Non-Invasive Home Neurostimulation for Mild to Moderate Alzheimer's Disease: Double-Blind, Sham Controlled Randomized Clinical Trial

摘要 阿尔茨海默病的患病率不断上升，且缺乏有效的治疗方案 需要开发针对阿尔茨海默病的新治疗方法，特别是 那些对医疗脆弱人群造成不利影响的风险最小的药物。风险最小，非 侵入性神经调节疗法，例如经颅直流电刺激（tDCS），可以缓解 症状并增强具有不同条件的老年人的功能。我们在家开发了一个 tDCS 并证明了这种方法的可行性，并在针对患有以下疾病的患者进行的一项试点研究中 早期阿尔茨海默病，在家进行 tDCS 改善认知能力和大脑稳定性 新陈代谢。 我们现在建议建立并扩展试点研究，以测试家庭 tDCS 的临床疗效 对 100 名轻度至中度患者采用严格的双盲随机临床试验设计 阿尔茨海默病患者将被随机分配接受 tDCS，每周 5 天，持续六个月 在家或以相同频率进行假治疗。所有参与者都将接受认知评估 在基线、干预后以及干预后一个月和三个月时探索和 记录效果的持久性。我们的主要结果是认知表现的变化（由 阿尔茨海默病评估量表 - 认知分量表测试）。次要结果包括 情绪、生活质量以及患者对设备和手术的满意度的衡量标准。 潜在神经可塑性的神经影像标记也将在基线、干预后、 以及干预后三个月。 我们预测主动 tDCS 将带来更好的认知表现和更高的生活质量，因为 与假手术相比，这将是患者及其家属满意的治疗方法。我们 还假设主动 tDCS 产生的临床反应将与改善 背外侧前额叶皮层的功能和结构连接以及相关的使用 网络（例如执行控制/显着网络）。 拟议的研究对 PAR-19-298 高度敏感，该研究征求申请以建立初步的 神经刺激/神经调节治疗阿尔茨海默病及相关疾病的疗效 失智。我们提议的临床试验将提供有关在家中的功效的高质量证据 tDCS 治疗阿尔茨海默病。如果疗效得到证实，这种非侵入性、非 药物干预可能成为痴呆症护理的重要组成部分。

Abstract The growing prevalence of Alzheimer’s Disease coupled with a dearth of effective treatment options necessitates the development of novel treatment approaches for Alzheimer’s Disease, particularly those that pose minimal risk of adverse effects in a medically fragile population. Minimal risk, non- invasive neuromodulatory therapies, such as transcranial direct current stimulation (tDCS), may relieve symptoms and enhance function in older adults with diverse conditions. We developed an at home tDCS and demonstrated the feasibility of this approach, and in a pilot study conducted in patients with early Alzheimer’s disease, at home tDCS improved cognitive performance as well as stability in brain metabolism. We now propose to build and expand on the pilot study to test the clinical efficacy of home based tDCS using a rigorous double blind randomized clinical trial design in 100 patients with mild to moderate Alzheimer’s disease who will be randomized to receive either tDCS five days per week for six months at home or to sham treatment at the same frequency. All participants will receive cognitive assessments at baseline, post-intervention, and at one month and three months after intervention to explore and document durability of effects. Our primary outcome is change in cognitive performance (assessed by the Alzheimer's Disease Assessment Scale - Cognitive subscale test). Secondary outcomes include measures of mood, quality of life, and patient satisfaction with both the device and procedure. Neuroimaging markers of potential neuroplasticity will also be evaluated at baseline, post-intervention, and at three months post-intervention. We predict that the active tDCS will result in better cognitive performance, and higher quality of life, as compared to sham, and will be a satisfactory treatment approach for patients and their families. We also hypothesize that the clinical response produced by active tDCS will be associated with improved functional and structural connectivity and use of the Dorsolateral Prefrontal Cortex and associated networks (e.g. executive control/salience networks). The proposed study is highly responsive to PAR-19-298, which solicits applications to establish initial efficacy of neurostimulation/neuromodulation in the treatment of Alzheimer’s disease and related dementia. Our proposed clinical trial will provide high-quality evidence about the efficacy of at-home tDCS in the treatment of Alzheimer’s Disease. If efficacy is demonstrated, this non-invasive, non- pharmacologic intervention may become an important part of dementia care.