Cholinergic Interneurons in Tourette Syndrome

描述（由申请人提供）：图雷特综合征（TS）是一种常见的儿童期发病的神经发育障碍，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。目前对TS的发病机制和病理生理了解甚少。越来越多的证据表明，在TS中纹状体功能障碍和少量的死后数据表明，纹状体中间神经元，特别是胆碱能中间神经元的一些群体的缺陷。纹状体胆碱能中间神经元是基底神经节内的重要行为体。这种相对稀疏的中间神经元群可能在纹状体的大量区域中起同步作用。纹状体胆碱能中间神经元缺陷可能是抽搐和TS相关症状的基础，我们假设在TS中纹状体胆碱能中间神经元减少。我们的团队开发了一种新的正电子发射断层扫描（PET）示踪剂，[18F]FEOBV，一种囊泡乙酰胆碱转运体（VChT）的配体，可以精确量化人类纹状体胆碱能末端。我们建议评估纹状体胆碱能神经元末端完整性在TS和对照组。我们将招募TS和年龄匹配的对照受试者进行[18F]FEOBV研究。受试者将接受标准的临床评估，包括抽动的严重程度和特征、强迫行为和注意力缺陷的评估。主要分析将比较实验组与对照组纹状体[18F]FEOBV结合情况。二级分析将包括纹状体[18F]FEOBV结合与临床评分和其他脑区胆碱能末端完整性评估的相关性。这一假设的验证将指出TS中特定的解剖-神经化学系统缺陷，这将有助于研究了解TS的发育基础，胆碱能系统为药物干预提供了多种潜在靶点，这一假设的验证将为TS的实验治疗开辟新的途径。

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.