PET STUDIES OF PARKINSONS DISEASE

帕金森病的宠物研究

• 批准号: 6112127
• 负责人: KIRK A. FREY
• 金额: --
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112127
• 关键词: GABA receptor; Parkinson's disease; abnormal involuntary movement; benzodiazepine receptor; brain mapping; brain metabolism; cerebellar ataxia /dyskinesia; corpus striatum; dopamine; human middle age (35-64); human old age (65+); human subject; muscarinic receptor; neuromuscular disorder diagnosis; positron emission tomography; radionuclide diagnosis; radiopharmacology; receptor binding; receptor sensitivity; synapses; tetrabenazine; tremor

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.

该项目提出的实验将检查神经化学 特发性帕金森氏病患者的腹膜外运动系统 疾病和基本震颤，以与年龄相似的正常 主题。 我们将确定临床措施之间的关系 帕金森氏症的严重程度和突触前多巴胺能的程度 正电子发射断层扫描揭示的纹状体功能障碍 （11c]二氢苯甲嗪与突触前单胺能结合的成像 囊泡。我们根据最近的研究来假设 实验动物，囊泡结合位点不太容易 疾病补偿性和药物诱导的调节比替代方案 基于图像的多巴胺终端测量。 我们将调查 二氢苯甲嗪的结合，作为多巴胺能的定量指数 突触完整性。首先，我们将研究 纹状体多巴胺能末端密度和帕金森氏症的严重程度 横断面研究中的症状。 我们还将进行纵向 研究表征多巴胺终端的进行性丧失的研究 个别患者。 该项目的第二个方面将检查 小脑皮层作为表达的潜在底物 基本震颤。我们最近的发现证明了与年龄相关的增加 在小脑苯二氮卓的结合位点中，并建议进一步增加 （根据年龄效应调整）中的基本震颤。 我们将表征两者 纹状体多巴胺能神经以及小脑苯二氮卓类药物 基本震颤和温和帕金森氏病的受体提供 与临床特征进行比较的神经化学数据。 此外，我们将评估固有纹状体的可能性 纹状体中的神经化学变化（反式突触重组） 患有晚期帕金森氏病的患者使用正电子 为毒蕈碱胆碱能受体发射配体。我们将比较 帕金森氏症患者的毒蕈碱受体密度 严重程度，特别强调那些复杂左旋多巴的患者 反应（突出的运动障碍，“开/关”或“佩戴” 波动），确定这些特征是否与 单独的多巴胺能神经治疗的进展，或者是次要的 存在固有的纹状体变化。在后一个实例中， 替代性症状干预措施，包括可能的胆碱能 疗法可能有望使患者受益。