Tai Ji on Cognitive Function Improvement in Parkinson’s Disease: A Meta-Analysis

Background : Tai Ji (TJ) can improve cognitive function, which in turn brings life quality to Parkinson’s disease (PD) patients. Cognitive function is thus important for PD patients. Analyzing the cognitive function and obtaining precise TJ exercise prescriptions are effective in treating PD patients. Objectives : The purpose of this review was to discuss the current Randomized Controlled Trials (RCTs) of TJ and cognitive function improvement in PD. Materials and Methods : Databases, including PubMed, Web of Science, Scopus, Cochrane Library, EBSCOhost, Wan Fang, and CNKI, were searched. Cochrane systematic evaluation method was adopted wherein 6 RCTs met the final inclusion criteria. Results : Among the 6 included RCTs, 3 were of high quality, and the rest were of medium quality. Quantitative analysis exhibited that TJ intervention improved the cognitive function of PD patients. TJ promoted the global cognitive function ( p < 0.05) and the executive function ( p = 0.09) compared with the control. However there was no significant improvement in cognitive motor. TJ training intervention doses of two times a week with 45–60 min sessions over ≤ 12 weeks could improve the cognitive function of PD patients. Conclusions : TJ affects the cognitive function of PD patients. However, this effect may have a reduced or no significant impact as the disease increases. PD patients can choose TJ as an intervention for 45–60 min twice a week for at least 12 weeks to accomplish maximum improvement in cognitive function.


Introduction
Parkinson's disease (PD) is one of the most prevalent neurodegenerative conditions which affects 1% of people worldwide of over 55 years of age and is characterized by movement slowness (bradykinesia), muscular stiffness, and rest tremors [1,2]. A range of non-motor symptoms (NMS) related to the condition is experienced by PD patients [3] along with essential motor components [4]. Debilitating NMS, such as sleep disruption, cognitive decline, and depression, are present in a large number of PD patients. Recent studies demonstrated NMS being present in the entire course of PD and affecting patient's life quality [5,6]. One common effect of PD is cognitive decline [7]. Physical activity improves cognitive function and delays cognitive deterioration in PD patients [8]. Research supporting the positive impact of non-pharmacological therapy is expanding [9].
Tai Ji (TJ) is a popular mind-body intervention that tackles a variety of motor and NMS associated with PD [10]. TJ is multi-faceted, having benefits for physical and mental health. It blends meditation with slow movements to relieve stress, improve mood, develop flexibility, and enhance the balance [11][12][13]. A large-scale randomized investigation by Li et al. [14] in 2012 revealed that TJ outperformed weight training and stretching, regarding improvement in balance impairments, increasing functional ability, and reducing falls. TJ lowers stress and improves life quality and motor performance [15]. TJ effects on non-motor outcomes in PD have been less focused [16]. No metaanalyses have examined the PD patients' cognitive performance which is linked to the overall life quality [17].
The purpose of this study was to combine TJ randomized controlled trials (RCTs) to evaluate the TJ's impact on PD patients' ability to improve cognitive function. It also covered surveys of exercise doses and the progress of interventions. It was expected that TJ had a considerable advantage over the control group in enhancing the cognitive performance of PD patients and had an impact on cognitive subdomains.

Search Strategy
This meta-analysis was conducted and reported in accordance with PRISMA principles [18]. Up to 19th December 2022, Jinling Y. and Yang L. made literature search from WBM, CNKI, PubMed, Web of Science (WOS), Scopus, Cochrane Library, and EBSCOhost databases by using the Boolean search technique, phrases and fields specific to the database (Appendix Table 3). For instance, the PubMed search string was: [title/abstract] [("Parkinson disease" [MeSH])] AND ("Tai Ji"[MeSH]) AND ("cognition"[MeSH] OR "cognitive behavioral") AND ("randomized controlled trial"[MeSH]).

Inclusion and Exclusion Criteria
The inclusion and exclusion criteria for the designed study were as follows: (i) Participants: people with PD and no other primary disease; (ii) Intervention and comparison: studies comparing TJ interventions with active and inactive controls were included; studies where TJ was specified as control condition or TJ combined with other practices or exercise forms were excluded; (iii) Outcomes: any data assessing the cognitive function; (iv) Study type: studies with randomized controlled trials (RCTs) were included.

