PET Imaging of Synaptic Density in Alzheimers Disease

项目摘要/摘要 阿尔茨海默病(AD)在美国困扰着600万人，到2019年，AD患者的数量将翻一番。 2050如果找不到治愈方法。阿尔茨海默病的临床痴呆与一种独特的病理有关，即β-淀粉样蛋白 斑块、神经原纤维缠结和突触丢失。突触对认知功能是必不可少的，它们的丧失 是阿尔茨海默病认知损害的主要结构性相关因素。公元一年的早期事件 发病机制方面，在MCI的前驱期个体中可检测到突触衰竭。正电子发射 断层扫描成像越来越多地应用于AD的研究，使用葡萄糖代谢的示踪剂，- 淀粉样蛋白和神经原纤维缠结。然而，目前还没有直接成像的PET放射性配体 体内突触密度，这将在AD的研究以及监测潜力方面具有很高的实用价值 治疗。突触密度显像剂的一个合适的分子靶点是突触小泡 糖蛋白2(SV2)是一种重要的囊泡膜蛋白，其亚型之一SV2a广泛存在 几乎在所有突触中都有表达。我们最近开发了11C-UCB-J作为一种很有前途的放射性配体 用正电子发射体层析(PET)定量测定SV2A。在我们对健康受试者进行的首个人类SV2APET研究中， 我们发现11C-UCB-J有可能成为一种优秀的PET示踪剂，用于SV2A的定量成像。 可以作为测量突触小泡密度的通用工具。我们建议 在AD患者中应用11C-UCB-J进行人体成像研究。在目标1中，我们将使用推注/输液来量化SV2A 进行高分辨率研究断层扫描(HRRT)并检测AD患者的SV2A密度 健康对照组(HC)。我们假设11C-UCB-J将显示AD脑中SV2A结合减少 这种模式可能不同于先前验证的18F-FDG的皮质区域。所有科目也将 评估淀粉样蛋白状态，并确定整体淀粉样蛋白状态对SV2A结合的影响。在……里面 目的2，我们将比较群体和个体在SV2A密度上的差异与葡萄糖代谢的差异 18F-FDG测量。两个示踪剂的区域赤字模式将与HC进行比较。我们假设 与HC相比，AD中11C-UCB-J的特异性结合减少的幅度将大于HC 在18F-FDG中发现。此外，我们将把突触密度降低的幅度与血糖联系起来。 新陈代谢与神经心理测试表现。目标3比较了群体和个体在 从11C-PIB到SV2A-PET以及FDG-PET的淀粉样蛋白分布，预计 11C-UCB-J引起的突触丢失将不同于淀粉样蛋白PET，特别是在早期阶段 AD频谱。总而言之，该项目将采取第一个关键步骤来验证新的成像 突触密度的生物标记物，用于AD和其他神经精神障碍的研究。

Project Summary/Abstract Alzheimer's disease (AD) afflicts 6 million people in the USA, and the number of AD patients will double by 2050 if no cure is identified. The clinical dementia of AD is coupled to a distinct pathology, with β-amyloid plaques, neurofibrillary tangles, and synaptic loss. Synapses are essential for cognitive function, and their loss is well established as the major structural correlate of cognitive impairment in AD. An early event in AD pathogenesis, synaptic failure is detectable in individuals with the prodromal stage of MCI. Positron Emission Tomography (PET) imaging is increasingly employed in studies of AD, using tracers for glucose metabolism, - amyloid, and neurofibrillary tangles. However, currently, there are no PET radioligands that directly image synaptic density in vivo, which would be of high utility in studies of AD as well as in monitoring potential therapies. One suitable molecular target for a synaptic density imaging agent is the synaptic vesicle glycoprotein 2 (SV2), an essential vesicle membrane protein, with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. We recently developed 11C-UCB-J as a promising radioligand for quantitative measurement of SV2A with PET. In our pilot first-in-human SV2A PET studies in healthy subjects, we found that 11C-UCB-J has the potential to be an excellent PET tracer for quantitative imaging of SV2A in the human brain, and can act as a general-purpose tool for measuring synaptic vesicle density. We propose to apply 11C-UCB-J with human imaging studies in AD. In Aim 1, we will quantify SV2A using bolus/infusion delivery on the High Resolution Research Tomography (HRRT) and examine SV2A density in AD compared to healthy controls (HC). We hypothesize that 11C-UCB-J will reveal decreased SV2A binding in the AD brain with a pattern that may differ from the cortical regions previously validated for 18F-FDG. All subjects will also be evaluated for amyloid status and the effect of overall amyloid status on SV2A binding will be determined. In Aim 2, we will compare group and individual differences in SV2A density to differences in glucose metabolism measured with 18F-FDG. Regional patterns of deficits will be compared to HC for the 2 tracers. We hypothesize that the magnitude of reduction in specific binding of 11C-UCB-J in AD compared to HC will be greater than that found with 18F-FDG. Further, we will correlate the magnitude of reduction in synaptic density and glucose metabolism with neuropsychological test performance. Aim 3 compares the group and individual differences in amyloid distribution from 11C-PIB to SV2A-PET as well as FDG-PET, with the expectation that patterns of synaptic loss produced by 11C-UCB-J will differ from that of amyloid PET, particularly in the earlier phases of the AD spectrum. In summary, this project will take the first critical steps to validating a novel imaging biomarker of synaptic density for studies in AD and other neuropsychiatric disorders.