Meta-analysis of the effect of cognitive stimulation therapy on cognitive function in patients with Alzheimer's disease

Abstract

BACKGROUND

There is no effective treatment for Alzheimer's disease (AD), and pharmacological treatment of AD in clinical settings is expensive and prolonged, resulting in a huge psychological and economic burden on the patient's family and caregivers and society as a whole, AD is characterized by progressive, worsening cognitive impairment, and there are currently no drugs that can effectively reverse cognitive impairment. However, it is important to intervene early or delay cognitive impairment so that the condition can be delayed and, ultimately, the burden on patients and families can be reduced through maintenance treatment. It may be that non-pharmacological interventions such as cognitive stimulation therapy (CST) can help with cognitive dysfunction.

AIM

To provide a better treatment plan for AD patients and delay the deterioration of cognitive function, the effect of CST on cognitive function in AD was studied by Meta-analysis.

METHODS

Comprehensive search the Chinese and English databases were comprehensively searched by computer. Chinese databases: China Biomedical Literature Database (CBM), Wanfang Database, VIP Database, and China Periodicals Full-text Database (CNKI). The collection time limit is from July 21, 2010 to July 21, 2022 randomized controlled trials literature on the effects of CST on cognitive function in patients with AD. According to the inclusion and exclusion criteria, literature screening, data extraction, and quality evaluation were performed. Standardized mean difference (SMD) and 95%CI were used as evaluation criteria to evaluate the cognitive function of CST in AD patients. Sensitivity analysis and publication bias detection were performed on the results. Publication bias was assessed using funnel plots, and funnel plot symmetry was assessed with Eggr's test.

RESULTS

CST can not improve Mental State Examination Scale (MMSE) scores in AD patients. Meta-analysis of CST on MMSE scores showed that the heterogeneity was P = 0.14, I² = 35%. I² = 35% < 50%, and the Q test P > 0.1, choose the random effect model to integrate statistics, get SMD = 0.02, 95%CI: -0.37, 0.42, P > 0.05. Meta-analysis of CST on AD Cognitive Functioning Assessment Scale scores showed that the heterogeneity was P = 0.13, I² = 36%. I² = 36% < 50 choose a fixed effect model to integrate statistics, get SMD = -0.01, 95%CI: -0.40, 0.39, P > 0.05, the difference is not statistically significant. Meta-analysis of CST on the cognitive function indicators of patients showed that the heterogeneity was P = 0.17, I² = 31%. I² = 31% < 50%, the fixed effect model showed SMD = 0.01, 95%CI: -0.37, 0.38, P > 0.05, the difference was not statistically significant.

CONCLUSION

CST may not improve the cognitive function of AD patients, not improve the cognitive function of AD patients, not improve the ability of daily living, and not reduce mental behavior can improve the cognitive function of AD patients.

Key Words: Cognitive stimulation therapy; Alzheimer's disease; Meta-analysis; Cognitive function

Core Tip: At present, there is no effective drug to cure Alzheimer's disease (AD), and how to delay the deterioration of the disease is the focus of research. Cognitive therapy is based on the theoretical hypothesis that cognitive process affects emotion and behavior proposed by cognitive psychology, and uses cognitive and behavioral techniques to improve patients' bad cognition. So what is the clinical effect of cognitive therapy on AD?

INTRODUCTION

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss, cognitive impairment, behavioral changes, and psychiatric abnormalities and is considered the most common cause of AD[1]. The usual presentation is insidious memory and cognitive impairment and personality changes. The process is generally progressive and eventually leads to mental and physical disability, as well as death from complications following inability to move[2]. AD is the leading cause of disability in the elderly, and the risk of developing AD increases exponentially with age[3]. The costs associated with AD exceed those of heart disease and cancer and are usually paid directly by families. Despite the enormous global economic burden and the impact on the patient's family, there is no definitive cure and therefore a need to seek better treatments[4].

