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

项目摘要/摘要 阿尔茨海默病(AD)是痴呆症的主要原因，目前在全球范围内呈上升趋势 缺乏有效的疾病修正治疗。一个可能缺失的环节是未能恢复正常的神经元 功能。脑电图法经颅磁刺激测量皮质兴奋性 (TMS-EEG)有可能通过测量神经元对受控扰动的反应来填补这一空白。 该项目的长期目标是确定大脑皮层兴奋性在多大程度上是重要的 AD的预后标记物和/或治疗靶点。这项研究评估了两个运动皮质的兴奋性。 特征性TMS部位和顶叶皮质-参与AD发病早期阶段的大脑 早期症状性AD患者队列(早期AD)。假设是增加的大脑皮层 顶叶皮质的兴奋性与神经退行性变有关，网络连接性降低，而且速度更快 临床表现下降。这将通过三个独立的目标进行测试，以评估皮质兴奋性如何与 1)局部皮质厚度；2)静息状态fMRI连接性；3)疾病进展。拟议中的项目 是高度创新的，使用TMS-EEG测量来捕捉AD患者的局部皮质兴奋性，整合 神经成像和神经生理学测量，并测试皮质兴奋性预测的程度 有意义的临床结果。这一贡献将是重要的，因为它将使我们了解 突触功能的测量如何与AD的疾病进展相关。这项研究将为下一步工作奠定基础 用于未来的AD临床试验，寻求使用新的生物标记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 相关的痴呆症和一个优秀的导师团队，包括Press博士、Fox博士、Shafi博士和Sperling博士。 她资助的为期5年的K23项目通过积累AD生物标志物的专业知识来支持她的职业发展， 先进的神经成像技术和临床试验的生物统计学。然而，在她23岁的第一年， 候选人在2021年10月25日经历了她的第一个孩子的出生，并休了3个月的假。这 补充奖励将抵消参与者招聘和与她的休假相关的计划课程工作的延误 不在的时候。该奖项还将帮助候选人克服在研究效率方面的挑战 由于家庭责任的增加，即将到来的一年。具体地说，该奖项将加快参与者的速度 招聘和数据分析，并加快提交稿件的速度。这将允许候选人 在1年补充期结束前恢复全部生产力，并为她申请奠定基础 在她23岁的第四年，从R01获得独立资金。这项补充奖将是 候选人正在进行的职业发展，因为她开始了使用NORITE作为独立调查员的职业生涯 促进AD预后和治疗的神经生理学工具。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the leading cause of dementia and is increasing worldwide, yet currently lacks effective disease-modifying treatments. 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. 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 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 disease progression in AD. 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 and an excellent mentorship team including Dr. Press, Dr. Fox, Dr. Shafi, and Dr. Sperling. Her funded 5-year K23 project supports her career development by building expertise in AD biomarkers, advanced neuroimaging techniques, and biostatistics for clinical trials. However, in the first year of her K23 the candidate experienced the birth of her first child on 10/25/2021 and took a 3-month leave of absence. This Supplemental Award will offset delays in participant recruitment and planned coursework related to her leave of absence. The Award will also help the candidate overcome challenges in research productivity during the upcoming year due to increased family responsibilities. Specifically, this Award will speed up participant recruitment and data analysis and increase the pace of manuscript submission. This will allow the candidate to return to full productivity by the end of the 1-year supplemental period and build the foundation for her to apply for independent funding from an R01 by Year 4 of her K23. This Supplemental Award will be integral to the candidate’s ongoing career development as she launches a career as an independent investigator using novel neurophysiologic tools to advance prognosis and treatment of AD.