PET Study of Biochemistry and Metabolism of the CNS

描述（由申请人提供）：本申请描述了一项计划项目，其研究计划侧重于帕金森病（PD）的神经化学正电子发射断层扫描（PET）研究。PD是最常见的神经退行性运动障碍，在理解和治疗静息性震颤、运动迟缓和僵硬等“典型”运动异常方面取得了相当大的进展。这些主要的PD功能最初都对多巴胺替代治疗有反应，并且已经深入研究了它们与黑质纹状体多巴胺投射退化的关系。最近，越来越多的注意力集中在PD的“非运动”临床方面，包括认知、情绪、时间生物学和外周自主神经缺陷。这些临床特征受多巴胺能治疗的影响不太可靠，并且可能与其他非多巴胺能神经变性相关。事实上，PD脑的详细尸检评估揭示了各种化学定义的神经元中的大量神经元损失，包括脑干5-羟色胺和去甲肾上腺素神经元和基底前脑胆碱能神经元。在我们的建议项目将集中在痴呆症，抑郁症，睡眠呼吸暂停和自主神经功能障碍的PD患者，采用PET测量突触前多巴胺能，胆碱能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会确定非运动PD体征和症状与非多巴胺能神经元损失的关联。这些发现将为对症治疗以及潜在的神经保护性PD治疗建立额外的治疗靶点。此外，大多数患者将通过所有3项CNS PET指标进行表征。PD神经变性中涉及的不同神经元群体的多种标志物的可用性将允许进行探索性分析，以评估变性是否相关（可能是常见病理生理学的表现）或明显独立（可能是多种PD亚型或病理生理学的表现）。最终，更好地了解这些非运动功能对于开发未来针对整个PD患者的治疗方法至关重要。

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.