Quantitative Neuropathological Correlates of In Vivo PiB Retention

体内 PiB 保留的定量神经病理学相关性

• 批准号: 8572482
• 负责人: WILLIAM E KLUNK
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8572482
• 关键词: Address; Alzheimer' s Disease; Amyloid; Atherosclerosis; Autopsy; Binding; Biochemistry; Biological Markers; Blood Vessels; Cerebrum; Clinical; Complement; Dementia; Detection; Development; Diagnosis; Diagnostic Imaging; Enzyme-Linked Immunosorbent Assay; Future; Goals; Histologic; Histology; Image; Immunohistochemistry; In Vitro; Infarction; Instruction; Lesion; Life; Maps; Measures; Metabolism; Monitor; Pathology; Pattern; Peptides; Pittsburgh Compound-B; Positron-Emission Tomography; Secure; Signal Transduction; Source; Synapses; Tissues; Universities; Validation; Variant; Vascular Diseases; amyloid imaging; amyloid pathology; brain tissue; clinical Diagnosis; density; in vivo; insight; neuropsychological; research clinical testing; white matter

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.

项目总结（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学的区域图，可以辅助阿尔茨海默病（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）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。这一想法得到了我们最近对AD的临床病理学研究的支持。然而，PiB PET信号反映认知正常、MCI和AD受试者的神经病理学变化的程度，以及体内阳性PiB PET信号所需的AB负荷仍有待确定。此外，PiB PET保留模式反映区域突触丢失（AD痴呆的最佳结构相关性）的程度，以及这如何受到脑血管病理学（AD发展的重要贡献者）的影响，目前尚不清楚。随着越来越多的PiB PET成像受试者进行尸检，我们现在可以解决这些重要问题。我们建议从三个方面深入了解这些问题。首先，我们将描述PiB PET扫描受试者死后脑组织中PiB的结合底物，以确定体内产生阳性PiB PET信号所需的AD病理类型和阈值水平。我们将在具有不同临床诊断的受试者的尸检脑组织中进行这项工作，这些脑组织在匹兹堡大学以及其他合作的PiB-PET成像中心的先前和当前PPG（项目4和5）中成像。在本提案的第二部分，我们将进行突触标记物的死后评估，并将其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）。本建议的第三部分将调查在何种程度上血管病变，确定死后和在体内（项目4和5），影响区域突触的变化和AB斑块负荷在同一主题的模式。这些尸检研究将补充项目4和项目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和血管病理学负担的更深入了解的同时，它们将确保在PiB PET成像的神经病理学相关性的本次和未来研究中使用的独特组织来源。