There is no effective treatment for AD, and pharmacological treatment of AD in clinical settings is expensive and prolonged, resulting in a huge psychological and economic burden on the patient's family and caregivers and society as a whole, AD is characterized by progressive, worsening cognitive impairment, and there are currently no drugs that can effectively reverse cognitive impairment. However, it is important to intervene early or delay cognitive impairment so that the condition can be delayed and, ultimately, the burden on patients and families can be reduced through maintenance treatment. Whereas non-pharmacological treatments can intervene in the early stages of AD[5]. Non-pharmacological treatment is of great significance in delaying the development of the disease, and non-pharmacological treatment is the treatment modality with more prominent therapeutic effects[6]. At this stage, there are various studies on non-pharmacological treatments for AD patients such as music therapy, nostalgia therapy, and creative storytelling therapy in China[7]. These non-pharmacological interventions mainly aim to improve the cognitive function of patients by increasing their social activities, improving their memory, learning ability, and self-expression[8]. However, the aforementioned non-pharmacological interventions also have certain limitations, the intervention is too single and the duration of the intervention effect is too short to solve the problem at the root[9].

Non-pharmacological interventions of cognitive stimulation therapy (CST) for AD patients in some studies are dedicated to maintaining patients' existing cognitive function, delaying further decline in cognitive function, and is helpful to the learning and memory ability of patients[10]. The focus of CST is "cognitive stimulation", which provides patients with a positive and effective way of stimulation, including target positioning, information screening, information recognition, information organization, information memory, information association, etc. Among them, the most important is information memory, many patients are facing the problem of memory decline, therefore, to help patients strengthen the memory ability, such as mnemonic training for patients, memory training, analog repetition and so on are needed[11]. Relevant studies have confirmed that the importance of cognitive stimulation training is also gradually being emphasized in China, and it is mostly reflected in interventions for patients with AD and mild cognitive deficits[12]. We used a comprehensive search of clinical studies on CST for AD to give statistical data on the effectiveness of CST for AD using meta-analysis to provide valid evidence-based medical evidence for clinical treatment.

MATERIALS AND METHODS

Literature search

A comprehensive search was conducted by computerized search of Chinese and English databases, Chinese databases: China Biomedical Literature Database (CBM), Wanfang Database, Wipu Database, and China Journal Full Text Database (CNKI) to obtain literature, with a collection time frame of July 21, 2010 to July 21, 2022 CST randomized controlled trials of the effects of CST on cognitive function in patients with AD were collected from July 21, 2010 to July 21, 2022. The restricted search terms were "AD", "Alzheimer's disease", "cognitive stimulation therapy ", "cognitive therapy" and their synonyms. English database: "dementia", “Alzheimer’s disease”, “cognitive stimulation therapy”, “cognitive therapy” and their synonyms. The search was for the effect of CST on cognitive function in patients with AD.

Exclusion criteria for inclusion in the literature

Study subjects: Patients with a clear diagnosis of mild to moderate AD and no statistically significant differences in the scales before non-pharmacological treatment.

Study methods: Clinical controlled trials of the effect of CST on the cognitive function of patients with mild to moderate AD.

Efficacy evaluation: Patients with AD treated with CST before and after at least stimulation therapy for AD patients before and after the application of CST contains at least 1 scale that explicitly assesses the cognitive function of patients [e.g., Mental State Examination Scale (MMSE) and AD Cognitive Functioning Assessment Scale (ADAS-COG) scores, etc.].

Data extraction: The literature is the original study report, and data such as sample size, subject age, intervention mode, intervention period, mean and SD can be extracted from the literature.

Exclusion criteria: (1) Literature with missing data, incomplete information, and poor quality of literature; (2) Literature with the same or repeated reports; (3) Literature with patients with major organ diseases in combination; and (4) Theoretical studies, case studies, reviews, or meta-analyses.

Search strategy

Search formula: Topic = cognitive stimulation therapy AND Topic = Alzheimer AND Topic = cognitive function OR (Title = cognitive stimulation therapy OR Title = Alzheimer OR Title = cognitive function) AND Publication time Between (2010-07-21 to 2022-07-21) (fuzzy match). The literature was obtained by computer search: China Journal Full Text Database (CNKI), Vipers Database (VIP), Wanfang Database, CBM, PubMed, Cochrane Library, EMBASE Library Database, and Clinical Registry. The Chinese search terms were: (1) "AD", "Alzheimer's disease", "cognitive stimulation therapy", "cognitive stimulation therapy" and their synonyms; and (2) Interventions: "Cognitive stimulation therapy"; English search terms: English database: "dementia", "Alzheimer's disease", "cognitive stimulation therapy", "cognitive therapy".

Outcome indicators

At least one scale in the literature to assess patients' cognitive function: The Simple MMSE, ADAS-COG. Mean and SD of scores before and after the intervention were provided.

