4 604610
03 5 2024
07 2 2024
24 4 2023
2024 THE AUTHORS
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) 4.0 License.
BACKGROUND

Exercise has been shown to reduce the rate of mild cognitive impairment (MCI) and Alzheimer’s disease. Although motor coordination movements and poses in Ruesi Dadton (RD) exercises may improve cognitive function, RD is rarely used for MCI. To date, there is insufficient evidence on whether 12 weeks of RD exercise correlates with blood biomarkers related to neurogenesis and plasticity.

AIM

To determine the effects on blood biomarkers of 12-week RD in MCI.

DESIGN

Two-group parallel randomized controlled trial.

SETTING

Community exercise.

POPULATION

Individual with MCI.

METHODS

Fifty-eight participants (n.=29 in each group). The RD group performed 60min of RD exercises (15 poses) three times weekly for 12 weeks. The control group received no intervention. In addition, both groups were given information regarding MCI symptoms by the physician on the first day. Peripheral blood was collected to measure serum brain-derived neurotrophic factor (BDNF) and sirtuin 1 (SIRT1) levels before and after intervention.

RESULTS

The effects of 12-week RD pre- and post-intervention were examined using 2×2 repeated multivariate analyses, which showed significant differences in interaction by group and time. Student’s t-tests and paired t-tests were employed in subsequent analyses to evaluate between-group and within-group differences for both biomarkers.

CONCLUSIONS

In each test, we discovered increased levels of BDNF and SIRT1 in the RD group but not in the control group. These findings suggested that RD could benefit MCI patients through enhanced BDNF and SIRT1 levels.

CLINICAL REHABILITATION IMPACT

Twelve weeks of RD might be helpful to patients with MCI and older people who experience cognitive impairment by improving blood biomarkers responsible for brain plasticity and amyloid plaque degradation.

Key words:

Biomarkers
Cognitive dysfunction
Exercise
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pmcAmnestic mild cognitive impairment (MCI) is the most common type of Alzheimer’s disease (AD). Individuals with MCI have normal daily function, except for loss of memory.1 MCI and AD are hypothesized to be caused by the accumulation of amyloid plaques and neurofibrillary tangles.2 Additionally, inflammatory processes involving microglia, astrocytes, oligodendrocytes, and neurons, contribute to AD neuropathology.3 The progression of MCI to AD or dementia is linked to brain atrophy and can be predicted.4 As treatment for dementia currently remains unsatisfactory, a complementary approach for addressing cognitive decline is necessary.5

Greater physical activity is associated with a reduction in cognitive decline in older adults, and exercise influences all stages of cognitive decline.6 Exercise not only improves cognition, but also brain volume7 and AD biomarkers.8, 9 Clinicians recommend exercise as the treatment of choice for people with MCI and dementia because physical exercise has been shown to have the highest empirical impact.10 This recommendation was confirmed by evidence from meta-analyses and systematic reviews showing improved cognitive function in patients with MCI and dementia.11 One of the biomarkers for cognitive decline that has gained attention in previous studies is brain-derived neurotrophic factor (BDNF), which promotes neuroplasticity and has been identified as a biomarker for cognitive function enhancement.12

BDNF exerts its effects on hippocampal neurogenesis by interreacting with neurotransmitters.13 Enhanced BDNF production during exercise is related to irisin and involves proteolytic cleavage of fibronectin type III domain containing 5 (FNDC5),14 which is expressed in the hypothalamus and hippocampus and is involved in learning and memory.15 Moreover, correlations between BDNF levels and amyloid beta pathology and cognition in patients with AD have been shown.16

Another biomarker of interest is sirtuin 1 (SIRT1), which, along with AMP-activated protein kinase (AMPK) and reactive oxygen species, acts on peroxisome proliferator-activated receptor gamma coactivator-1-alpha.13 BDNF expression is enhanced through the lactate-SIRT1-FNDC5 axis.17 Moreover, BDNF and SIRT1 levels in individuals with MCI are lower than in healthy individuals.18 Furthermore, a recent study found a reduction in amyloid plaques and tangles due to dementia pathology caused by SIRT1 in a mouse model.19 Additionally, SIRT1 levels were found to be decreased in the cerebellum of aging mice20 and were enhanced after exercise in AD mice.21

