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

TMS 在临床前和前驱 AD 中的应用：大脑网络和记忆的调节

• 批准号: 9815073
• 负责人: Jessica A Collins
• 金额: $ 13.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815073
• 关键词: Address; Adult; Affect; Aftercare; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Atrophic; Behavior; Behavioral; Biological; Biometry; Brain; Clinical Trials Design; Cognition; Cognitive; Data; Data Analyses; Data Collection; Dementia; Development; Disease; Distal; Elderly; Episodic memory; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; General Hospitals; Goals; Hippocampus (Brain); Impairment; Individual; Intervention; Lateral; Magnetic Resonance Imaging; Magnetism; Massachusetts; Measures; Medial; Memory; Mentors; Metabolism; Nerve Degeneration; Neurologic; Outcome Measure; Outcomes Research; Parietal; Parietal Lobe; Pathology; Patients; Phase; Positron-Emission Tomography; Prediction of Response to Therapy; Publishing; Research; Rest; Role; Secure; Short-Term Memory; Site; Structure; Synapses; Testing; Therapeutic; Training; Translating; Work; age related; amnestic mild cognitive impairment; base; behavior measurement; beta amyloid pathology; biomarker development; clinical Diagnosis; cognitive testing; episodic memory impairment; healthy aging; improved; improved functioning; in vivo; insight; machine learning algorithm; medical schools; multimodality; neural network; neuroimaging; neuron loss; older patient; patient population; pre-clinical; relating to nervous system; repetitive transcranial magnetic stimulation; tau Proteins; theories; young adult

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.

项目概要 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 整个默认模式网络（DMN）导致神经元丢失和突触功能障碍。情景式 AD 中的记忆障碍被认为是由结构和功能连接的丧失引起的 DMN 的节点。重复经颅磁刺激 (rTMS) 研究中的新证据 年轻人证明 DMN 可以通过促进持久情景记忆的方式进行调节 改进。然而，关于控制 rTMS 是否有效的因素，仍然存在一些基本问题。 对患有阿尔茨海默病和神经退行性疾病的患者有效。 该提案的主要目标是加深我们对机制和治疗的理解 rTMS 在增强阿尔茨海默病患者的 DMN 完整性和情景记忆方面的潜力。 30 名前驱 AD 患者、30 名 AB+ 认知正常的老年人和 30 名 AB- 认知正常的老年人 成人将分别接受 5 天的假手术对照 rTMS，随后进行多模式 MRI 治疗 和认知测试。 rTMS 目标将使用源自以下的基线功能连接来建立： 静息态功能 MRI (rsfMRI) 用于确定外侧顶叶皮层中具有最大功能的区域 与海马体的连接。 rsfMRI 结果测量将包括 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、τ、 FDG 正电子发射断层扫描 (PET) 扫描和结构 MRI 将用于量化 阿尔茨海默病病理、代谢低下和萎缩对各组 rTMS 治疗效果的影响。全部 结果测量将与情景记忆的行为测量立即和两周后相关 治疗结束。拟议项目的目标 1 将确定 rTMS 对情景记忆的影响 每组。目标 2 将在每组中建立 rTMS 的功能网络效应。目标 3 将使用多元 回归和机器学习算法来识别对预测最有用的生物特征 个人是否会从 rTMS 中受益。 所有数据收集和分析将在马萨诸塞州总医院和哈佛医学院进行 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 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志物开发和治疗反应预测。这 这项研究的结果将深入了解最有可能从 rTMS 中受益的个人，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基础知识的长期目标奠定基础 从健康老龄化到对阿尔茨海默病患者的直接益处的神经影像学发现。