Inflammation-Induced CNS Glutamate as a Function of Depression in Middle Age

炎症引起的中枢神经系统谷氨酸与中年抑郁症的关系

基本信息

批准号：
9030604
负责人：
Ebrahim Haroon
金额：
$ 45.17万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030604
关键词：
Adult Age Aging Anisotropy Anterior Anti-Inflammatory Agents Antidepressive Agents Basal Ganglia Behavior Behavior assessment Behavioral Biological Markers Blood Vessels Brain Brain region Brain-Derived Neurotrophic Factor Cells Chemical Shift Imaging Chemicals Cognition Cognitive Communication Creatine Cytokine Receptors Data Depressed mood Diffusion Magnetic Resonance Imaging Ensure Excitatory Amino Acid Antagonists Exhibits Future Glutamates Goals Hippocampus (Brain)Impaired cognition Individual Inflammation Inflammatory Inflammatory Response Interferon-alpha Internal Capsule Kynurenine Lead Light Link Magnetic Resonance Spectroscopy Major Depressive Disorder Maps Measures Mental Depression Myelin Neuroglia Neurons Neurotransmitters Pathology Pathway interactions Patients Peripheral Plasma Production Proteins Quinolinic Acid Radial Recruitment Activity Reporting Research Research Domain Criteria Risk Risk Factors Subgroup Testing Time Toxic effect White Matter Disease base behavioral impairment cingulate cortex cognitive function cognitive performance cognitive task cytokine depressed patient depressive cognitions depressive symptoms functional decline functional outcomes human old age (65+)indexing inflammatory marker insight middle age molecular marker neurofilament new therapeutic target personalized care polypeptide prevent protein biomarkers public health relevance response statistics tau Proteins tau-1 white matter

项目摘要

DESCRIPTION (provided by applicant): This project will examine the impact of inflammation on CNS glutamate, white matter pathology and alterations in behavior and cognition in middle-aged patients with major depression. Depression is associated with significant alterations in white matter integrity which has been associated with decreased antidepressant response, poor functional outcome, and cognitive impairment. One pathway that may contribute to white matter pathology in depression is inflammation. A significant subgroup of depressed patients exhibit increased inflammation. Moreover, increasing age along with increasing vascular risk is associated with an exaggerated inflammatory response, potentially leading to a greater inflammatory load in depressed, middle-aged individuals. The mechanisms by which inflammation may contribute to white matter pathology in depression are only beginning to be explored. Of relevance in this regard, using magnetic resonance spectroscopy (MRS), the PI has demonstrated that administration of interferon (IFN)-alpha leads to significant increases in glutamate in brain regions known to be targets of inflammation including the basal ganglia. Interestingly, older subjects treated with IFN-alpha showed significantly greater increases in glutamate in basal ganglia than older controls and younger IFN-alpha-treated and control subjects. Increased glutamate in the basal ganglia of older subjects also correlated with increased inflammatory markers as well as symptoms of depression and cognitive dysfunction. Finally, the PI has new preliminary data showing a correlation between the inflammatory marker c- reactive protein (CRP) and basal ganglia glutamate in middle-aged depressed individuals. Glutamate is an excitatory neurotransmitter which at high concentrations is toxic to both glia and neurons. Thus, glutamate may serve as a final common pathway by which aging and inflammation interact in depressed subjects, resulting in accelerated white matter pathology. To explore this hypothesis, we plan to measure 1) CNS glutamate using single voxel and chemical shift MRS, 2) microstructural white matter integrity using diffusion tensor imaging/tract-based spatial statistics and myelin mapping, 3) peripheral and central biomarkers of inflammation and the kynurenine pathway which when activated by inflammation can increase glutamate and glutamate toxicity, and 4) depressive symptoms and cognition in 80 depressed and 80 non-depressed subjects 50-65 years old with a range of inflammation from low to high as determined by CRP. CNS glutamate and white matter integrity will be evaluated as a continuous function of inflammation and age. In addition, the relationship among CNS glutamate, white matter integrity and behavioral domains (defined using RDoC) will be examined. These data will be the first to link inflammation, glutamate, and white matter pathology as a function of middle age in depression, while also helping personalize care through identifying biomarkers of risk and pathophysiological targets to guide future studies using anti-inflammatory agents or glutamate antagonists alone or in combination to prevent cognitive and functional decline among aging depressed individuals.

描述（由适用提供）：该项目将检查炎症对谷氨酸中枢神经系统的影响，白质病理学以及严重抑郁症患者的行为和认知改变。抑郁症与白质完整性的显着改变有关，这与抗抑郁反应降低，功能效果不良和认知障碍有关。可能导致抑郁症白质病理的一种途径是炎症。大量抑郁症患者的亚组表现出增加的感染。此外，增加的年龄以及增加的血管风险与夸张的炎症反应有关，可能导致抑郁症的中年个体的炎症负荷更大。炎症可能导致抑郁症的白质病理的机制才开始探索。在这方面，使用磁共振光谱（MRS）的相关性，PI表明，干扰素（IFN）-Alpha的给药会导致脑区域中谷氨酸的显着增加，已知是包括基底神经神经的炎症靶标。有趣的是，用IFN-α治疗的老年受试者在基底神经节中的谷氨酸和较年轻的IFN-Alpha治疗和对照受试者的谷氨酸显示出明显更大的增加。老年受试者基底神经节中谷氨酸的增加也与炎症标记的增加以及抑郁症和认知功能障碍的症状有关。最后，PI具有新的初步数据，显示了中年抑郁个体中炎症标记C反应蛋白（CRP）和基本神经节谷氨酸之间的相关性。谷氨酸是一种兴奋性神经递质，在高浓度下对神经胶质和神经元有毒。这是谷氨酸可以作为衰老和炎症在抑郁受试者中相互作用的最终常见途径，从而导致白质病理加速。为了探索这一假设，我们计划测量1）使用单个体素和化学转移MRS的CNS谷氨酸MRS，2）使用扩散张量成像/基于扩散的空间统计和髓磷脂图的微结构白质完整性，3）炎症和kynurenine themation and hynurenine themation and Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut Glut 4）在80名抑郁症和80名未抑郁的受试者中，抑郁症状和认知50-65岁，炎症范围从低到高的炎症，如CRP所确定。 CNS谷氨酸和白质完整性将被评估为炎症和年龄的连续功能。此外，将检查CNS谷氨酸，白质完整性和行为域（使用RDOC定义）之间的关系。这些数据将是第一个将炎症，谷氨酸和白质病理学与抑郁症的关系联系起来的数据，同时还可以通过鉴定风险和病理生理靶标的生物标志物来帮助个性化护理，以指导未来的研究，使用抗炎药或谷氨酸拮抗剂或单独或结合结合使用抗认知和功能性下降的人，以防止认知和功能下降的人在衰老压缩的人群中。