The recommended exercise duration for older adults according to the World Health Organization (WHO) is 150 min/week.22 In addition, exercise may delay cognitive decline in AD and in related AD stages such as MCI.23 This does not specify the duration per session or the frequency of exercise, indicating that it can be applied to suit the individual but requires multiple components.22 Although resistance and multicomponent exercises showed more marked effects than other types of exercise,11 mind-body exercises such as Tai Chi, yoga, and Qigong, also improve cognitive function.24, 25 Ruesi Dadton (RD), sometimes called Thai yoga, is a traditional Thai exercise that originates from yoga which could be more acceptable for Thai people than other types of exercise derived from other countries. RD is a brief intervention that is performed through slow movements together with deep breathing. Other components include self-massage, stretching, and balancing in various positions. The RD exercise positions consist of sitting, standing, supine, prone, and side lying. RD has been evidenced to support improved oxidative stress and antioxidant levels in healthy older adults,26 suggesting that RD may reduce neurodegeneration and aging by improving both oxidative stress and antioxidant levels. Furthermore, cognitive and physical functions in individuals with MCI have been shown to be improved after participation in RD.27 Moreover, the positive impact of RD extends to the improvement of oxidative stress levels in this population.28

We hypothesized that RD would improve cognitive blood biomarkers. Therefore, this study aimed to evaluate the effectiveness of RD for improving the blood biomarkers of MCI. The results of our study may contribute to the implementation of RD in MCI recovery.

Materials and methods

Study design and ethical approval

This randomized controlled trial (RCT) was approved by the Human Research Ethics Committee No. 1, Faculty of Medicine, Thammasat University, Thailand (no. 119/2562) and the Thai Clinical Trials Registry (TCTR20200727001). All participants had given informed consent before participation. This study was carried out in compliance with the Declaration of Helsinki and adhered to all applicable items on the TIDieR checklist, which is a standardized guideline for reporting interventions in research studies.29

Participants

Fifty-eight eligible participants were recruited from June to July 2020 and enrollment was completed by Village Health Volunteers in four zones under the supervision of the Huadon Health Promoting Hospital. The Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines for randomized controlled trial was followed, and the flow diagram of the 58 participants in the parallel-group study is shown in Figure 1.

Figure 1 —Flow chart diagram.

The inclusion criteria were as follows: 1) age, 50-80 years; 2) Body Mass Index, 19-27.5 kg/m2; and 3) a confirmed diagnosis of MCI by a neurologist using baseline screening tools, specifically, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Exclusion criteria included: 1) risk factors for dementia such as history of brain injury and cardiovascular diseases; 2) contraindications for exercise including an inability to sit cross legged or severe knee pain; 3) individuals already regularly exercising three times a week; and 4) experience of exercise mind-body methods (yoga or Tai Chi) within the previous three months. The number of participants was recorded during the first day of enrollment. Individuals were randomly allocated to an RD group or a control group. The group allocation was further stratified using randomized block sizes based on non-modifiable risk factors for early-life dementia.

The first block was base on age group (<70 y, ≥70 y),30 and the second block was based on education level group (<6 y, ≥6 y).31 The allocation sequence was generated by online researcher VJ and the participants assignments were done by researcher PK and the Village Health Volunteers.

Intervention

Global cognition was measured using the Thai version of MMSE and MoCA. Both tools were completed by an author (PK) who was experienced in their use. Results were confirmed through evaluation, consultation, and decision scores by another researcher (CK) with more than five years of experience of MoCA screening research with the dementia association of Thailand. On the baseline assessment date, RD and control groups received education related to MCI and AD, including causes of the disease and lifestyle adjustments to prevent AD besides exercise recommendations.

