Preliminary studies of muscarinic M1 receptor availability and cognition in schizophrenia

项目摘要和摘要 背景：来自尸检研究的一致证据提供了强有力的证据表明 精神分裂症(SZ)患者中存在M_1受体缺陷。M1受体是一种 深圳地区认知障碍的重要靶点。然而，到目前为止，还不可能检查 SZ与M1受体在体内可利用性的异质性。一种新型正电子发射装置的研制 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， 检测在体脑M_1受体在深圳的可用性，同时阐明 M1受体与深圳地区认知缺陷的关系。该配体对M1受体具有高亲和力，高脑摄取率， 适当的动力学，良好的重测重复性(皮质区域的≤6%的重测变异性)，以及 阻断研究证明存在一个合适的参照区(即小脑)。这允许一个 使用动力学模型可靠地估计与M1受体的特异性结合(BPND)。这样做的目的是 探索性研究是检查SZ患者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，即脑电和言语中诱发的ɣ振荡 记忆。此外，还探讨了海马区[11C]EMO利用度、诱发ɣ振荡、 将探索言语记忆和疾病严重程度的测量方法。 假设：使用[11C]EMO测量，SZ受试者将显示较低的海马区M1受体利用率 BPND。此外，M1受体的可用性([11C]emo BPND)将与言语记忆能力和 在SZ的言语记忆任务中，编码的脑电指标(γ功率)。 方法：我们将比较SZ和年龄、性别匹配的健康对照中M1受体的可用性 [11C]EMO和高分辨率研究断层扫描仪(HRRT)，一种具有高灵敏度和 可用于人脑成像的分辨率。大鼠海马区[11C]EMO结合、 在言语记忆任务、言语记忆、性别和血清乙酰胆碱水平过程中编码相关的γ能力 将会被探索。这项探索性研究将提供必要的先导数据，以进行更大规模的研究，以充分 研究SZ与M1受体可用性的异质性。

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.