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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。以前的研究在阿尔茨海默病（AD）的神经化学缺陷评估个人的神经递质系统在死后的脑组织在疾病的末期或在血浆或脑脊液（CSF）。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。几条证据表明，AD的神经化学病理学不仅仅涉及胆碱能缺陷：（1）通过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的，并且没有阻止疾病进展，（2）涉及胆碱能系统损伤的AD动物模型仅模拟了AD的某些方面，并且，（3）神经病理学研究报告了其他神经递质系统（例如5-羟色胺、多巴胺、谷氨酸）的缺陷。虽然AD中的神经病理学可能是由多种神经递质缺陷产生的，但基于AD中胆碱能缺陷的一致性和严重性，胆碱能系统必须仍然是AD病理生理学的中心。整合目前的知识，关于AD的神经化学和一致的神经解剖学和神经生理学的观察，神经递质系统的功能协同，而不是孤立的，拟议的研究将测试新的假设，即AD代表一个失败的乙酰胆碱调节其他功能相关的神经递质和胆碱能治疗的作用机制涉及其他神经递质的调制。该研究将评估胆碱酯酶抑制剂长期治疗是否会影响轻度AD患者的5-羟色胺功能，以及这些次要作用是否与临床改善有关。选择用于本研究的胆碱酯酶抑制剂（加兰他敏）可增加乙酰胆碱的浓度，并变构调节烟碱受体，与其他可用的胆碱酯酶抑制剂相比，这应会对多巴胺和5-羟色胺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5-羟色胺释放中的作用。

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.