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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：
10304204
负责人：
DEEPAK Cyril D'SOUZA
金额：
$ 20.94万
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 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304204
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.

项目总结和摘要背景：来自死后研究的证据提供了强有力的证据，毒蕈碱M1受体缺陷存在于精神分裂症（SZ）患者的一个子集中。M1受体是一种 SZ中认知缺陷的重要靶点。然而，到目前为止，还不可能检查 SZ与体内M1受体利用率的异质性。一种新的正电子发射技术的发展断层扫描（PET）配体，[11 C]EMO，在耶鲁PET中心提供了一个独特的机会，首次，检查SZ体内脑毒蕈碱M1受体的可用性，同时阐明 SZ中认知缺陷的M1受体。该配体对M1受体具有高亲和力，高脑摄取，适当的动力学，良好的重复检测重现性（皮质区域的重复检测变异性≤ 6%），以及存在合适的参考区域（即，小脑）在阻断研究中证实。这允许使用动力学建模可靠估计与M1受体的特异性结合（BPND）。这样做的目的探索性研究是检查SZ患者的M1受体可用性，并将M1受体可用性与认知表现的近端和远端测量，即诱发的EEG和言语振荡，记忆此外，海马[11 C]EMO可用性（BPND），诱发的EMO振荡，语言记忆和疾病严重程度的测量将被探索。假设：使用[11 C]EMO测量，SZ受试者的海马M1受体可用性较低 BPND。此外，M1受体可用性（[11 C]EMO BPND）将与非文字记忆表现相关， SZ儿童言语记忆过程中的脑电编码指标（γ功率）方法：我们将比较SZ和年龄、性别匹配的健康对照组的M1受体可用性， [11C]EMO和高分辨率研究断层扫描仪（HRRT），一种具有高灵敏度和分辨率可用于人脑成像。海马[11 C]EMO结合，言语记忆任务中编码相关γ功率、言语记忆、性别和血清乙酰胆碱水平将被探索。这项探索性研究将提供必要的试点数据，以进行更大规模的研究，研究SZ在M1受体利用率方面的异质性。