Cholinergic Receptors in Aging and Early Alzheimer's Disease: Longitudinal Change

胆碱能受体在衰老和早期阿尔茨海默病中的纵向变化 大卫Sultzer，医学博士 VA大洛杉矶医疗保健系统 摘要 本研究的总体目标是评估脑胆碱能神经递质系统在 认知老化和阿尔茨海默病（AD）的进展。这项研究检查了尼古丁含量的变化， 健康老年退伍军人和轻度认知障碍患者随时间推移的胆碱能受体结合 (MCI)并测量受体结合变化和临床认知变化之间的关联。 随着老年人的年龄增长，记忆力下降和AD现在是关键的医疗保健挑战。 虽然几种神经生物学因素有助于认知老化和AD的神经退行性级联反应， 他们的个人和互动的作用知之甚少，神经递质系统的参与， 没有得到充分研究，有效的靶向治疗一直难以捉摸。 胆碱能神经递质系统已被证明在认知变化中起关键作用 与衰老和AD有关。最近，我们的小组使用了一种新的PET成像配体，2-18F-fluoro-3- （2（S）氮杂环丁烷甲氧基）吡啶（2FA）用于测量健康老年人体内烟碱胆碱能受体结合 成人和MCI和AD患者。结果表明，MCI患者的结合率在区域上适度降低， 在轻度和中度AD中更广泛地减少。在健康组和MCI组中，2FA结合呈反比。 与年龄和认知缺陷有关。结合减少不仅仅是海马萎缩的反映， 初步分析。新出现的模型假设烟碱受体结合功能障碍是一种主要的 衰老和早期AD神经退行性变。这种受体功能障碍改变了下游神经递质 释放，关键结构的突触可塑性，以及神经系统的功能，具有不同的临床 后果 拟议的项目采取下一步措施来评估烟碱胆碱能系统的纵向变化： 健康的老年退伍军人和MCI患者接受2FA PET成像和认知评估， 至少两年后的评估。局部烟碱胆碱能受体结合的变化将是 结合变化与记忆、注意力和整体认知变化之间的关系 将被评估。两种结构萎缩的相对贡献与乙酰胆碱的可用性有关， 受体翻译后的影响，基底前脑和海马，也进行了探讨。此外，本发明还提供了一种方法， 参与者接受FDG-PET成像，以测量已知受影响的皮质区域的代谢活动 的AD。因此，烟碱胆碱能受体结合的下降，与认知变化的关联，以及 基底前脑和海马萎缩的影响可以在可能的AD背景下评估 神经退化过程 这项研究的结果可以更好地确定区域胆碱能受体结合在表达中的作用。 与年龄相关的认知变化和向AD的进展，并考虑了 大脑关键结构萎缩总的来说，该项目有助于一个特定的胆碱能模型的认知 老化和早期AD，并可以提供一个体内工具，以帮助治疗的发展。

Cholinergic receptors in aging and early Alzheimer’s disease: longitudinal change David Sultzer, MD VA Greater Los Angeles Healthcare System Abstract The overall goal of this study is to evaluate the role of the brain cholinergic neurotransmitter system in cognitive aging and the progression to Alzheimer’s disease (AD). The study examines changes in nicotinic cholinergic receptor binding over time among healthy older Veterans and those with mild cognitive impairment (MCI) and measures the association between receptor binding change and clinical cognitive change. Memory decline with aging and AD are now critical healthcare challenges as the Veteran population ages. While several neurobiological factors contribute to cognitive aging and the neurodegenerative cascade of AD, their individual and interactive roles are poorly understood, the involvement of neurotransmitter systems has not been well-studied, and efficacious targeted treatments have been elusive. The cholinergic neurotransmitter system has been shown to play a key role in the cognitive changes associated with aging and AD. Recently, our group has used a novel PET imaging ligand, 2-18F-fluoro-3- (2(S)azetidylmethoxy) pyridine (2FA) to measure nicotinic cholinergic receptor binding in vivo in healthy older adults and those with MCI and AD. Results indicate that binding is modestly reduced regionally in MCI and more extensively reduced in mild and moderate AD. In the healthy and MCI groups, 2FA binding is inversely associated with age and cognitive deficits. Reduced binding is not solely a reflection of hippocampal atrophy in a preliminary analysis. The emerging model postulates that nicotinic receptor binding dysfunction is a primary event in aging and early AD neurodegeneration. This receptor dysfunction alters downstream neurotransmitter release, synaptic plasticity in key structures, and function across neural systems, with distinct clinical consequences. The proposed project takes the next step to evaluate longitudinal change in the nicotinic cholinergic system: Healthy older Veterans and those with MCI undergo 2FA PET imaging and cognitive assessment, with repeat assessments at least two years later. Change in regional nicotinic cholinergic receptor binding will be measured and relationships between binding changes and changes in memory, attention, and global cognition will be assessed. The relative contribution of atrophy in two structures related to acetylcholine availability and post-receptor translational effects, the basal forebrain and hippocampus, are also explored. In addition, participants undergo FDG-PET imaging to measure metabolic activity in cortical regions known to be affected by AD. Thus, the decline in nicotinic cholinergic receptor binding, associations with cognitive changes, and the influence of basal forebrain and hippocampal atrophy can be assessed in the context of a likely AD neurodegenerative process. Results from this study can better define the role of regional cholinergic receptor binding in the expression of aging-related cognitive changes and the progression towards AD, and considers the interactive contribution of atrophy in key brain structures. Overall, the project contributes to a specific cholinergic model of cognitive aging and early AD and can offer an in vivo tool to aid treatment development.