PET imaging of alpha 7 and alpha4beta2-nAChR in schizophrenia: Cognitive Relationships

这是R 01的竞争性更新，最初是在验证第一个正电子发射时获得资助的。 断层扫描（PET）放射性示踪剂，[18 F] ASEM，特异性结合烟碱乙酰胆碱的α7亚型 受体（α7-nAChR）在人体研究中的成功。我们的发展和验证[18F]亚欧会议在我们以前的 资金期限是未来的关键，在当前的应用中，我们提出了α7-nAChR的体内研究 精神分裂症（SCZ）和认知功能。认知功能缺陷是SCZ的核心特征。人 SCZ患者在注意力、工作和长期记忆以及执行功能方面表现出明显的缺陷。一个强大 低α7-nAChR密度和认知缺陷的严重性之间的关联已经在动物中被证实 模型，并与SCZ诊断在人类死后的研究。本提案的总体目标是 确定与认知缺陷相关的体内SCZ中α7-nAChR的可用性。在上一个供资期间， 我们建立了年龄效应、极好的试验/重复试验重现性和[18 F] ASEM与α7- nAChR。在这次更新中，我们计划招募60名SCZ患者和60名吸烟状态匹配的对照， 年龄性别种族和父母的社会经济地位将对受试者进行SCZ连锁多态性基因分型 α7-nAChR基因（rs3087454）的表达水平将作为协变量纳入我们的分析。我们计划中的大多数 预计SCZ受试者人群将接受非典型抗精神病药（AP）治疗。预见到可能的混乱 我们将在狒狒中测试我们SCZ人群中最常见的3种非典型AP的作用， Subaim证实我们在小鼠和1例SCZ患者中的非典型AP发现对利培酮和停用利培酮没有影响。 目的1我们将检验在尸检研究和我们的初步数据中证明的假设，即[18F] 在SCZ中ASEM结合将减少。AP对[18F] ASEM结合的影响将在狒狒中进行测试， 子目标1.目的2由于SCZ与烟草使用的高共患病率，以及严重程度与吸烟的相关性， SCZ的认知缺陷和高亲和力α4β2-nAChR亚型的可用性，我们将在相同的 使用我们的α4 β 2-nAChR选择性PET示踪剂，SCZ和对照受试者的α4 β 2-nAChR特征，[18 F] 阿赞。我们的假设是，[18F] AZAN结合在吸烟参与者的大脑区域中会较低， SCZ，与匹配的吸烟对照相比。在目标3中，我们将检查阴性症状和认知 使用经验证的认知成套测验和SCZ的临床量表作为主要结局。我们将确定 认知缺陷是否与α7-或α4β2-nAChR的可用性相关，或者可能与 这两种亚型。这将是首次使用两种人类PET示踪剂对SCZ中的认知缺陷进行研究， 对α7-和α4β2-nAChR选择性高。长期的结果是确定这两者之间的关系 nAChR亚型和SCZ的认知功能，最终将提供更好的理解nAChR 病理生理学和指导未来烟碱类药物的开发SCZ。

This is a competitive renewal of an R01 that initially was funded on validation of the first positron emission tomography (PET) radiotracer, [18F] ASEM, which binds specifically to α7 subtype of nicotinic acetylcholine receptors (α7-nAChR) successfully in human studies. Our development and validation of [18F] ASEM in our prior funding period was critical for future and in the current application we proposed in vivo investigation of α7-nAChR in schizophrenia (SCZ), and cognitive function. Deficits in cognitive function are a core feature of SCZ. People with SCZ show marked deficits in attention, working and long-term memory, and executive functioning. A strong association between low α7-nAChR density and severity of cognitive deficits has been demonstrated in animal models, and with SCZ diagnosis in human post-mortem studies. The overarching goal of the current proposal is to determine α7-nAChR availability in SCZ in vivo in connection with cognitive deficits. In the prior funding period, we established age effects, excellent test/retest reproducibility, and specificity of binding of [18F] ASEM to α7- nAChR. In this renewal, we propose to enroll 60 patients with SCZ and 60 controls matched for smoking status, age, sex, race, and parental socioeconomic status. Subjects will be genotyped for a SCZ-linked polymorphism of α7-nAChR gene (rs3087454) which will be included as a covariate in our analysis. The majority of our planned SCZ subject population is anticipated to be on atypical antipsychotics (AP). To anticipate possible confounds of medication we will test the effects of 3 of the most common atypical APs of our SCZ population in baboons as a SubAim to confirm our no-effect of atypical AP findings in mice and 1 SCZ patient on- and off-Risperidone. Aim 1 We will test the hypothesis demonstrated in post-mortem studies and in our preliminary data, that [18F] ASEM binding will be decreased in SCZ. Effect of AP on [18F] ASEM binding will be tested in baboons as a SubAim1. Aim 2 Because of the high comorbidity of SCZ and tobacco use, and association between severity of cognitive deficits in SCZ and availability of the high-affinity α4β2-nAChR subtype, we will examine in the same SCZ and control subjects for α4β2-nAChR characteristics using our α4β2-nAChR selective PET tracer, [18F] AZAN. Our hypothesis is that [18F] AZAN binding will be lower in the brain regions of smoking participants with SCZ, when compared to matched smoking controls. In Aim 3 we will examine negative symptoms and cognitive deficits using a validated cognitive battery and in clinical scales for SCZ as primary outcomes. We will determine whether cognitive deficits are related to the α7- or the α4β2-nAChR availability, or, possibly, synergistically with these two subtypes. This will be the first study of cognitive deficits in SCZ using two human PET tracers with high selectivity for α7- and α4β2-nAChR. The long-term results is to determine a relationship between these two nAChR subtypes and cognitive function in SCZ, which ultimately will provide a better understanding of nAChR pathophysiology and guidance for future nicotinic drug development for SCZ.