Feasibility gamma stimulation to reduce beta-amyloid load across species

伽玛刺激减少物种间β-淀粉样蛋白负荷的可行性

• 批准号: 9586728
• 负责人: THEODORE P ZANTO
• 金额: $ 15.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9586728
• 关键词: Accommodation phosphene; Acute; Adult; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Experimentation; Animal Model; Animals; Back Pain; Behavioral; Biological Markers; Data; Dementia; Diagnosis; Disease Progression; Dizziness; Drowsiness; Elderly; Electric Stimulation; Electrodes; Episodic memory; Esthesia; Feedback; Goals; Growth; Headache; Hippocampus (Brain); Hour; Human; In Vitro; Individual; Knowledge; Learning; Magnetic Resonance Imaging; Measures; Methods; Modeling; Moods; Mus; Neck Pain; Older Population; Outcome Measure; Outcomes Research; Pain; Participant; Pathogenesis; Patients; Performance; Play; Population; Positioning Attribute; Positron-Emission Tomography; Pruritus; Randomized Controlled Trials; Rattus; Recovery; Redness; Research; Role; Safety; Scalp structure; Seizures; Skin; Techniques; Testing; Therapeutic; Therapeutic Effect; Translating; Visual Cortex; amnestic mild cognitive impairment; arm; base; demented; design; electric field; experimental study; high risk; improved; in vivo; mouse model; optogenetics; prevent; primary outcome; relating to nervous system; secondary outcome

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.

项目摘要 遗忘型轻度认知障碍（aMCI）是阿尔茨海默病的痴呆前阶段， 其特征是情景记忆下降，并且通常伴有β-淀粉样蛋白负荷，这在 在阿尔茨海默病发病机制中的作用。随着老年人口的不断增长， 更有必要了解可以采取什么措施，以尽量减少伴随的 aMCI和阿尔茨海默病人群的增长。先前在5XFAD小鼠中的研究， 阿尔茨海默病模型，已经证明40 Hz（伽马波段）神经夹带可以减少 β-淀粉样蛋白负荷的神经区域，其中夹带发生。在这里，我们建议复制和扩展 这些关于神经夹带的治疗潜力的研究结果，并评估翻译的可行性， 这项基于动物的研究应用于aMCI患者。为了实现这一点，我们提出了两个实验。第一 实验将使用40 Hz交流电刺激同时携带多个皮层区域， 5XFAD小鼠在全球范围内减少β-淀粉样蛋白负荷比以前的研究。此外，我们将 参数化地操纵刺激强度以识别减少β-淀粉样蛋白负荷的最佳电流。 而β-淀粉样蛋白负荷将作为主要的结果测量，情节记忆的表现将 作为次要结果指标。第二个实验将应用最佳电流强度， 实验1通过经颅交流电刺激（tACS）在aMCI患者中进行。我们的主要成果 测量与该方法的安全性和耐受性有关：电极下的皮肤发红， 烧灼感、头痛、头皮痛、背痛、颈部痛、头晕、刺痛、瘙痒、嗜睡、不适 注意力集中，情绪急剧变化，光幻视和癫痫发作。次要结局指标包括β- 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。为 在实验中，刺激将在连续五天（周一至周五）施加一小时， 然后在接下来的三个星期一的每个星期一进行一小时的刺激，总共进行八次刺激 在一个月的时间里，会议。测试情节记忆以及β-淀粉样蛋白负荷将被测量 刺激前和刺激后（一个月结束时）。重要的是，tACS在aMCI患者中的可行性将是 通过观察数据和患者反馈在每次刺激会话期间连续评估。的 这项研究的结果将推进我们对神经夹带治疗潜力的认识， 阿尔茨海默病的小鼠模型，并提供了一个关键的可行性评估的潜力， 将动物研究转化为人类疗法。如果tACS在aMCI患者中被证明是安全和可耐受的， 将促进未来的研究部署随机对照试验，以评估这种方法的有效性。