Data extraction

Combined with the purpose of the study, two independent reviewers, the following factors were finally selected by detailed reading of the included literature, including the number of patients included in the experimental and control groups, the proportion of males, baseline indicators, mean age, form of CST, frequency of CST, CST cycle, and outcome indicators. The above information was made into a table.

Literature screening and quality evaluation

The meta-analysis strictly followed PRISMA guidelines. Duplicate literature, reviews, Meta-analysis, etc. were excluded first, and then 2 reviewers evaluated the literature as a whole according to the type of study, study protocol, outcome indicators, and study population, etc. When there was disagreement between 2 reviewers, a third reviewers could be consulted. Because the included literature was all clinical randomized controlled trials, the quality evaluation of the included literature was assessed by 2 evaluators applying the Cochrane Quality Rating Scale for risk of bias, which included 7 entries: (1) Random sequence generation; (2) Allocation protocol concealment; (3) Execution blinding; (4) Blinding of outcome assessment; (5) Completeness of outcome data; (6) Publication bias; and (7) Other biases. If a literature is low risk in all of the above 7 aspects, it is low risk of bias and is evaluated as grade A. If a literature has one or more uncertain risks, it can be considered as unclear risk of bias and evaluated as level B. If a literature has one or more high risk of bias, it is considered as high risk of bias and evaluated as level C.

Statistical analysis

The data processing software was ReMan 5.3. P values and I² used to test for heterogeneity, and if there was statistical heterogeneity among the findings (I² ≥ 50%, P < 0.10), a random-effects model was selected, and vice versa, a fixed-effects model was used. The treatment outcomes, represented by continuous data, are presented using a 95%CI. Sensitivity analysis was performed using the individual study-by-study exclusion method. Revman 5.3 were applied to perform meta-analysis of all included literature for outcome indicators. Stata 2.0 was used, with the effect size of the study intervention as the dependent variable and factors that may affect heterogeneity in meta-analysis (years of publication, sample size, age) as covariates. Meta-regression analysis was performed using the restricted maximum likelihood method.

RESULTS

Literature search results

After database retrieval, 778 articles were initially detected, including 34 articles from CNKI, 133 articles from Wanfang, 1 article from VIP, 556 articles from PubMed, and 54 articles from other databases. Strictly according to the inclusion and exclusion criteria, 556 papers were excluded after reading the titles and abstracts, 35 animal experiments, 35 reviews and empirical papers, and 98 repeated papers. Twenty-six studies were excluded due to the number of cases, courses of treatment, inconsistencies in intervention measures, inconsistencies in efficacy indicators, repeated studies, and non-randomization, and 8 were finally included in the study.

Basic information of included studies

A total of 8 articles were included, including 572 patients, of which 286 patients in the observation group received CST, and 286 patients in the control group received conventional therapy. Eight studies had clear diagnostic criteria; all eight studies had a balanced baseline (Table 1).

Table 1 Basic characteristics of the included literature.

Ref.	Sample size (observation group/comparison group)	Age (years)	Frequency of cognitive stimulation therapy (times/week)
Arcoverde et al[40], 2014	26/26	76.78 ± 4.32	3
Qiang et al[41], 2022	55/55	81.06 ± 4.55	5
Zhao et al[42], 2019	30/30	73.78 ± 9.69	3
Zhao and Zhang[43], 2018	37/37	63.74 ± 6.65	3
Yang[44], 2019	21/21	69.34 ± 5.25	3
Jin and Hu[45], 2020	43/43	66.71 ± 3.56	5
Liu et al[46], 2020	93/93	72.34 ± 0.25	3
Liu et al[47], 2017	24/24	67.63 ± 2.32	3

Literature quality evaluation

According to 4.2.6 of the Cochrane System Reviewer's Handbook, two researchers independently read the title and abstract of the literature, and obtained the full text of the literature to check whether the inclusion criteria were met. After the conclusion, the two investigators cross-checked the results separately, discussing in case of disagreement or deciding whether to include the article or not by a third investigator. According to the RevMan5.3 tool to evaluate the included literature, the content includes the risk of bias, whether the random allocation method and allocation scheme are hidden, whether the treatment scheme, research subjects, and evaluators of the research results are blinded, the data integrity of the results, and other sources of bias, Selective reporting of research results, etc. If the research fully meets the quality standards, it indicates that the possibility of bias is minimal, and it is rated as A; if the research partially meets the quality standards, it indicates that the possibility of bias is moderate, and it is rated as B; if the research does not meet the quality standards at all, it is rated as B. Indicates a high possibility of bias and is rated as C (Figures 1 and 2).

