Multimodal MR Imaging of the Glutamate System in Schizophrenia

 描述（由申请人提供）：尽管基础神经科学和临床精神病学取得了进展，但精神分裂症（SCZ）的治疗仍然有限。这些局限性的一个主要原因是缺乏能够测量SCZ病理生理学和实验药剂的靶点参与的生物标志物。因此，作为这个指导职业发展奖（K23）的一部分，我建议获得精神分裂症谷氨酸系统的多模态磁共振（MR）成像的培训，具体培训目标如下：1）深入了解使用高分辨率，稳态，钆增强功能磁共振成像[即，脑血容量（CBV）]; 2）获得使用质子磁共振波谱（MRS）检查SCZ中谷氨酸系统的深入知识; 3）发展谷氨酸系统在SCZ的神经生物学及其治疗中的作用的专业知识。这些培训和科学目标，再加上我在三年T32奖学金和三年KL 2培训中获得的PET和治疗学培训，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点参与。 在这个指导以患者为导向的研究职业发展奖的科学重点将是谷氨酸系统，重点是慢性疾病对谷氨酸在海马和内侧前额叶皮层（mPFC）区域在SCZ的影响。另一个目的是检查CBV和谷氨酸（Glu）MRS在这两个脑区之间的关系。我最近高级撰写了两篇关于SCZ中谷氨酸的重要评论，特别是关于SCZ中谷氨酸的成像。SCZ中谷氨酸系统的成像研究结果强烈支持谷氨酸在SCZ中的作用。特别是，发现海马CA 1区的CBV可预测临床高风险（CHD）队列中向精神病的转化，而谷氨酸被认为是致病驱动因素。此外，MRS已确定海马和mPFC中谷氨酸升高为SCZ的关键病理生理学标志物。然而，CBV从未被用于研究谷氨酸系统在沿着SCZ谱的沿着不同阶段的电位差异（例如，在慢性与早期SCZ中），并且虽然CBV信号已显示在啮齿动物中是神经元能的，但尚未在人类中进行类似的验证。这项工作对于全面了解SCZ中的谷氨酸至关重要。例如，它们可能有助于解释为什么mGluR 2/3激动剂仅在早期SCZ人群中表现出益处（布鲁斯·金农博士在精神分裂症国际研究学会一年两次的会议上的演讲，佛罗伦萨，意大利，2014年4月），而不是在整个组中。此外，虽然在荟萃分析和我们自己的氯胺酮数据中已经提出了通过MRS测量的谷氨酸盐的年龄效应，其中急性氯胺酮激发导致通过MRS测量的谷氨酸盐增加，而在慢性氯胺酮使用者中没有观察到这一点，但我们自己的MRS数据的探索性分析表明，这是药物状态（即，服用或不服用药物），而不是年龄影响谷氨酸水平。因此，我的具体目标是：1）研究年龄和慢性疾病对SCZ患者海马和mPFC中Glu MRS和CBV的影响。我们假设，在SCZ患者中，年龄/慢性疾病与CBV/Glu之间存在负相关关系。2)探讨海马CBV和Glu MRS与mPFC的关系。我们推测，在SCZ患者中，CBV和Glu MRS之间存在直接的正相关。3)检查SCZ患者和对照受试者海马和mPFC中CBV和Glu MRS之间的差异，并检查患者海马和mPFC中CBV和Glu MRS与临床（PANSS）和神经认知（MATRICS）测量之间的关系。我们假设，在这两个地区的CBV和Glu MRS将在SCZ的个人比对照组更大，CBV和Glu在这两个地区的水平较高，将与更大的痴呆症和更差的神经认知功能的患者。为了获得多模式CBV/MRS成像的培训，检查年龄/慢性疾病对CBV和Glu MRS的影响，并检查CBV和Glu MRS之间的关系，我们建议招募30名无药物治疗的SCZ患者和30名匹配的健康对照受试者，并在mPFC和海马中进行全脑CBV和Glu MRS。这些职业，培训和研究目标建立在我作为T32研究员和K12学者获得的培训和数据之上。我将在纽约州立精神病研究所和哥伦比亚大学医学中心的培养环境中执行拟议的研究项目并实施职业发展计划。这些机构拥有所需的资源和跟踪记录，使我能够获得必要的技能和经验，以建立自己作为一个独立的，以患者为导向的研究人员，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目标参与方面的专家，并与我的导师不同的重点。

 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.