PET Study of Biochemistry and Metabolism of the CNS

该项目主要研究人类神经功能障碍的体内神经化学，强调皮质下结构及其在神经退行性和特发性运动功能障碍中的相互作用。该提案中的研究将神经化学表型与功能测量相结合，后者包括运动表现、血流激活、神经递质释放和睡眠生理学方面。该计划包括4个科学项目和3个核心。基尔伯恩的项目“神经PET的新放射性示踪剂”将引入一种新的功能方法，通过氯离子载体的变构配体来评估GABAA受体。GABA能项目是纹状体输出和其他锥体外区的重要组成部分。对GABAA功能的评估将补充可能优先反映兴奋性谷氨酸能途径的葡萄糖代谢研究。Frey的项目“老化和帕金森病中的纹状体多巴胺和运动表现”将确定衰老和帕金森病中黑质纹状体多巴胺能损失的功能运动相关性，并将评估它们在急性多巴胺能挑战中的逆转。Gilman的项目“多系统萎缩中的神经化学和睡眠障碍”将评估锥体外神经退行性变中睡眠中断与脑干胆碱能投射之间的关系。Albin的项目“Tourette综合征中的多巴胺突触机制”将从多方面评估纹状体多巴胺能项目及其功能，包括测量它们的密度、它们重新摄取多巴胺的能力、它们释放多巴胺的能力，以及评估环境中突触多巴胺在D2型多巴胺受体上的占据情况。回旋加速器/放射化学、断层扫描和数据分析以及管理核心功能为每个项目提供支持。总体而言，本计划研究的疾病的发病机制尚不清楚，只有对症治疗。拟议的研究将导致对锥体外神经化学的更深入的了解，并将解决这些疾病中功能障碍和残疾的重要方面。新的和改进的治疗方法以及新的病理生理机制和洞察力最终可能会产生。

This Program Project focuses on in vivo neurochemistry of human neurological disorders, emphasizing subcortical structures and their interactions in neurodegenerative and idiopathic functional disorders of movement. Studies in the proposal combine neurochemical phenotypes with functional measures, the latter including motor performance, blood flow activation, neurotransmitter release, ans aspects of sleep physiology. The Program consists of 4 Scientific Projects and 3 Cores. Project by Kilbourn, "New Radiotracers for Neurological PET", will introduce a novel functional approach to assessment of GABAA receptors through allosteric ligands of the chloride ionophore. GABAergic projects are critical components of striatal output and other extrapyrimidal sites. Assessment of GABAA function will complement glucose metabolism studies that may preferentially reflect excitatory glutamatergic pathways. Project by Frey, "Striatal Dopamine and Motor Performance in Aging and Parkinson's Disease" will determine functional motor correlates of nigrostriatal dopaminergic losses in aging and Parkinson's disease and will assess their reversal by acute dopaminergic challenge. Project by Gilman, "Neurochemical and Sleep Disorders in Multiple System Atrophy", will assess the relationships between disrupted sleep in extrapyrimidal neurodegeneration and brain stem cholinergic projections. Project by Albin, "Dopamine Synaptic Mechanisms in Tourette Syndrome", will assess striatal dopaminergic projects and their function from a multi-faceted approach, including measures of their density, their capacity for dopamine re-uptake, their capacity for dopamine release, and an assessment of ambient synaptic dopamine occupancy of D2-type dopamine receptors. Cyclotron/Radiochemistry, Tomography and Data Analysis, and Administrative Core functions support each Project. Overall , the disorders under study in this Program are of unknown pathogenesis and have only symptomatic therapies. The proposed studies will lead to enhanced insight into extrapyrimidal neurochemistry and will address important aspects of dysfunction and disability in these disorders. Novel and improved therapies and new pathophysiological mechanisms and insight may ultimately result.