Figure 1  The proportion of literature methodology quality assessment.

Figure 2  Literature bias risk assessment.

Effects of CST on daily living ability scores

Meta-analysis was performed on the outcome indicators, and the heterogeneity showed P < 0.001, I² = 98%,indicating that there is strong heterogeneity among the included studies, the literatures were eliminated one by one for sensitivity analysis and detection, the heterogeneity was significantly lower than before, and the random model was used to integrate statistics, and the result showed standardized mean difference (SMD) = -0.27 (95%CI: -0.85, 0.30, P > 0.05), indicating that CST may can not improve the MMSE score of AD patients. And the mean difference was not significant (Figure 3A).

Figure 3 Effect of cognitive stimulation therapy. A: Daily living ability; B: Mental State Examination Scale score; C: Alzheimer's disease Cognitive Functioning Assessment Scale score; D: Cognitive function of patients.

The publication bias of the included literature was evaluated by drawing a funnel plot in Stata. And the funnel plot was symmetrical, it meant that there was no obvious bias. The Figure 4 be clearly seen that the funnel plot of our study is basically symmetrical (P < 0.05). It can be judged that the literature in this study has no obvious publication bias.

Figure 4  Funnel plot of cognitive stimulation therapy on daily living ability scores.

Effects of CST on MMSE scores

Meta-analysis of CST on MMSE scores showed that the heterogeneity was I² = 35% (P = 0.14). select the fixed effect model to integrate statistics, and get the results: SMD = 0.02 (95%CI: -0.37, 0.42; P > 0.05), the difference is statistically not significant (Figure 3B).

Effects of CST on ADAS-COG scores

Meta-analysis of CST on ADAS-COG scores showed that the heterogeneity was I² = 36% (P = 0.13). Choose a fixed effect model to integrate statistics, get SMD = -0.01 (95%CI: -0.40, 0.39; P > 0.05), the difference is not statistically significant (Figure 3C).

The effect of CST on cognitive function of patients

Meta-analysis of CST on the cognitive function indicators of patients showed that the heterogeneity I² = 31% (P = 0.17). the fixed effect model was selected to integrate statistics, and SMD = 0.01 (95%CI: -0.37, 0.38; P > 0.05), the difference was not statistically significant (Figure 3D).

