PET STUDIES OF PARKINSONS DISEASE

这个项目中提出的实验将检验神经化学。 特发性帕金森病患者锥体外系运动系统的研究 疾病和特发性震颤，与年龄相似的正常对照 研究对象。我们将确定临床措施之间的关系 帕金森病严重程度和突触前多巴胺能 正电子发射断层扫描显示的纹状体功能障碍 (11C)二氢四苯肼与突触前单胺能结合的显像学研究 水泡。我们假设，根据我们最近在 实验动物，即囊泡结合部位不太容易 疾病补偿性调节和药物诱导调节是可替代的 基于图像的多巴胺终末测量。我们会调查的 二氢四苯肼结合作为多巴胺能定量指标的研究 突触的完整性。首先，我们将考察两者之间的关系 纹状体多巴胺能终末密度与帕金森病严重程度的关系 横断面研究中的症状。我们还将进行纵向 多巴胺终末进行性丢失的研究 个别病人。 该项目的第二个方面将检查苯二氮卓类受体 小脑皮质作为潜在的底物表达 严重震颤。我们最近的发现证明了与年龄相关的增长 在小脑苯二氮卓类药物结合部位，并提示进一步增加 (根据年龄效应调整)在特发性震颤中。我们将对这两种情况进行描述 纹状体多巴胺能神经支配与小脑苯二氮 特发性震颤和轻度帕金森病中的受体，提供 将神经化学数据与临床特征进行比较。 此外，我们将评估固有纹状体的可能性。 大鼠纹状体的神经化学变化(跨突触重组) 晚期帕金森氏症患者使用正电子- 毒扁豆碱胆碱能受体的发射配体。我们会比较一下 帕金森病患者脑脊液中的M受体密度 严重，特别强调那些复杂的左旋多巴患者 反应(明显的运动障碍、“开/关”或“疲惫” 波动)，以确定这些特征是否与 单纯性或继发性多巴胺能失神经的研究进展 存在固有的纹状体改变。在后一种情况下， 替代对症干预措施，包括可能的胆碱能 治疗，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.