Microglial activation in alcohol dependence: A [C-11]PBR28 PET study.

描述(申请人提供)：酒精依赖影响1800万美国人。酒精依赖的治疗只显示出适度的疗效，需要更好的治疗方法。全身炎症、神经炎症和小胶质细胞激活可能在酒精中毒的发病机制中发挥作用。我们和其他人的工作表明，全身性炎症对大脑有重要影响，包括对动机和情绪的影响，以及小胶质细胞的激活。在啮齿动物中，长期酒精暴露会导致小胶质细胞的激活， 释放导致神经元功能障碍和死亡的物质，例如炎性细胞因子。由促炎信号激活的小胶质细胞在酒精中毒中系统性增加，这可能是酒精干扰神经功能从而导致渴求和持续饮酒的一种机制。啮齿动物和尸检人类的研究表明，这种激活是长期饮酒的结果，而且是持续的。正电子发射断层扫描(PET)的转运蛋白(TSPO)成像被用来测量活体人脑中激活的小胶质细胞的存在。我们发现在酒精依赖的受试者和对照组中，TSPO放射性示踪剂[11C]PBR28的结合强度更高，这表明PET成像可以用来检测体内酒精中毒者的小胶质细胞激活。我们建议扩展这一令人兴奋的发现，并使用[11C]PBR28来评估酒精依赖个人的小胶质细胞激活，[11C]PBR28对目前可用的TSPO示踪剂中的TSPO具有最高的特异性，以及高分辨率研究断层扫描仪，高分辨率研究断层扫描仪是可用的最高分辨率的人类PET相机。酒精依赖(AD)组(n=15)与健康对照组(HC)在年龄、性别、种族和教育水平方面进行配对。PET扫描将在他们最后一次饮酒后24小时内进行。HC受试者将作为门诊患者进行评估和扫描。一组AD受试者(n=8)将进入住院研究单元，并在7天后进行第二次PET扫描，以评估小胶质细胞激活的短期持久性。将获得行为评级(渴望、认知功能、抑郁和焦虑)和血液细胞因子水平。[11C]PBR28将作为一剂注射，并将在HRRT上获得两小时的排放扫描。分布体积(VT)将从适合每个感兴趣区域的模型中估计，并将与行为测量和细胞因子水平(TNFpha、IL-6)相关。我们假设，作为长期饮酒的结果，AD患者在最后一次饮酒后24小时内，其PBR28结合水平将显著高于对照组(15%)，并且这种更高的小胶质细胞激活将持续存在，并在7天后保持更高水平。如果AD受试者有更高的小胶质细胞激活，这有助于酒精中毒的核心行为，那么可以测试减少小胶质细胞激活和神经炎症的药物干预措施来治疗酒精中毒。

DESCRIPTION (provided by applicant): Alcohol dependence affects 18 million Americans. Treatments for alcohol dependence show only modest efficacy, and better treatments are needed. Systemic inflammation, neuroinflammation, and microglial activation may play a role in the pathogenesis of alcoholism. Our work and that of others has shown that systemic inflammation has important effects on the brain, including effects on motivation and emotion, and activation of microglia. In rodents, chronic alcohol exposure leads to activation of microglia, which release substances that cause neuronal dysfunction and death, e.g. inflammatory cytokines. Activation of microglia by pro-inflammatory signals, which are increased systemically in alcoholism, may be a mechanism through which alcohol interferes with neuronal function, thus contributing to craving and continued drinking. Rodent and postmortem human studies suggest this activation is a consequence of chronic alcohol drinking and that it is persistent. Positron emission tomography (PET) imaging of the Translocator Protein (TSPO) is used to measure the presence of activated microglia in the human brain in vivo. We found robust, higher binding of the TSPO radiotracer [ 11C]PBR28 in an alcohol-dependent vs. control subject, suggesting that PET imaging can be used to detect microglial activation in individuals with alcoholism in vivo. We propose to extend this exciting finding and assess microglial activation in alcohol-dependent individuals using [11C]PBR28, which has the highest specificity for TSPO of currently-available TSPO tracers, and the High Resolution Research Tomograph, the highest resolution human PET camera available. Alcohol-dependent (AD) subjects (n=15) will be matched with healthy control (HC) subjects (n=15) for age, sex, race and education level. A PET scan will be performed within 24 hours of their last drink. HC subjects will be assessed and scanned as outpatients. A subset of AD subjects (n=8) will be admitted to the inpatient research unit and will have a second PET scan 7 days later to assess short-term persistence of microglial activation. Behavioral ratings (craving, cognitive function, depression and anxiety) and blood cytokine levels will be obtained. [11C]PBR28 will be injected as a bolus, and a two-hour emission scan will be acquired on the HRRT. Volume of distribution (VT) will be estimated from the model fits for each region of interest and will be correlated with behavioral measures and cytokine levels (TNFalpha, IL-6). We hypothesize that as a consequence of chronic alcohol drinking, AD subjects will have significantly higher (>15%) levels of PBR28 binding vs. controls within 24 hours of the last drink and that this higher microglial activation will persist and remai higher 7 days later. If AD subjects have higher microglial activation, and this contributes to the core behaviors of alcoholism, pharmacological interventions that reduce microglial activation and neuroinflammation may be tested for the treatment of alcoholism.