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

 描述(申请人提供)：本项目将研究炎症对中枢谷氨酸、脑白质病理的影响以及中年抑郁症患者行为和认知的变化。抑郁症与白质完整性的显著改变有关，而白质完整性与抗抑郁药反应降低、功能结局差和认知障碍有关。炎症可能是导致抑郁症患者脑白质病变的一个途径。抑郁症患者中的一个重要亚组表现出炎症增加。此外，随着年龄的增长和血管风险的增加，炎症反应被夸大了，这可能会导致抑郁的中年人的炎症负荷更大。炎症可能导致抑郁症白质病理的机制才刚刚开始探索。在这方面，使用磁共振波谱(MRS)，PI已经证明，给予干扰素(干扰素)-α导致包括基底节在内的已知炎症靶点的大脑区域中谷氨酸显著增加。有趣的是，接受干扰素-α治疗的老年受试者表现出显著高于老年对照组、年轻受试者和对照组的基底神经节中谷氨酸的增加。老年人基底节中谷氨酸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有了新的初步数据，表明炎症标记物C反应蛋白(CRP)与中年抑郁症患者的基底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，谷氨酸可能是抑郁症患者衰老和炎症相互作用的最终共同途径，导致脑白质病理加速。为了探索这一假说，我们计划使用单体素和化学位移MRS来测量1)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的微观结构白质完整性，3)外周和中枢炎症生物标记物以及犬尿氨酸途径，当炎症激活时，它可以增加谷氨酸和谷氨酸的毒性，以及4)80名抑郁症和80名非抑郁症受试者的抑郁症状和认知能力，根据CRP确定的炎症程度从低到高。中枢神经系统谷氨酸和白质的完整性将作为炎症和年龄的持续功能进行评估。此外，还将研究中枢谷氨酸、白质完整性和行为域(使用RDoC定义)之间的关系。这些数据将首次将炎症、谷氨酸和白质病理作为中年抑郁症的一种功能联系起来，同时还通过识别风险的生物标记物和病理生理目标来帮助个性化护理，以指导未来单独或联合使用抗炎药或谷氨酸拮抗剂的研究，以防止老年抑郁症患者的认知和功能衰退。

 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.