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.

项目摘要/摘要 阿尔茨海默氏病（AD）被称为突触失败。确实，突触损失是一种突出的AD病理 以及AD认知障碍的主要结构相关。广告的特征是一种独特的病理， 由淀粉样蛋白β（Aβ）组成的斑块，由过度磷酸化的神经纤维缠结（NFTS）组成 tau和突触丧失。在AD的最早阶段观察到突触损伤，具有轻度认知 损伤（MCI）患者表现出突触损失和几种突触前蛋白质。那，能力 评估体内突触密度在AD研究以及监测潜在疗法方面具有很高的效用。 正电子发射断层扫描（PET）成像越来越多地用于测量葡萄糖 代谢（18F-氟脱氧葡萄糖，18F-FDG），Aβ和NFTS。但是，新分子靶标的示踪剂 需要直接监视突触密度的丧失。一个合适的目标是合成囊泡糖蛋白 2（SV2），一种必需的囊泡膜蛋白。它的同工型之一SV2A无处不在 几乎所有的突触都参与了突触贩运的调节。 我们最近开发了11C-UCB-J，这是一种用于体内定量SV2A成像的宠物示踪剂，并进行了 首先是人类研究，这些研究表明大脑的吸收高和出色的可重复性。我们的初步 早期AD中11C-UCB-J的经验显示海马SV2A的显着降低（44％） 结合，与投影到 海马（通过穿孔路径）和海马SV2A在死后研究中观察到。 但是，我们至关重要的是将突触密度与11C-UCB-J与AD发病机理的其他标记相关联（在 特别是Tau沉积）并将突触损失的研究扩大到最早的（预先统一的）阶段 疾病，使用已建立的队列。这是我们提出以下具体目标： 目标1：在有症状的AD的个体中调查SV2A结合的关联（使用11C-UCB-J） 使用Tau沉积（使用18F-MK6240）。 目的2：研究家庭和遗传AD风险在认知正常（CN）中年的关联 患者：a）海马SV2A结合和b）ERC-TAU沉积。 目标3：研究SV2A结合与Aβ之间的关联，以及在认知上的TAU沉积 正常的中年人处于不同的AD风险。 突触密度的体内评估将使突触损失的早期出现和 将此信息与其他疾病的生物标志物（包括Aβ和TAU沉积）整合在一起，提供了A 疾病的更全面模型。