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

自闭症纹状体多巴胺结合的同时 PET/MR 研究

• 批准号: 9245385
• 负责人: GABRIEL S DICHTER
• 金额: $ 21.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-06 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245385
• 关键词: Accounting; Address; Animal Model; Autistic Disorder; Binding; Biomedical Research; Bolus Infusion; Brain; Clinical; Clinical Research; Control Groups; Corpus striatum structure; Country; Data; Disease model; Dopamine; Dopamine Antagonists; Drug Evaluation; Etiology; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Grant; Human; Image; Incentives; Institution; Ligands; Link; Matched Group; Measures; Modality; Molecular; Positioning Attribute; Positron-Emission Tomography; Process; Protocols documentation; Raclopride; Research; Sampling; Severities; Signal Transduction; Symptoms; Translating; autism spectrum disorder; blood oxygen level dependent; clinically relevant; cohort; drug discovery; innovation; mesolimbic system; molecular imaging; neuroimaging; new therapeutic target; novel; novel therapeutics; pre-clinical; pre-clinical research; programs; radiotracer; receptor; receptor binding; response; reward processing; young adult

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.

项目摘要 这项资助旨在评估孤独症患者奖赏处理过程中纹状体的多巴胺能功能。 同时使用正电子发射断层扫描(PET)和功能磁学检查发现的精神障碍(ASD) 磁共振成像(FMRI)。临床前研究强烈暗示中脑边缘多巴胺功能受损 在ASD的病因学上。此外，fmri证据表明ASD以纹状体为特征。 奖赏处理过程中的失活。然而，由于功能磁共振只对血氧水平敏感 依赖信号，尚不清楚是否观察到ASD患者在奖赏加工过程中纹状体活动不足 功能性磁共振成像与纹状体多巴胺功能受损有关。此外，目前尚不清楚 ASD患者奖赏加工过程中纹状体活性低下与时相多巴胺释放减少或 减少的背景多巴胺音调，抑制相性多巴胺释放。最后，是否受损 ASD中的多巴胺功能与ASD症状的严重程度相关，目前尚不清楚。这些都是严重的差距 在我们对ASD病理生理学的理解中，鉴于对ASD模式生物的研究开始 明确ASD的具体分子机制，而不是单一的分子 到目前为止，成像研究针对的是ASD的中脑边缘多巴胺系统。PET成像技术非常适合于 弥合临床前ASD研究和临床神经成像研究之间的差距 ASD.我们建议从ASD和配对的年轻人队列中收集同步的PET和功能磁共振成像 通常在奖赏处理任务中使用D2/D3多巴胺受体来发育年轻人 拮抗剂[11C]拉克洛必利。使用团注+输注放射性示踪剂给药方案将提供 提高了对测量多巴胺释放的敏感性，这是该项目的一个关键特征。我们将评估 背景自闭症患者的多巴胺能张力和时相多巴胺能释放对刺激的反应(目标1)， D2/D3纹状体受体占位率的PET测量与fMRI测量的相关性 纹状体激活(目标2)，以及D2/D3纹状体受体的PET测量之间的关系 ASD组的占有率和症状严重程度(目标3)。这个项目代表着我们漫长的- 学期目标是建立一个PET ASD研究计划，该计划旨在将新发现转化为 挽救临床前ASD模型中受体结合电位的化合物用于临床ASD的靶向研究 由这些相同的化合物所吸引。这条临床前药物发现到临床药物评价的管道 非常适合于PET神经成像，因为它能够测量靶向受体的类别 特定的配体。