Peripheral blood samples were collected before and after the 12-week intervention period at Huadon Health Promoting Hospital. The RD group received demonstrations and performed practice exercises for two days before the sessions began. The study protocol was conducted in August, and the follow-up period was in October 2021 (as shown in Figure 2).

Figure 2 —Study protocol.

The 15 RD poses illustrated in Figure 2 were also part of the study protocol. If individuals in the RD group experienced movement limitations while practicing, safe adjusted positions were offered by Thai medicine and physical therapist instructors. Furthermore, we also created a video displaying the 15 RD poses used during the intervention (Figure 3) as recommended by the Ministry of Public Health, Thailand, with instructions in the local language. Participants were instructed to perform RD for 60 min/session, three times per week, for a total of 12 weeks, resulting in a total of 36 sessions.

Figure 3 —Practice Ruesi Dadton in the community.

The appointments were scheduled by the researchers after session completion on a day-to-day basis. Participants were again requested to avoid scheduling any duty or meetings in their village to avoid potential conflicts. The program was set for every Monday, Wednesday, and Friday but was sufficiently flexible to accommodate most of the participants’ free time. After the three appointments per week were completed, the next appointment was set and confirmed every week. The control group was appointed a date for a global cognitive assessment and blood sample collection by the Village Health Volunteers.

Laboratory assessments

Laboratory assessments were performed by a researcher (AD) with more than 15 years of experience in biochemistry laboratory research. Peripheral blood (10 mL) was collected from the median cubital vein of the participants between 6.00-8.00 AM after fasting from midnight (water was allowed) at Huadon Health Promoting Hospital, Ubon Ratchathani Province. Blood was obtained by sterilized venipuncture, collected in clot-activator tubes and centrifuged at 2000 rpm at 4 °C for 15 min to isolate serum, which was stored at -80°C until use. Assessors were blinded by attaching only the participant number to clot-activator tubes. BDNF (Sigma Aldrich, Burlington, MA, USA) and SIRT1 (MyBioSource, San Diego, CA, USA) levels were measured using enzyme-linked immunosorbent assays according to the manufacturer’s instructions, at the Ubon Ratchathani Rajabhat University. After completing this protocol, raw data was recorded by an assistant researcher and statistical analysis was completed by a senior researcher (VC).

Statistical analysis

SPSS, version 24 (IBM SPSS Inc., Armonk, NY), was used for statistical analysis. Additionally, outliers were excluded from the laboratory assessments data of both groups because they could not be interpreted by Multivariate Analysis of Variance (MANOVA) (as shown in Figure 1). The normality test was run before using MANOVA to assume normal distribution before statistical tests.32 It found acceptable normality by Skewness and Kurtosis criterion not larger than 1.96.33 Descriptive statistics were presented as mean and standard deviation. The independent samples t-test was used to calculate baseline characteristics. To report multivariate outcomes, we chose a 2 × 2 (group by time) repeated-measures MANOVA on the two biomarkers (BDNF and SIRT1), using Wilks’ Lambda (Λ).

Before calculating the repeated-measures MANOVA, a sample size of 58 individuals (two groups and two measurement) was determined a priori using G*power estimation to achieve an α level of 0.05 and a power (1-β) of 0.80. We reported a medium effect size at 0.374. Further analysis to compare the differences between time points and groups was conducted using independent and paired sample t-tests. Effect size was calculated using Cohen’s d with small, medium, and large effect sizes defined as 0.2, 0.5, and 0.8, respectively.34 Additionally, statistical differences were reported if the omnibus multivariate significance was <0.05.

Data availability

The data associated with the paper are not publicly available but are available from the corresponding author on reasonable request.

Results

Characterization of baseline participants

Cognitive blood biomarkers of twenty-nine individuals from the RD and control group were assessed after excluding outlier data from both groups. The baseline characteristics of the participants in the total sample and each group are shown in Table I. In this study, an average of 86.7% (31 of 36) exercise sessions were completed in the RD group (range=21-36 sessions).

Table I —Baseline characteristics of the participants.

