BACKGROUND Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions. METHODS/DESIGN In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action. DISCUSSION The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field. TRIAL REGISTRATION Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. PROTOCOL VERSION This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

中文翻译：

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重复经颅磁刺激对患有轻度认知障碍的老年人的影响：随机对照三臂试验方案。


背景技术轻度认知障碍（MCI）具有进展为阿尔茨海默病（AD）痴呆的高风险。先前的临床试验测试胆碱酯酶抑制剂是否可以减缓从 MCI 到 AD 痴呆的进展速度，但结果令人失望。然而，最近关于重复经颅磁刺激 (rTMS) 对 AD 效果的研究表明，认知功能有所改善。由于在 MCI 中进行的 rTMS 试验很少，我们设计了一项试验来测试 rTMS 在 MCI 中的短期疗效。然而，在 MCI 和 AD 中，我们对什么刺激部位最适合改善认知功能知之甚少。因此，本试验将研究两个皮质部位：（1）背外侧前额叶皮层（DLPFC），该部位已被广泛研究用于治疗重度抑郁症； (2) 外侧顶叶皮层 (LPC)，这是一个与 AD 相关边缘区域有连接的新位点。方法/设计 在这个单中心试验中，我们计划招募 99 名患有单域或多域遗忘 MCI 的参与者。我们将参与者随机分为三组之一：(1) 活跃 DLPFC rTMS； (2) 主动LPC rTMS； (3) Sham rTMS（在 DLPFC 和 LPC 位置之间均匀分配）。完成 20 次双边 rTMS 治疗疗程后，参与者将被跟踪 6 个月，以测试短期疗效并跟踪效果的持久性。主要疗效指标是加州语言学习测试 II (CVLT-II)，在干预后 1 周进行评估。二次分析将检查 rTMS 对其他认知测量、抑郁症状以及刺激部位的大脑功能的影响。最后，将分析选定的生物标志物，以探索反应的预测因子和作用机制。 讨论 本试验的主要目的是测试 rTMS 在 MCI 中的短期疗效。此外，该项目还将提供有关认知效应的持久性以及刺激 DLPFC 与 LPC 区域的潜在不同效应的信息。未来的努力将致力于更好地了解治疗机制并优化 rTMS 以治疗 MCI。最终，如果 rTMS 可用于减缓 AD 痴呆的进展速度，这将是该领域的重大进步。试验注册 临床试验 NCT03331796。 2017 年 11 月 6 日注册，https://clinicaltrials.gov/ct2/show/NCT03331796。世界卫生组织试验注册数据集中的所有项目均列于附录 A。 协议版本 本报告基于版本 1，由 DSMB 于 2017 年 11 月 30 日批准，并于 2018 年 8 月 14 日和 2019 年 9 月 19 日修订。