Effects of three kinds of anti-amyloid-ß drugs on clinical, biomarker, neuroimaging outcomes and safety indexes: A systematic review and meta-analysis of phase II/III clinical trials in Alzheimer's disease.

OBJECTIVE: To investigate the effects of the three kinds of anti-amyloid-ß (Aß) drugs on cognitive and other functions, fluid and neuroimaging biomarkers, and safety on patients with Alzheimer's disease (AD), and rank the three kinds of anti-Aß drugs. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and AlzForum from inception to January 21, 2023 to include randomized controlled clinical trials. Random effects meta-analyses were performed. RESULTS: Forty-one clinical trials (20929 participants, 9167 male) were included. Anti-Aß drugs had significant but relatively low efficacy in preventing cognitive decline (ADAS-Cog SMD -0.07, 95% CI: -0.10 to -0.03, p < 0.001; CDR-SOB -0.05, -0.09 to -0.01, p = 0.017). Instrumental variable meta-analysis and trial sequential analysis confirmed the reliability of the pooled estimation. Beneficial effects were also observed by assessing other cognitive and activity of daily living scales and biomarkers, with acceptable safety of anti-Aß drugs. Meta-regression demonstrated significant association between higher baseline mini-mental statement examination scores (MMSE) and better cognitive protective effects on cognitive function (ADAS-Cog ß: -0.02, -0.05 to 0.00, p = 0.017) and clearance of pathological productions of anti-Aß drugs. Network meta-analysis ranked the passive immunotherapy drugs to have the best cognitive efficacy, followed by active immunotherapy and small molecule drugs. CONCLUSION: Anti-Aß drugs have relatively low efficacy in preventing cognitive decline, and they reduce pathological productions with acceptable safety. Patients with higher baseline MMSE scores benefit more from anti-Aß drugs. Passive immunotherapy anti-Aß drugs show relatively better efficacy than active immunotherapy and small molecule anti-Aß drugs.

Effects of different kinds of anti-Alzheimer's disease drugs on cognitive improvement: protocol for a systematic review and network meta-analysis of phase III clinical trials.

BACKGROUND: Alzheimer's disease is a neurodegenerative disease characterized by progressive cognitive decline and dysfunction of independent living ability, with huge economic and healthy burden worldwide. However, there is still a lack of effective long-term drugs to improve cognitive function and reduce or halt disease progression. Phase III clinical trials of anti-AD drugs based on different hypotheses were in the pipeline, and this protocol for a systematic review and meta-analysis aims to determine what is the most effective direction for the development of drugs on cognitive improvement. METHODS/DESIGN: We will search the following literature databases for eligible studies from inception to December 2021: Ovid MEDLINE, Ovid Embase, PubMed MEDLINE, and Cochrane Central Register of Controlled Trials. Google Scholar, ClinicalTrials.gov registration platform, and the AlzForum website will also be searched for additional studies. Studies will be included irrespective of publication status or language. Phase III clinical trials reporting on the effect of anti-AD drugs on participants with AD will be included. Two independent reviewers will screen the hit articles and identify phase III clinical trials, extract data, and assess the quality of each study individually. The Cochrane Risk of Bias tool 2 (RoB 2) will be used to assess the risk of bias. For each kind of drugs based on the corresponding hypothesis, we will compare the study design and demographic features of the clinical trials and include appropriate studies in the network meta-analysis. The primary outcomes will be the indicators of cognitive improvement. The secondary outcomes will be activities of daily living, neuroimaging changes, biomarkers, and safety. Through network meta-analysis, we will suggest the hypothesis that most likely to improve cognitive function and provide the ranks of all kinds of drugs. We will give recommendation grade of each comparison using the Confidence In Network Meta-Analysis (CINeMa) tool. DISCUSSION: This study will provide helpful evidence for further drug development and clinical practice for treating Alzheimer's disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021251507.

Resting-state functional reorganisation in Alzheimer's disease and amnestic mild cognitive impairment: protocol for a systematic review and meta-analysis.

INTRODUCTION: The incidence of Alzheimer's disease (AD) is increasing rapidly, causing a growing burden to health and economic worldwide. Several clinical trials in the past decade failed to find solutions, and there remains a lack of an effective treatment. The evidence suggests that early intervention for neurodegeneration would likely be effective in preventing cognitive decline. Cognitive decline in AD occurs continuously over a long period; however, there remains a lack of simple, rapid and accurate approach for diagnosis of amnestic mild cognitive impairment or subjective cognitive decline due to underlying Alzheimer's pathology. Resting-state functional MRI (rs-fMRI) determines the functional activities of the human brain non-invasively. The amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF) and regional homogeneity (ReHo) are rs-fMRI indicators with high repeatability. They have been studied as early diagnostic imaging markers for other diseases and may be promising markers also for AD. METHODS AND ANALYSIS: The following electronic literature databases will be searched from inception to December 2021: Medline-Ovid, Medline-PubMed, EMBase-Ovid, Cochrane Central and ClinicalTrials.gov. Two independent reviewers will select studies with eligible criteria, extract data and assess the quality of the original studies with our quality assessment tool individually. Missing data will be requested by sending emails to the corresponding authors. Brain regions will be presented for ALFF/fALFF and ReHo by performing activation likelihood estimation with the Seed-based d Mapping-Permutation of subject images V.6.21 software. Meta-regression will be performed to determine the potential brain regions that may strongly correlate with cognitive decline progression. Subgroup analysis, funnel plot, Egger's test and sensitivity analysis will be conducted to detect and explain potential heterogeneity. ETHICS AND DISSEMINATION: This study does not require formal ethical approval. The findings will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42021229009.

