Examining the dynamic and metabolic underpinnings of functional connectivity in preclinical Alzheimer's disease

项目总结 阿尔茨海默病(AD)病理对大脑功能的影响尚不完全清楚， 尤其是在疾病的早期阶段，在广泛的突触和神经元丧失之前，当认知 功能在很大程度上仍然保持不变。该R21探索性项目的目标是调查AD的影响 临床特征良好的正常受试者的脑代谢(FDG-PET)病理等 功能连接(FcMRI)，利用哈佛衰老大脑研究(HABS)的参与者。我们是 寻找神经元功能紊乱导致与以下疾病相关的多动期的具体证据 FDG信号增强和功能一致性增强，与兴奋性毒性的预测一致 阿尔茨海默病分子病理学对神经元过度活动的假说。我们还专注于协会 FDG和fcMRI之间的关系，以更好地了解这些突出功能成像之间的关系 医疗模式。这个项目有三个组成部分，它们将利用和加强当前的研究工作。 1)同时采集FDG功能磁共振成像，这将是将功能测量捆绑在一起的关键 连接性(FMRI)和代谢(FDG)。2)长时间的fcMRI收购，这对调查至关重要 动态功能连接。3)受限的行为状态，这将引入一种度量 了解大脑连通性和脑动力学变化的实验对照 不受约束的休眠状态。这些独特的数据，再加上之前对淀粉样蛋白-PET，tau-PET， 而广泛的临床和神经心理学评估将使我们能够更仔细地询问 与AD分子病理学相关的代谢活性、功能连接性和连接性动力学。 我们的目标是更好地了解过度连接是否与脑内代谢活动增加有关 具有临床前阿尔茨海默病生物标志物证据的个人。这一总体目标的一个重要扩展是 受限和非受限行为状态下的功能动力学研究以及 受限和非受限行为在连通性和动力学方面的对比差异 各州。我们的中心论点是AD的早期分子病理与FDG升高有关 新陈代谢，这将与动态灵活性的丧失有关，这将表现为增加 连接强度；我们假设当参与者处于 受限的认知状态。该项目将生成一个信息量很大的数据集，将指导未来 研究方向，并为临床试验中功能成像的实施和解释提供信息。这 探索性研究将有助于指明约束状态fcMRI的前进方向，告知FDG 与连接影响有关或有助于将连接影响与上下文联系起来，并为有关函数读数的预测提供信息 阿尔茨海默病不同进展阶段临床试验中介入治疗的影像反应。

PROJECT SUMMARY The consequences of Alzheimer’s disease (AD) pathology on brain function are not fully understood, particularly in earlier stages of disease, prior to widespread synaptic and neuronal loss, when cognitive function is still largely maintained. The goal of this R21 exploratory project is to investigate the effect of AD pathology in well-characterized clinically normal participants on brain metabolism (FDG-PET), and on functional connectivity (fcMRI), utilizing participants from the Harvard Aging Brain Study (HABS). We are looking for specific evidence of disrupted neuronal function resulting in a phase of hyperactivity associated with both elevated FDG signal and increased functional coherence, consistent with predictions from the excitotoxic hypothesis of induced neuronal hyperactivity by AD molecular pathology. We also focus on associations between FDG and fcMRI to better understand the relationships between these prominent functional imaging modalities. There are three components to this project that will leverage and augment current research efforts. 1) Simultaneous FDG fMRI acquisition, which will be critical for tying together measures of functional connectivity (fMRI) and metabolism (FDG). 2) Long fcMRI acquisitions, which are essential for investigating dynamic functional connectivity. 3) Constrained behavioral state, which will introduce a measure of experimental control for understanding changes in brain connectivity and in brain dynamics as compared to unconstrained resting state. These unique data, coupled with prior assessment with amyloid-PET, tau-PET, and extensive clinical and neuropsychological assessment will allow us to more carefully query links between metabolic activity, functional connectivity, and connectivity dynamics with respect to AD molecular pathology. Our goal is to better understand whether hyperconnectivity is associated with elevated metabolic activity in individuals with biomarker evidence of preclinical AD. An important extension of that general goal is the investigation of functional dynamics within constrained and unconstrained behavioral states as well as contrastive differences in connectivity and dynamics between constrained and unconstrained behavioral states. Our central thesis is that early stage AD molecular pathology will be associated with elevated FDG metabolism, which will be associated with a loss of dynamic flexibility, which will manifest as increased connectivity strength; and we hypothesize that these effects will be accentuated when participants are in a constrained cognitive state. This project will generate a highly informative dataset that will guide future research directions and inform the implementation and interpretation of functional imaging in clinical trials. This exploratory study will help point the way forward for constrained state fcMRI, inform the degree to which FDG relates to or helps contextualize connectivity effects, and inform predictions regarding the readout of functional imaging response to interventional treatment in clinical trials across different stages of AD progression.