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

突触完整性的多模式神经影像评估：病理学和认知的联系（项目 3）

• 批准号: 10541813
• 负责人: Aaron P Schultz
• 金额: $ 46.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541813
• 关键词: AMPA Receptors; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Blood flow; Brain; Brain imaging; Cerebrovascular Circulation; Cognition; Cognitive; Data; Dementia; Development; Disease; Evaluation; Excision; Exhibits; Face; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Grant; Health; Hippocampus; Image; Impaired cognition; Investigation; Kinetics; Link; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Metabolic; Names; Neurons; Outcome; Participant; Pathologic; Pathology; Pattern; Physical activity; Positron-Emission Tomography; Predisposition; Property; Proteins; Proxy; Receptor Signaling; Regulation; Resources; Rest; Risk; Rotation; Scanning; Signal Transduction; Source; Synapses; System; Testing; Time; Tracer; Visual; Work; actigraphy; age effect; age related; aged; aging brain; cardiovascular risk factor; cohort; effective intervention; effective therapy; expectation; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; formycin triphosphate; genetic regulatory protein; high reward; high risk; imaging capabilities; imaging modality; improved; innovation; molecular pathology; multimodal neuroimaging; multimodality; neural network; novel; pedometer; preservation; radioligand; resilience; synaptic function; tau Proteins; tau-1

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.

总结：项目3-突触功能 阿尔茨海默病（AD）认知功能障碍的最接近的原因是突触功能障碍和突触 损失正如项目1和4中所总结的，有一致的证据表明淀粉样蛋白β（aβ）与 认知能力下降，仅aβ是不够的，认知能力下降的速度相当大， 异质的因此，突触完整性的评估是关键的联系的有害影响， AD和其他年龄相关的病理，具有恢复力或对认知下降的易感性。项目3的目标 是探索和建立在我们的理解和能力，以评估突触完整性内的AD 通过创新的多模式PET和MRI成像和定量技术，在目标1中，我们 扩展并建立在我们先前关于静息状态功能连接的工作基础上，专注于将纵向 功能网络连接性的复合测量值的变化与认知变化、aβ、tau或 调节因子（项目2）。在目标2中，我们将扩展并建立在我们的多模态功能成像基础上 通过纳入和表征来自于 1998年，《中国共产党章程》（ PiB-R1）。结合FDG-PET和静息状态功能连接MRI （rs-fcMRI），我们将评估是否 PiB-R1是一个有用的FDG代理，如果改变， PiB-R1是一个信息丰富的 测量认知，分子病理学或调节因素，以及PiB-R1是否可以控制流量 其他功能成像模式的影响。在目标3中，我们将超越现有的功能性 测量，探索性研究TARPγ8的新突触成像放射性配体，调节 AMPA受体蛋白，在海马体中高度表达。这是一个高风险，但潜在的高 奖励，目标，这是朝着更直接评估突触完整性迈出的重要一步。利用子集 的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相关的测量（年龄、认知、海马体积、FDG， 和fMRI），以及阿尔茨海默病分子病理学的PET测量。如果成功，TARPγ8-PET 成像将提供一个机会，比较我们的功能成像措施，从目标1和2， 直接的突触评估，使我们能够更好地表征电流的程度和方式， 功能成像测量反映与AMPA受体信号传导相关的突触完整性。通过利用 对HABS队列进行了丰富的纵向描述，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将专注于突触完整性， 弥合具有异质性时间依赖性影响的病理标志物与认知之间的差距 下降，以便更好地了解大脑老化和早期AD。