Effect of antiamyloid-ß drugs on Alzheimer's disease: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease with a complex aetiology involving multiple targets and pathways. With the continuous growth of the ageing population, the burden of AD is increasing year by year. However, there has not been new drug approved for over a decade. In addition, the efficacy of memantine and cholinesterase inhibitors is not satisfactory. As amyloid-ß (Aß) is regarded as the core pathological change and the trigger mechanism of AD, anti-Aß therapy may be an effective therapy. In recent years, a lot of clinical trials have been carried out in this field, but the results have not been well summarised and analysed. METHODS AND ANALYSIS: In this study, we will study the effect of anti-Aß antibodies versus placebo on the clinical efficacy, biomarkers, neuroimaging and safety in different stages of AD, as well as the factors that may affect the efficacy. Drugs that only target the existing Aß are regarded as anti-Aß antibodies. Following electronic databases will be searched from inception to April 2021: Medline-Ovid, EMBase-Ovid, Cochrane Central and clinical trial registration platform ClinicalTrials.gov. After identifying eligible studies through screening title, abstract and read full text of each retrieved literature, we will contact the correspondence authors for additional information and grey literatures. To get more reliable results, random effect model will be conducted for meta-analysis and analysis of subgroups or subsets. Funnel plot, Egger's test and sensitivity analysis will be conducted to explore potential heterogeneity. Meta-regression will be conducted to identify the factors that may affect clinical efficacy. Evidence quality assessment and trial sequential analysis will be conducted to assess the quality of evidence and confirm the reliability of the results in this study. ETHICS AND DISCUSSION: This study does not require formal ethical approval. The findings will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42020202370.

Effect of Tai Chi on post-stroke non-motor disorders: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the state of evidence for the beneficial and harmful effects of Tai Chi on non-motor disorders in post-stroke patients. DESIGN: Systematic review and meta-analysis of published studies. SUBJECTS: Stroke survivors who received conventional rehabilitation therapy or Tai Chi training. DATA SOURCES: We searched seven electronic literature databases and one clinical registry platform to collect data from randomized controlled trials published up to July 26, 2020. RESULTS: A total of 11 randomized controlled trials with 723 stroke survivors met the inclusion criteria, of which six were included in the meta-analysis. Among the 11 studies, one was assessed as "low", eight were assessed as "moderate", and only two were assessed as "high" for the assessment of methodologic quality. Compared to patients who received conventional rehabilitation therapy, those who received Tai Chi training showed greater improvement in scores of depression (standardized mean difference (SMD) [95% confidence interval (CI)] = 0.36 [0.10, 0.61], Grading of Recommendations Assessment, Development, and Evaluation [GRADE]: very low). There were no differences in the improvements in post-stroke global mental disorders (mean difference (MD [95% CI] = 6.15 [-3.05, 15.36], GRADE: moderate) or sleep disorders (MD [95% CI] = 0.33 [-1.51, 1.81], GRADE: low) between Tai Chi and control groups. CONCLUSION: Tai Chi may alleviate post-stroke depression in stroke survivors but has no clear effects on post-stroke cognitive and sleep disorders.

Tai Chi for Stroke Rehabilitation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Stroke is a major cause of poor health and has numerous complications. Tai Chi (TC) may have positive effects on the rehabilitation of stroke survivors, but recent clinical findings have not been included in previously published reviews. Objectives: We conducted this systematic review and meta-analysis to determine the effectiveness of all types of TC vs. conventional rehabilitation therapy for all aspects of stroke survivors' rehabilitation that have been studied. Method: We searched seven electronic literature databases (three in English, four in Chinese) and one clinical registry platform using established strategies to identify randomized controlled trials performed up to October 2017. Screening, quality assessment, and data collection were performed by two researchers separately, using the same standard. The results were analyzed using RevMan 5.3.0. The quality of evidence was evaluated with GRADEpro. Results: A total of 21 studies with 1,293 stroke survivors met inclusion criteria; 14 were included in the quantitative synthesis to evaluate four aspects and five outcomes. Nine studies indicated that TC was able to improve independent activities of daily living (ADL), especially TC vs. conventional rehabilitation therapy [mean difference (MD) [95% confidence interval (CI)] = 9.92 [6.82, 13.02], P < 0.00001]. Five studies reported significant effects of TC plus conventional rehabilitation therapy in increasing scores on the Fugl-Meyer Assessment for the upper limb [MD (95%CI) = 8.27 [4.69, 11.84], P < 0.0001], lower limb [MD (95%CI) = 2.75 [0.95, 4.56], P = 0.003], and overall [MD (95%CI) = 4.49 [1.92, 7.06], P = 0.0006]. The Berg Balance Scale revealed significant improvements according to pooled estimates for TC vs. conventional rehabilitation therapy [MD (95%CI) = 5.23 [3.42, 7.05], P < 0.00001]. TC plus conventional rehabilitation therapy also improved walking ability as measured by the Holden scale [MD (95%CI) = 0.61 [0.38, 0.85], P < 0.00001] and up-and-go time [MD (95%CI) = 2.59 [1.76, 3.43], P < 0.00001]. Conclusion: TC has an overall beneficial effect on ADL, balance, limb motor function, and walking ability among stroke survivors, based on very low-quality evidence, and may also improve sleep quality, mood, mental health, and other motor function. Well-designed, higher-quality trials with longer-term follow-up periods are needed to develop better-quality evidence.