SV2A PET imaging in Alzheimer's Disease

摘要 突触丢失是症状性阿尔茨海默病（AD）的主要特征。新型正电子发射断层扫描 (PET)已经开发了结合突触囊泡糖蛋白2A（SV 2A）的放射性配体， 在整个大脑的突触前神经末梢中发现的囊泡蛋白。虽然这些示踪剂的开发是 虽然这是AD领域的一个重大进展，但在临床和病理学上对突触丢失知之甚少。 目前缺乏对AD谱的研究和大型队列的纵向研究。为了弥补这一知识差距， 我们建议对从研究中心招募的受试者进行[C-11]UCB-J纵向SV 2A PET成像。 威斯康星州阿尔茨海默病研究中心。样本将包括认知未受损的AD生物标志物 阴性受试者、认知未受损生物标志物阳性受试者、轻度认知功能障碍受试者 （MCI）和AD所致痴呆的参与者。参与者将在基线和两个- 年的后续。假设区域性突触丢失将作为一个敏感的标记， 在斑块和缠结积累的背景下，神经变性，并将解释认知能力下降。为了 为了解决这一假设，我们提出了以下三个具体目标：1）确定[C- 11]UCB-J提供了来自MRI的关于神经变性的独特信息; 2）确定突触的速率， [C-11]UCB-J信号反映的损失;和3）确定[C-11]UCB-J与 认知能力下降除[C-11]UCB-J PET外，我们还将采集[C-11]PIB PET以确定空间淀粉样蛋白 噬菌斑负荷以及[F-18] MK 6240 PET以确定tau缠结负荷。这项研究将是第一个获得 这三个标志物的串联，这将允许-第一次-的能力，以确定如何这些病理 在AD中进化，并确定它们如何在空间和时间上相互关联。国家研究所 一项关于衰老的研究称SV 2A PET成像是“AD和AD相关疾病中潜在的改变游戏规则的生物标志物”。 痴呆症”。突触丢失预计与认知能力下降最密切相关，但没有大的 人类研究已经开始检查AD谱系中的区域突触损失。的 拟议的项目解决了这一知识差距。这项研究计划可望早日改进 AD的检测，改善认知功能下降的预测，并为新的治疗策略的开发提供信息。

ABSTRACT Synaptic loss is a major feature of symptomatic Alzheimer’s disease (AD). New positron emission tomography (PET) radioligands have been developed which bind to synaptic vesicle glycoprotein 2A (SV2A), a synaptic vesicle protein found in presynaptic nerve terminals throughout the brain. While development of these tracers is a major advance for the field of AD, very little is yet known about synapse loss across the clinical and pathological spectrum of AD, and longitudinal studies in large cohorts are lacking. In order to address this gap in knowledge, we propose to perform longitudinal SV2A PET imaging with [C-11]UCB-J in participants recruited from the Wisconsin Alzheimer’s Disease Research Center. The sample will include cognitively unimpaired AD biomarker negative participants, cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will be imaged at baseline and at two- year follow-up. The hypothesis is that regional synaptic loss will serve as a sensitive marker of neurodegeneration in the context of plaque and tangle accumulation and will explain cognitive decline. In order to address this hypothesis, we propose the following three specific aims: 1) determine the extent to which [C- 11]UCB-J provides unique information from MRI regarding neurodegeneration; 2) determine the rate of synapse loss as reflected by [C-11]UCB-J signal; and 3) determine the extent to which [C-11]UCB-J associates with cognitive decline. In addition to [C-11]UCB-J PET, we will acquire [C-11]PIB PET to determine spatial amyloid plaque burden, as well as [F-18]MK6240 PET to determine tau tangle burden. This study will be the first to obtain these three markers in tandem, which will allow—for the first time—the ability to determine how these pathologies evolve in AD, and determine how they are spatially and temporally related to one another. The National Institute on Aging has called SV2A PET imaging a “potentially game-changing biomarker in AD and AD-related dementias”. Synapse loss is expected to be the most closely associated with cognitive decline, yet no large human studies have yet been undertaken to examine regional synapse loss across the spectrum of AD. The proposed project addresses this gap in knowledge. This program of research is expected to improve early detection of AD, improve prediction of cognitive decline, and inform the development of new treatment strategies.