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

项目摘要 在阿尔茨海默病(AD)前驱期，β-淀粉样蛋白(AB)和tau优先扩散 整个默认模式网络(DMN)导致神经元丢失和突触功能障碍。插曲 阿尔茨海默病患者的记忆障碍被认为是由于 DMN的节点。重复性经颅磁刺激(RTMS)研究中的新证据 年轻人证明，DMN可以以一种促进持续情节记忆的方式进行调节 进步。然而，关于控制rtms是否有效的因素，仍存在几个基本问题。 对阿尔茨海默病和神经退行性变患者有效。 这项建议的主要目标是完善我们对其发病机制和治疗方法的理解。 RTMS在增强阿尔茨海默病患者DMN完整性和情景记忆方面的潜力。 30例先兆AD患者，30例AB+认知正常老年人和30例AB-认知正常老年人 成人每人将在接受多模式磁共振检查之前和之后接受为期5天的假控制rTMS 和认知测试。将使用以下来源的基准功能连接性建立RTMS目标 静息状态功能磁共振成像(RsfMRI)确定顶叶外侧皮质最大功能区域 连接到海马体。RsfMRI结果衡量标准将包括 刺激部位和海马体，以及刺激部位和海马体内的内在活动。AB，Tau， FDG正电子发射断层扫描(PET)和结构磁共振将被用来量化 阿尔茨海默病病理、低代谢、萎缩对rTMS治疗效果的影响。全 结果测量将与即刻和2周后情景记忆的行为测量相关 治疗的结束。拟议项目的目标1将确定rTMS对小鼠情景记忆的影响。 每组。目的2建立各组间rTMS的功能网络效应。目标3将使用多变量 回归和机器学习算法，以确定在预测中最有用的生物特征 个人是否会从rTMS中受益。 所有数据收集和分析都将在马萨诸塞州综合医院和哈佛医疗中心进行 学校。在项目完成期间，候选人将接受理论和应用方面的培训 TMS调节网络功能，使用PET成像测量AD的病理，临床试验设计， 以及使用先进的生物统计学进行生物标记物开发和治疗反应预测。这个 这项研究的结果将提供对最有可能从rTMS中受益的个人的洞察，以及 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， 该项目的完成将为候选人翻译BASIC的长期目标奠定基础 从健康老龄化的神经成像结果到阿尔茨海默病患者的直接好处。

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.