Quantitative Neuropathological Correlates of In Vivo PiB Retention

项目摘要(参见说明)：使用匹兹堡化合物B(PIB)的正电子发射断层扫描(PET)成像提供了活体受试者淀粉样蛋白病理的区域地图，可以辅助阿尔茨海默病(AD)的临床诊断。了解体内PIB PET滞留模式与导致PIB滞留的潜在病理负担之间的关系，对于验证PIB作为AD的生物标志物是必要的。先前对PIB与合成β-淀粉样蛋白(AP)多肽和AD患者尸检脑组织的体外结合研究表明，PIB PET滞留可能反映了PIB与斑块和脑血管中AB聚集体的结合。这一观点得到了我们最近对AD的临床病理研究的支持。然而，PIB PET信号在多大程度上反映了认知正常、MCI和AD患者的神经病变，以及体内PIB PET信号阳性所需的AB负荷仍有待确定。此外，PIB PET保留模式在多大程度上反映了局部突触丢失(AD痴呆的最佳结构相关性)，以及脑血管病理(AD的一个重要贡献因素)如何影响这一点目前尚不清楚。随着越来越多的PIB PET成像对象来尸检，我们现在可以解决这些重要的问题。我们建议通过三种方式来洞察这些问题。首先，我们将鉴定PIB PET扫描受试者死后脑组织中PIB的结合底物，以确定在体内产生阳性PIB PET信号所必需的AD病理的类型和阈值水平。我们将在匹兹堡大学以前和现在的PPG(项目4和5)以及其他合作的PIB-PET成像中心对具有不同临床诊断的受试者的尸检脑组织进行成像。在这项建议的第二部分，我们将对突触标志物进行死后评估，并将它们与生前记录的区域匹配的PIB和FDG PET水平相关联(项目4和5)。这项建议的第三部分将调查死后和在体确定的血管损伤(项目4和5)对同一受试者局部突触变化和AB斑块负荷的影响程度。这些尸检研究将补充项目4和5中的临床成像和神经心理学分析；在提供对影响PIB PET信号的AB和血管病理负担的更深入了解的同时，它们将确保获得一个独特的组织来源，用于本次和未来对PIB PET成像的神经病理相关性的研究。

PROJECT SUMMARY (See instructions): Positron emission tomography (PET) imaging using Pittsburgh Compound-B (PiB) provides a regional map of amyloid pathology in living subjects and can assist clinical diagnosis of Alzheimer's disease (AD). Understanding the relationship between PiB PET retention patterns in vivo and the underlying pathological burden responsible for PiB retention is necessary to validate PiB as a biomarker in AD. Previous in vitro studies of PiB binding to synthetic p-amyloid (AP) peptide and autopsy brain tissues from AD subjects indicated that PiB PET retention likely reflects PiB binding to AB aggregates in plaques and cerebral vasculature. This idea is supported by our recent clinical-pathological study of AD. However the degree to which PiB PET signal is reflective of neuropathological changes in cognitively normal, MCI, and AD subjects, as well as the AB burden required for positive PiB PET signal in vivo remains to be determined. Furthermore, the degree to which regional synapse loss (the best structural correlate of AD dementia) is reflected by PiB PET retention patterns, and how this is influenced by cerebral vascular pathology (a significant contributor to the development of AD) is currently unknown. With increasing numbers of PiB PET imaged subjects coming to autopsy, we can now address these important issues. We propose to gain insight into these questions in three ways. First, we will characterize PiB's binding substrates in postmortem brain tissues from PiB PET scanned subjects, to determine the type and threshold level of AD pathology which is necessary to produce a positive PiB PET signal in vivo. We will do this in autopsy brain tissues from subjects with different clinical diagnoses, imaged in the previous and current PPG (Projects 4 and 5) at the University of Pittsburgh as well as in other collaborating PiB-PET imaging centers. In the second part of this proposal, we will perform postmortem assessment of synaptic markers and correlate them with region-matched PiB PET and FDG PET levels recorded antemortem (Projects 4 and 5). The third part of this proposal will investigate the extent to which vascular lesions, determined both postmortem and in vivo (Projects 4 and 5), influence the patterns of regional synapse changes and AB plaque load in the same subjects. These autopsy studies will complement clinical imaging and neuropsychological analyses in Projects 4 and 5; while providing greater insight into the AB and vascular pathology burden that influences PiB PET signal, they will secure a unique source of tissues to be utilized in this and future studies of neuropathological correlates of PiB PET imaging.