Multimodal MR Imaging of the Glutamate System in Schizophrenia

精神分裂症谷氨酸系统的多模态 MR 成像

• 批准号: 9149329
• 负责人: Ragy Ramsis Girgis
• 金额: $ 18.45万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-24 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149329
• 关键词: Academia; Academic Medical Centers; Acute; Adverse effects; Age; Agonist; Area; Basic Science; Biological Markers; Brain; Brain region; Chronic; Clinical; Data; Development; Development Plans; Disease; Dopamine Receptor; Environment; Fellowship; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gadolinium; Genetic; Glutamate Receptor; Glutamates; Goals; Government; Health; Hippocampus (Brain); Human; Image; Impairment; Individual; Institutes; Institution; International; Italy; K-Series Research Career Programs; Ketamine; Knowledge; Lead; Learning; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Medial; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Mentors; Meta-Analysis; Methods; Multimodal Imaging; N-Methylaspartate; Neurobiology; Neurocognitive; Neurosciences; New York; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Population; Positioning Attribute; Positron-Emission Tomography; Prefrontal Cortex; Process; Protons; Psychiatry; Psychotic Disorders; Public Health; Recruitment Activity; Research; Research Personnel; Research Project Grants; Research Training; Resolution; Resources; Rodent; Role; SECTM1 gene; Schizophrenia; Signal Transduction; Societies; Staging; Synapses; System; Therapeutic; Training; Translating; Validation; Work; age effect; base; burden of illness; career; career development; cerebral blood volume; cohort; disability; experience; gadolinium oxide; high risk; imaging modality; in vivo; insight; meetings; neurochemistry; novel; novel therapeutics; patient oriented; skills; symptomatology; theories; therapeutic development

 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.

 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步，但精神分裂症（SCZ）的治疗仍然有限。这些限制的主要原因之一是缺乏能够测量 SCZ 病理生理学和实验药物靶点参与的生物标志物。因此，作为指导职业发展奖（K23）的一部分，我建议获得精神分裂症谷氨酸系统多模态磁共振（MR）成像培训，具体培训目标如下：1）深入了解在SCZ中使用高分辨率、稳态、钆增强功能磁共振成像[即脑血容量（CBV）]； 2) 深入了解如何使用质子磁共振波谱 (MRS) 检查 SCZ 中的谷氨酸系统； 3) 发展谷氨酸系统在 SCZ 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 KL2 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态成像来评估新型谷氨酸能化合物对 SCZ 的靶点参与。 这项以患者为导向的研究职业发展奖的科学重点将放在谷氨酸系统上，重点是慢性疾病对 SCZ 海马和内侧前额皮质 (mPFC) 区域谷氨酸的影响。另一个目的是检查这两个大脑区域的 CBV 和谷氨酸 (Glu) MRS 之间的关系。我最近撰写了两篇关于 SCZ 中谷氨酸的重要评论，特别是关于 SCZ 中谷氨酸成像的重要评论。 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，海马 CA1 区的 CBV 被发现可以预测临床高危 (CHR) 人群向精神病的转变，而谷氨酸被认为是致病驱动因素。此外，MRS 还发现海马和 mPFC 中谷氨酸升高是 SCZ 的关键病理生理标志物。然而，CBV 从未被用于研究 SCZ 谱不同阶段谷氨酸系统的潜在差异（例如，慢性与早期 SCZ），虽然 CBV 信号已被证明在啮齿动物中具有谷氨酸能，但尚未在人类中进行类似的验证。这项工作对于充分了解 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 激动剂仅对早期 SCZ 人群显示出益处（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协会两年一次的会议上发表的演讲），但对整个组却没有效果。此外，虽然荟萃分析和我们自己的氯胺酮数据表明，通过 MRS 测量的谷氨酸存在年龄效应，其中急性氯胺酮挑战导致通过 MRS 测量的谷氨酸增加，而在长期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，影响谷氨酸的是药物状态（即服用或不服用药物）而不是年龄。 水平。因此，我的具体目标是： 1) 检查年龄和慢性疾病对 SCZ 个体海马和 mPFC 的 Glu MRS 和 CBV 的影响。我们假设 SCZ 患者的年龄/慢性疾病与 CBV/Glu 之间存在反比关系。 2) 检查海马和 mPFC 中 CBV 和 Glu MRS 之间的关系。我们假设 SCZ 患者的 CBV 和 Glu MRS 之间存在直接的正相关关系。 3) 检查 SCZ 患者和对照受试者海马和 mPFC CBV 和 Glu MRS 之间的差异，并检查患者海马和 mPFC 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 SCZ 患者这两个区域的 CBV 和 Glu MRS 均高于对照组，并且这两个区域的 CBV 和 Glu 水平较高将与患者更严重的症状和更差的神经认知功能相关。为了获得多模态 CBV/MRS 成像培训，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 SCZ 个体和 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迄今为止作为 T32 研究员和 K12 学者所获得的培训和数据的基础上。我将在纽约州精神病学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并实施职业发展计划。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，使自己成为一名独立的、以患者为导向的研究人员、使用多模式谷氨酸成像检查 SCZ 病理生理学和目标参与实验治疗的专家，并且重点与我的导师不同。

项目成果

Exploring the Relationship Between Body Mass Index and Positive Symptom Severity in Persons at Clinical High Risk for Psychosis.

• DOI: 10.1097/nmd.0000000000000736
• 发表时间: 2017-11
• 期刊: The Journal of nervous and mental disease
• 作者: Caravaggio F;Brucato G;Kegeles LS;Lehembre-Shiah E;Arndt LY;Colibazzi T;Girgis R
• 通讯作者: Girgis R