At last, 15 eligible studies were finally included and reflected in the network relationship plot (Fig. 6A). Our analysis revealed that only PE had a significantly greater improvement than CG (Fig. 7A). The accumulate histogram (Fig. 8A) presents the probability of rank for each cognitive intervention, which indicated that PE was the highest in probability among all the 4 cognitive interventions (SUCRA = 0.45), followed by CCT (SUCRA = 0.30), and MT (SUCRA = 0.17). In contrast, NT seemed to have the lowest probability.
To the best of our knowledge, no previous study has solved the problem that which cognitive intervention is the relatively best intervention for AD or MCI. Therefore, as the first NMA of cognitive interventions for patients with AD or MCI in which indirect evidence was used appraising the relative effectiveness and safety of cognitive interventions across trials simultaneously, our study attempted to summarize available data to suggest that the highest probability of being the best intervention for cognitive decline and neuropsychiatric symptoms lies in PE (SUCAR = 0.45) and CCT (SUCAR = 0.87) respectively. The above findings will be reinforced by our analysis of previous meta-analyses.
We applied a trial sequential analysis to detect the robustness and reliability of evidence for relative effectiveness of each cognitive intervention. The trials in previous meta-analyses [50–59] (PUBMED search March 1, 2017) only investigated the efficacy and safety of PE, MT, CCT, and NT, respectively, and lacked a synthesized analysis among them. By contrast, our NMA assessed PE, MT, CCT and incorporated NT using 4 pairwise MDs. Integrating indirect comparisons in our NMA resulted in higher statistical precision in scientific comparisons of cognitive interventions against a control group. This integration makes the comparison of different interventions more explicit and facilitates interpretation. The potential correlations between these 4 MDs were accounted for in our NMA, and linking to modeling of indirect comparisons provided greater statistical power and more precise estimates.[60–62] The totality of the evidence we extracted, largely based on trials in PE, MT, CCT, NT showed that further trials of cognitive interventions versus no cognitive interventions or control group are likely to have positive effect, except for some specific trials.[30,32]
Based on relative effect estimates and SUCAR, nowadays, PE seems to be the most effective cognitive intervention when we consider a cognitive therapy and CCT is the most effective cognitive intervention for neuropsychiatric symptoms. The cumulative probability ranking obtained through the Bayesian NMA cannot be considered as decisive conclusion because it was probably compromised by the lack of a significant difference among the cognitive interventions. For example, PE ranked the first in cognition but did not have superiority over any of the other cognitive interventions, which might be due to the fact that PE-relevant studies contributed a relatively greater deal of evidence in the network (6 out of 15 studies), and thus significant differences between these cognitive interventions were not found.
In summary, PE had the best effective improvement in cognitive ability and the second best in neuropsychiatric symptoms. CCT had the best result in improving neuropsychiatric symptoms and was relatively inexpensive. MT has a relatively low probability of being the best intervention for cognitive ability and neuropsychiatric symptoms. However, its safety factor and cost is relatively the best compared with other cognitive interventions. It should be noted the efficacy of a series of nondrug interventions to improve cognitive ability of AD and MCI patients have all been proven by research, such as estrogen replacement therapy,[67,68] psychotherapy.[69,70] But quite a number of trails were restricted by appropriate endpoints, which resulted in this individually cognitive interventions lack of the relevant endpoints whose efficacy we must adopt to analysis. Therefore, from our conclusion above, PE, MT, CCT all have beneficial effects on older adults with AD and MCI, especially PE[58,71] and MT[72,73] as relatively obtained easily interventions. AD and MCI are progressive neurodegenerative disorders, and are still incurable. Any cognitive intervention that could possibly slow down the progressive of AD and MCI patients, it worth disseminating. We may create an assumption that PE and MT as a potent, convenient, selective cognitive interventions were play a positive role in helping improve the cognitive function for older adults with AD or MCI.
