Gamma Induction for Amyloid Clearance in Alzheimer's Disease

伽马诱导清除阿尔茨海默病中的淀粉样蛋白

• 批准号: 10554736
• 负责人: Emiliano Santarnecchi
• 金额: $ 66.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10554736
• 关键词: Abeta clearance; Acute; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Behavioral; Brain; Cerebellum; Cerebrum; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Collaborations; Data; Dementia; Deposition; Development; Diffuse; Disease; Dose; Elderly; Electrodes; Electrophysiology (science); Frequencies; Guidelines; Human; Impaired cognition; Individual; Inflammatory; Intervention; Lead; Life Expectancy; Link; Longevity; Magnetic Resonance Imaging; Maps; Measures; Medical Imaging; Medical center; Medicine; Memory; Microglia; Mus; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Participant; Pathogenesis; Pathologic; Patients; Periodicity; Pilot Projects; Play; Population; Positron-Emission Tomography; Process; Proteins; Public Health; Randomized; Risk Factors; Role; Safety; Seminal; Senile Plaques; Societies; Symptoms; Testing; Time; Tracer; Translating; Translations; United States; Work; attenuation; clinically relevant; cognitive change; cognitive function; cognitive testing; design; electric field; experience; first-in-human; follow-up; genetic predictors; insight; mouse model; neuroinflammation; neurophysiology; neuroregulation; novel; novel therapeutic intervention; pre-clinical; predicting response; prevent; research clinical testing; response; side effect; tau-1; translation to humans; uptake; β-amyloid burden

Project Summary Thanks to advances in public health and medicine, the life expectancy of the world population continues to lengthen. While longer lifespan is a unique opportunity for society to benefit from the wisdom and experience of the elderly, aging is however also the greatest risk factor for neurodegenerative disorders such as Alzheimer's disease (AD). A fundamental neurobiological substrate of cognitive decline and neurodegeneration appears to involve alteration of neuroinflammatory processes with associated deposition of aberrant proteins, such as amyloid- β (Aβ) and phosphorylated tau (p-tau). Recent pre-clinical work from MIT's Li-Huei Tsai, Ed Boyden and collaborators reveals that induction of gamma oscillations in mice can modulate activity of microglia, modify inflammatory brain processes, and lead to clearance of Aβ and p-tau deposition. Translation of such findings to humans could have transformative impact. In recent years, transcranial Alternating Current Stimulation (tACS) has been shown effective in modulating brain activity and cortical rhythmic activity by means of low-amplitude alternating (sinusoidal) currents applied transcranially. In humans, work at the Berenson-Allen (BA) Center and elsewhere reveals that tACS can be applied safely if appropriate guidelines are followed, and that when applied at the appropriate alternating frequency it is possible to entrain gamma oscillations and enhance cognition. Furthermore, repeated sessions of tACS on consecutive days are safe and lead to an additive effect with longer lasting neuromodulatory impact on brain oscillation. Given the potential for gamma entrainment in humans via tACS, we propose a first- to-human translation of the preclinical data on the effect of induction of gamma oscillations on Aβ and p-tau in patients with mild to moderate AD, leveraging the close collaboration with Georges El Fakhri, director of the Gordon Center for medical imaging at MGH. Our central hypothesis is that repeated daily sessions of gamma-tACS in patients with AD will significantly decrease Aβ plaques and p-tau deposition in neurofibrillary tangles as measured by PET imaging. This will be correlated with changes on electrophysiological (EEG) measures of brain function, and on cognitive testing. This pilot study will provide the critical first step in the development of a novel intervention to prevent and treat AD, demonstrating the potential mechanisms of action, establishing a dose response relation, and informing the design of an eventual clinical trial.

项目摘要 感谢您在公共卫生和医学的进步，世界人口的预期寿命 继续长度。较长的寿命是社会从中受益的独特机会 然而，老化的智慧和经验也是最大的风险因素 神经退行性疾病，例如阿尔茨海默氏病（AD）。基本神经生物学 认知下降和神经退行性的底物似乎涉及改变 神经炎症过程伴随异常蛋白的相关沉积，例如淀粉样蛋白 β（Aβ）和磷酸化的tau（p-tau）。麻省理工学院的Li-Huei Tsai的临床前工作，Ed 博伊登和合作者透露，小鼠伽马振荡的诱导可以调节 小胶质细胞的活性，修饰炎症性脑过程，并导致Aβ和P-TAU的清除 沉积。将这种发现向人类的翻译可能会产生变革性的影响。最近 多年，thrancranial交流电流刺激（TAC）已显示为有效 通过低振幅交替调节大脑活动和皮质节奏活动 （正弦）经经颅施用的电流。在人类中，在Berenson-Allen（BA）中心工作 在其他地方表明，如果遵循适当的准则，可以安全应用TAC， 而且，当以适当的替代频率应用时，可能会纳入伽玛 振荡和增强认知。此外，连续的TAC的重复会议 天气安全，会导致额外的效果，对大脑的神经调节影响更长 振荡。鉴于通过TACS在人类中进入伽马的潜力，我们提出了一个首先 临床前数据的人类翻译有关伽马振荡对诱导影响的影响 轻度至中度AD患者的Aβ和P-TAU，利用与 MGH戈登医学成像中心主任Georges El Fakhri。我们的中心 假设是，AD患者的γ​​-TAC的每日重复会议将显着 通过PET测量，减少Aβ斑块和神经原纤维缠结中的P-TAU沉积 成像。这将与大脑电生理（EEG）测量的变化有关 功能和认知测试。这项试验研究将为关键的第一步 开发新的干预措施以防止和治疗AD，证明了潜力 作用机制，建立剂量响应关系并告知设计 最终的临床试验。