IN-VIVO PROBES OF NIGROSTRIATAL CELL DEGENERATION

描述(调查者摘要)：这一点的中心假设 工作是突触前多巴胺能的放射性标记酶 正电子发射断层扫描(PET)使用的函数不是线性的 黑质纹状体细胞丢失的指标。预计轴突 带有突触的萌芽会对早期的迹象做出快速反应 黑质纹状体多巴胺能变性作为代偿性的一部分 维持功能活动的机制正在发挥作用。如果是这样的话，就会很大 芳香族氨基酸脱羧酶(AAAD)活性和 在这种调整过程中，预计不会发生多巴胺再摄取部位。 因此，AAAD依赖的动力学和多巴胺再摄取 配基结合不会对这些初始变化敏感。 为了验证这一假设，我们将使用帕金森氏症的MPTP猴子模型 疾病(包括有症状和无症状)与受控的 环境对黑质纹状体细胞丢失对突触前的影响 功能与放射性标记的生物化学和中枢动力学 探测器。我们将重点关注细胞退化的初始阶段， 目的是提供将检测到调查的探测器 神经化学缺陷先于临床症状。我们将联合起来 世界上两个领先中心的独特专业知识和资源， 即帕金森研究所(W.朗斯顿博士，埃克托尔)在I-甲基-4- 苯基-1，2，3，6-四氢吡啶(MPTP)--非人类接触 灵长类动物和人类，以及加州大学洛杉矶分校，用正电子进行功能成像 发射断层扫描。“黄金标准”随之而来 细胞学和神经化学信息，体内PET数据将 与多巴胺能系统的功能完整性相关。 如果这项工作成功，我们将开发出新的体内 实现以下目标的方法： 1)揭示未被发现的黑质纹状体细胞的早期迹象 退化； 2)追踪纹状体AAAD活性，以评估特定的 药理相互作用 (如甲基苯丙胺)和细胞退化的影响。 多巴胺酶探针和净多巴胺再摄取的结合 配体(“可卡因受体”配体)将提供必要的工具 并有助于非侵入性评估所需的逻辑 中枢多巴胺能机制在健康中的功能活性 疾病状态。

DESCRIPTION (Investigator's Abstract): The central hypothesis of this work is that radiolabeled enzyme markers of presynaptic dopaminergic function used with positron emission tomography (PET) are not linear indicators of nigrostriatal cell losses. It is expected that axonal sprouting with synapses would respond quickly to early signs of nigrostriatal dopaminergic degeneration as part of the compensatory mechanisms at play to maintain functional activity. If so, substantial changes in aromatic amino acid decarboxylase (AAAD) activities and dopamine reuptake sites are not expected to occur during this adjustment period and, therefore, the AAAD-dependent kinetics and dopamine reuptake ligand binding will not be sensitive to these initial changes. To test this hypothesis, we will use the MPTP-monkey-model of Parkinson's disease (both symptomatic and asymptomatic) to correlate in a controlled environment the graded effects of nigrostriatal cell loss on presynaptic function with the biochemistry and central kinetics of the radiolabeled probes. We will focus our in on the initial stages of cell degeneration, with the aim of providing probes that will detect vestigation neurochemical deficiencies preceding clinical symptoms. We will combine the unique expertise and resources of two leading centers in the world, namely the Parkinson's Institute (Dr. W. Langston, ector) in I methyl-4- phenyl- I ,2,3,6 tetrahydropyridine (MPTP)-exposure to non-humans primates and humans, and UCLA, in functional imaging with positron emission tomography. With a "gold standard" provide-by concomitant cytological and neurochemical information, in-vivo PET data will be correlated with the functional integrity of the dopaminergic system. If this work is successful, we will have developed new in-vivo approaches to: 1) unveil otherwise undetected, early signs of nigrostriatal cell degeneration; 2) trace striatal AAAD activity allowing for evaluation of specific pharmacological interactions (e.g., methamphetamine) and the effects of cell degeneration. The combination of dopamine enzyme probes and, net dopamine re-uptake ligands ("cocaine receptor" ligands), will provide the necessary tools and contribute to the logic necessary for the non-invasive evaluation of the functional activity of central dopaminergic mechanisms in health disease states.