PET Study of Biochemistry and Metabolism of the CNS

描述(由申请人提供)：本申请描述了一个计划项目，研究计划集中在帕金森病(PD)的神经化学正电子发射断层扫描(PET)研究上。帕金森病是最常见的神经退行性运动障碍，在认识和治疗静止性震颤、运动迟缓和僵直等典型运动异常方面取得了长足进展。这些主要的PD特征最初都对多巴胺替代治疗有反应，并已就它们与黑质纹状体多巴胺投射退化的关系进行了深入的研究。最近，人们越来越关注帕金森病的“非运动性”临床方面，包括认知、情绪、时间生物学和外周自主神经缺陷。这些临床特征不太可靠地受到多巴胺能治疗的影响，并且可能与其他非多巴胺能神经退行性变有关。事实上，对帕金森病大脑的详细尸检评估显示，在各种化学定义的神经元中，包括脑干5-羟色胺和去甲肾上腺素神经元以及基底前脑胆碱能神经元，都有大量的神经元丢失。我们提案中的项目将专注于PD患者的痴呆症、抑郁症、睡眠呼吸暂停和自主神经功能障碍，使用正电子发射计算机断层扫描(PET)测量突触前多巴胺能、5-羟色胺和胆碱能中枢神经系统神经元和外周交感神经元。我们的研究结果可能确定非运动性帕金森病的体征和症状与非多巴胺能神经元丢失之间的关系。这些发现将为对症和潜在的神经保护性帕金森病疗法建立更多的治疗靶点。此外，大多数患者将接受所有3项CNS PET检查。参与帕金森病神经退行性变的不同神经元群体的多个标记的可用性将使探索性分析能够评估这些退行性变是相关的(可能是共同的病理生理学的表现)还是明显独立的(可能是多种帕金森病亚型或病理生理学的表现)。最终，对这些非运动功能的更好理解将对开发未来针对整个PD患者的治疗至关重要。

DESCRIPTION (provided by applicant): This application describes a Program Project with research plan focused on neurochemical positron emission tomography (PET) studies of Parkinson disease (PD). PD is the most common neurodegenerative movement disorder, and considerable progress has been made in understanding and treating the "typical" movement abnormalities of resting tremor, bradykinesia and rigidity. These cardinal PD features are all initially responsive to dopamine replacement therapy, and have been investigated intensively with respect to their relationships to degeneration of the nigrostriatal dopamine projection. More recently, increased attention has focused on the "non-motor" clinical aspects of PD, including cognitive, mood, chronobiological and peripheral autonomic defects. These clinical features are less reliably affected by dopaminergic therapy, and are likely to be associated with other, non-dopaminergic neural degenerations. Indeed, detailed postmortem assessments of PD brain reveal substantial neuronal losses in a variety of chemically-defined neurons, including brainstem serotonin and norepinepherine neurons and basal forebrain cholinergic neurons. Projects in our proposal will focus on dementia, depression, sleep-apnea and dysautonomia in PD patients, employing PET measures of presynaptic dopaminergic, serotoninergic and cholinergic CNS neurons and of peripheral sympathetic neurons. Results of our investigations may identify associations of non-motor PD signs and symptoms with the non-dopamiergic neuronal losses. These findings will establish additional therapeutic targets for symptomatic, but also for potential neuroprotective PD therapies. In addition, a majority of patients will be characterized with all 3 CNS PET measures. The availability of multiple markers of distinct neuronal populations involved in PD neurodegeneration will permit exploratory analyses to assess whether the degenerations are correlated (possibly manifestations of a common pathophysiology) or apparently independent (possibly a manifestation of multiple PD subtypes or pathophysiologies). Ultimately, better understanding of these non-motor features will be essential to developing future treatments that address the entire PD patient.