TMS in preclinical and prodromal AD: Modulation of brain networks and memory

项目摘要 在阿尔茨海默病（AD）的前驱期，β-淀粉样蛋白（AB）和tau蛋白优先扩散 在整个默认模式网络（DMN）中，导致神经元损失和突触功能障碍。幕式 AD中的记忆障碍被认为是由于大脑皮层和皮层之间结构和功能连接的丧失而引起的。 DMN的节点。来自重复经颅磁刺激（rTMS）研究的新证据， 年轻人证明DMN可以以促进持久情景记忆的方式调节 改进.然而，关于决定rTMS是否 对阿尔茨海默病和神经变性患者有效。 这项提案的主要目标是完善我们对机制和治疗的理解。 rTMS增强阿尔茨海默病患者DMN完整性和情景记忆的潜力。 30例前驱AD患者，30例AB+认知正常老年人，30例AB-认知正常老年人 成年人将分别接受5天假对照rTMS，在此之前和之后进行多模式MRI检查 和认知测试。rTMS目标将使用从以下来源获得的基线功能连接来确定 静息状态功能性MRI（rsfMRI），以确定顶叶外侧皮质中最大功能性MRI区域。 连接到海马体。rsfMRI结果指标将包括 刺激位点和海马内的固有活性。AB，tau， 和FDG正电子发射断层扫描（PET）和结构MRI将用于量化的影响， 阿尔茨海默病病理学、代谢减退和萎缩对每组中rTMS治疗的功效的影响。所有 结果测量将与事件记忆立即和2周后的行为测量相关。 治疗的结束。该项目的目标1将确定rTMS对儿童情景记忆的影响。 每组目的2建立rTMS在各组的功能网络效应。Aim 3将使用多变量 回归和机器学习算法，以确定最有用的生物特征， 一个人是否会从rTMS中受益。 所有数据收集和分析将在马萨诸塞州总医院和哈佛医疗中心进行 学校在项目完成期间，候选人将接受以下方面的理论和应用培训： TMS调节网络功能，使用PET成像测量AD病理学，临床试验设计， 以及使用先进的生物统计学进行生物标志物开发和治疗反应预测。的 这项研究的结果将提供对最有可能从rTMS中受益的个体的深入了解， 将为未来寻求优化rTMS治疗以改善痴呆症认知的研究提供信息。此外，委员会认为， 该项目的完成将为候选人的长期目标奠定基础， 从健康老龄化的神经影像学发现到阿尔茨海默病患者的直接益处。

Project Summary In the prodromal phase of Alzheimer's disease (AD), beta-amyloid (AB) and tau preferentially spread throughout the default mode network (DMN) leading to neuronal loss and synaptic dysfunction. Episodic memory impairments in AD are thought to arise from the loss of structural and functional connectivity between nodes of the DMN. Emerging evidence from studies with repetitive transcranial magnetic stimulation (rTMS) in young adults demonstrate that the DMN can be modulated in a manner that promotes lasting episodic memory improvement. However, several fundamental questions remain regarding the factors that govern whether rTMS is effective in patients with Alzheimer's pathology and neurodegeneration. The primary goal of this proposal is to refine our understanding of the mechanisms and therapeutic potential of rTMS for enhancing DMN integrity and episodic memory in individuals with Alzheimer's pathology. 30 patients with prodromal AD, 30 AB+ cognitively normal older adults, and 30 AB- cognitively normal older adults will each undergo 5 days of sham-controlled rTMS preceded and followed by multimodal MRI sessions and cognitive testing. rTMS targets will be established using baseline functional connectivity derived from resting state functional MRI (rsfMRI) to determine the region in lateral parietal cortex with maximal functional connectivity to the hippocampus. rsfMRI outcome measures will include functional connectivity between the stimulation site and hippocampus, and intrinsic activity within the stimulation site and hippocampus. AB, tau, and FDG positron emission tomography (PET) scans and structural MRI will be used to quantify the impact of Alzheimer's pathology, hypometabolism, and atrophy on the efficacy of rTMS treatments in each group. All outcome measures will be related to behavioral measures of episodic memory immediately and 2 weeks after the end of treatment. Aim 1 of the proposed project will establish the effects of rTMS on episodic memory in each group. Aim 2 will establish functional network effects of rTMS in each group. Aim 3 will use multivariate regression and machine learning algorithms to identify the biological features that are most useful in predicting whether an individual will benefit from rTMS. All data collection and analyses will take place at Massachusetts General Hospital and Harvard Medical School. During the completion of the project the candidate will receive training in the theory and application of TMS to modulate network function, the use of PET imaging to measure pathology in AD, clinical trial design, and the use of advanced biostatistics for biomarker development and treatment response prediction. The outcome of this research will provide insight into the individuals that are most likely to benefit from rTMS, and will inform future studies seeking to optimize rTMS treatments to improve cognition in dementia. Furthermore, the completion of this project will lay the foundation for the candidate's long-term goal of translating basic neuroimaging findings from healthy aging to direct benefits for patients with Alzheimer's disease.