IMAGING SEROTONIN FUNCTIONING IN ASPERGER'S DISORDERS

有几条证据表明，5-羟色胺能系统与阿斯伯格病的病理生理学有关。具体地说，选择性5-羟色胺再摄取抑制剂(SSRI)和5-HT2A拮抗剂的治疗效果、外周标志物研究的数据、5-羟色胺合成的脑成像研究以及5-羟色胺药物药理学挑战的结果都表明，5-羟色胺传递的缺陷可能是导致这种疾病症状的原因之一。然而，目前关于大脑5-羟色胺的具体信息很少 阿斯伯格障碍患者的系统。在过去的几年里，新的高选择性放射性示踪剂的发展极大地提高了用正电子发射断层扫描(PET)对活体人脑中5-羟色胺功能进行成像的能力。结合扫描仪分辨率和灵敏度的进步，这些技术能够测量5-羟色胺的参数 在活着的大脑的离散区域中发挥作用。项目II的目的是量化与阿斯伯格病有关的5-羟色胺系统的两个关键成分的解剖分布：5-羟色胺转运体(SERT)和5-HT2A受体。Ssert的可用性将用[11C]DASB来衡量，5-HT2A的可用性将用[11C]MD L 100907来衡量。这两种放射性示踪剂都是新开发的具有良好成像性能的PET试剂。 40名患有阿斯伯格障碍的成人受试者和40名年龄、性别、智商和种族相匹配的对照受试者将分别接受磁共振成像扫描和两次正电子发射计算机断层扫描，分别使用[11C]DASB和[11C]MDL 100907。受试者将由中心的临床核心进行招募和评估。扫描后，受试者将在另一项研究中接受氟西汀治疗。假说是阿斯伯格综合症患者会表现出SERT密度降低和边缘系统几个区域5-HT2A受体代偿性上调。根据先前的脑功能成像研究结果，我们预计这些变化将在前脑皮质边缘区域最为严重。将评估临床核心评估的区域性5-羟色胺异常和症状群之间的关系。成像研究的结果还将与氟西汀的临床试验结果相关联，该试验假设5-羟色胺功能缺陷较大的患者将最有可能从氟西汀治疗中受益。

Several lines of evidence implicate the serotonergic system in the pathophysiology of Asperger's disorder. Specifically, the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) and 5-HT2A antagonists, data from studies of peripheral markers, brain imaging studies of 5-HT synthesis and the results of pharmacological challenges with 5-HT agents converge in suggesting that a deficit in 5-HT transmission might contribute to the symptoms of this illness. However, very little specific information is currently available regarding the brain 5-HT system in patients with Asperger's disorder. Over the last few years, the development of new and highly selective radiotracers has greatly increased the ability to image 5-HT function in the living human brain with Positron Emission Tomography (PET). Combined with progress in scanner resolution and sensitivity, these techniques enable the measurement of parameters of 5-HT function in discrete areas of the living brain. The aim of project II is to quantify the anatomical distribution of two key elements of the 5-HT system that have been implicated in Asperger's disorder: the 5-HT transporter (SERT) and the 5-HT2A receptor. SERT availability will be measured with [11C]DASB and 5-HT2A availability will be measured with [11C]MD L 100907. Both radiotracers are newly developed PET agents with excellent imaging properties. Forty adult subjects with Asperger's disorder and forty controls matched for age, gender, IQ and ethnicity will undergo an MRI scan and two PET scans with [11C]DASB and [11C]MDL 100907, respectively. Subjects will be recruited and evaluated by the Clinical Core of the Center. Following the scans, subjects will be treated with fluoxetine in another study. The hypothesis is that patients with Asperger's disorder will show reduced density of SERT and a compensatory upregulation of 5-HT2A receptors in several areas of the limbic system. Based on results of previous functional brain imaging studies, we anticipate that these changes will be most severe in forebrain cortico-limbic areas. The relationship between regional 5-HT abnormalities and symptom clusters as evaluated by the Clinical Core will be assessed. The results of the imaging studies will also be correlated with the results of a clinical trial with fluoxetine, with the hypothesis that patients who show larger deficits in 5-HT function will be the most likely to benefit from fluoxetine treatment.