Multimodal neuroimaging assessments of synaptic integrity: Linking pathology and cognition (Project 3)

摘要：项目3-突触功能 阿尔茨海默病(AD)认知功能障碍的近端原因是突触功能障碍和突触 损失。正如项目1和4中总结的那样，有一致的证据表明，淀粉样β蛋白(β)与 认知下降，仅有β是不够的，认知下降的速度是相当大的 异质的。因此，对突触完整性的评估对于将突触的有害影响联系起来至关重要。 AD和其他与年龄相关的病理，具有恢复力或认知能力下降的易感性。项目3的目标 是探索和建立我们对AD内突触完整性的理解和能力 通过创新的多模式正电子发射计算机断层扫描和核磁共振成像和定量，进一步扩展波谱范围。在目标1中，我们将 在我们之前关于静息状态功能连接的工作的基础上扩展和发展，重点放在相关的纵向 功能网络连通性的综合测量的变化与认知、β、tau或 调制因素(项目2)。在目标2中，我们将扩展和构建我们的多模式功能成像 通过包含和表征从 PIB示踪剂的洗入( PIB-R1)。结合FDG-PET和静息状态功能连接性MRI (RS-fcMRI)，我们将评估 PIB-R1是FDG的有用代理，如果 PIB-R1是一个信息量很大的 测量认知、分子病理或调节因素，以及PIB-R1是否可以控制血流 在其他功能成像方式中的影响。在目标3中，我们将超越现有的功能 措施，探索性地研究了一种新的突触成像放射性配基TARPγ8，调节性 AMPA受体的蛋白质，在海马区高表达。这是一个高风险，但潜在的高风险 奖励，目标，这是朝着更直接地评估突触完整性迈出的重要一步。利用子集 对于HABS参与者，我们将获得TARPγ8-PET成像，并评估TARPγ8-PET之间的关系 以及假设与突触功能障碍有关的指标(年龄、认知、海马体体积、FDG、 和功能磁共振成像)，以及阿尔茨海默病分子病理的PET测量。如果成功，TARPγ8-PET 成像将提供机会，将我们的功能成像测量从AIMS 1和AIMS 2与更多 直接的突触评估，并使我们能够更好地表征电流的程度和方式 功能成像测量反映了与AMPA受体信号相关的突触完整性。通过利用 HABS队列的丰富纵向特征，包括在前两个赠款周期收集的数据， 以及其他项目和核心的资源，项目3将重点关注突触完整性作为一种手段 弥合具有不同时间依赖性影响的病理标记物和认知之间的差距 以期为更好地了解脑老化和早期AD提供依据。

SUMMARY: PROJECT 3- SYNAPTIC FUNCTION The proximal cause of cognitive impairment in Alzheimer’s disease (AD) is synaptic dysfunction and synaptic loss. As summarized in Projects 1 and 4, there is consistent evidence that amyloid-beta (aβ) is associated with cognitive decline, that aβ alone is not sufficient, and that rates of cognitive decline are considerably heterogeneous . Consequently, assessment of synaptic integrity is pivotal for linking the deleterious effects of AD and other age related pathology with resilience or susceptibility to cognitive decline. The goal of Project 3 is to explore and build upon our understanding and capacity to assess synaptic integrity within the AD spectrum and beyond through innovative multimodal PET and MRI imaging and quantitation. In Aim 1, we will extend and build upon our prior work with resting state functional connectivity, focusing on relating longitudinal change in a composite measure of functional network connectivity to change in cognition, aβ, tau, or modulating factors (Project 2). In Aim 2, we will extend and build upon our multimodal functional imaging capabilities through inclusion and characterization of a proxy measure of relative blood flow derived from the wash-in of the PiB tracer ( PiB-R1). In conjunction with FDG-PET and resting state functional connectivity MRI (rs-fcMRI), we will evaluate whether PiB-R1 is a useful proxy for FDG, if change in PiB-R1 is an informative measure for cognition, molecular pathology, or modulating factors, and whether PiB-R1 can control for flow effects in other functional imaging modalities. In Aim 3, we will go beyond the available arsenal of functional measures, with an exploratory investigation of a new synaptic imaging radioligand for TARPγ8, the regulatory protein for AMPA receptors, that is highly expressed in hippocampus. This is a high risk, but potentially high reward, aim that is an important step towards a more direct assessment of synaptic integrity. Utilizing a subset of HABS participants, we will acquire TARPγ8-PET imaging and assess relationships between TARPγ8-PET and measures hypothesized to be related to synaptic dysfunction (age, cognition, hippocampal volume, FDG, and fMRI), as well as PET measures of Alzheimer’s disease molecular pathology. If successful, TARPγ8-PET imaging will provide an opportunity to compare our functional imaging measures from Aims 1 and 2 to a more direct synaptic assessment and allow us to better characterize the extent and manner in which current functional imaging measures reflect synaptic integrity related to AMPA receptor signaling. By leveraging the rich longitudinal characterization of the HABS cohort, including data collected during the first two grant cycles, and the resources of the other projects and cores, Project 3 will focus on synaptic integrity as a means to bridge the gap between pathological markers with heterogeneous time-dependent influences and cognitive decline in order to provide a better understanding of brain aging and early AD.