Planning an Adaptive Clinical Trial of Cognitive Training to Improve Function and Delay Dementia

项目总结 我们对这项积极研究的分析表明，一种有针对性的认知训练(CT)可以降低罹患 痴呆症的发病率在10年内下降了48%。虽然这些结果令人鼓舞，但证据并不确凿。 推荐CT用于预防痴呆。现在存在许多有效的CT技术，但有不同的认知 效果。鉴于患痴呆症的风险人群存在不同的认知缺陷，CT技术的组合-- 尼克斯可能是最有效的。新出现的证据表明，结合CT技术可以增加- 增强或削弱认知能力的提高。然而，目前还没有研究确定最有效的药物。 CT组合。此外，还没有设计研究来检验CT对患者的纵向影响 痴呆症诊断。我们将聘请CT、轻度认知障碍(MCI)/痴呆症方面的国际专家， 招募和保留，神经心理评估，神经成像，生物标记物和适应性试验去 签署计划和试点测试适应性随机临床试验(RCT)。RCT将决定最有效的- CT锻炼的重要组合可减轻老年人的功能衰退和延缓痴呆 MCI带来的风险。我们将首先制定一项有效的社区参与招聘计划，以包括 通常在临床研究中代表性不足，并招募美国老年人口的样本代表- 在性别、种族、种族和教育方面的歧视。在第一阶段，将进行一项试点试验，以完善重新 巡航和保留计划，建立可行性和最后确定的程序，并检查潜在的效果 相对于主动对照的4个CT臂。我们将应用改进的方法，将CT臂与 认知刺激的严格主动控制条件：参与者期望与社会期望相等。 诡异。措施将包括创新的日常生活工具活动指数(IADL)，标准齿数- 神经评估，以及神经成像和基于血液的生物标志物。CT的潜在主持人也将 被评估。第一阶段试点数据将为统计模拟提供信息，以设计一种无缝的第二阶段/第三阶段自适应 RCT。我们将模拟参与者应计和几种处理方案。对于每一种情况，我们都会阻止- 地雷统计能力和试验成功所需的样本量。这些统计模拟的结果将 应用于II/III期自适应RCT的优化设计和功率。由此产生的RCT将是Innova- 我们认为，在应用适应性试验方法以有效地确定最有效的 CT锻炼的组合可以延缓痴呆的发病。我们将计划第一次试验，以比较两种药物的组合 MCI患者转化为痴呆的CT检查。我们将记录与CT相关的更改 对大脑进行神经成像，并探索基于血液的生物标志物作为CT潜在中间结果的可能性。 长期目标是应用最好的CT技术来延迟痴呆症的发病，从而促进公众 健康。这些贡献将是重要的，促进了我们对如何实施CT的理解 遏制痴呆症的流行。

PROJECT SUMMARY Our analyses from the ACTIVE study showed that one type of targeted cognitive training (CT) reduced risk of dementia by up to 48% across 10 years. While these results are encouraging, evidence is inconclusive to rec- ommend CT for dementia prevention. Many efficacious CT techniques now exist, but have distinct cognitive effects. Given that cognitive deficits are varied among those at risk for dementia, a combination of CT tech- niques may be most efficacious. Emerging evidence indicates that combining CT techniques can either en- hance or attenuate cognitive gains. However, no studies have been designed to determine the most efficacious CT combinations. Furthermore, no studies have been designed to examine the longitudinal effects of CT on dementia diagnoses. We will engage international experts in CT, mild cognitive impairment (MCI)/dementia, recruitment and retention, neuropsychological assessment, neuroimaging, biomarkers, and adaptive trial de- sign to plan and pilot test an adaptive randomized clinical trial (RCT). The RCT will determine the most effica- cious combinations of CT exercises to attenuate functional decline and delay dementia among older adults at risk due to MCI. We will first develop an effective recruitment plan of community engagement to include those often under-represented in clinical research and enroll a sample representative of the US older adult popula- tion with regard to sex, ethnicity, race, and education. In phase I a pilot trial will be conducted to refine the re- cruitment and retention plan, establish feasibility and finalize procedures, and examine the potential efficacy of 4 CT arms relative to an active control. We will apply improved methodology by comparing the CT arms to a stringent active control condition of cognitive stimulation with equivalent participant expectations and social in- teraction. Measures will include innovative indices of instrumental activities of daily living (IADL), standard cog- nitive assessments, as well as neuroimaging and blood-based biomarkers. Potential moderators of CT will also be assessed. The phase I pilot data will inform statistical simulations to design a seamless phase II/III adaptive RCT. We will simulate participant accrual and several treatment scenarios. For each scenario, we will deter- mine statistical power and sample size required for trial success. The results of these statistical simulations will be applied to optimize design and power for the phase II/III adaptive RCT. The resulting RCT will be innova- tive, in our opinion, in the application of adaptive trial methodology to efficiently identify the most efficacious combinations of CT exercises to delay dementia onset. We will plan the first trial to compare combinations of CT exercises on conversion to dementia among persons with MCI. We will document CT-related changes in the brain with neuroimaging and explore blood-based biomarkers as potential intermediary outcomes of CT. The long term goal is to apply the best CT techniques to delay dementia onset, thereby promoting public health. The contributions will be significant, advancing our understanding of how CT may be implemented to curb dementia prevalence.