DISCUSSION

AD patients are often accompanied by progressive memory impairment, intellectual decline, etc., which seriously affect their quality of life[13]. Our findings suggest that CST has no effect on quality of life in AD patients. The reasons for this analysis may be related to the short duration of CST, the different subjects of evaluators, the small sample size, and the different disease courses of the study subjects[14]. Studies have shown that CST is an interactive tool that can improve the quality of life of patients, and the mood of patients is significantly improved after CST[15]. The highlight of this CST is that patients associate their past memories with the content of CST, and when they recognize the projected pictures, they spontaneously talk about their past experiences, which is an emotional response[16]. Depression is the first symptom of emotional abnormalities in AD patients, and the two are closely related and have a comorbidity basis. Desires for family, companionship, dignity, and security are potential needs of AD patients, but they are not easily noticed by caregivers[14]. Although AD patients have progressive degeneration of brain function, resulting in a decline in their behavioral abilities, they still want to gain a sense of self-esteem and feel self-worth[18]. If these needs are not met for a long time, the patient will have depression[19]. Relevant literature reports that the prevalence of depression in AD patients is 45%, and our results show that cognitive stimulation may not improve the emotional state of patients, this may be related to the theory that the decline in cognitive function is associated with a decrease in the amount of brain activity, and that environmental factors are responsible for the decline in the amount of brain activity in old age[20]. But stimulating and stressful CST can accelerate the blood circulation in the brain of AD patients, and has a certain therapeutic effect[21]. CST is a non-pharmacological treatment regimen that explores the potential favorable factors of each non-drug intervention therapy for AD after extensive literature analysis and incorporates them into the design of the regimen to improve patients' cognitive function and quality of life[22]. CST should be implemented according to the following principles: Use the five senses to facilitate experiential learning of cognitive stimulation and memory processes[23]. Strengthening the psychological intervention of patients to deal with difficulties in daily life: Improving memory, emotional life learning skills in AD patients[24]. Implicit learning, not explicit teaching. Extensively train and consolidate the necessary information about what they perceive to be the most beneficial[25]. Interacting psychological processes, AD patients and caregivers can learn more about each other's capabilities and vulnerabilities. CST will talk about time, place, season, etc. in the prelude to each activity, and it will also stimulate the patient's strengthening of orientation in the core part of the scene and reality positioning[26]. In the prelude part of the activity, the patient will play warm-up games, talk about recent interesting events and carry out short-term memories. In the core part, recalling childhood, discussing current events, and using and classifying items will make the patient's memory ability subtly get better[27]. Statistical analysis of the effect of each study intervention on the MMSE score indicated that CST can not improve the MMSE score of AD patients. The included literature has high heterogeneity. Sensitivity analysis of the literature shows that when the literature is excluded, the heterogeneity is significantly lower than before. The high heterogeneity of the literature is considered as follows: Patients are allowed to include mixed AD, and other literatures strictly include patients diagnosed with AD; the difference between the scores after MMSE intervention is not the final value, which may lead to the possibility of conversion to the final value. There is a bias[28]. Some patients lack adherence to CST, and physical activity levels outside the CST session were not monitored in both groups, and it cannot be ruled out that changes in physical activity levels outside of the CST intervention may have contributed to the difference in outcomes[29]. The effect of CST intervention on MMSE and ADAS-COG scores can be concluded that CST intervention can not improve the cognitive function of patients[30]. The relationship between CST and overall cognitive improvement was consistent with improvements in MMSE and ADAS-COG scores. The mechanism by which CST improves cognition appears to be complex and unclear, possibly due to the following aspects: Increased blood volume and capillary vascularization, cardiovascular-related risk factors are thought to play a role in the progression of the disease and the acceleration of cognitive deterioration plays a key role in cerebral perfusion, as it reduces cerebral perfusion and promotes barriers to amyloid clearance[31]. Current evidence supports hypertension, hypotension, heart failure, stroke, and coronary artery disease as potential factors for cognitive decline in AD patients[32]. CST can reduce these risk factors, thereby potentially improving cognitive function in patients[33]. Reduce reactive oxygen species and oxidative stress. Studies have shown that lipid peroxidation markers are elevated in AD patients, and the activities of antioxidant enzymes superoxide dismutase and glutathione peroxidase are elevated after CST[34]. Reduce AB load. In a transgenic AD mouse model, CST reduced AB content in the frontal cortex and hippocampus, and since the expression of the key enzymes Neprilysin and insulin-degrading enzymes did not change, CST has been mechanistically proven to be comparable to classical AB degradation. Pathway independent[35]. Short-term CST reduces proteolytic fragments of amyloid precursor protein (APP), suggesting that CST reduces APP metabolism by modulating the cholinergic system. Increased receptor density for dopamine and physostigmine[36]. CST is an important regulator of neurotrophic factors such as brain-derived neurotrophic factor, insulin-like growth factor-1, and vascular endothelial growth factor[37]. Studies have shown that CST can upregulate the expression of brain-derived neurotrophic factor, and CST can also modulate downstream signaling pathways[38].

Limitations and implications

The limitations and implications of our meta-analysis are as follows: It is not described whether blinding is performed, there may be implementation and measurement bias, and whether allocation concealment is performed is not described, and there may be selection bias; there may be selective reporting of study results, and reporting bias may occur[39]. The obtained results showed that CST intervention may not improved the MMSE score, and the difference was not statistically significant, that is, no significant evidence can support CST intervention could improve cognitive function in AD patients. Besides, there is a large heterogeneity in the intervention characteristics of the study, which has an impact on the study results, and it is still unclear which program is most suitable for patients and has the best effect; CST The forms of exercise are more diverse, and how to choose a suitable CST method for patients, while meeting their needs and improving their compliance deserves further discussion; AD is a long-term chronic disease, which is difficult to reverse and the intervention effect is not significant, while most trials The duration of intervention is short and follow-up varies, and future studies should focus on the long-term effects of combination therapy, increase the duration of intervention, and conduct long-term, regular follow-up. If the observed outcome indicators are inconsistent, more comprehensive evaluation scales and evaluation methods should be developed and used. The language of our research and retrieval is Chinese and English, which may cause the literature to be incomplete.

CONCLUSION

In conclusion, CST may not improve the cognitive function of AD patients, not improve the cognitive function of AD patients, not improve the ability of daily living, and not reduce mental behavior can improve the cognitive function of AD patients.