DAT Binding by Pet in Adult ADHD

成人 ADHD 中宠物的 DAT 结合

• 批准号: 7017092
• 负责人: Thomas J Spencer
• 金额: $ 54.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-24 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7017092
• 关键词: age difference; attention deficit disorder; bioimaging /biomedical imaging; clinical research; comorbidity; dopamine transporter; functional ability; gender difference; genetic susceptibility; human middle age (35-64); human subject; interpersonal relations; interview; iodine; mental disorders; molecular genetics; neurobiology; neuropsychological tests; neuropsychology; patient oriented research; positron emission tomography; protein binding; radionuclides; young adult human (21-34)

DESCRIPTION (provided by applicant): This is the second resubmission of an R01 application. We recently measured dopamine transporter (DAT) binding in adults with ADHD, using single photon emission computed tomography (SPECT) with the highly selective radiopharmaceutical, altropane.[9] DAT binding in was 70% greater Jn adults with ADHD. Our findings were partially replicated by Krause et al., (17% increase) but not replicated by van Dyck et al. (no increase), both using less specific radioligands. Positron emission tomography (PET) with 11C- altropane is ideal to measure DAT. It produces higher resolution, improved signal-to-noise ratio and less artifact than SPECT over a shorter acquisition time and permits kinetic modeling and estimates of affinity and density. To date, 6 adults and 6 controls have been imaged at MGH using [11C]altropane and PET which revealed a 34% increase in DAT binding. Moreover, Cook and others have demonstrated an association between ADHD and the 480-bp allele of the dopamine transporter gone. To this end, the primary goal of this molecular imaging proposal is to firmly establish the magnitude of increased DAT binding in adult ADHD with expert diagnostic methodology, a much larger N (66), a technically superior ligand (11C- altropane) and state-of-the-art imaging (PET). In addition, we seek to extend the previous findings to examine density (B'max) and affinity (Kd). The proposed work should move the field of ADHD research into a new direction in which molecular genetic and imaging studies are combined. Our specific aims are the following: 1. To examine DAT receptor bindinq in adults with ADHD usinq PET scanninq with 11C altropane as the li.qand. We hypothesize that compared to adults without ADHD, adults with ADHD will have greater DAT binding that will not be accounted for by psychiatric comorbidity, gender or age. Furthermore, we will separately examine density of DAT sites and affinity. 2. To examine the relationship of DAT binding to clinical features of ADHD. We hypothesize that DAT binding will be positively correlated with a) severity of ADHD symptoms; and b) neuropsychological and interpersonal dysfunction. 3. To examine the relationship between DAT bindinq and .qenetic risk factors, a) We hypothesize that DAT binding will be associated with the 480 allele of the 40-bp VNTR in the 3'-untranslated region of the dopamine transporter gene.

描述(申请人提供)：这是R01申请的第二次重新提交。我们最近利用高选择性放射性药物阿托品的单光子发射计算机断层扫描(SPECT)测量了ADHD成人的多巴胺转运体(DAT)结合。Krause等人(增加了17%)部分复制了我们的发现，但van Dyck等人没有复制。(不增加)，两者都使用较不特定的放射性配体。~(11)C-阿托品正电子发射断层扫描(PET)是测量DAT的理想方法。与SPECT相比，它能在更短的采集时间内产生更高的分辨率、更高的信噪比和更少的伪影，并允许进行动力学建模和亲和力和密度估计。到目前为止，6名成人和6名对照已经在MGH使用[11C]阿托品和PET进行了成像，结果显示DAT结合增加了34%。此外，库克和其他人已经证明了ADHD与多巴胺转运蛋白GONE的480个碱基的等位基因之间存在关联。为此，这项分子成像建议的主要目标是通过专家诊断方法、更大的N(66)、技术上优越的配体(11C-阿托品)和最先进的成像(PET)来确定成人ADHD患者DAT结合增加的幅度。此外，我们试图将以前的发现推广到密度(B‘max)和亲和力(Kd)。这项拟议的工作应该会将ADHD的研究领域推向一个新的方向，在这个方向上，分子遗传学和成像研究相结合。目的：1.以~(11)C阿托品为显像剂，用正电子发射计算机断层扫描检测成人ADHD患者的DAT受体结合量。我们假设，与没有ADHD的成年人相比，患有ADHD的成年人将有更大的DAT结合，这将不会被精神疾病、性别或年龄所解释。此外，我们将分别检测DAT位点的密度和亲和力。2.探讨DAT结合与ADHD临床特征的关系。我们假设DAT结合与a)ADHD症状的严重程度以及b)神经心理和人际功能障碍呈正相关。3.为了研究DAT bindinq与遗传危险因素的关系，a)我们假设DAT结合可能与多巴胺转运体基因3‘-非翻译区的480个等位基因相关。