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

精神分裂症中 α7 和 α4β2-nAChR 的 PET 成像：认知关系

• 批准号: 9762230
• 负责人: Andrew G Horti
• 金额: $ 73.19万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-05 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762230
• 关键词: Address; Affect; Affinity; Age; Agonist; Agreement; Animal Model; Antipsychotic Agents; Attention; Autopsy; Binding; Brain region; Characteristics; Clinical; Cognition; Cognitive; Cognitive deficits; Comorbidity; Data; Data Analyses; Development; Diagnosis; Education; Enrollment; Functional disorder; Funding; Future; Generations; Genetic Polymorphism; Genotype; Glutamates; Goals; Grant; Human; Impaired cognition; Investigation; Joints; Link; Methodology; Mus; Nicotinic Receptors; Papio; Participant; Patients; Pharmaceutical Preparations; Pilot Projects; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; Race; Receptor Gene; Reporting; Reproducibility; Research; Risperidone; Rodent; Role; Schizophrenia; Severities; Short-Term Memory; Smoke; Smoker; Smoking; Smoking Status; Socioeconomic Status; Specificity; Symptoms; System; Testing; Time; Tobacco use; Tracer; Transcutaneous Electric Nerve Stimulation; Validation; age effect; alpha-bungarotoxin receptor; atypical antipsychotic; base; cholinergic; cognitive function; cognitive performance; cohort; cost; demographics; drug development; executive function; experimental study; gamma-Aminobutyric Acid; healthy volunteer; human subject; improved; in vivo; long term memory; neurotransmission; novel; primary outcome; radiotracer; receptor binding; receptor density; recruit; sex; single photon emission computed tomography; therapeutic target

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.

这是R01的竞争性更新，最初的资金来自于第一次正电子发射的验证 与烟碱型乙酰胆碱α7亚型特异结合的放射示踪剂[18F] 受体(α7-nAChR)在人体研究中成功。我们在之前的[18F]亚欧会议上的开发和验证 资助期是未来的关键，在目前的应用中，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的一个核心特征。人民 患有SCZ的患者在注意力、工作和长期记忆以及执行功能方面显示出明显的缺陷。一个坚强的人 低α7-nAChR密度与动物认知障碍严重程度的相关性已在动物中得到证实 模型，以及人类尸检中的SCZ诊断。当前提案的首要目标是 测定α7-nAChR在脊髓灰质内的体内可用性与认知功能障碍的关系。在前一个供资期间， 我们确定了[18F]亚欧会议与α7结合的年龄效应、出色的测试/重测重复性和特异性。 NAChR。在这次更新中，我们建议招募60名SCZ患者和60名与吸烟状况匹配的对照组， 年龄、性别、种族和父母的社会经济地位。受试者将接受SCZ连锁多态的基因分型。 α7-nAChR基因(Rs3087454)，将作为协变量纳入我们的分析。我们计划的大部分 预计SCZ受试者人群将服用非典型抗精神病药物(AP)。预见到可能的混乱 药物治疗，我们将测试我们的SCZ种群中最常见的3种非典型AP作为一种 目的证实我们在服用和不服用利培酮的小鼠和1名SCZ患者身上发现的非典型AP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[18F] 在SCZ，ASEM的结合将会减少。AP对[18F]ASEM结合的影响将作为一种 SubAim1.目的2由于SCZ与烟草使用的高共患率，以及严重程度之间的关联 和高亲和力的α4β2-nAChR亚型的可用性，我们将在相同的 使用我们的α4β2-nAChR选择性α示踪剂[18F]，对SCZ和对照受试者进行β4-nAChR特性的研究。 阿赞。我们的假设是，吸烟者大脑中的[18F]Azan结合量将较低 与匹配的吸烟对照组相比，SCZ。在目标3中，我们将检查阴性症状和认知 使用经过验证的认知电池的缺陷和SCZ的临床量表作为主要结果。我们将决定 认知缺陷是否与α7-或α4β2-nAChR的可用性有关，或者可能与 这两个子类型。这将是第一次使用两种人类PET示踪剂对SCZ的认知缺陷进行研究 对α7-和α4β2-nAChR具有高选择性。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，最终将提供对nAChR更好的理解 SCZ的病理生理学和未来尼古丁类药物开发的指导。