Treatment response in schizophrenia: bridging imaging and postmortem studies

描述（由申请人提供）：该提案的目标是进行包括人脑成像和人类死后研究的实验，旨在确定抗精神病药物（APD）治疗反应的神经元标志物。我们的影像学研究取得了重大进展，揭示了边缘神经元网络与精神病和APD治疗反应有关。在无药物患者中，我们发现精神病症状与前扣带皮层（ACC）和海马体（HIP）的rCBF模式有关。治疗一周后观察到apd诱导的腹侧纹状体（VS）和HIP功能变化可预测治疗反应。我们对纹状体的死后研究表明，对治疗有反应的患者有更多的多巴胺能（DA）突触，这表明纹状体DA的升高与治疗反应有关。此外，在治疗良好（GR）应答者和治疗不良（PR）应答者之间，谷氨酸（GLU）突触的数量也有显著差异，表明GLU的传递受到了不同的影响。这些研究的结果证实了我们的假设，即在GR中，DA受体阻断在VS中恢复了因DA升高而被抑制的GLU传递。因此，GLU在VS和GLU介导的边缘区域（如ACC和HIP）的投射中有更大的活性，导致神经元完整性恢复。我们假设，导致APD治疗获益的早期生理过程与GLU在VS内传递和GLU介导的边缘区域投射的变化有关，并且反应良好和反应不良的治疗反应的特点是影响神经元突触完整性和功能的不同改变模式。我们将使用补充成像和尸检数据来验证这一假设，这些数据将允许制定严重精神疾病受试者APD反应的综合模型。我们将试图用fMRI复制和扩展我们的PET发现，使用已知的激活HIP（情景记忆任务）和ACC （Stroop任务）的任务。这一目标将进一步寻求解析出HIP和ACC对治疗反应的差异贡献。同时，n -乙酰天冬氨酸（NAA）是一种神经元完整性和GLU测量的标记物，通过质子磁共振波谱（1H-MRS）可以直接探测活脑中神经元完整性、GLU功能和治疗反应之间的关系。同时，尸检工作将集中在前扣带区，因为该区域显示了最可靠的成像数据。我们将通过检测GR和PR中ACC的输入和输出层，试图确定NAA和GLU变化的机制。我们将量化谷氨酸神经元神经元完整性的形态学指标，计算GLU神经元中线粒体的数量和结构完整性，以及计算谷氨酸突触的数量和大小。这些研究应该允许关于治疗反应的病理生理学假设的发展，并为功能成像数据的解释提供基础。总体目标是确定预测治疗反应的成像标记，并通过死后组织的解剖研究来确认或验证这些生物标记。药物反应的早期检测将产生针对个体的特定治疗策略，从而提高患者的生活质量，并大幅降低与失败治疗策略相关的成本。公共卫生相关性；该提案的目标是进行包括人脑成像和人类死后研究在内的实验，旨在确定精神分裂症抗精神病药物治疗反应的神经元标志物。药物反应的早期检测将产生针对个体的特定治疗策略，从而提高患者的生活质量，并大幅降低与失败治疗策略相关的成本。

DESCRIPTION (provided by applicant): The goal of the proposal is to perform experiments encompassing human brain imaging and human postmortem studies aimed at identifying neuronal markers of treatment response to antipsychotic medication (APD). Our imaging studies have made significant progress by revealing that limbic neuronal networks are related to psychosis and treatment response to APD. In drug-free patients we found psychotic symptoms to be related to rCBF patterns in the anterior cingulate cortex (ACC) and the hippocampus (HIP). APD-induced functional changes in ventral striatum (VS) and HIP observed after one week of treatment are predictive of treatment response. Our postmortem studies of the striatum indicate that patients who responded to treatment had more dopaminergic (DA) synapses, suggesting that elevated striatal DA relates to treatment response. In addition, the number of glutamate (GLU) synapses was significantly different between treatment good (GR) and poor (PR) responders, suggesting that GLU transmission is affected differentially. The results of these studies informed our hypothesis that in GR, DA receptor blockade in VS restores GLU transmission that was inhibited through elevated DA. Consequently, there is greater GLU activity in VS and GLU-mediated projections to limbic regions, such as the ACC and HIP, leading to restored neuronal integrity. We have hypothesized that the early physiological processes that lead to therapeutic benefit with APD are related to changes in GLU transmission within the VS and in GLU-mediated projections to limbic regions and that treatment response in good and poor responders is characterized by differential pattern of alterations affecting the integrity and function of neuronal synapses. We will test this hypothesis using complementary imaging and postmortem yielding data that will permit the formulation of a comprehensive model for APD responses in subjects with severe mental illness. We will seek to replicate and extend our PET findings with fMRI using tasks that are known to activate the HIP (Episodic memory task) and the ACC (Stroop task). This aim will further seek to parse out the differential contribution of the HIP and ACC to treatment response. At the same time, N-acetylaspartate (NAA), a marker of neuronal integrity and GLU measurements obtained with proton magnetic resonance spectroscopy (1H-MRS) will directly probe in the living brain the relation between neuronal integrity, GLU-function and treatment response. In parallel, the postmortem work will concentrate on the ACC, as this region shows the most reliable imaging data. We will attempt to determine the mechanism by which changes in NAA and GLU are made by examining input and output layers of the ACC in GR and PR. We will quantify morphological indicies of neuronal integrity in glutamte neurons, count the number and structural integrity of mitochondria in GLU neurons and count the number and size of glutamatergic synapses.These studies should allow the development of hypotheses about the pathophysiology of treatment response and provide a basis for the interpretation of functional imaging data. The overarching goal is to identify imaging markers that will predict treatment response, and to confirm or validate these biomarkers using anatomical studies of postmortem tissue. Early detection of drug response would yield specific treatment strategies that are tailored to the individual, thus improving both the quality of life of the patients and drastically reducing the costs associated with unsuccessful treatments strategies. PUBLIC HEALTH RELEVANCE; The goal of the proposal is to perform experiments encompassing human brain imaging and human postmortem studies aimed at identifying neuronal markers of treatment response to antipsychotic medication in schizophrenia. Early detection of drug response would yield specific treatment strategies that are tailored to the individual, thus improving both the quality of life of the patients and drastically reducing the costs associated with unsuccessful treatments strategies.