PET STUDIES OF PARKINSONS DISEASE

本项目中提出的实验将检查神经化学 特发性帕金森病患者锥体外系运动系统 疾病和原发性震颤，与年龄相似的正常人比较 科目 我们将确定临床指标之间的关系 帕金森病的严重程度和突触前多巴胺能神经元 正电子发射断层扫描显示纹状体功能障碍 （11 C]二氢丁苯那嗪与突触前单胺能神经元结合的成像 囊泡我们假设，根据我们最近的研究， 实验动物，囊泡结合位点不太容易 疾病补偿和药物诱导调节 基于图像的多巴胺末梢测量。 我们将调查 二氢丁苯那嗪结合作为多巴胺能的定量指标 突触完整性。首先，我们将研究 纹状体多巴胺能末梢密度与帕金森病严重程度 症状在横断面研究。 我们还将进行纵向 研究，以表征多巴胺终端内的进行性损失， 个别患者。 该项目的第二个方面将研究苯二氮卓受体， 小脑皮质作为表达的潜在底物， 特发性震颤。我们最近的研究结果表明， 在小脑苯二氮卓结合位点，并建议进一步增加 （根据年龄效应调整）。 我们将描述这两个 纹状体多巴胺能神经支配以及小脑苯二氮卓类 受体在原发性震颤和轻度帕金森病，提供 神经化学数据与临床特征进行比较。 此外，我们将评估内在纹状体的可能性， 纹状体的神经化学变化（跨突触重组） 晚期帕金森病患者使用正电子- 毒蕈碱胆碱能受体的发射配体。我们将比较 帕金森病患者的毒蕈碱受体密度 严重程度，特别强调那些患有复杂左旋多巴的患者 反应（突出的运动障碍，“开/关”，或“磨损” 波动），以确定这些特征是否与 多巴胺能去神经支配单独进展，或是否继发 存在内在的纹状体变化。在后一种情况下， 替代对症干预，包括可能的胆碱能药物 这些治疗方法可能会使患者受益。

The experiments proposed in this project will examine the neurochemistry of the extrapyramidal motor system in patients with idiopathic Parkinson's disease and with essential tremor, for comparison with age-similar normal subjects. We will determine the relationships between clinical measures of parkinsonian severity and the degree of presynaptic dopaminergic dysfunction in the striatum, as revealed by positron emission tomographic imaging of (11C]dihydrotetrabenazine binding to presynaptic monoaminergic vesicles. We hypothesize, on the basis of our recent studies in experimental animals, that the vesicular binding sites are less prone to disease-compensatory and drug-induced regulation than are alternative image-based measures of dopamine terminals. We will investigate dihydrotetrabenazine binding as a quantitative index of dopaminergic synaptic integrity. First, we will examine the relationship between striatal dopaminergic terminal density and the severity of parkinsonian symptoms in cross-sectional studies. We will also conduct longitudinal studies to characterize the progressive loss of dopamine terminals within individual patients. A second aspect of the project will examine benzodiazepine receptors in the cerebellar cortex as a potential substrate for the expression of essential tremor. Our recent findings document an age-associated increase in cerebellar benzodiazepine binding sites, and suggest further increase (adjusted for age effect) in essential tremor. We will characterize both striatal dopaminergic innervation as well as cerebellar benzodiazepine receptors in essential tremor and mild Parkinson's disease, providing neurochemical data for comparison with clinical features. Further, we will evaluate the possibility of intrinsic striatal neurochemical change (trans-synaptic reorganization) in the striatum of patients with advanced Parkinson's disease with the use of a positron- emitting ligand for the muscarinic cholinergic receptor. We will compare muscarinic receptor density in parkinsonian patients across a spectrum of severity, with particular emphasis on those patients with complex levodopa responses (prominent dyskinesias, "on/off"', or "wearing-off" fluctuations), to determine whether these features are associated with progression of dopaminergic denervation alone, or whether secondary intrinsic striatal changes are present. In the latter instance, alternative symptomatic interventions, including possible cholinergic therapies, may be expected to benefit patients.