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: 2675633
• 负责人: Gwenn S Smith
• 金额: $ 28.89万
• 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/2675633
• 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; raclopride; 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（Alzheimer~s disease，AD）的原发病学 归因于突触前胆碱能缺陷，主要基于突触后 在疾病的最后阶段对大脑的尸检。 胆碱能系统的药理学增强尚未被证实。 持续有效且不阻止疾病进展。 基于诱导胆碱能的AD动物和人类模型 功能减退仅模拟AD中的某些方面的病理学。 最近的神经病理学研究报告， 神经递质系统（例如多巴胺，血清素， 去甲肾上腺素）。作为现有知识的整合 关于AD的神经化学和观察， 神经递质系统协同地发挥作用，而不是孤立地， 拟议中的研究将测试新的假设，即认知 而AD中的行为学表现出了 乙酰胆碱调节其他功能相关的 神经递质，这些赤字发生在临床之前， AD的诊断 最近开发的研究方法， 正电子发射断层扫描（PET）将用于联合收割机 神经受体放射性示踪剂研究与药理学挑战 测量胆碱能调节（Smith等人，1996年，Dewey等人， 1993年）。 这种方法是最直接，非侵入性， 测量神经递质活性的定量方法， 在活体大脑中的调制。 这些研究将衡量 单胺功能的胆碱能调节（5-羟色胺， 多巴胺）在正常老年人和AD患者中。 一个很好的- 特征性药理学激发范式（给予 选择性毒蕈碱胆碱能拮抗剂东莨菪碱）将被 与PET和放射性示踪剂一起用于多巴胺能（D2，[1]C]- 雷氯必利）和多巴胺能（5-HT 2A，[18F]-阿坦色林）受体。 在进行了拟议的研究后， 获得关于多巴胺的胆碱能调节， 血清素受体系统 这些研究将提供一个基线 用于随后的患者纵向随访和相关性 与遗传学和尸检结果（由阿尔茨海默氏症 疾病研究中心）以确定 单胺能反应性与AD亚组相关（例如Lewy 身体痴呆症）更好地了解神经化学物质 AD的缺陷可能会指导新治疗方法的开发 可以改善生殖医学的干预措施， 疾病进展。