Understanding the structural, functional, and prognostic implications of cortical excitability in Alzheimer's disease

了解阿尔茨海默病皮质兴奋性的结构、功能和预后影响

• 批准号: 10404100
• 负责人: Stephanie Buss
• 金额: $ 16.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404100
• 关键词: Accounting; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Area; Atrophic; Biological Markers; Biometry; Brain; Brain region; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Dementia; Development Plans; Diagnosis; Disease Progression; Electroencephalography; Failure; Foxes; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Goals; Image; Inferior; Investigation; Israel; Link; Magnetic Resonance Imaging; Measurement; Measures; Medial; Medical center; Memory; Mentorship; Mission; Modeling; Motor; Motor Cortex; Nerve Degeneration; Neurologist; Neurology; Neuronal Dysfunction; Neurons; Outcome; Parietal; Parietal Lobe; Participant; Pathogenesis; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Prevention; Prognosis; Prognostic Marker; Public Health; Research Personnel; Research Project Grants; Resolution; Rest; Sampling; Scientist; Site; Stimulus; Techniques; Temporal Lobe; Testing; Therapeutic; Thick; Training; Transcranial magnetic stimulation; United States; United States National Institutes of Health; base; career; career development; clinical predictors; cognitive testing; cohort; demographics; design; experience; human disease; improved; innovation; instructor; medical schools; neuroimaging; neurophysiology; noninvasive brain stimulation; novel; novel marker; practical application; prodromal Alzheimer' s disease; prognostic; prognostic value; response; restoration; skills; synaptic function; therapeutic target; tool

PROJECT SUMMARY/ABSTRACT Recent therapeutic drug trials in Alzheimer’s disease (AD) have failed to improve cognitive outcomes despite improvements on imaging-based targets (e.g., amyloid PET). One possible missing link is a failure to restore normal neuronal function. Measures of cortical excitability using transcranial magnetic stimulation with electroencephalography (TMS-EEG) have the potential to fill this gap by measuring the neuronal response to controlled perturbation. However, practical applications of TMS-EEG measures are currently limited by a dearth of data from brain regions involved in early-stage AD pathophysiology, and a lack of understanding of how cortical excitability is related to clinically useful metrics. The long-term goal of this project is to determine the extent to which cortical excitability is an important prognostic marker and/or treatment target in AD. This study assesses excitability in both motor cortex—a well-characterized TMS site—and parietal cortex—a brain involved in the early stages of AD pathogenesis. The objective of the present proposal is to understand how parietal cortical excitability is related to neuroimaging abnormalities and prognosis in a cohort of early-stage symptomatic AD participants (early AD). The hypothesis is that increased cortical excitability in parietal cortex is related to neurodegeneration, decreased network connectivity, and more rapid clinical decline. This will be tested with three independent Aims to assess how cortical excitability is related to 1) local cortical thickness, 2) resting state fMRI connectivity; and 3) disease progression. The proposed project is highly innovative, using TMS-EEG measures to capture local cortical excitability in AD, integrating neuroimaging and neurophysiologic measurements, and testing the extent to which cortical excitability predicts meaningful clinical outcomes. This contribution will be significant because it will inform our understanding of how measures of synaptic function are related to progression of AD pathology. Findings from this study will lay the groundwork for future clinical trials in AD seeking to measure restoration of neuronal function using novel biomarkers. The candidate has a strong commitment to a clinical research career in Alzheimer’s disease and related dementias. She is a practicing cognitive neurologist at Beth Israel Deaconess Medical Center and Instructor in Neurology at Harvard Medical School. Her training plan and research project are specifically designed to build her expertise in AD biomarkers, advanced neuroimaging techniques, and biostatistics for AD clinical trials. Her mentorship team, led by Dr. Daniel Press and Dr. Michael Fox, will provide critical guidance on the integration of TMS measures with neuroimaging. Additional mentorship will be provided by Dr. Mouhsin Shafi on TMS-EEG, Dr. Reisa Sperling on AD biomarkers, and Dr. Long Ngo on biostatistics. Completion of this five-year career development plan will allow the candidate to launch a career as an independent investigator using novel neurophysiologic tools to advance prognosis and treatment of AD.

项目摘要/摘要 最近治疗阿尔茨海默病(AD)的药物试验未能改善认知结果 尽管基于成像的靶点(例如，淀粉样PET)有所改进。一个可能缺失的环节是未能 恢复正常的神经功能。使用经颅磁刺激测量皮质兴奋性 脑电图学(TMS-EEG)有可能通过测量神经反应来填补这一空白 受控微扰。然而，TMS-EEG测量的实际应用目前受到 缺乏涉及早期AD病理生理学的大脑区域的数据，以及对 大脑皮层兴奋性与临床有用指标的关系。这个项目的长期目标是确定 皮质兴奋性在多大程度上是AD的重要预后标志和/或治疗靶点。这 研究评估了运动皮质和顶叶皮质的兴奋性，前者是TMS的典型部位，后者是大脑。 参与AD发病的早期阶段。本提案的目标是了解如何 一组早期患者顶叶皮质兴奋性与神经影像异常和预后相关 有症状的AD参与者(早期AD)。假设是顶叶皮质兴奋性增强 与神经退行性变、网络连通性降低以及更快的临床衰退有关。这将是 测试有三个独立的目标，以评估皮质兴奋性如何与1)局部皮质厚度有关，2) 静息状态下的fMRI连接性；以及3)疾病进展。拟议的项目具有很高的创新性，使用 TMS-EEG结合神经成像和神经生理学测量AD患者的局部皮质兴奋性 测量，并测试皮质兴奋性预测有意义的临床结果的程度。这 贡献将是巨大的，因为它将告诉我们对突触功能的测量如何 与AD的病理进展有关。这项研究的发现将为未来的临床奠定基础 阿尔茨海默病的试验寻求使用新的生物标志物来衡量神经元功能的恢复。 候选人对阿尔茨海默病的临床研究生涯有着坚定的承诺，并 相关痴呆症。她是贝丝以色列女执事医疗中心的执业认知神经学家， 哈佛医学院神经学讲师。她的培训计划和研究项目特别是 旨在积累她在AD生物标记物、高级神经成像技术和AD生物统计学方面的专业知识 临床试验。她的指导团队由丹尼尔·普莱斯博士和迈克尔·福克斯博士领导，将提供批判性指导 关于TMS测量与神经成像的整合。穆欣博士将提供额外的指导 Shafi博士研究TMS-EEG，Reisa Sperling博士研究AD生物标记物，Long Ngo博士研究生物统计学。完成 这项为期五年的职业发展计划将允许候选人以独立人士的身份开始职业生涯 研究人员使用新的神经生理学工具来改善AD的预后和治疗。