Multimodal MR Imaging of the Glutamate System in Schizophrenia

 描述(申请人提供)：尽管基础神经科学和临床精神病学取得了进步，但精神分裂症(SCZ)的治疗仍然有限。造成这些限制的一个主要原因是缺乏能够测量SCZ病理生理学和实验试剂靶向结合的生物标记物。因此，作为指导职业发展奖(K23)的一部分，我建议接受精神分裂症患者谷氨酸系统的多模式磁共振成像培训，具体培训目标如下：1)深入了解如何在精神分裂症患者中使用高分辨率、稳态、Gd增强的功能磁共振成像[即脑血容量(CBV)]；2)深入了解如何使用质子磁共振波谱仪(MRS)检查精神分裂症患者的谷氨酸系统；3)发展谷氨酸系统在精神分裂症神经生物学中的作用及其治疗方面的专业知识。这些培训和科学目标，再加上我在三年的T32奖学金和三年的KL2培训中获得的PET和治疗学方面的培训，将使我处于一个理想的位置，可以使用谷氨酸系统的多模式成像来评估SCZ的新型谷氨酸能化合物的靶参与情况。这项以患者为导向的指导研究职业发展奖的科学焦点将放在谷氨酸系统上，重点是疾病的慢性化对SCZ的海马区和内侧前额叶皮质(MPFC)区域谷氨酸的影响。另一个目标是研究CBV和谷氨酸(Glu)MRS在这两个大脑区域的关系。我最近写了两篇关于SCZ中谷氨酸的重要评论，特别是关于SCZ中谷氨酸的成像。对SCZ中谷氨酸系统的成像研究结果有力地支持了谷氨酸在SCZ中的作用。特别是，海马区CA1区的CBV被发现在临床高危(CHR)队列中预测转化为精神病，谷氨酸被认为是致病驱动因素。此外，MRS已确定海马区和mPFC中谷氨酸升高是SCZ的关键病理生理标志。然而，CBV从未被用来研究SCZ谱不同阶段谷氨酸系统的潜在差异(例如，在慢性和早期SCZ中)，尽管CBV信号在啮齿类动物中被证明是谷氨酸能的，但在人类中还没有进行类似的验证。这项工作对于全面了解SCZ中的谷氨酸是至关重要的。例如，它们可能有助于解释为什么mGluR2/3激动剂只在早期SCZ人群中显示出益处(Bruce Kinon博士在2014年4月意大利佛罗伦萨举行的精神分裂症国际研究会一年两次的会议上发表的报告)，而不是在整个人群中。此外，虽然在荟萃分析和我们自己的氯胺酮数据中提出了MRS测量的谷氨酸的年龄效应，其中急性氯胺酮激发导致MRS测量的谷氨酸增加，但在慢性氯胺酮使用者中没有观察到这种情况，但对我们自己的MRS数据的探索性分析表明，影响谷氨酸水平的是药物状态(即服用或停药)，而不是年龄。因此，我的具体目标是：1)研究年龄和慢性病对SCZ患者海马区Glu MRS和CBV及mPFC的影响。我们假设在患有SCZ的个体中，年龄/慢性病与CBV/Glu成反比。2)探讨海马区CBV和Glu MRS与mPFC的关系。我们假设在患有SCZ的个体中，CBV和Glu MRS之间存在直接的、正的关系。3)研究SCZ患者与正常对照组之间海马区和mPFC区CBV和Glu MRS的差异，以及与临床(PANSS)和神经认知(Matrics)评分的关系。我们假设SCZ患者两个区域的CBV和Glu MRS都比对照组更大，两个区域的CBV和Glu水平较高将与患者的症状加重和神经认知功能下降相关。为了获得多模式CBV/MRS成像的训练，检查年龄/慢性疾病对CBV和Glu MRS的影响，以及检查CBV和Glu MRS之间的关系，我们建议招募30名SCZ患者和30名匹配的健康对照受试者，在mPFC和海马区进行全脑CBV和Glu MRS检查。这些职业、培训和研究目标建立在我作为T32研究员和K12学者迄今获得的培训和数据的基础上。我将在纽约州精神病研究所和哥伦比亚大学医学中心的培育环境中执行拟议的研究项目和职业发展计划。这些机构拥有所需的资源和记录，使我能够获得必要的技能和经验，将自己确立为一名独立的、以患者为中心的研究人员，在使用多模式谷氨酸成像检查SCZ的病理生理学和实验治疗的靶向方面的专家，并以不同于我导师的重点。

 DESCRIPTION (provided by applicant): Despite advances in basic neuroscience and clinical psychiatry, treatments for schizophrenia (SCZ) remain limited. One main reason for these limitations is the lack of biomarkers capable of measuring SCZ pathophysiology and target engagement of experimental agents. Therefore, as part of this Mentored Career Development Award (K23), I propose to obtain training in multimodal Magnetic Resonance (MR) imaging of the glutamate system in schizophrenia, with the following specific training goals: 1) Obtain in depth knowledge of using high resolution, steady-state, gadolinium enhanced functional magnetic resonance imaging [i.e., cerebral blood volume (CBV)] in SCZ; 2) Obtain in depth knowledge of using proton Magnetic Resonance Spectroscopy (MRS) to examine the glutamate system in SCZ; 3) Develop expertise in the role of the glutamate system in the neurobiology of SCZ and its treatment. These training and scientific goals, combined with the training in PET and therapeutics that I have obtained as part of my three year T32 fellowship and three year KL2 training, will put me in an ideal position to use multimodal imaging of the glutamate system to assess target engagement of novel glutamatergic compounds for SCZ. The scientific focus in this Mentored Patient-Oriented Research Career Development Award will be on the glutamate system with a focus on the effects of chronicity of disease on glutamate in hippocampal and medial prefrontal cortex (mPFC) regions in SCZ. An additional aim will be to examine the relationship between CBV and glutamate (Glu) MRS in these two brain regions. I recently senior authored two important reviews on glutamate in SCZ and in particular on imaging glutamate in SCZ. Findings from imaging studies of the glutamate system in SCZ strongly