Cholinergic Interneurons in Tourette Syndrome

描述(申请人提供)：抽动症候群(TS)是一种常见的儿童起病的神经发育障碍，以多个运动和语音为特征。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机制目前知之甚少。越来越多的证据表明TS患者存在纹状体功能障碍，少量的尸检数据表明某些纹状体中间神经元，特别是胆碱能中间神经元存在缺陷。纹状体胆碱能中间神经元是基底神经节内的重要因子。这种相对稀疏的中间神经元群体可能在纹状体的大量区域起到同步作用。纹状体胆碱能中间神经元的缺乏可能是TS抽动及相关表现的一个可能的底物，我们假设TS的纹状体胆碱能中间神经元减少。在活体内量化纹状体胆碱能中间神经元的完整性是不可行的。我们团队开发了一种新的正电子发射断层扫描(PET)示踪剂[18F]FEOBV，它是囊泡乙酰胆碱转运体(VChT)的配体，可以准确地定量人类纹状体胆碱能终末。我们建议在TS和对照组中评估纹状体胆碱能神经元终末的完整性。我们将招募TS和年龄匹配的对照组受试者进行[18F]FEOBV研究。受试者将接受标准的临床评估，包括抽动严重程度和特征、强迫行为和注意力缺陷的评估。主要的分析将是比较TS和对照组之间的纹状体[18F]FEOBV结合。二次分析将包括纹状体[18F]FEOBV结合与临床分级的相关性以及其他脑区胆碱能终末完整性的评估。这一假说的验证将指向TS中特定的解剖-神经化学系统缺陷。这将有助于了解TS的发育基础的研究。胆碱能系统为药物干预提供了多个潜在靶点，这一假说的验证将开启TS实验治疗的新途径。

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.