Quantitative Neuropathological Correlates of In Vivo PiB Retention

项目概述（见说明）：使用匹兹堡化合物b （PiB）进行正电子发射断层扫描（PET）成像，可提供活体受试者淀粉样蛋白病理区域图，有助于阿尔茨海默病（AD）的临床诊断。了解体内PiB PET保留模式与导致PiB保留的潜在病理负担之间的关系是验证PiB作为AD生物标志物的必要条件。先前的PiB与合成p-淀粉样蛋白（AP）肽结合的体外研究和AD受试者的尸检脑组织表明，PiB PET保留可能反映了PiB与斑块和脑血管系统中AB聚集体的结合。我们最近对阿尔茨海默病的临床病理研究支持了这一观点。然而，PiB PET信号在多大程度上反映认知正常、MCI和AD受试者的神经病理变化，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区域突触丧失（AD痴呆的最佳结构相关性），以及这如何受到脑血管病理（AD发展的重要因素）的影响，目前尚不清楚。随着越来越多的PiB PET成像对象进入尸检，我们现在可以解决这些重要问题。我们建议从三个方面来深入了解这些问题。首先，我们将从PiB PET扫描对象的死后脑组织中表征PiB的结合底物，以确定AD病理的类型和阈值水平，这是在体内产生PiB PET阳性信号所必需的。我们将对具有不同临床诊断的受试者的脑组织进行尸检，这些脑组织在匹兹堡大学的先前和当前的PPG（项目4和5）以及其他合作的PiB-PET成像中心进行成像。在本提案的第二部分，我们将对突触标记进行死后评估，并将它们与死前记录的区域匹配的PiB PET和FDG PET水平相关联（项目4和5）。该提案的第三部分将研究在死后和体内（项目4和5）确定的血管病变对同一受试者区域突触变化模式和AB斑块负荷的影响程度。这些尸检研究将补充项目4和项目5中的临床影像学和神经心理学分析；在为影响PiB PET信号的AB和血管病理负担提供更深入的了解的同时，它们将确保一个独特的组织来源，用于PiB PET成像的神经病理相关研究。

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.