Dopamine Transporter Binding by PET in Adult ADHD

成人 ADHD 中 PET 与多巴胺转运蛋白的结合

• 批准号: 7187397
• 负责人: Thomas J Spencer
• 金额: $ 46.39万
• 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 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7187397
• 关键词: 3' Untranslated Regions; Accounting; Adult; Affinity; Age; Alleles; Altropane; Arts; Attention deficit hyperactivity disorder; Binding; Childhood; Clinical; Comorbidity; Corpus striatum structure; Data; Diagnostic; Disease; Dopamine; Elevation; Facility Construction Funding Category; Functional disorder; Gender; Genes; Genetic Polymorphism; Goals; Image; Imaging technology; Iodine; Isotopes; Kinetics; Label; Left; Ligands; Link; Measurement; Measures; Methodology; Methods; Minisatellite Repeats; Modeling; Molecular Genetics; Morphologic artifacts; Neurobiology; Noise; Pilot Projects; Positron-Emission Tomography; Property; Radioactive; Radiopharmaceuticals; Reporting; Research; Research Personnel; Resolution; Risk Factors; Sampling; Severities; Signal Transduction; Site; Symptoms; Testing; Time; Work; base; cooking; density; disorder control; dopamine transporter; experience; genetic risk factor; improved; interest; molecular imaging; neuropsychological; novel; problem drinker; programs; radioligand; receptor; receptor density; research study; single photon emission computed tomography

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（由申请人提供）：这是第二次重新提交 R01 申请。 我们最近使用单光子发射计算机断层扫描 (SPECT) 和高选择性放射性药物阿托烷，测量了患有 ADHD 的成人中的多巴胺转运蛋白 (DAT) 结合。 [9]患有 ADHD 的成年人中 DAT 结合率高出 70%。 Krause 等人部分重复了我们的研究结果（增加了 17%），但 van Dyck 等人没有重复我们的发现。 （没有增加），两者都使用特异性较低的放射性配体。 使用 11C-阿托烷的正电子发射断层扫描 (PET) 是测量 DAT 的理想选择。与 SPECT 相比，它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，并允许动力学建模以及亲和力和密度的估计。迄今为止，MGH 使用 [11C]altropane 和 PET 对 6 名成人和 6 名对照进行了成像，结果显示 DAT 结合增加了 34%。此外，库克等人还证明了 ADHD 与多巴胺转运蛋白消失的 480 bp 等位基因之间存在关联。 为此，该分子成像提案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-阿托烷) 和状态，牢固确定成人 ADHD 中 DAT 结合增加的程度。最先进的成像（PET）。此外，我们试图扩展之前的研究结果来检查密度 (B'max) 和亲和力 (Kd)。拟议的工作应该将多动症研究领域推向分子遗传学和影像学研究相结合的新方向。我们的具体目标如下： 1. 使用 11C 阿托烷作为液体的 PET 扫描检查成人 ADHD 中的 DAT 受体结合。我们假设，与没有 ADHD 的成年人相比，患有 ADHD 的成年人将具有更高的 DAT 结合力，这不能用精神合并症、性别或年龄来解释。此外，我们将分别检查 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 症状的严重程度呈正相关； b) 神经心理和人际功能障碍。 3. 为了检查 DAT 结合和遗传风险因素之间的关系，a) 我们假设 DAT 结合将与多巴胺转运蛋白基因 3'-非翻译区中 40 bp VNTR 的 480 等位基因相关。

项目成果

Further evidence of dopamine transporter dysregulation in ADHD: a controlled PET imaging study using altropane.

ADHD 中多巴胺转运蛋白失调的进一步证据：使用阿托烷的对照 PET 成像研究。

• DOI: 10.1016/j.biopsych.2006.12.008
• 发表时间: 2007
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Spencer,ThomasJ;Biederman,Joseph;Madras,BerthaK;Dougherty,DarinD;Bonab,AliA;Livni,Elijahu;Meltzer,PeterC;Martin,Jessica;Rauch,Scott;Fischman,AlanJ
• 通讯作者: Fischman,AlanJ