support a role for glutamate in SCZ. In particular, CBV in the CA1 region of the hippocampus was found to predict conversion to psychosis among a clinical high risk (CHR) cohort, and glutamate was implicated as the pathogenic driver. In addition, MRS has identified elevated glutamate in hippocampus and mPFC as key pathophysiological markers in SCZ. However, CBV has never been used to study potential differences in the glutamate system at different stages along the SCZ spectrum (e.g., in chronic vs. early stage SCZ), and while the CBV signal has been shown to be glutamatergic in rodents, a similar validation has not been performed in humans. This work is critical for a full understanding of glutamate in SCZ. For example, they may help to explain why an mGluR 2/3 agonist demonstrated benefit in only an early stage SCZ population (presentation by Dr. Bruce Kinon at the biannual meeting of the Schizophrenia International Research Society, Florence, Italy, April, 2014) but not in the full group. In addition, while an age effect n glutamate as measured by MRS has been suggested in a meta-analysis and by our own ketamine data in which acute ketamine challenge leads to increases in glutamate as measured by MRS while this is not observed in chronic ketamine users, an exploratory analysis of our own MRS data suggests that it is medication status (i.e., on or off medications) rather than age that effects glutamate levels. Therefore, my specific aims are to: 1) To examine the effects of age and chronicity of illness on Glu MRS and CBV in hippocampus and mPFC in individuals with SCZ. We hypothesize that there will be an inverse relationship between age/chronicity of disease and CBV/Glu in individuals with SCZ. 2) To examine relationships between CBV and Glu MRS in hippocampus and mPFC. We hypothesize that there will be a direct, positive relationship between CBV and Glu MRS in individuals with SCZ. 3) To examine differences between CBV and Glu MRS in hippocampus and mPFC between patients with SCZ and control subjects and to examine relationships between CBV and Glu MRS in hippocampus and mPFC and clinical (PANSS) and neurocognitive (MATRICS) measures in patients. We hypothesize that both CBV and Glu MRS in both areas will be greater in individuals with SCZ than in controls, and that higher levels of CBV and Glu in both regions will correlate with greater symptomatology and worse neurocognitive functioning in patients. To obtain training in multimodal CBV/MRS imaging, examine age/chronicity of illness effects on CBV and Glu MRS, and examine the relationships between CBV and Glu MRS, we propose to recruit 30 medication-free individuals with SCZ and 30 matched healthy control subjects and perform whole brain CBV and Glu MRS in mPFC and hippocampus. These career, training, and research goals build on the training and data that I have obtained to date as a T32 fellow and K12 scholar. I will perform the proposed research projects and implement the career development plan in a nurturing environment at the New York State Psychiatric Institute and Columbia University Medical Center. These institutions have the resources and track record needed to enable me to acquire the skills and experience necessary to establish myself as an independent, patient-oriented researcher, expert in using multimodal glutamate imaging to examine the pathophysiology of SCZ and target engagement of experimental treatments, and with a focus that is different from that of my mentors.