PET STUDIES OF CHOLINERGIC MODULATION IN ALZHEIMERS

阿尔茨海默病胆碱能调节的 PET 研究

• 批准号: 2035708
• 负责人: Gwenn S Smith
• 金额: $ 28.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2035708
• 关键词: Alzheimer's disease; acetylcholine; aging; antipsychotic agents; cerebral cortex; clinical research; corpus striatum; dopamine receptor; human middle age (35-64); human old age (65+); human subject; limbic system; magnetic resonance imaging; muscarinic receptor; neuropharmacology; positron emission tomography; receptor expression; scopolamine; serotonin; serotonin receptor

Primary symptomatology in Alzheimer~s disease (AD) has been attributed to a presynaptic cholinergic deficit, based mainly on post- mortem examination of the brain at the end stages of the illness. Pharmacologic enhancement of the cholinergic system has not been consistently efficacious and does not stop disease progression. Animal and human models of AD based on inducted cholinergic hypofunction only mimic some aspects of symptomatology in AD. More recent neuropathologic studies have reported deficits in other neurotransmitter systems (e.g. dopamine, serotonin, norepinephrine). As an integration of the present knowledge concerning the neurochemistry of AD and the observation that neurotransmitter systems function synergistically, not in isolation, the proposed studies will test the novel hypothesis that the cognitive and behavioral symptomatology in AD represents a failure of acetylcholine to modulate other functionally-linked neurotransmitters, and that these deficits occur prior to the clinical diagnosis of AD. A recently developed research approach with Positron Emission Tomography (PET) will be used to combine neuroreceptor radiotracer studies with pharmacologic challenges to measure cholinergic modulation (Smith et al., 1996, Dewey et al., 1993). This approach is the most direct, non-invasive and quantitative method of measuring neurotransmitter activity and modulation in the living brain. These studies will measure cholinergic modulation of monoamine function (serotonin, dopamine) in the normal elderly, and in AD patients. A well- characterized pharmacologic challenge paradigm (administration of the selective muscarinic cholinegic antagonist scopolamine) will be used with PET and radiotracers for dopaminergic (D2, [1]C]- raclopride) and serotonergic (5-HT2A, [18F]-altanserin) receptors. Having performed the proposed studies, unique information will be obtained regarding cholinergic modulation of dopamine and serotonin receptor systems. These studies will provide a baseline for subsequent longitudinal follow-up of patients and for correlation with genetics and post-mortem findings (by the Alzheimer~s Disease Research Center) to determine how differences in monoaminergic responsiveness relate to AD subgroups (e.g. Lewy Body Dementia) A better understanding of the neurochemical deficits in AD may direct the development of novel treatment interventions that would improve symptomatology and perhaps stop disease progression.

阿尔茨海默病的主要症状学~S病(AD) 可归因于突触前胆碱能缺陷，主要基于后遗症 在疾病末期对大脑进行的尸检。 胆碱能系统的药理增强尚未得到 一贯有效，但不能阻止疾病的发展。 基于诱导型胆碱能的AD动物和人体模型 功能减退仅模拟AD症状的某些方面。 最近的神经病理学研究报告说，在其他 神经递质系统(例如，多巴胺、5-羟色胺、 去甲肾上腺素)。作为对现有知识的整合 关于阿尔茨海默病的神经化学和观察 神经递质系统的功能是协同的，而不是孤立的， 拟议的研究将检验这一新的假设，即认知 而AD的行为症状学代表着 乙酰胆碱调节其他官能链 神经递质，这些缺陷发生在临床之前 诊断阿尔茨海默病。最近开发的一种研究方法， 正电子发射断层扫描(PET)将用于联合 神经受体放射性示踪剂研究与药理学挑战 测量胆碱能调制(Smith等人，1996，Dewey等人， 1993年)。这种方法是最直接、非侵入性和 测定神经递质活性的定量方法和 在活着的大脑中进行调制。这些研究将测量 胆碱能调节单胺功能(5-羟色胺， 多巴胺)在正常老年人和AD患者中。一口井- 具有特征的药理学挑战范例(给药 选择性毒扁豆碱胆碱拮抗剂东莨菪碱) 与PET和多巴胺能(D2，[1]C]放射性示踪剂一起使用- 拉氯普利)和5-羟色胺能(5-HT2A，[18F]-Altanserin)受体。 在执行了拟议的研究后，独特的信息将是 关于胆碱能调节多巴胺和 5-羟色胺受体系统这些研究将提供一个基线 用于随后对患者的纵向随访和相关性 遗传学和尸检结果(作者：阿尔茨海默病患者~S 疾病研究中心)来确定 单胺类反应性与AD亚群有关(例如，路易 躯体痴呆症)更好地了解神经化学物质 阿尔茨海默病的缺陷可能指导新疗法的发展 干预措施将改善症状，并可能停止 疾病的发展。