Inflammation-Induced CNS Glutamate Changes in Depression

抑郁症中炎症引起的中枢神经系统谷氨酸变化

• 批准号: 9981047
• 负责人: Ebrahim Haroon
• 金额: $ 40.82万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981047
• 关键词: Acute; Adult; Affect; Age; Anhedonia; Anterior; Anti-Inflammatory Agents; Antidepressive Agents; Astrocytes; Attention; Basal Ganglia; Behavior; Behavioral; Biological Markers; Biological Products; Brain; Brain region; C-reactive protein; Cerebrospinal Fluid; Chemical Shift Imaging; Clinical; Data; Development; Dorsal; Enrollment; Excitatory Amino Acid Antagonists; Exhibits; Foundations; Functional disorder; Future; Gene Expression; Glutamates; Goals; Immunologics; Inflammation; Inflammatory; Infusion procedures; Intelligence; Interferon-alpha; Left; Link; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Measures; Medial; Mental Depression; Mental disorders; Monoclonal Antibodies; Mood Disorders; Motivation; Motor Activity; Mus; Nature; Negative Valence; Neuraxis; Neurotransmitters; Parietal Lobe; Pathology; Pathway interactions; Patient Self-Report; Patients; Peripheral; Pharmaceutical Preparations; Placebos; Positive Valence; Proteins; Psychomotor Performance; Research; Research Design; Research Domain Criteria; Resistance; Speed; System; TNF gene; Targeted Research; Techniques; Testing; biomarker-driven; cingulate cortex; cytokine; depressed patient; depressive symptoms; excitotoxicity; glutamatergic signaling; improved; inflammatory marker; infliximab; neuropsychiatric disorder; neuropsychiatry; neurotoxicity; novel therapeutics; performance based measurement; peripheral blood; personalized care; protein expression; recruit; reduce symptoms; reuptake; targeted treatment; therapy resistant

Project Summary The proposed research will test the hypothesis that increased inflammation causes increased basal ganglia glutamate and consequently anhedonia and psychomotor retardation in patients with major depressive disorder (MDD). Excessive inflammation and glutamate excitotoxicity are two pathways that have received increasing attention regarding the pathophysiology of neuropsychiatric disease including mood disorders. Patients with depression exhibit increased peripheral and central nervous system (CNS) markers of inflammation as well as altered CNS glutamate as measured by magnetic resonance spectroscopy (MRS). In addition, drugs that block either inflammation or glutamate signaling can reverse depressive symptoms, especially in depressed patients with treatment resistance. Interestingly, recent data suggest there may be convergence of these two pathways to pathology. Inflammatory cytokines are known to inhibit glutamate reuptake and increase glutamate release from astrocytes, and glutamate antagonists have been shown to block inflammation-induced depressive-like behavior in mice. Moreover, using MRS, our data has shown that administration of the inflammatory cytokine interferon (IFN)-alpha significantly increases glutamate in the basal ganglia in association with IFN-alpha-induced anhedonia and psychomotor slowing. In addition, our group has demonstrated that increased inflammation as reflected by peripheral blood C-reactive protein (CRP) is correlated with increased basal ganglia glutamate in association with decreased motivation and psychomotor speed in patients with MDD. Nevertheless, the data to date has been correlational, and whether increased inflammation causes increased glutamate in the basal ganglia, which in turn contributes to behavioral changes in patients with depression has not been established. To test this hypothesis, we plan to determine the cause and effect relationship between increased inflammation and increased CNS glutamate by blocking inflammation in depressed patients with high inflammation (CRP>3mg/L) using the highly specific TNF antagonist infliximab (n=30) versus placebo (n=30). In addition, we will examine whether changes in basal ganglia glutamate are linked to changes in behaviors related to the basal ganglia including anhedonia and psychomotor retardation (as measured by performance-based, clinical administered and self-report assessments targeting research domain criteria that examine positive and negative valence systems). Finally, we will explore the specific immunologic pathways that affect basal ganglia glutamate. These data will be the first to establish a link between pathophysiologic mechanisms involving inflammation and glutamate, while also helping personalize care through the identification of peripheral biomarkers of inflammation to guide future studies using anti-inflammatory agents and/or glutamate antagonists to treat patients with depression and other psychiatric disorders with increased inflammation.

项目摘要 这项拟议中的研究将检验炎症增加导致基底神经节增加的假设 重性抑郁症患者的谷氨酸与快感缺乏和精神发育迟滞的关系 疾病（MDD）。过度炎症和谷氨酸兴奋毒性是两个途径， 越来越多的关注神经精神疾病，包括情绪障碍的病理生理学。 抑郁症患者的外周和中枢神经系统（CNS）标记物增加， 炎症以及通过磁共振波谱（MRS）测量的改变的CNS谷氨酸。在 此外，阻断炎症或谷氨酸信号的药物可以逆转抑郁症状， 尤其是对治疗有抵抗力的抑郁症患者。有趣的是，最近的数据表明， 这两种病理学途径的融合。已知炎性细胞因子抑制谷氨酸 再摄取和增加谷氨酸从星形胶质细胞的释放，谷氨酸拮抗剂已被证明， 阻断炎症诱导的小鼠抑郁样行为。此外，使用MRS，我们的数据表明， 给予炎性细胞因子干扰素（IFN）-α显著增加了基底膜中的谷氨酸， 神经节与IFN-α诱导的快感缺乏和精神发育迟缓有关。此外，我们集团还 表明外周血C-反应蛋白（CRP）反映的炎症增加是 与基底神经节谷氨酸盐增加相关，与动机和精神障碍降低相关 MDD患者的速度。然而，迄今为止的数据是相关的， 炎症导致基底神经节谷氨酸盐增加，这反过来又导致行为改变 在抑郁症患者中的作用尚未确立。为了验证这一假设，我们计划确定 通过阻断炎症增加和CNS谷氨酸增加之间的关系 高炎症（CRP> 3 mg/L）抑郁症患者使用高度特异性TNF 拮抗剂英夫利西单抗（n=30）与安慰剂（n=30）。此外，我们还将检查基础胰岛素水平的变化是否 谷氨酸神经节与基底神经节相关的行为变化有关，包括快感缺乏， 精神发育迟滞（通过基于表现、临床管理和自我报告测量 针对研究领域标准的评估，检查正和负效价系统）。最后， 我们将探讨影响基底神经节谷氨酸的特定免疫途径。这些数据将是 第一次建立了涉及炎症和谷氨酸的病理生理机制之间的联系，同时也 通过识别炎症的外周生物标志物来帮助个性化护理， 使用抗炎剂和/或谷氨酸拮抗剂治疗抑郁症患者的研究， 其他炎症增加的精神疾病。

项目成果

A randomized proof-of-mechanism trial of TNF antagonism for motivational anhedonia and related corticostriatal circuitry in depressed patients with high inflammation.

一项 TNF 拮抗作用对患有高炎症的抑郁症患者的动机性快感缺失和相关皮质纹状体回路的随机机制验证试验。

• DOI: 10.21203/rs.3.rs-3957252/v1
• 发表时间: 2024
• 期刊: Research square
• 作者: Treadway,Michael;Etuk,Sarah;Cooper,Jessica;Hossein,Shabnam;Hahn,Emma;Betters,Samantha;Liu,Shiyin;Arulpragasam,Amanda;DeVries,Brittany;Irfan,Nadia;Nuutinen,Makiah;Wommack,Evanthia;Woolwine,Bobbi;Bekhbat,Mandakh;Kragel,Philip;F
• 通讯作者: F