PET Study of Biochemistry and Metabolism of the CNS

描述（由申请人提供）：本申请书描述了一项研究计划，其研究计划集中于帕金森病（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，在了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PD的主要特征最初都对多巴胺替代疗法有反应，并且已经深入研究了它们与黑质纹状体多巴胺投射变性的关系。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、时间生物学和周围自主神经缺陷。这些临床特征不太受多巴胺能治疗的影响，并且可能与其他非多巴胺能神经变性有关。事实上，PD脑的详细死后评估揭示了多种化学定义的神经元的大量神经元损失，包括脑干5 -羟色胺和去甲肾上腺素神经元以及基底前脑胆碱能神经元。我们的提案项目将集中在PD患者的痴呆，抑郁症，睡眠呼吸暂停和自主神经障碍，利用PET测量突触前多巴胺能，血清素能和胆碱能中枢神经系统神经元和周围交感神经元。我们的研究结果可能会确定非运动PD的症状和体征与非多巴胺能神经元损失的关联。这些发现将为症状性PD的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，大多数患者将具有所有3种CNS PET测量的特征。PD神经退行性变涉及的不同神经元群的多个标记的可用性将允许探索性分析，以评估退行性变是相关的（可能是共同病理生理的表现）还是明显独立的（可能是多种PD亚型或病理生理的表现）。最终，更好地了解这些非运动特征对于开发针对整个PD患者的未来治疗方法至关重要。

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.