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: 10165041
• 负责人: Andrew G Horti
• 金额: $ 70.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165041
• 关键词: Address; Affect; Affinity; Age; Agonist; Agreement; Animal Model; Antipsychotic Agents; Attention; Autopsy; Binding; Brain region; Characteristics; Clinical; Cognition; Cognitive; Cognitive deficits; 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; comorbidity; 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，最初是在验证首次正电子发射时资助的 断层扫描 (PET) 放射性示踪剂，[18F] ASEM，与烟碱乙酰胆碱的 α7 亚型特异性结合 受体（α7-nAChR）在我们之前的人类研究中成功地开发和验证了[18F] ASEM。 资助期限对于未来至关重要，在当前的申请中，我们提出了 α7-nAChR 的体内研究 认知功能缺陷是精神分裂症 (SCZ) 的核心特征。 患有 SCZ 的人在注意力、工作记忆、长期记忆以及执行功能方面表现出明显的缺陷。 低 α7-nAChR 密度与认知缺陷严重程度之间的关联已在动物身上得到证实 模型，以及人类尸检研究中的 SCZ 诊断 当前提案的总体目标是 确定 SCZ 体内与认知缺陷相关的 α7-nAChR 可用性。 我们确定了年龄效应、出色的测试/再测试重现性以及 [18F] ASEM 与 α7- 结合的特异性 在本次更新中，我们建议招募 60 名 SCZ 患者和 60 名与吸烟状况相匹配的对照， 将对受试者的年龄、性别、种族和父母的社会经济地位进行 SCZ 连锁多态性基因分型。 α7-nAChR 基因 (rs3087454) 将作为协变量包含在我们计划的大部分分析中。 SCZ 受试者人群预计将服用非典型抗精神病药物 (AP)，以预测可能出现的混淆。 我们将测试 SCZ 种群中 3 种最常见的非典型 AP 对狒狒的影响，作为 子目标是确认我们对小鼠和 1 名 SCZ 患者服用和停用利培酮时的非典型 AP 发现没有影响。 目标 1 我们将测试尸检研究和初步数据中证明的假设，即 [18F] AP 对 [18F] ASEM 结合的影响将在 SCZ 中降低，并将在狒狒中进行测试。 子目标 1. 目标 2 由于 SCZ 和吸烟的合并症很高，并且严重程度之间存在关联。 SCZ 认知缺陷的影响和高亲和力 α4β2-nAChR 亚型的可用性，我们将在相同的研究中进行检查 使用我们的 α4β2-nAChR 选择性 PET 示踪剂对 SCZ 和对照受试者进行 α4β2-nAChR 特征分析，[18F] 我们的假设是，吸烟参与者的大脑区域中的[18F] AZAN 结合力会较低。 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能力。 我们将使用经过验证的认知电池和 SCZ 临床量表来确定缺陷作为主要结果。 认知缺陷是否与 α7- 或 α4β2-nAChR 可用性有关，或者可能与 这将是首次使用两种人类 PET 示踪剂对 SCZ 认知缺陷进行研究。 对 α7- 和 α4β2-nAChR 的高选择性 长期结果是确定这两者之间的关系。 SCZ 中的 nAChR 亚型和认知功能，最终将提供对 nAChR 更好的理解 SCZ 的病理生理学和未来烟碱类药物开发的指导。