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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

基本信息

批准号：
10614067
负责人：
Emiliano Santarnecchi
金额：
$ 69.4万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10614067
关键词：
Abeta clearance Acute Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Animal Model Animals Behavioral Brain Cephalic 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 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 improved insight mouse model neuroinflammation neurophysiology neuroregulation novel novel therapeutic intervention pre-clinical predicting response prevent research clinical testing response safety assessment side effect tau-1 translation to humans uptake β-amyloid burden

项目摘要

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.

项目摘要由于公共卫生和医学的进步，世界人口的预期寿命继续延长。虽然更长的寿命是一个独特的机会，社会受益于老年人的智慧和经验，但老化也是最大的风险因素，神经退行性疾病，如阿尔茨海默病（AD）。一个基本的神经生物学认知下降和神经变性的底物似乎涉及神经炎症过程与异常蛋白质的相关沉积，如淀粉样蛋白， β（Aβ）和磷酸化tau（p-tau）。麻省理工学院的Li-Huei Tsai，艾德最近的临床前工作 Boyden及其合作者揭示，在小鼠中诱导γ振荡可以调节小胶质细胞的活性，改变炎症性脑过程，并导致Aβ和p-tau的清除证词将这些发现转化为人类可能会产生变革性的影响。近几多年来，经颅交流电刺激（tACS）已被证明有效，通过低幅度交替调节大脑活动和皮层节律活动经颅施加的（正弦）电流。在人类中，在Berenson-Allen（BA）中心工作和其他地方揭示，如果遵循适当的指导方针，tACS可以安全地应用，并且当以适当的交变频率施加时振荡和增强认知。此外，连续的tACS重复会话天是安全的，并导致累加效应，对大脑的神经调节影响更持久振荡考虑到通过tACS在人类中携带伽马的可能性，我们提出了第一个- 诱导伽马振荡对人的影响的临床前数据的翻译轻度至中度AD患者中的Aβ和p-tau，利用与乔治·埃尔·法赫里，MGH戈登医学成像中心主任。我们的中央假设AD患者每天重复接受γ-tACS治疗，通过PET测量，减少神经元缠结中的Aβ斑块和p-tau沉积显像这将与脑电生理（EEG）测量的变化相关功能和认知测试。这项试验性研究将提供关键的第一步开发一种新的干预措施来预防和治疗AD，作用机制，建立剂量反应关系，并告知设计最终的临床试验。