Preliminary studies of muscarinic M1 receptor availability and cognition in schizophrenia

精神分裂症毒蕈碱 M1 受体可用性和认知的初步研究

基本信息

批准号：
10156577
负责人：
DEEPAK Cyril D'SOUZA
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10156577
关键词：
Acetylcholine Address Affinity Age Agonist Anti-Cholinergics Antipsychotic Agents Autopsy Autoradiography Binding Brain Brain imaging Cerebellum Cessation of life Chlorpromazine Clinical Research Cognition Cognitive deficits Collection Data Development Disease Distal Dopamine Electroencephalography Functional disorder Future Gender Gene Expression Genetic Heterogeneity Hippocampus (Brain)Human Immunohistochemistry In Vitro Kinetics Knock-out Ligands Measures Mediating Memory Methods Modeling Morbidity - disease rate Muscarinic M1 Receptor Muscarinics N-Methylaspartate Nature Nicotine Patients Performance Pharmaceutical Preparations Positron-Emission Tomography Preclinical Drug Development Prefrontal Cortex Reproducibility Research Resolution Risperidone Schizophrenia Sensory Receptors Serum Severity of illness Signal Transduction Site Slice Specificity Specimen Testing Therapeutic Time cognitive performance cognitive testing density imaging study improved in vivo independent component analysis indexing kinetic model mRNA Expression neural circuit novel patient subsets performance tests positive allosteric modulator postsynaptic pre-clinical psychiatric symptom response tool uptake

项目摘要

PROJECT SUMMARY AND ABSTRACT Background: Converging lines of evidence from postmortem studies provide strong evidence that brain muscarinic M1 receptor deficit is present in a subset of schizophrenia (SZ) patients. M1 receptors are an important target for cognitive deficits in SZ. However, until now, it has not been possible to examine the heterogeneity of SZ with respect to M1 receptor availability in vivo. The development of a novel positron emission tomography (PET) ligand, [11C]EMO, at Yale PET Center provides a unique opportunity to, for the first time, examine in vivo brain muscarinic M1 receptor availability in SZ and, concurrently, elucidate the relationship of M1 receptors to cognitive deficits in SZ. The ligand has high affinity for the M1 receptor, high brain uptake, appropriate kinetics, excellent test-retest reproducibility (≤ 6% test-retest variability in cortical regions), and presence of a suitable reference region (i.e., cerebellum) demonstrated in blocking studies. This allows for a reliable estimation of specific binding to M1 receptors (BPND) using kinetic modeling. The purpose of this exploratory study is to examine M1 receptor availability in SZ patients and to relate M1 receptor availability to proximal and distal measures of cognitive performance, namely evoked ɣ oscillations in the EEG and verbal memory. Furthermore, the relationship between hippocampal [11C]EMO availability (BPND), evoked ɣ oscillations, verbal memory, and measures of illness severity will be explored. Hypotheses: SZ subjects will show lower hippocampal M1 receptor availability as measured using [11C]EMO BPND. Additionally, M1 receptor availability ([11C]EMO BPND) will correlate with verbal memory performance and EEG indices of encoding (γ power) during a verbal memory task in SZ. Methods: We will compare M1 receptor availability in SZ and age-, gender-matched healthy controls using [11C]EMO and the High Resolution Research Tomograph (HRRT), a PET scanner with high sensitivity and resolution available for human brain imaging. The relationship between hippocampal [11C]EMO binding, encoding related γ power during a verbal memory task, verbal memory, gender and serum acetylcholine level will be explored. This exploratory study will provide the necessary pilot data to conduct a larger study to fully investigate the heterogeneity of SZ with respect to M1 receptor availability.

项目概要和摘要背景：来自尸检研究的一系列证据提供了强有力的证据表明大脑一部分精神分裂症 (SZ) 患者存在毒蕈碱 M1 受体缺陷。 SZ 认知缺陷的重要目标然而，到目前为止，还无法检查 SZ 与 M1 受体体内可用性的异质性新型正电子发射的发展。耶鲁大学 PET 中心的断层扫描 (PET) 配体 [11C]EMO 首次提供了一个独特的机会：检查 SZ 中体内脑毒蕈碱 M1 受体的可用性，同时阐明 M1 受体对 SZ 认知缺陷的配体对 M1 受体具有高亲和力，大脑摄取高，适当的动力学、出色的重测重现性（皮质区域的重测变异性≤ 6%），以及在阻断研究中证明存在合适的参考区域（即小脑），这允许进行。使用动力学模型可靠地估计与 M1 受体的特异性结合 (BPND)。探索性研究的目的是检查 SZ 患者中 M1 受体的可用性，并将 M1 受体的可用性与认知表现的近端和远端测量，即脑电图和言语中诱发的 ɣ 振荡此外，海马[11C]EMO可用性（BPND）与诱发的ɣ振荡之间的关系。将探讨语言记忆和疾病严重程度的衡量标准。假设：使用 [11C]EMO 测量，SZ 受试者的海马 M1 受体可用性较低此外，M1 受体可用性 ([11C]EMO BPND) 将与言语记忆表现和相关性相关。 SZ 言语记忆任务期间的脑电图编码指数（γ 功率）。方法：我们将使用 SZ 和年龄、性别匹配的健康对照组来比较 M1 受体的可用性 [11C]EMO 和高分辨率研究型断层扫描仪 (HRRT)，一种具有高灵敏度和可用于人脑成像的分辨率。海马 [11C]EMO 结合之间的关系，语言记忆任务期间编码相关γ功率、语言记忆、性别和血清乙酰胆碱水平这项探索性研究将为进行更大规模的研究提供必要的试点数据。研究 SZ 在 M1 受体可用性方面的异质性。