A Simultaneous PET/MR Study of Striatal Dopamine Binding in Autism

项目摘要 该基金旨在评估自闭症谱系中纹状体多巴胺能在奖励处理过程中的功能 通过使用同步正电子发射断层扫描（PET）和功能磁共振成像（MRI） 共振成像（fMRI）。临床前研究强烈暗示中脑边缘多巴胺功能受损 ASD的病因学此外，fMRI证据表明ASD的特征是纹状体 奖励处理过程中的低激活。然而，由于fMRI仅对血氧水平敏感， 依赖的信号，尚不清楚是否在ASD中观察到的奖励处理过程中纹状体低激活 与纹状体多巴胺功能受损有关。此外，尚不清楚是否 在ASD的奖赏处理过程中，纹状体的低激活与减少的阶段性多巴胺释放有关， 降低背景多巴胺张力，抑制阶段性多巴胺释放。最后，是否受损 多巴胺在ASD中的作用与ASD症状严重程度的关系尚不清楚。这些都是关键的差距 在我们对ASD病理生理学的理解中，考虑到ASD模型生物体的研究开始 精确定位ASD中涉及的特定分子机制，而不是单个分子 迄今为止的成像研究已经针对ASD中的中脑边缘多巴胺系统。PET成像非常适合于 填补了ASD临床前研究和奖励处理的临床神经影像学研究之间的空白， 自闭症我们建议从一组年轻的ASD患者中同时收集PET和fMRI， 通常在使用D2/D3多巴胺受体的奖励处理任务中， 拮抗剂[11C]雷氯必利。使用推注+输注放射性示踪剂给药方案将提供 增加测量多巴胺释放的灵敏度，这是该项目的一个关键特征。我们将评估 在ASD中响应于刺激的背景多巴胺能张力和阶段性多巴胺能释放（目的1）， PET衍生的D2/D3纹状体受体占有率测量值与fMRI衍生测量值之间的相关性 纹状体激活（Aim 2），以及PET衍生的D2/D3纹状体受体测量之间的关系 ASD组的占用率和症状严重程度（目的3）。这个项目是我们长期以来的第一步- 长期目标是建立一个PET ASD研究计划，定位于将新的研究结果转化为 将临床前ASD模型中的受体结合潜力拯救到靶向临床ASD研究的化合物 同样的化合物。这条从临床前药物发现到临床药物评价的管道 是PET神经成像的理想选择，因为它能够测量靶向受体的类别， 特异性配体

Project Summary This grant seeks to evaluate striatal dopaminergic functioning during reward processing in autism spectrum disorder (ASD) through the use of simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Preclinical research strongly implicates impaired mesolimbic dopamine functioning in the etiology of ASD. Additionally, fMRI evidence suggests that ASD is characterized by striatal hypoactivation during reward processing. However, since fMRI is sensitive only to blood oxygen level dependent signals, it is not known whether striatal hypoactivation during reward processing in ASD observed with fMRI is associated with impaired striatal dopamine functioning. Additionally, it is not known whether striatal hypoactivation during reward processing in ASD is linked to reduced phasic dopamine release or to reduced background dopamine tone that inhibits phasic dopamine release. Finally, whether impaired dopamine functioning in ASD is related to ASD symptom severity is poorly understood. These are critical gaps in our understanding of ASD pathophysiology given that studies of ASD model organisms are starting to pinpoint the specific molecular mechanisms that are implicated in ASD, whereas not a single molecular imaging study to date has targeted the mesolimbic dopamine system in ASD. PET imaging is ideally suited to bridge this gap between preclinical ASD research and clinical neuroimaging studies of reward processing in ASD. We propose to collect simultaneous PET and fMRI from a cohort of young adults with ASD and matched typically developing young adults during a reward processing task using the D2/D3 dopamine receptor antagonist [11C]raclopride. The use of a bolus+infusion radiotracer administration protocol will provide increased sensitivity towards measuring dopamine release, a critical feature of this project. We will evaluate background dopaminergic tone and phasic dopaminergic release in response to incentives in ASD (Aim 1), correlations between PET-derived measures of D2/D3 striatal receptor occupancy and fMRI-derived measures of striatal activation (Aim 2), and relationships between PET-derived measures of D2/D3 striatal receptor occupancy and symptom severity in the ASD group (Aim 3). This project represents the first step of our long- term goal to establish a program of PET ASD research that is positioned to translate findings of novel compounds that rescue receptor binding potentials in preclinical ASD models to clinical ASD studies of target engagament by these same compounds. This pipeline of preclinical drug discovery to clinical drug evaluation is ideally suited to PET neuroimaging because of its capacity to measure classes of receptors targeted by specific ligands.