Feasibility gamma stimulation to reduce beta-amyloid load across species

项目摘要 遗忘性轻度认知障碍是阿尔茨海默病的痴呆前期阶段，即 以情景记忆下降为特征，并经常伴随β-淀粉样蛋白负荷，这发挥着一种 在阿尔茨海默病发病机制中的作用。随着老年人人口的持续增长，它 了解可以采取哪些措施以将随之而来的问题降至最低变得更加迫切 AMCI和阿尔茨海默病人群的增长。之前在5XFAD小鼠上的研究，一个公认的 阿尔茨海默病模型的研究表明，40赫兹(伽马波)神经夹带可以减少 发生夹带的神经区的β-淀粉样蛋白负荷。在这里，我们建议复制和推广 这些关于神经夹带的治疗潜力的发现和评估翻译的可行性 这项以动物为基础的研究针对急性MCI患者。为了实现这一目标，我们提出了两个实验。第一 实验将使用40赫兹交流电刺激来同时夹带多个皮质区域 与之前的研究相比，5XFAD小鼠在全球范围内更多地减少了β-淀粉样蛋白负荷。此外，我们还将 参数控制刺激强度，以确定降低β-淀粉样蛋白负荷的最佳电流。 虽然β-淀粉样蛋白负荷将作为主要的结果衡量标准，但情节记忆能力将 作为次要的结果衡量标准。第二个实验将应用最佳电流强度 实验一：经颅交流电刺激(TACS)治疗急性脑梗塞患者。我们的主要成果 措施与该方法的安全性和耐受性有关：电极下的皮肤发红， 灼热感，头痛，头皮痛，背痛，脖子痛，头晕，刺痛，发痒，困倦，烦恼 注意力集中，情绪剧烈变化，膦类物质和癫痫。次要结果衡量标准包括Beta- 通过正电子发射断层扫描和情景记忆表现评估淀粉样蛋白负荷。对两个人都是 实验，连续五天(星期一到星期五)进行一小时的刺激， 然后在接下来的三个星期一分别进行一小时的刺激，总共八次刺激 为期一个月的课程。将测量情景记忆和β淀粉样蛋白负荷的测试 刺激前和刺激后(一个月末)。重要的是，在aMCI患者中应用Tacs的可行性将是 通过观察数据和患者反馈，在每次刺激过程中持续评估。这个 这项研究的结果将促进我们对神经夹带在脑血管疾病中的治疗潜力的认识 阿尔茨海默病小鼠模型，并提供关键的可行性评估，为快速 将动物研究转化为人类疗法。如果Tacs被证明对aMCI患者是安全和可耐受的，这 将促进未来的研究部署随机对照试验来评估这一方法的有效性。

Project Summary Amnestic mild cognitive impairment (aMCI) is a pre-dementia stage of Alzheimer’s disease that is characterized by declines in episodic memory, and is often accompanied by beta-amyloid load, which plays a role in the pathogenesis of Alzheimer’s disease. As the population of older adults continues to grow, it becomes more imperative to understand what measures may be taken in order to minimize the concomitant growth of the aMCI and Alzheimer’s disease populations. Previous research in 5XFAD mice, a well-established model of Alzheimer’s disease, has demonstrated that 40 Hz (gamma band) neural entrainment can reduce beta-amyloid load in the neural regions where entrainment occurs. Here, we propose to replicate and extend these findings regarding the therapeutic potential of neural entrainment and assess the feasibility of translating this animal-based research to aMCI patients. To achieve this, we propose two experiments. The first experiment will use 40 Hz alternating current stimulation to entrain multiple cortical regions simultaneously in 5XFAD mice to reduce beta-amyloid load more globally than prior research. Furthermore, we will parametrically manipulate stimulation intensity to identify the optimal current that reduces beta-amyloid load. Whereas beta-amyloid load will serve as the primary outcome measure, episodic memory performance will serve as a secondary outcome measure. The second experiment will apply the optimal current intensity from experiment 1 in patients with aMCI via transcranial alternating current stimulation (tACS). Our primary outcome measures are concerned with the safety and tolerability of this method: skin redness under the electrodes, burning sensations, headache, scalp pain, back pain, neck pain, dizziness, tingling, itching, sleepiness, trouble concentrating, acute mood change, phosphenes and seizure. Secondary outcome measures include beta- amyloid load as assessed by positron emission tomography and episodic memory performance. For both experiments, stimulation will be applied for one hour on five consecutive days (Monday through Friday), followed by one hour of stimulation on each of the three following Mondays for a total of eight stimulation sessions over a one month period. Tests of episodic memory as well as beta-amyloid load will be measured pre- and post-stimulation (at the end of one month). Importantly, feasibility of tACS in aMCI patients will be continuously assessed during each stimulation session via observational data and patient feedback. The outcome of this research will advance our knowledge of the therapeutic potential of neural entrainment in a mouse model of Alzheimer’s disease and provide a critical feasibility assessment for the potential to rapidly translate animal research to human therapeutics. If tACS proves to be safe and tolerable in aMCI patients, this will facilitate future research to deploy randomized controlled trials to assess efficacy of this approach.