Cholinergic Receptors in Aging and Alzheimers Disease Ligand Neuroimaging

描述(由申请人提供)： 该项目的总体目标是使用正电子发射断层扫描(PET)成像来评估阿尔茨海默病(AD)和轻度认知障碍(MCI)的胆碱能受体密度。AD导致巨大的发病率，随着人口老龄化，AD正在成为退伍军人的一个主要医疗问题。阿尔茨海默病发生了几个不同的神经病理事件。每个事件对临床症状和疾病进展的相对贡献尚不清楚，根据AD中已知的异常蛋白质和过程开发有效的治疗方法一直难以捉摸。目前，可用于研究神经病理学或疾病在体内表达的工具很少。胆碱能神经传递改变是AD的一个核心神经生物学特征。近年来，AD的研究主要集中在其他细胞和分子事件上，如β-淀粉样蛋白的产生和沉积。然而，最近的研究继续支持胆碱能受体系统在阿尔茨海默病中的关键作用--通过与神经病理蛋白如β-淀粉样蛋白的相互作用，或通过调节认知缺陷的表达，作为阿尔茨海默病的“主要”病理。最近，2-18F-氟-3-(2(S)叠氮二甲氧基)吡啶(2-FA)被开发用于体内测定局部烟碱受体(NAChR)。改进后的技术在人类身上使用是安全的，而且是敏感和可靠的。关于它在AD中的应用经验有限，尽管我们团队和其他人的初步研究表明，AD患者可以准确测量皮质nAChRs，AD患者的结合减少，密度降低可能与认知障碍有关。这项拟议的项目使用2-FA PET成像来比较AD患者和健康老年人中nAChR的结合。本文讨论了三个相关问题：1)AD患者nAChRs减少的程度如何？MCI患者是否存在进展为AD的风险？2)AD患者大脑中nAChR异常的部位？3)AD患者nAChR结合的区域性减少是否与整体认知障碍或特定的记忆或注意力缺陷有关？为了回答这些问题，轻至中度AD患者、遗忘型MCI患者和健康老年人将接受临床评估和2-FA PET成像。我们将比较两组之间的全局和区域性nAChR结合，并检查全脑、颞叶皮质和额叶皮质的局部nAChR结合与全球认知、记忆和注意力指标之间的关联。MCI组将被跟踪两年，并将评估基线nAChR结合与随后认知变化之间的关系。这项研究的结果可以确定AD和MCI患者体内特定脑区nAChRs减少的程度，以及它们对整体和独特认知缺陷的贡献。这项研究还将2-FA成像作为AD和MCI中胆碱能功能障碍的生物标志物，可用于未来的研究，以识别AD的非常早期的胆碱能变化，测量随时间的变化，评估与其他AD神经病理的相关性，评估对治疗干预的反应，并为新药开发提供靶点

DESCRIPTION (provided by applicant): The overall goal of this project is to assess cholinergic receptor density in Alzheimer's disease (AD) and mild cognitive impairment (MCI) using positron emission tomography (PET) imaging. AD causes enormous morbidity and is becoming a major healthcare problem among veterans as the population ages. Several distinct neuropathological events occur in AD. The relative contribution of each event to clinical symptoms and disease progression is unclear, and developing effective treatments based on known abnormal proteins and processes in AD has been elusive. Currently, there are few tools available to study neuropathology or disease expression in vivo. Altered cholinergic neurotransmission is a core neurobiological feature of AD. In recent years, AD research has focused largely on other cellular and molecular events, such as beta-amyloid production and deposition. Nonetheless, recent work continues to support a critical role for the cholinergic receptor system in AD - as a "primary" AD pathology, via interactions with neuropathological proteins such as beta-amyloid, or by mediating the expression of cognitive deficits. Recently, the PET ligand 2-18F-fluoro-3-(2(S)azetidinylmethoxy) pyridine (2-FA) was developed to measure regional nicotinic 1422 receptors (nAChR) in vivo. The improved technique is safe for use in humans, and is sensitive and reliable. There is limited experience with its use in AD, although preliminary studies by our group and others suggest that cortical nAChRs can be measured accurately in AD, and binding is reduced in AD and lower density may be associated with cognitive deficits. The proposed project uses 2-FA PET imaging to compare nAChR binding in AD patients and healthy older adults. Three related questions are addressed: 1) What is the extent of reduced nAChRs in AD? Are alterations present in those with MCI and at risk for progression to AD?, 2) Where in the brain are nAChRs abnormal in AD?, and 3) Are regional reductions in nAChR binding in AD associated with global cognitive impairment or with specific deficits in memory or attention? To answer these questions, patients with mild to moderate AD, those with amnestic MCI, and healthy older adults will undergo clinical assessment and 2-FA PET imaging. We will compare global and regional nAChR binding between the groups and examine the association between regional nAChR binding in whole brain, temporal cortex, and frontal cortex, and measures of global cognition, memory, and attention. The MCI group will be followed for two years and the relationship between baseline nAChR binding and subsequent change in cognition will be assessed. Results of this study can define the extent of reduced nAChRs in specific brain regions in AD and MCI in vivo and their contribution to global and distinct cognitive deficits. The study also advances 2-FA imaging as a biomarker for cholinergic dysfunction in AD and MCI that can be used in future studies to identify very early cholinergic changes in AD, measure change over time, evaluate associations with other AD neuropathologies, assess response to therapeutic interventions, and provide a target for new medication development