Study Selection
Titles and abstracts were used to filter distinct items (after removing duplicates) retrieved from electronic bibliographic database searches for inclusion. The searched literature was vetted based on inclusion and exclusion criteria. JY and YL organized and executed the research project, designed and executed statistical analysis. WL, conception and organization of research project. YF, conception of research project. Additional papers were regarded as complementary but used in the data collection process. Text reporting the most comprehensive data was chosen as the main text.

Quality Assessment and Bias Risk
The searches used the article quality assessment criteria manual recommended by Cochrane Manual 5.1.0 to assess the quality of included literature [19] and evaluated each sub-item as "low risk", "unclear" and "high risk".

Data Extraction
The two studies extracted the following information: first author, publication year, sample size, age, disease severity, intervention method, intervention dose, and outcome. The methods used to test various cognitive functions in humans were divided into executive function, global cognition, and cognitive motor [20].

Data Analysis
Forest maps were plotted for included publications using Review Manager 5.3 (RevMan 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark), and the calculated effect sizes were analyzed through standardized mean differences (SMD). The fixed-effects and random-effects models' 95% confidence intervals (95% CI) were estimated. I 2 was the main indicator of heterogeneity; If I 2 was <50%, the heterogeneity could be ignored, and a fixed-effect model was applied; if I 2 was between 50% and 75%, heterogeneity was mod-erate; and if I 2 was >75%, the random effect model was applied, and heterogeneity causes were discussed and ana-lyzed. SMD ≥0.2 was the modest, ≥0.5 was medium, and ≥0.8 was large when calculating the effect size. A significant impact was considered with p < 0.05.

Study Identification and Selection
The databases yielded a total of 43 articles, where 16 were excluded before screening. Thirteen articles were disregarded after reading the titles and abstracts. The remaining 14 were required to be read in their entirety. One article was not retrieved. Seven articles were excluded because of too low quality (n = 2), TJ intervention present in both experimental and control groups (n = 1), outcome indexes did not mention cognitive component (n = 2), and the outcome data unavailable (n = 2). The remaining 6 articles were quantitatively synthesized and analyzed (Fig. 1).

Quality Assessment
Five studies (83.3%) reported the random sequence generation methods. Four (66.7%) mentioned the allocation concealment techniques. Three (50%) managed to blind the subjects and staff. They thus had low bias risk because of assessors' blinding. Regarding bias reporting, every study reported the anticipated findings. The majority of studies lacked a description of additional bias risks. Three studies (50%) were of excellent quality providing an overview of 6 RCTs' quality ratings. A quality assessment summary of 6 RCTs was presented in Figs. 2,3.

Subgroup Analysis
Disease duration: In the disease duration subgroup analysis ( Table 2). TJ had the greatest impact on improving cognitive function in PD patients having the disease of

Summary of Findings
A meta-analysis of 6 RCTs was performed with 251 participants. The findings revealed that TJ led to cognition improvements (overall cognitive function, p < 0.05). TJ training also improved the global cognitive function (p < 0.05) and executive function (p = 0.09) compared with control. However there was no significant improvement of cognitive motor. In subgroup analysis, TJ training improved cognitive function in PD patients with a disease duration of <4 years, while there was slight improvement with a disease duration >7 years which was not statistically significant. For TJ training intervention, doses of two times per

