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实验，包括人脑成像和人类尸检研究，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，揭示边缘神经元网络与精神病和APD的治疗反应。在无药物的患者中，我们发现精神病症状与前扣带皮层（ACC）和海马（HIP）的rCBF模式相关。治疗一周后观察到的腹侧纹状体（VS）和HIP中APD诱导的功能变化可预测治疗反应。我们对纹状体的尸检研究表明，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升高与治疗反应有关。此外，谷氨酸（GLU）突触的数量在治疗良好（GR）和治疗不良（PR）反应者之间存在显著差异，表明GLU传递受到不同影响。这些研究的结果通知我们的假设，在GR，DA受体阻断VS恢复GLU传输，通过升高DA抑制。因此，有更大的GLU活性VS和GLU介导的投影到边缘区域，如ACC和HIP，导致恢复神经元的完整性。我们假设，导致APD治疗获益的早期生理过程与VS内GLU传输和GLU介导的边缘区投射的变化相关，并且良好和不良反应者的治疗反应特征在于影响神经元突触完整性和功能的差异性改变模式。我们将测试这一假设，使用互补的成像和尸检产生的数据，将允许制定一个全面的模型APD反应的严重精神疾病的主题。我们将试图复制和扩展我们的PET研究结果与功能磁共振成像使用的任务，已知激活HIP（情节记忆任务）和ACC（Stroop任务）。这一目标将进一步寻求解析出HIP和ACC对治疗反应的不同贡献。同时，N-乙酰天冬氨酸（NAA），神经元完整性的标志物和GLU测量获得的质子磁共振波谱（1H-MRS）将直接探测在活脑神经元的完整性，GLU功能和治疗反应之间的关系。与此同时，尸检工作将集中在ACC上，因为该区域显示了最可靠的成像数据。我们将试图通过检查GR和PR中ACC的输入和输出层来确定NAA和GLU变化的机制。我们将量化谷氨酸神经元中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，并计算突触的数量和大小。这些研究应该允许发展关于治疗的病理生理学的假设反应，并提供了一个基础的功能成像数据的解释。总体目标是确定将预测治疗反应的成像标记物，并使用死后组织的解剖学研究来确认或验证这些生物标记物。药物反应的早期检测将产生针对个体的特定治疗策略，从而改善患者的生活质量并大幅降低与不成功的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实验，包括人脑成像和人类尸检研究，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，从而改善患者的生活质量并大幅降低与不成功的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.