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

 描述（由申请人提供）：本项目将研究炎症对中枢神经系统谷氨酸、白色物质病理学以及中年抑郁症患者行为和认知改变的影响。抑郁症与白色物质完整性的显著改变相关，而白色物质完整性与抗抑郁反应降低、功能结局差和认知障碍相关。炎症可能是导致抑郁症白色病变的一个途径。抑郁症患者的显著亚组表现出增加的炎症。此外，随着年龄的增加沿着血管风险的增加，与过度的炎症反应相关，可能导致抑郁的中年个体的炎症负荷增加。炎症可能导致抑郁症白色病变的机制才刚刚开始探索。与此相关的是，PI使用磁共振波谱（MRS）证明干扰素（IFN）-α给药导致已知为炎症靶点的脑区域（包括基底神经节）中谷氨酸盐显著增加。有趣的是，用IFN-α治疗的老年受试者比老年对照组和年轻的IFN-α治疗组和对照组显示出显著更大的基底神经节谷氨酸盐增加。老年受试者基底神经节中谷氨酸盐的增加也与炎症标志物的增加以及抑郁和认知功能障碍的症状有关。最后，PI有新的初步数据显示，在中年抑郁症患者中，炎症标志物C反应蛋白（CRP）和基底神经节谷氨酸之间存在相关性。谷氨酸是一种兴奋性神经递质，高浓度时对神经胶质细胞和神经元都有毒性。因此，谷氨酸可能作为一个最终的共同途径，衰老和炎症相互作用，在抑郁症的受试者，导致加速白色物质病理。为了探索这一假设，我们计划1）使用单体素和化学位移MRS测量CNS谷氨酸，2）使用扩散张量成像/基于束的空间统计和髓鞘映射测量微结构白色物质完整性，3）炎症和犬尿氨酸途径的外周和中枢生物标志物，当被炎症激活时，犬尿氨酸途径可以增加谷氨酸和谷氨酸毒性，（4）对80例50-65岁的抑郁症患者和80例非抑郁症患者的抑郁症状和认知功能进行研究。CNS谷氨酸和白色物质完整性将作为炎症和年龄的连续函数进行评价。此外，将检查CNS谷氨酸、白色物质完整性和行为域（使用RDoC定义）之间的关系。这些数据将是第一个将炎症，谷氨酸和白色病理学联系起来作为抑郁症中年的功能，同时也有助于通过识别风险和病理生理学目标的生物标志物来指导未来的研究，使用抗炎药或谷氨酸拮抗剂单独或联合使用，以防止老年抑郁症患者的认知和功能下降。

 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.