Cholinergic Interneurons in Tourette Syndrome

描述（由申请人提供）：Tourette综合征（TS）是一种常见的儿童期发作的神经发育障碍，其特征是多发性运动和语音抽搐。TS通常伴有行为共病，包括强迫症（OCD）和注意力缺陷。TS的发病机制和病理生理学仅知之甚少。汇聚的证据表明，纹状体功能障碍的TS和适度量的尸检数据表明，在某些人群的纹状体中间神经元，特别是胆碱能中间神经元的赤字。纹状体胆碱能中间神经元是基底神经节内的重要演员。这种相对稀疏的中间神经元群体可能在大体积的纹状体中起同步作用。缺乏纹状体胆碱能中间神经元是一个合理的基板抽搐和TS的相关表现，我们假设减少纹状体胆碱能中间神经元TS。它还没有以前可行的定量纹状体胆碱能神经元的完整性在体内。我们的小组开发了一种新的正电子发射断层扫描（PET）示踪剂，[18 F]FEOBV，囊泡乙酰胆碱转运蛋白（VChT）的配体，可以精确定量人类纹状体胆碱能末梢。我们建议评估纹状体胆碱能神经元终端的完整性TS和对照组。我们将招募TS和年龄匹配的对照受试者进行[18 F]FEOBV研究。受试者将接受标准临床评价，包括评估抽搐严重程度和特征、强迫行为和注意力缺陷。主要分析将比较TS和对照受试者之间的纹状体[18 F]FEOBV结合。次要分析将包括纹状体[18 F]FEOBV结合与临床评级的相关性以及其他脑区中胆碱能末端完整性的评估。验证这一假设将指出一个特定的解剖-神经化学系统缺陷的TS。这将有助于研究了解TS的发展基础。胆碱能系统提供了多个潜在的药物干预和验证这一假设的目标将启动一个新的方法，TS的实验治疗。

DESCRIPTION (provided by applicant): Tourette syndrome (TS) is a common childhood-onset neurodevelopmental disorder characterized by multiple motor and phonic tics. TS is accompanied commonly by behavioral co-morbidities, including obsessive compulsive disorder (OCD) and attentional deficits. The pathogenesis and pathophysiology of TS are understood only poorly. Converging evidence points to striatal dysfunction in TS and a modest amount of post-mortem data suggests deficits in some populations of striatal interneurons, notably cholinergic interneurons. Striatal cholinergic interneurons are important actors within the basal ganglia. This relatively sparse population of interneurons may serve a synchronizing role across large volumes of the striatum. Deficient striatal cholinergic interneurons are a plausible substrate for tics and related manifestations of TS and we hypothesize diminished striatal cholinergic interneurons in TS. It has not been previously feasible to quantify striatal cholinergi interneuron integrity in vivo. Our group developed a novel positron emission tomography (PET) tracer, [18F]FEOBV, a ligand for the vesicular acetylcholine transporter (VChT), that allows accurate quantification of striatal cholinergic terminals in humans. We propose to evaluate striatal cholinergic neuron terminal integrity in TS and control subjects. We will recruit TS and age-matched control subjects for study with [18F]FEOBV. Subjects will undergo a standard clinical evaluation including assessment of tic severity and character, obsessive-compulsive behaviors, and attentional deficits. Primary analysis will be comparison of striatal [18F]FEOBV binding between TS and control subjects. Secondary analyses will include correlation of striatal [18F]FEOBV binding with clinical ratings and assessment of cholinergic terminal integrity in other brain regions. Validation of this hypothesis would point to a specific anatomic - neurochemical system deficit in TS. This would facilitate research on understanding the developmental basis for TS. Cholinergic systems offer multiple potential targets for pharmacologic intervention and validation of this hypothesis would initiate a new approach to experimental therapeutics in TS.