Cholinergic Receptors in Aging and Alzheimers Disease Ligand Neuroimaging

描述（由申请人提供）： 本项目的总体目标是使用正电子发射断层扫描（PET）成像评估阿尔茨海默病（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，并正在成为一个主要的医疗保健问题，退伍军人作为人口老龄化。AD中发生了几种不同的神经病理学事件。每个事件对临床症状和疾病进展的相对贡献尚不清楚，并且基于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，几乎没有工具可用于研究体内神经病理学或疾病表达。胆碱能神经传递的改变是AD的核心神经生物学特征。近年来，AD研究主要集中在其他细胞和分子事件上，例如β-淀粉样蛋白的产生和沉积。尽管如此，最近的研究继续支持胆碱能受体系统在AD中的关键作用-作为“原发性”AD病理学，通过与神经病理学蛋白如β-淀粉样蛋白的相互作用，或通过介导认知缺陷的表达。最近，PET配体2- 18 F-fluoro-3-（2（S）azetidinylmethoxy）pyridine（2-FA）被开发用于测量体内局部烟碱1422受体（nAChR）。改进后的技术可安全用于人类，并且灵敏可靠。尽管我们小组和其他人的初步研究表明，在AD中可以准确测量皮质nAChR，并且在AD中结合减少，并且较低的密度可能与认知缺陷相关，但其在AD中的使用经验有限。拟议的项目使用2-FA PET成像来比较AD患者和健康老年人的nAChR结合。解决了三个相关的问题：1）AD中nAChR减少的程度如何？在MCI患者中是否存在改变并有进展为AD的风险？，2)在AD中，nAChR在大脑中的哪个部位异常？和3）AD患者nAChR结合的区域性减少是否与整体认知障碍或记忆或注意力的特定缺陷相关？为了回答这些问题，轻度至中度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。我们将比较各组之间的全局和区域nAChR结合，并研究全脑，颞叶皮层和额叶皮层中区域nAChR结合与全局认知，记忆和注意力测量之间的关联。MCI组将随访两年，并评估基线nAChR结合与随后认知变化之间的关系。这项研究的结果可以定义在AD和MCI体内特定脑区域中nAChR减少的程度及其对整体和不同认知缺陷的贡献。该研究还将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中的极早期胆碱能变化，测量随时间的变化，评估与其他AD神经病理学的相关性，评估对治疗干预的反应，并为新药开发提供目标 公共卫生相关性： 这项研究项目是对阿尔茨海默病和“轻度认知障碍”患者的研究。在轻度认知障碍中，记忆受损，但没有达到阿尔茨海默病的程度。该研究项目使用大脑成像来测量大脑中对记忆和思维非常重要的一种化学受体。这些受体在阿尔茨海默病中可能是异常的，该研究项目检查了它们的异常程度，它们在大脑中的异常位置，以及它们的异常与记忆问题和其他认知困难的关系。该项目与退伍军人的健康有关，因为它可以更好地定义患有阿尔茨海默病的退伍军人大脑中的异常，并可以解释为什么患有阿尔茨海默病的退伍军人有记忆问题。这些信息可用于帮助确定可以逆转受体异常的治疗策略，脑成像可用于监测对这些重要受体的治疗效果，以改善退伍军人的健康。

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 PUBLIC HEALTH RELEVANCE: This research project is a study of people with Alzheimer's disease and with "mild cognitive impairment". In mild cognitive impairment, memory is impaired but not to the extent of Alzheimer's disease. The research project uses brain imaging to measure a type of chemical receptor in the brain that is very important for memory and thinking. These receptors are probably abnormal in Alzheimer's disease and the research project examines how abnormal they are, where in the brain they are prominently abnormal, and how their abnormality is related to memory problems and other cognitive difficulties. The project is relevant to veterans' health in that it can define better what is abnormal in the brain of veterans with Alzheimer's disease, and can explain why veterans with Alzheimer's disease have memory problems. This information can be used to help identify treatment strategies that can reverse the receptor abnormality, and brain imaging can be used to monitor treatment effects on these important receptors to improve the health of veterans.