Rather than only grouping various interventions into CCT or human intervention, as the biggest strength, our NMA assessed each intervention individually and compared all major interventions simultaneously. Then, potential bias was reduced in the conduction of our review by having 2 independent authors (J-hL, H-bZ) scan through the search output, extract the relevant data, classify each intervention, and assess the methodological quality of each trial. We performed an extensive search strategy across several databases and sources to obtain an adequate number of eligible studies, with no language restriction. We also extensively searched the bibliographies of published studies. In addition, the cognitive intervention of CCT is complex and multifaceted and the number of relevant trials is very small, which proves the particular significance of our NMA.
From the methodological point of view, our NMA demonstrates a series of preponderance of Bayesian NMA for comparing various cognitive interventions and for evaluating the relative effectiveness and safety of multifarious interventions. In this context, the results of our NMA are likely to be more useful for decision makers, service commissioners and caregivers when they are making choices among different alternatives than results from multiple separate traditionally meta-analyses, because several relevant outcomes have been assessed simultaneously. It uses common random parameters to compare different interventions, which combines experimental evidence from indirectly randomized comparisons with observational evidence from adjusted indirect comparisons derived from trials.
The limitations of our study also need to be acknowledged. Firstly, as the biggest limitation, the number of studies and the number of patients included in the study were relatively small. The studies included in our NMA used the same scale as the basis, the outcomes of which were presented as a continuous variable. In the analysis section, we extracted the mean, SD, and sample size values at baseline and at last observation for analysis. However, a few studies lost their data, which made the number of available studies even less. There are significant differences among cognitive interventions such as in the method section. The above-mentioned reasons explain why the number of our included studies was limited. In particular, the informative evidence of the direct comparisons between cognitive interventions was limited by the absence of relevant studies. Because no direct comparative trial was found through our search strategy, our study lacked direct evidence. No direct evidence was available when we performed NMA, and thus the evaluation of consistency could not be achieved. Secondly, only 5 of 17 studies included in the analyses were double-blind, and details of allocation were noted in 15 of 17 studies, indicating that publication bias and selective reporting biases could not be ruled out. Specific intervention regimens and patient populations varied across studies, which might cause heterogeneity. In addition, our study data were limited by the outcome of the intersection, a number of studies used their specific scales to present outcomes. And quite a number of trials were restricted by appropriate endpoints, which resulted in individual cognitive intervention lacking the relevant endpoints we must adopt, for example MT lack NPI data that only 5 studies included. That is the reason why we could not evaluate this intervention objectively in the end. Moreover, similar to previous traditional meta-analyses, our study yielded heterogeneity due to the small number of studies, although funnel plots did not suggest presence of heterogeneity and an extensive search strategy was used to identify relevant trials. The NMA is complex, and it is difficult for decision makers to explain the results. For example, under the accumulate histogram analysis of MMSE, PE was most likely to be the best cognitive intervention. This might be because the PE intervention had a relative larger sample size used for NMA. At last, we have not extracted the number of patients who have been observed in trials of numerous AEs or other reasons, which is because only three studies[29,30,32] mentioned the AEs and we could not evaluate them in this analysis.
In conclusion, our NMA suggested that PE is the optimum cognitive intervention for patients with AD or MCI while CCT is the optimum one for neuropsychiatric symptoms. Relatively speaking, MT is the most safe intervention but its efficacy is moderate. And NT is the last choice to manage AD or MCI because of its 2-sidedness. The results of our NMA suggest that nonpharmacological therapies are better than pharmacological therapies. In the future, there is a need to include more studies of high methodological quality related to comprehensive cognitive interventions to help establish a more extensive literature foundation. Researchers should shift their research interest to outcomes other than MMSE, such as ADL and Clinical Dementia Rating (CDR) so that more network meta-analyses of cognitive interventions for AD or MCI patients can be performed.
We would like to gratefully acknowledge the help by the following authors: Chun-Hua Zhao, Deng-Juan Qian. All authors agreed to contribute to this study.
J-hL conducted the database search, screened and extracted data for the meta-analysis, prepared extracted data for the procedures, and had primary responsibility in writing this article. LL performed statistical analysis and interpretation of data. H-bZ and LH contributed to the discussion and editing. YX critically revised the draft manuscript. All authors read and approved the final manuscript.
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