POSITRON EMISSION TOMOGRAPHY (PET) STUDIES OF CHOLINERGIC MODULATION IN ALZHEIME

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。先前对阿尔茨海默病（AD）神经化学缺陷的研究已经评估了疾病末期死后脑组织或血浆或脑脊液（CSF）中的单个神经递质系统。这些研究最一致地暗示突触前胆碱能缺陷，这些发现的强度导致记忆功能障碍和AD的胆碱能假说。一些证据表明，阿尔茨海默病的神经化学病理涉及的不仅仅是胆碱能缺陷：(1)通过使用胆碱能药物治疗来逆转胆碱能缺陷的尝试并不总是有效，也不能阻止疾病的进展；(2)涉及胆碱能系统病变的阿尔茨海默病动物模型只模拟了阿尔茨海默病的某些方面；(3)神经病理学研究报道了其他神经递质系统（如血清素、多巴胺、谷氨酸）的缺陷。虽然阿尔茨海默病的症状可能是由多种神经递质缺陷引起的，但基于阿尔茨海默病胆碱能缺陷的一致性和严重性，胆碱能系统仍然是阿尔茨海默病病理生理的核心。为了整合目前关于阿尔茨海默病神经化学的知识，以及一致的神经解剖学和神经生理学观察，即神经递质系统协同作用，而不是孤立地起作用，本研究将检验新的假设，即阿尔茨海默病代表乙酰胆碱无法调节其他功能相关的神经递质，以及胆碱能疗法的作用机制涉及其他神经递质的调节。该研究将评估慢性胆碱酯酶抑制剂治疗是否会影响轻度AD患者的血清素功能，以及这些继发效应是否与临床改善有关。本研究选择的胆碱酯酶抑制剂（加兰他明）增加乙酰胆碱浓度，并变构调节烟碱受体，与其他可用的胆碱酯酶抑制剂相比，这应该对多巴胺和血清素系统产生更大的净效应。神经解剖学和神经生理学研究已经证明突触前烟碱受体在调节多巴胺和血清素释放中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous investigations of neurochemical deficits in Alzheimer's disease (AD) have evaluated individual neurotransmitter systems in post-mortem brain tissue at the end stage of the disease or in plasma or cerebrospinal fluid (CSF). These studies have most consistently implicated a presynaptic cholinergic deficit and the strength of these findings led to a cholinergic hypothesis of memory dysfunction and AD. Several lines of evidence indicate that the neurochemical pathology in AD involves more than a cholinergic deficit: (1) attempts to reverse the cholinergic deficit by treatment with cholinergic agents have not been consistently efficacious and have not stopped disease progression, (2) animal models of AD involving lesions of the cholinergic system have only mimicked some aspects of AD, and, (3) neuropathologic studies have reported deficits in other neurotransmitter systems (e.g. serotonin, dopamine, glutamate). While it is likely that the symptomatology in AD is produced by multiple neurotransmitter deficits, based on the consistency and severity of the cholinergic deficit in AD, the cholinergic system must still be central to the pathophysiology of AD. To integrate the present knowledge concerning the neurochemistry of AD and the consistent neuroanatomic and neurophysiologic observations that neurotransmitter systems function synergistically, not in isolation, the proposed study will test the novel hypotheses that AD represents a failure of acetylcholine to modulate other functionally-linked neurotransmitters and that the mechanism of action of cholinergic therapies involves the modulation of other neurotransmitters. The study will evaluate whether chronic treatment with cholinesterase inhibitors affects serotonin function in mild AD patients and whether these secondary effects relate to clinical improvement. The cholinesterase inhibitor selected for use in this study (galantamine) increases concentrations of acetylcholine and allosterically modulates the nicotinic receptor, which should result in a greater net effect on dopamine and serotonin systems as compared to the other available cholinesterase inhibitors. Neuroanatomic and neurophysiologic studies have demonstrated the role of presynaptic nicotinic receptors in modulating the release of dopamine and serotonin.