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: 9980744
• 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 2020-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980744
• 关键词: Address; Adult; Affect; Aftercare; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; 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; algorithm training; 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 circuit; neural network; neuroimaging; neuron loss; older patient; patient population; pre-clinical; prodromal Alzheimer' s disease; 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.

项目摘要 在阿尔茨海默氏病（AD），β-淀粉样蛋白（AB）和TAU的前驱阶段优先传播 在整个默认模式网络（DMN）中，导致神经元丢失和突触功能障碍。情节 AD的记忆障碍被认为是由于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（RTM）的研究的新证据 年轻人证明DMN可以以促进持久性记忆的方式调节 改进。但是，关于控制RTMS的因素仍然存在几个基本问​​题 对于患有阿尔茨海默氏病的病理和神经退行性的患者有效。 该提案的主要目标是完善我们对机制和治疗性的理解 RTM的潜力增强了患有老年痴呆症患者的DMN完整性和情节记忆。 30例前驱AD的患者，30例AB+认知正常的老年人和30个ABSAB-认知正常年龄较大 成人将每人进行5天的假控制RTM，然后进行多模式MRI会议 和认知测试。 RTMS目标将使用基线功能连通性建立 静息状态功能MRI（RSFMRI）确定具有最大功能的侧壁皮层中的区域 与海马的连通性。 RSFMRI结果指标将包括 刺激部位和海马，以及刺激部位和海马内的内在活性。 AB，Tau， 和FDG正电子发射断层扫描（PET）扫描和结构MRI将用于量化 阿尔茨海默氏症的病理，低代谢和萎缩对RTMS治疗在每组中的功效。全部 结局指标将立即与情节记忆的行为度量有关 治疗的结束。拟议项目的目标1将确定RTM对情节记忆的影响 每个组。 AIM 2将在每个组中建立RTM的功能网络效应。 AIM 3将使用多元 回归和机器学习算法，以识别最有用的生物学特征 个人是否会从RTM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 学校。在项目完成期间，候选人将接受有关理论和应用的培训 TMS调节网络功能，使用PET成像测量AD中的病理学，临床试验设计， 以及使用高级生物统计学来生物标志物发育和治疗反应预测。这 这项研究的结果将提供对最有可能从RTM中受益的个人的见解， 将告知未来的研究，以优化RTMS治疗以改善痴呆症的认知。此外， 该项目的完成将为候选人翻译基本的长期目标奠定基础 从健康衰老到阿尔茨海默氏病患者的直接益处的神经影像学发现。