PET Imaging of SV2A and Other Biomarkers in Alzheimer's Disease

项目摘要/摘要 阿尔茨海默病(AD)被称为突触衰竭。事实上，突触丢失是AD的一种突出病理 阿尔茨海默病认知损害的主要结构相关因素。AD的特征是一种独特的病理， 斑块由淀粉样蛋白-β(Aβ)、神经原纤维缠结(NFT)组成 Tau和突触丢失。突触损害见于AD的早期阶段，伴有轻度认知障碍 表现为突触和几种突触前蛋白丢失的损害(MCI)患者。因此，有能力 评估体内突触密度对AD的研究以及监测潜在的治疗方法具有很高的实用价值。 正电子发射断层扫描(PET)成像在AD研究中越来越多地用于测量血糖 代谢(18F-脱氧葡萄糖、18F-脱氧葡萄糖)、A-β和NFT。然而，新分子靶标的示踪剂 是直接监测突触密度丢失所必需的。一个合适的靶点是突触小泡糖蛋白。 2(SV2)，是一种必需的囊泡膜蛋白。它的一个亚型，SV2a，普遍表达在 几乎所有的突触，并参与调节突触运输。 我们最近开发了11C-UCB-J，一种用于体内SV2A定量成像的PET示踪剂，并进行了 这是第一项人类研究，显示出大脑的高摄取率和极好的重复性。我们的预赛 在AD早期使用11C-UCB-J的经验表明，海马区SV2a的表达显著减少(44%) 结合，与内嗅皮层(ERC)细胞的早期退化一致，ERC细胞投射到 在尸检研究中观察到海马区(通过穿通径)和海马区SV2a减少。 然而，我们迫切需要将11C-UCB-J的突触密度与AD发病机制的其他标记物(in 特别是tau沉积)，并将突触丢失的研究扩大到临床前的早期阶段。 疾病，使用已建立的队列。因此，我们提出以下具体目标： 目的1：研究症状性AD患者中SV2A结合(使用11C-UCB-J)的相关性 使用tau沉积(使用18F-MK6240)。 目的2：探讨认知正常(CN)中年人家族性和遗传性AD风险的关系 有：a)海马区SV2a结合和b)ERC-tau沉积的个体。 目的3：研究Sv2a结合与Aβ的关系以及Tau在认知中的沉积 具有不同AD风险的正常中年个体。 对突触密度的活体评估将有助于研究突触丢失的早期出现和 将这些信息与疾病的其他生物标志物，包括Aβ和tau沉积相结合，提供了 更全面的疾病模型。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) has been called a synaptic failure. Indeed, synaptic loss is a prominent AD pathology and the major structural correlate of cognitive impairment in AD. AD is characterized by a distinct pathology, with plaques composed of amyloid-β (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, and a loss of synapses. Synaptic damage is observed in the earliest stages of AD, with Mild Cognitive Impairment (MCI) patients demonstrating a loss of synapses and several presynaptic proteins. Thus, the ability to assess synaptic density in vivo is of high utility in studies of AD as well as in monitoring potential therapies. Positron Emission Tomography (PET) imaging is increasingly employed in AD studies to measure glucose metabolism (18F-fluorodeoxyglucose, 18F-FDG), Aβ, and NFTs. However, tracers for new molecular targets are needed to directly monitor loss of synaptic density. One suitable target is the synaptic vesicle glycoprotein 2 (SV2), an essential vesicle membrane protein. One of its isoforms, SV2A, is ubiquitously expressed in virtually all synapses and is involved in regulation of synaptic trafficking. We recently developed 11C-UCB-J, a PET tracer for quantitative SV2A imaging in vivo and carried out the first-in-human studies, which have shown high brain uptake and excellent reproducibility. Our preliminary experience with 11C-UCB-J in early AD has demonstrated significant reductions (44%) in hippocampal SV2A binding, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to the hippocampus (via the perforant path) and hippocampal SV2A reductions observed in postmortem studies. However, we critically need to relate synaptic density with 11C-UCB-J to other markers of AD pathogenesis (in particular, tau deposition) and to expand the study of synaptic loss to the earliest—preclinical—stages of disease, using an established cohort. Thus, we propose the following Specific Aims: Aim 1: To investigate in individuals with symptomatic AD the association of SV2A binding (using 11C-UCB-J) with tau deposition (using 18F-MK6240). Aim 2: To investigate the association of familial and genetic AD risk in cognitively normal (CN) middle-aged individuals with: a) hippocampal SV2A binding and b) ERC-tau deposition. Aim 3: To investigate the associations between SV2A binding and Aβ, as well as tau deposition in cognitively normal middle-aged individuals at varying AD risk. In vivo assessment of synaptic density will enable the study of the early emergence of synaptic loss and the integration of this information with other biomarkers of disease, including Aβ and tau deposition, providing a more comprehensive model of disease.