CEREBRAL CHEMICAL PATTERNS IN ALZHEIMERS DISEASE

该项目的上一个资助期支持使用 正电子发射断层扫描（PET）和单光子发射 计算机断层扫描（SPECT），以研究区域 阿尔茨海默病（AD）的脑血流和代谢。 本申请提出使用PET来研究 这些灌注异常之间的关系，认知 缺陷和患者多巴胺代谢的区域变化 与AD和帕金森病（PD）相关的疾病， 一种痴呆症分享临床，病理，和成像 AD的特征。 虽然纹状体多巴胺缺乏 在PD中是公认的，来自PET和神经心理学的证据 调查还表明额叶是 受到疾病的影响。 在AD中，临床和病理学研究 表明多巴胺能功能障碍在病理生理学中的作用 额叶和锥体外系症状 的使用 高分辨率多巴胺代谢示踪剂（18F）-6-氟多巴 PET将允许确定额叶的作用， 壳状核和尾状核多巴胺缺乏， 额叶低灌注和认知功能障碍 疾病 研究设计需要评估PD和AD患者， 对照组，特别是额叶的存在 灌注异常、锥体外系症状和额叶 认知缺陷 所有患者将从一个较大的 入组正在进行的纵向研究， 血流，并将接受持续的临床随访 最终的尸检结果 PET-600 将使用分辨率为2.6毫米的断层扫描仪， 问题研究 在研究评估局部血液后立即进行 使用示踪剂（122 I）-HIPDM（210秒半衰期）的血流，受试者 将接受氟多巴PET检查 定量分析 数据将利用经由动脉确定的输入函数 导管与在线技术，以及动态PET脑 摄取数据。 将使用血液和大脑时间-活动曲线 结合血流和多巴胺代谢模型 导出描述局部脑血流的参数， 多巴胺代谢 多巴胺代谢模型将采用 示踪剂重要代谢产物的已知时间进程 以定量运输和代谢的速率常数。 主要的假设是多巴胺的壳核异常 代谢将与锥体外系症状有关， PD和AD受试者 此外，额叶灌注 缺陷和认知缺陷预计与 额叶多巴胺代谢减少 这些研究将 扩展我们对多巴胺的特定模式的理解 缺乏这些国家和将涉及神经递质 认知缺陷和血流异常， 对理解病理生理学的重要意义， 这两种疾病的潜在治疗方法。

The previous funding period of this project supported the use of positron emission tomography (PET) and single photon emission computed tomography (SPECT) to study the changes in regional cerebral blood flow and metabolism in Alzheimer's disease (AD). This application proposes to use PET to investigate the relationship between these perfusion abnormalities, cognitive deficits, and regional changes in dopamine metabolism in patients with AD and Parkinson's disease (PD), an illness associated with a dementia sharing clinical, pathological, and imaging characteristics with AD. While the striatal dopamine deficiency in PD is well established, evidence from PET and neuropsychological investigations also implicates the frontal lobes as an area affected by the disease. In AD, clinical and pathologic studies suggest a role for dopaminergic dysfunction in the pathophysiology of frontal lobe and extrapyramidal symptoms. The use of the dopamine metabolic tracer (18F)-6-fluorodopa with high resolution PET will allow the determination of the role of frontal lobe, putaminal, and caudate dopamine deficiency in the production of frontal lobe hypoperfusion and cognitive symptomatology in these diseases. The study design entails the evaluation of PD and AD patients and controls, with specific reference to the presence of frontal lobe perfusion abnormalities, extrapyramidal symptoms, and frontal cognitive deficits. All patients will be selected from a larger cohort enrolled in an ongoing longitudinal study of changes in blood flow using SPECT, and will receive continued clinical follow up with a view to ultimate autopsy correlation. The PET-600 tomograph, which has a resolution of 2.6 mm, will be used for all studies. Immediately following a study to evaluate regional blood flow using the tracer (122I)-HIPDM (210 sec half life), subjects will undergo a fluorodopa PET study. Quantitative analysis of the data will utilize an input function determined via an arterial catheter with an on-line technique, together with dynamic PET brain uptake data. The blood and brain time-activity curves will be used in conjunction with models for blood flow and dopamine metabolism to derive parameters describing regional cerebral blood flow and dopamine metabolism. The dopamine metabolkc model will employ the known time course of significant metabolic products of the tracer in order to quantitate rate constants for transport and metabolism. The major hypothesis is that putaminal abnormalities of dopamine metabolism will be related to the extrapyramidal symptoms seen in PD and AD subjects. In addition, the frontal lobe perfusion deficits ans cognitive deficits are expected to be associated with diminished frontal lobe dopamine metabolism. Such studies will expand our understanding of the specific pattern of dopamine deficiency in these states and will relate neurotransmitter deficits to cognitive and blood flow abnormalities which have important implications for understanding the pathophysiology and potential treatments for both diseases.