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.

项目概要由于公共卫生和医学的进步，世界人口的预期寿命而更长的寿命是社会受益的独特机会。就老年人的智慧和经验而言，衰老也是最大的危险因素神经退行性疾病，例如阿尔茨海默病 (AD)，这是一种基本的神经生物学疾病。认知能力下降和神经退行性变的基础似乎涉及与异常蛋白质（例如淀粉样蛋白）沉积相关的神经炎症过程 β (Aβ) 和磷酸化 tau (p-tau) 的最新临床前工作来自麻省理工学院的 Li-Huei Tsai，Ed。博伊登和合作者揭示了在小鼠中诱导伽马振荡可以调节小胶质细胞的活性，改变大脑炎症过程，并导致 Aβ 和 p-tau 的清除最近，将这些发现转化为人类可能会产生变革性的影响。多年来，经颅交流电刺激 (tACS) 已被证明在通过低幅度交替调节大脑活动和皮质节律活动（正弦）电流应用于人类，在 Berenson-Allen (BA) 中心工作。和其他地方表明，如果遵循适当的指南，tACS 可以安全应用，当以适当的交变频率应用时，可以夹带伽玛此外，连续重复 tACS 课程。几天是安全的，并会产生附加效应，对大脑产生更持久的神经调节影响考虑到通过 tACS 人体中伽马夹带的可能性，我们提出了第一个- 将有关伽马振荡感应对人体的影响的临床前数据转译为人类利用与 Aβ 和 p-tau 的密切合作，治疗轻度至中度 AD 患者 Georges El Fakhri，麻省总医院戈登医学影像中心主任。假设每天重复进行 γ-tACS 治疗 AD 患者将显着减少 PET 测量的神经原纤维缠结中的 Aβ 斑块和 p-tau 沉积这将与大脑电生理（EEG）测量的变化相关。这项试点研究将提供关键的第一步。开发一种预防和治疗 AD 的新型干预措施，展示了其潜力作用机制，建立剂量反应关系，并为设计提供信息最终的临床试验。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The multifactorial nature of healthy brain ageing: Brain changes, functional decline and protective factors.

健康大脑老化的多因素性质：大脑变化、功能衰退和保护因素。

DOI：
发表时间：
2023-07
期刊：
影响因子：
13.1
作者：
Turrini, Sonia;Wong, Bonnie;Eldaief, Mark;Press, Daniel Z;Sinclair, David A;Koch, Giacomo;Avenanti, Alessio;Santarnecchi, Emiliano
通讯作者：
Santarnecchi, Emiliano

Microgravity and Cosmic Radiations During Space Exploration as a Window Into Neurodegeneration on Earth.

太空探索期间的微重力和宇宙辐射是了解地球神经退行性变的窗口。

DOI：
发表时间：
2020
期刊：
影响因子：
29
作者：
Sprugnoli, Giulia;Cagle, Yvonne D;Santarnecchi, Emiliano
通讯作者：
Santarnecchi, Emiliano

The role of the parietal lobe in task-irrelevant suppression during learning.

顶叶在学习过程中与任务无关的抑制中的作用。

DOI：
发表时间：
2023
期刊：
影响因子：
7.7
作者：
Contò, F;Tyler, S;Paletta, P;Battelli, L
通讯作者：
Battelli, L

The benefits of simultaneous tDCS and working memory training on transfer outcomes: A systematic review and meta-analysis.

同时 tDCS 和工作记忆训练对转移结果的好处：系统回顾和荟萃分析。

DOI：
发表时间：
2022
期刊：
影响因子：
7.7
作者：
Pergher, Valentina;Au, Jacky;Alizadeh Shalchy, Mahsa;Santarnecchi, Emiliano;Seitz, Aaron;Jaeggi, Susanne M;Battelli, Lorella
通讯作者：
Battelli, Lorella

The Role of Cognitive Reserve in Alzheimer's Disease and Aging: A Multi-Modal Imaging Review.

认知储备在阿尔茨海默病和衰老中的作用：多模态成像综述。