TJ and Cognitive Function
TJ training, compared to control, enhanced cognitive function of PD patients as per this meta-analysis. This was consistent with the findings of Horstink M et al. [27] that TJ training enhanced cognitive function in both normal cognitive function and cognitive impairment. TJ delayed cognitive decline in moderate PD patients. Previous studies revealed that physical activity interventions improved cognitive function in adults regardless of their cognitive status, and TJ significantly improved cognitive function [28][29][30][31]. This study summarized TJ effectiveness in PD patients of various degrees, providing a theoretical foundation for precise exercise prescriptions.
The vital part of a person's cognition is executive function. These results initially suggested that TJ might not be the best treatment for enhancing the cognitive executive function of PD patients (p < 0.1). The brain frontal lobe was recognized for controlling tasks like memory renewal, attention switching, and multi-task coordination, but the executive function was higher cognitive activity connected to it [32]. The prefrontal, parietal, and temporal lobes of the brain could modify their form and function [33]. TJ training as moderate-intensity aerobic exercise thus improved people's executive function. Considering that one study was included [23], there was a trend of significant differences in outcomes, although not significant. The hypothesis that TJ training improved executive function in PD patients would be clearly demonstrated if more RCTs were analyzed.
Dual tasks were used for the outcomes regarding TJ effect on cognitive motor [26]. A dual-task design was employed to compare the young and older adults executing specific cognitive tasks while standing [34], walking [35], or in response to postural perturbation [36,37]. It assessed postural control with concurrent cognitive processing. According to the Vergara-Diaz G study, the dual-task gait stride-time variability was sensitive and logical outcome for evaluating the combined cognitive motor was affected by TJ in PD [26]. However, because of the small sample size and high RCT bias in the TJ intervention group of the Vergara-Diaz G study, there was insufficient evidence in our study to support that TJ exercise significantly improved cognitive motor in PD (p = 0.19).
Parkinson's Disease Questionnaire 39 (PDQ-39), the Trail Making Test A and B, and Montreal Cognitive Assessment (MoCA) were the often utilized tools in evaluating the global cognitive function. Mini-Mental State Ex-amination (MMSE) was employed for cognitive screening. MMSE was a comprehensive instrument for detecting cognitive deficits [38]. MMSE exhibited ceiling effects on mild cognitive impairment and floor effects on severe cognitive impairment [39]. MMSE was less sensitive to mild cognitive impairment in PD [40]. K-MMSE performed like MMSE. MoCA was created as a screening tool for mild cognitive impairments (MIC) and was an often used instrument for these investigations [41]. MoCA assessed the executive and visuospatial abilities, memory, language, and attention. The scale's psychometric qualities were sufficient for a quick evaluation of global cognition in PD [42]. Trail Making Test (TMT) was another often used instrument. TMT could be affected by cognitive changes in PD [43]. The 39 items on self-administered PDQ-39 were divided into eight categories, one of which was the cognitive domain [44].
In the present study, it was found that signal intensity of global cognition in PD was improved (p < 0.05) by TJ intervention. However, a thorough analysis of these findings was required. There was no agreement on ideal intervention frequency and length because of the heterogeneity of cognitive tests employed in evaluating the global cognitive performance in included trials. This did not change the conclusion that TJ exercises considerably enhanced PD global cognitive function.

Exercise Prescription
TJ intervention modalities performed more than 3 times a week for 45 to 60 min over at least 12 weeks are preferred in PD patients of short disease duration.

Limitations
Despite our clarifications of TJ application in PD patients, some issues need further explorations in future experimental protocols. Firstly, which cognitive domains of PD are better enhanced by TJ cannot be accurately judged because of the limitations of current RCTs. Second, there is a need for accurate exercise prescriptions for PD patients of different disease courses. Third, the number of high qualities RCTs is insufficient, and subjective assessment processes may have confounded the results.

Conclusions
The findings of this study indicate that TJ affects cognitive function in PD patients. This effect may diminish or become insignificant as a person's disease progresses. The best improvement of cognitive function in PD can be achieved by TJ intervention of 45-60 min twice a week for at least 12 weeks.

Availability of Data and Materials
All data generated or analyzed during this study are included in this published article.

Author Contributions
JY: organization and execution of research project, design and execution of statistical analysis, writing of the first draft of manuscript; YL: organization and execution of research project, design and execution of statistical analysis; WL: conception and organization of research project, review and critique of manuscript; YF: conception of research project, review and critique of manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate
Not applicable.

Acknowledgment
We would like to extend our special thanks to all the participants in the studies, whose data and participation have enabled us to conduct this research. Additionally, we sincerely appreciate the invaluable comments and suggestions provided by the anonymous reviewers, which have played a significant role in enhancing the quality of this study.

Funding
This research received no external funding.