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

阿尔茨海默氏病 SV2A 和其他生物标志物的 PET 成像

• 批准号: 10404022
• 负责人: CHRISTOPHER H VAN DYCK
• 金额: $ 110.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404022
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Autopsy; Binding; Biological Markers; Brain; Brain region; Cells; Cognitive; Data; Dementia; Deposition; Development; Diagnostic; Disease; Disease model; Failure; Family history of; Funding; Future; Genetic; Genotype; Glucose; Glycoproteins; Hippocampus (Brain); Impaired cognition; Individual; Measures; Membrane Proteins; Methods; Molecular Target; Monitor; Neurofibrillary Tangles; Participant; Pathogenesis; Pathology; Patients; Pattern; Perforant Pathway; Positron-Emission Tomography; Protein Isoforms; Proteins; Regulation; Reproducibility; Research; Sampling; Scanning; Scientist; Senile Plaques; Symptoms; Synapses; Synaptic Vesicles; Therapeutic Trials; Tracer; Vesicle; abeta deposition; aged; cognitive ability; cohort; density; experience; first-in-human; fluorodeoxyglucose; glucose metabolism; high risk; hyperphosphorylated tau; in vivo; in vivo imaging; middle age; mild cognitive impairment; pre-clinical; presynaptic; prevent; sex; synaptic failure; tau Proteins; trafficking; uptake; virtual

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.

项目总结/摘要 阿尔茨海默病（AD）被称为突触失效。事实上，突触丢失是AD的一个突出病理学 和AD认知障碍的主要结构相关性。AD的特征在于独特的病理学， 由β淀粉样蛋白（A β）组成的斑块，由过度磷酸化的 tau蛋白和突触缺失。在AD的最早阶段观察到突触损伤，轻度认知功能障碍， 神经功能损害（MCI）患者表现出突触和几种突触前蛋白的损失。因此， 评估体内突触密度在AD研究以及监测潜在治疗中具有很高的实用性。 正电子发射断层扫描（PET）成像越来越多地用于AD研究，以测量葡萄糖 代谢（18 F-氟脱氧葡萄糖，18 F-FDG）、A β和NFT。然而，新分子靶点的示踪剂 来直接监测突触密度的损失。一个合适的靶点是突触囊泡糖蛋白 2（SV2），一种必需的囊泡膜蛋白。它的一种亚型SV2A，广泛表达于 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，一种用于定量SV2A体内成像的PET示踪剂， 这是首次在人体内进行的研究，已显示出高脑摄取率和出色的可重复性。我们的初步 在早期AD中使用11C-UCB-J的经验表明，海马SV2A显著降低（44%）， 结合，符合内嗅皮层（ERC）细胞的早期变性，这些细胞投射到 海马（通过穿通路径）和海马SV2A减少在死后研究中观察到。 然而，我们迫切需要将突触密度与11C-UCB-J与AD发病机制的其他标志物（在AD发病机制中）联系起来。 特别是tau沉积），并将突触丢失的研究扩展到早期临床前阶段。 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：在症状性AD患者中研究SV2A结合的相关性（使用11 C-UCB-J） 使用tau沉积（使用18F-MK6240）。 目的2：探讨认知功能正常（CN）的中年人中家族性和遗传性AD风险的关系 具有：a）海马SV2A结合和B）ERC-tau沉积的个体。 目的3：探讨SV2A结合与A β及tau蛋白沉积在认知功能障碍中的关系。 不同AD风险的正常中年人。 突触密度的体内评估将使得能够研究突触损失的早期出现和突触损伤的发生。 将这些信息与其他疾病生物标志物（包括A β和tau沉积）整合， 更全面的疾病模型。