SV2A PET imaging in Alzheimer's Disease

SV2A PET 成像在阿尔茨海默病中的应用

基本信息

批准号：
9919489
负责人：
Barbara Brigitta Bendlin
金额：
$ 113.34万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919489
关键词：
Address Age Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer’s disease biomarker Amyloid Amyloid beta-42 Anatomy Binding Biological Markers Brain Cerebrospinal Fluid Clinical Clinical Trials Cognitive Dementia Development Diffusion Magnetic Resonance Imaging Disease Disease Progression Early Diagnosis Enrollment Glycoproteins Goals Growth Associated Protein 43 Health Hippocampus (Brain)Human Image Impaired cognition Individual Knowledge Lead Light Location Longitudinal Studies Magnetic Resonance Imaging Measures Medial National Institute on Aging Nerve Degeneration Neurofibrillary Tangles Neurons Participant Pathologic Pathology Patient Recruitments Positron-Emission Tomography Proteins Protocols documentation ROC Curve Research S-nitro-N-acetylpenicillamine Sampling Scanning Senile Plaques Signal Transduction Staging Synapses Synaptic Vesicles Temporal Lobe Testing Time Tracer Wisconsin base cohort dementia risk density follow-up improved in vivo mild cognitive impairment neural correlate neurofilament neurogranin neuropathology new therapeutic target non-demented novel presynaptic neurons prevent prognostic programs public health relevance radioligand recruit relating to nervous system resilience sex success synaptotagmin I tau Proteins tau-1 tool treatment strategy

项目摘要

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.

抽象的突触丧失是有症状的阿尔茨海默病 (AD) 的一个主要特征。已开发出与突触小泡糖蛋白 2A (SV2A) 结合的 (PET) 放射性配体，突触小泡糖蛋白 2A 在整个大脑的突触前神经末梢中发现了囊泡蛋白，而这些示踪剂的开发正在进行中。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。为了弥补这一知识差距，缺乏 AD 的谱系和大型队列的纵向研究。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的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、轻度认知的个体参与者将在基线和两周时进行成像。一年的随访假设是区域突触损失将作为一个敏感标志。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。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 信号反映的损失；以及 3) 确定 [C-11]UCB-J 关联的程度除了 [C-11]UCB-J PET 之外，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]MK6240 PET 以确定 tau 缠结负荷，本研究将是第一个获得的。这三个标记串联起来，这将首次能够确定这些病理学如何发生 AD 中的进化，并确定它们在空间和时间上如何相互关联。 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”预计突触损失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。拟议的项目解决了这一知识差距，预计该研究计划将尽早得到改善。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。