PET Imaging of Synaptic Density in Alzheimers Disease

项目总结/摘要 阿尔茨海默氏病（AD）在美国折磨着600万人，并且AD患者的数量将在2020年翻一番。 第2050章如果没有治愈AD的临床痴呆与β-淀粉样蛋白的独特病理学有关， 斑块、神经纤维缠结和突触丢失。突触对认知功能至关重要， 是AD认知障碍的主要结构相关因素。AD早期的一个事件 在发病机制中，在MCI前驱期的个体中可检测到突触失效。正电子发射 断层扫描（PET）成像越来越多地用于AD的研究，使用葡萄糖代谢示踪剂， 淀粉样蛋白和神经纤维缠结。然而，目前还没有直接成像的PET放射性配体， 突触密度在体内，这将是高效用的研究，以及在监测潜在的AD 治疗突触密度成像剂的一个合适的分子靶是突触囊泡 糖蛋白2（SV 2）是一种重要的囊泡膜蛋白，其亚型之一SV 2A广泛存在于囊泡中， 几乎在所有的突触中都有表达我们最近开发了11 C-UCB-J作为一种有前途的放射性配体， 用PET定量测量SV 2A。在我们对健康受试者进行的首次人体SV 2A PET试验研究中， 我们发现11 C-UCB-J有可能成为一种优秀的PET示踪剂，用于SV 2A的定量成像。 人脑，并可作为测量突触囊泡密度的通用工具。我们建议 将11 C-UCB-J与AD中的人体成像研究结合使用。在目标1中，我们将使用推注/输注定量SV 2A 在高分辨率研究断层扫描（HRRT）上提供，并检查AD中的SV 2A密度， 健康对照（HC）。我们假设11 C-UCB-J将揭示AD脑中SV 2A结合的减少， 一种可能不同于先前针对18F-FDG验证的皮质区域的模式。所有受试者也将 评估淀粉样蛋白状态，并确定总体淀粉样蛋白状态对SV 2A结合的影响。在 目的2，我们将比较SV 2A密度的组和个体差异与葡萄糖代谢的差异 用18F-FDG测量。对于2种示踪剂，将区域缺陷模式与HC进行比较。我们假设 与HC相比，AD中11 C-UCB-J特异性结合的降低幅度将大于 18F-FDG发现。此外，我们将关联突触密度和葡萄糖减少的幅度 代谢与神经心理测试表现。目的3比较组和个体差异， 从11 C-PIB到SV 2A-PET以及FDG-PET的淀粉样蛋白分布，预期 由11 C-UCB-J产生的突触丢失将不同于淀粉样PET，特别是在早期阶段， AD频谱总之，该项目将采取第一个关键步骤，以验证一种新的成像 用于AD和其他神经精神疾病研究的突触密度生物标志物。

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.