Baseline characteristics	RD group
(N.=29)	CO group
(N.=29)	t	P value	
Age (y)	60.31 (5.69)	60.93 (7.71)	-3.729	0.728	
Education (y)	7.00 (3.64)	8.21 (4.27)	-1.159	0.251	
BMI (km/m2)	22.94 (2.14)	23.22 (2.45)	-0.460	0.647	
Waist circumference (cm)	81.55 (7.76)	81.79 (5.55)	-0.136	0.892	
MMSE (scores)	26.86 (1.77)	26.28 (1.73)	1.277	0.207	
MoCA (scores)	19.76 (3.33)	18.62 (2.81)	1.406	0.165	
BDNF (pg/mL)	2.21 (3.71)	2.40 (1.94)	-0.250	0.803	
SIRT1 (pg/mL)	111.47 (83.61)	120.77 (93.60)	-0.399	0.691	
MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive Assessment; BDNF: brain-derived neurotrophic factor; SIRT1: sirtuin1; CO: control; RD: Ruesi Dadton.

Effects of BDNF and SIRT1 levels on cognition

In Table II, we presented the mean and standard error (SE) from repeated-measures MANOVA.

Table II —Biomarker levels by groups across treatment time point.

Measures	Main effects	Group vs. time	
RD	CO	
Mean	SE	N.	Mean	SE	Mean	SE	
BDNF									
Time	Pre	2.31	0.39	58	2.21	0.55	2.40	0.55	
Post	4.48	0.67	58	6.88	0.94	2.08	0.94	
Group	RD	4.55	0.54	29					
CO	2.24	0.54	29					
SIRT1									
Time	Pre	116.12	11.65	58	111.36	16.48	180.38	16.01	
Post	139.92	11.32	58	120.77	16.48	99.47	16.01	
Group	RD	145.93	14.39	29					
CO	110.12	14.39	29					
BDNF: brain-derived neurotrophic factor; SIRT1: sirtuin 1; RD: Ruesi Dadton; CO: control; SE: standard error.

This table reported significant multivariate effects for group (Λ=0.825, F(2,55)=5.833, P=0.005, d=0.46), time (Λ=0.848, F(2,55)=4.925, P=0.011, d=0.42), and interaction between group and time (Λ=0.715, F(2,55)=10.941, P<0.001, d=0.63). Univariate between-group analysis found significant effects of BDNF levels (F(1,56)=9.219, P=0.004, d=0.41), but not for SIRT1 levels (F(1,56)=3.098, P=0.084, d=0.23). Within-group analysis showed that both BDNF (F(1,56)=7.686, P=0.008, d=0.37) and SIRT1 (F(1,56)=4.964, P=0.030, d=0.30) levels improved in the time between pre- and postintervention. Finally, the interaction between groups and time showed significance for BDNF (F(1,56)=10.113, P=0.002, d=0.43) and SIRT1 (F(1,56)=17.831, P<0.001, d=0.57).

Further analysis of the interaction exhibited significantly higher effects of RD on both BDNF (t(56)=3.598, P=0.001) and SIRT1 (t(56)=3.573, P=0.001) levels after 12-weeks of intervention compared with the control group. There were significant within-group differences between pre- and post-analysis results of RD on both BDNF (t(56)=-3.453, P=0.002) and SIRT1 (t(56)=-3.744, P=0.001) levels, while no significant difference was found in the control group (BDNF:t(56)=0.402, P=0.691; and SIRT1:t(56)=1.964, P=0.060).

