SV2A PET imaging in Alzheimer's Disease

摘要 突触丢失是症状性阿尔茨海默病(AD)的一个主要特征。新型正电子发射断层扫描 已开发出能与突触囊泡糖蛋白2A(SV2A)结合的放射性配体 存在于整个大脑的突触前神经末梢中的囊泡蛋白。虽然这些示踪剂的开发是 这是阿尔茨海默病领域的一项重大进展，目前对临床和病理上的突触丢失知之甚少 阿尔茨海默病的频谱，以及在大队列中的纵向研究是缺乏的。为了解决这一知识差距， 我们建议使用[C-11]UCB-J在从 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生物标记物 阴性参与者、认知未受损的生物标记物阳性参与者、轻度认知障碍的个体 损害(MCI)，以及因阿尔茨海默病而患痴呆症的参与者。参与者将在基线和两点进行成像- 一年的随访。假设区域突触丢失将作为一个敏感的标志 神经退行性变在斑块和缠结堆积的背景下，并将解释认知能力下降。按顺序 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提供来自MRI的关于神经退行性变的独特信息；2)确定突触的比率 损失由[C-11]UCB-J信号反映；以及3)确定[C-11]UCB-J与 认知能力下降。除了[C-11]UCB-J PET，我们还将获得[C-11]PIB PET来确定空间淀粉样蛋白 斑块负荷，以及[F-18]MK6240PET测定tau缠结负荷。这项研究将是第一次获得 这三个标记物串联在一起，这将首次允许--能够确定这些病理如何 在公元后演变，并确定它们在空间和时间上如何相互关联。国家研究院 On Aging将SV2APET成像称为AD和AD相关的潜在改变游戏规则的生物标记物 痴呆症“。突触缺失被认为是与认知功能下降最密切的联系，但不是很大 人类研究还没有进行，以检查整个阿尔茨海默病的区域突触丢失。这个 拟议的项目解决了这一知识差距。这项研究计划可望早日得到改进 检测阿尔茨海默病，改善对认知能力下降的预测，并为开发新的治疗策略提供信息。

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.