SV2A PET imaging in Alzheimer's Disease

摘要 突触丧失是有症状的阿尔茨海默病 (AD) 的一个主要特征。新型正电子发射断层扫描 (PET) 放射性配体已被开发出来，可与突触小泡糖蛋白 2A (SV2A) 结合，突触小泡糖蛋白 2A (SV2A) 是一种突触小泡糖蛋白。 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正在 这是 AD 领域的一项重大进展，但我们对临床和病理过程中的突触丢失知之甚少。 AD 的谱系和大型队列的纵向研究都缺乏。为了弥补这一知识差距， 我们建议对从 [C-11]UCB-J 招募的参与者进行纵向 SV2A PET 成像 威斯康星州阿尔茨海默病研究中心。该样本将包括认知未受损的 AD 生物标志物 阴性参与者、认知未受损的生物标志物阳性参与者、轻度认知的个体 损伤（MCI），以及因 AD 导致痴呆的参与者。参与者将在基线和两次时进行成像 年随访。假设区域突触丢失将作为一个敏感标记 斑块和缠结堆积背景下的神经退行性变将解释认知能力下降。按顺序 为了解决这个假设，我们提出以下三个具体目标：1）确定[C- 11]UCB-J 提供来自 MRI 的有关神经退行性变的独特信息； 2）确定突触率 [C-11]UCB-J 信号反映的损耗； 3) 确定 [C-11]UCB-J 与 认知能力下降。除了 [C-11]UCB-J PET 之外，我们还将获取 [C-11]PIB PET 来测定空间淀粉样蛋白 斑块负荷，以及 [F-18]MK6240 PET 以确定 tau 缠结负荷。这项研究将是第一个获得 这三个标记串联起来，这将首次能够确定这些病理如何发生 AD 中的进化，并确定它们在空间和时间上如何相互关联。国家研究所 on Aging 将 SV2A PET 成像称为“可能改变 AD 和 AD 相关领域游戏规则的生物标志物” 痴呆症”。突触损失预计与认知能力下降最密切相关，但影响不大 目前尚未开展人类研究来检查整个 AD 范围内的区域突触损失。的 拟议的项目解决了这一知识差距。该研究计划有望尽早得到改善 检测 AD，提高认知能力下降的预测，并为新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.