Discussion

This RCT investigated two blood biomarker levels and compared them between the RD and the control group. Repeated-measures MANOVA confirmed in omnibus multivariate tests that 12-week RD participation significantly boosted these blood biomarker levels. In summary, based on the univariate results, the only significant differences were observed in BDNF levels between the groups. According to the results, the effect of RD on blood biomarkers is associated with neurogenesis and neuroplasticity in MCI. BDNF and SIRT1 were targeted as they are related to the mechanism involved in exercise-induced reduction in amyloid plaques that are involved in the underlying neurophysiology of AD and MCI.35

BDNF is involved in hippocampal neuroplasticity and is involved in the pathogenesis of MCI and dementia, based on empirical evidence of a relationship between decreased brain volume and BDNF and worsening of MCI and AD.36 However, when BDNF levels were compared between healthy controls and patients with early-onset AD, there was a significant decrease in BDNF in the early-onset AD group, but this difference was not found between patients with MCI and healthy controls.37 When comparing the change in BDNF levels among four groups of participants with MCI (physical, mental, physical plus mental, and control), we found significantly different elevations only in the physical plus mental exercise and physical exercise groups.8 Moreover, evidence from a systematic review and meta-analysis indicated that physical exercise increased BDNF in cognitive impairment and other neurodegenerative diseases,38, 39 but an increase was not found in one study of aerobic exercise.40 For mind-body exercise, Baduanjin and Tai Chi enhance BDNF levels, cognition, and hippocampal brain volume after 6 months in MCI.7, 9 Furthermore, a previous study revealed amelioration of both global and executive cognitive functions in the RD group.27 Therefore, BDNF is a representative blood biomarker related to the mechanisms involved in cognitive decline through the induction of neuroplasticity in MCI and dementia. Taken together with the findings of the present study, RD could be beneficial in MCI by increasing BDNF levels.

SIRT1 exerts its neuroprotective effects by activating lysosomes which degrade amyloid beta, where amyloid beta is known to be involved in AD pathogenesis.41 Previous studies demonstrated that physical exercise affects pathways involving AMPK phosphorylation to stimulate SIRT113, 39 and inhibit Forkhead box-O1 induced cell death.41, 42 In another study, a yoga and meditation-based lifestyle was found to promote circulation of SIRT1 in major depressive disorder.18 However, there are few studies investigating the effects of physical exercise on SIRT1 levels in the context of MCI and AD because the exact mechanism of action is unknown. SIRT1 is thought to be associated with longevity43 and has a related neuroprotective mechanism.44 Therefore, as RD influences active circulation of SIRT1, it can likely provide beneficial effects in terms of longevity and prevent cognitive decline by increasing SIRT1 levels.

Limitations of the study

This study has several limitations. First, risk factors, such as apolipoprotein E ε4 allele, mental conditions and other diseases were not known. We used two exercise periods, at 8.00 AM and 10.00 AM, with equal numbers of participants under the social distancing rules pertaining to the coronavirus disease. The effect of RD may thus involve the social contact obtained during group exercise. The two biomarkers are not only related to cognitive decline and MCI, but also to many other symptoms and pathological conditions. Nevertheless, no previous RCT has yet examined the effects of RD on BDNF and SIRT1. It has been well established that exercise can play a role in ameliorating cognitive decline in older adults, but it has to be an exercise that would be acceptable both on a physical and personal level if they take part in the practice.

We recommend that further studies with larger sample sizes should be conducted to confirm these results. In terms of exercise intensity, although the average was 86.7%, one-third (31.4%) of individuals in the RD group had not reached the WHO-recommended exercise intensity. The average number of exercise sessions completed was confirmed to be higher than the average attendance rate.45 Exercise intensity is an indicator of exercise efficacy and might be related to cognitive biomarker levels. Consequently, the total exercise intensity that may be effective in improving cognitive function needs to be considered. Therefore, further investigation of the difference in the RD group to find the appropriate intensity or recommendation should be done.

Conclusions

In conclusion, RD, which is a mind-body exercise, was shown to significantly improve brain plasticity and amyloid plaque degradation by activating BDNF and SIRT1. Our study suggested that RD has the potential to improve cognitive decline in MCI through BDNF and SIRT1. Additionally, RD would be physically possible for older persons and culturally acceptable to Thai people and may have higher than average attendance rates.

Conflicts of interest: The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Funding: This research was funded by a grant from the Thai Traditional Medical Knowledge Fund, Department of Thai Traditional and Alternative Medicine, Ministry of Public Health (grant no: 33/2563). The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work.
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