Inflammation-Induced CNS Glutamate During Breast Cancer Treatment

描述（由申请人提供）：高达70%的乳腺癌女性患者在诊断和治疗期间的某个时候会出现明显的抑郁、疲劳或认知功能障碍，高达30%的乳腺癌患者在治疗完成后很长时间内仍会出现这些症状。我们小组和其他人的数据表明，这些行为变化与外周血炎症标志物的增加有关。一种可能将外周炎症与行为改变联系起来的机制是中枢神经系统（CNS）谷氨酸。过量的谷氨酸已被证明会导致神经元毒性，并且在许多以行为和认知障碍为特征的疾病中已被证明增加中枢神经系统谷氨酸。此外，众所周知，炎症细胞因子可抑制谷氨酸再摄取，增加星形胶质细胞的谷氨酸释放，并激活犬尿氨酸途径，导致喹啉酸，一种谷氨酸受体激动剂，也可抑制谷氨酸再摄取。谷氨酸拮抗剂也被证明可以阻断小鼠炎症诱导的抑郁样行为，同时逆转人类的抑郁症状。使用单体素磁共振波谱（MRS）的初步数据显示，慢性给药炎症细胞因子干扰素(IFN)- α导致已知是炎症刺激目标的大脑区域谷氨酸显著增加，包括背前扣带皮层（dACC）和基底神经节。值得注意的是，IFN- α诱导的中枢神经系统谷氨酸增加与行为改变以及血浆可溶性肿瘤坏死因子（TNF）受体2相关，这是一种炎症标志物，与乳腺癌患者的疲劳有关。有趣的是，最近的一项研究表明谷氨酸受体拮抗剂美金刚可降低接受全脑放疗的癌症患者的认知功能障碍，这表明阻断谷氨酸可能对炎症负荷增加的癌症患者具有神经保护作用。综上所述，这些数据支持了一个假设，即炎症的增加可能导致大脑特定区域谷氨酸的增加，进而可能导致行为和认知的改变。为了验证这一假设，我们计划在60名乳腺癌女性中使用单体素和化学位移（短TE多体素）MRS测量1)dACC、基底神经节和海马中的CNS谷氨酸，2)炎症和狗尿氨酸途径的外周生物标志物，以及3)抑郁、疲劳和认知功能。因为之前的研究表明，化疗的炎症标志物比未化疗的乳腺癌患者更高，其中30名女性将同时接受手术和化疗，30名仅接受手术。30名未患乳腺癌的健康妇女将作为对照。这些数据将首次检验中枢神经系统谷氨酸是否是炎症对大脑和行为影响的重要介质，同时提供谷氨酸可能是治疗乳腺癌女性行为和认知变化的治疗靶点的初步迹象。

DESCRIPTION (provided by applicant): Up to 70% of women with breast cancer experience significant depression, fatigue or cognitive dysfunction at some point during diagnosis and treatment, and up to 30% of breast cancer patients experience these symptoms long after treatment completion. Data from our group and others have linked these behavioral changes with increases in peripheral blood markers of inflammation. One mechanism that may link peripheral inflammation to behavioral alterations is central nervous system (CNS) glutamate. Excessive glutamate has been shown to lead to neuronal toxicity, and increased CNS glutamate has been demonstrated in a number of disorders that are characterized by disturbances in behavior and cognition. Moreover, inflammatory cytokines are well known to inhibit glutamate reuptake and increase glutamate release from astrocytes and activate the kynurenine pathway which leads to quinolinic acid, a glutamate receptor agonist that can also inhibit glutamate reuptake. Glutamate antagonists have also been shown to block inflammation-induced depressive-like behavior in mice, while reversing depressive symptoms in humans. Preliminary data using single voxel magnetic resonance spectroscopy (MRS) have shown that chronic administration of the inflammatory cytokine interferon (IFN)-alpha leads to significant increases in glutamate in brain regions known to be targets of inflammatory stimuli including the dorsal anterior cingulate cortex (dACC) and the basal ganglia. Of note, IFN- alpha-induced increases in CNS glutamate were correlated with behavioral changes as well as plasma soluble tumor necrosis factor (TNF) receptor 2, an inflammatory marker that has been associated with fatigue in breast cancer patients. Interestingly, a recent study demonstrated that the glutamate receptor antagonist memantine reduced cognitive dysfunction in cancer patients undergoing whole brain radiotherapy, indicating that blocking glutamate may have neuroprotective effects in cancer patients with an increased inflammatory load. Taken together, these data support the hypothesis that increased inflammation may cause increased glutamate in specific brain regions which in turn may contribute to behavioral and cognitive changes. To test this hypothesis, we plan to measure 1) CNS glutamate in the dACC, basal ganglia and hippocampus using single voxel and chemical shift (short TE multivoxel) MRS, 2) peripheral biomarkers of inflammation and the kynurenine pathway, and 3) depression, fatigue and cognitive function in 60 women with breast cancer. Because previous work has shown that inflammatory markers are higher in chemotherapy versus non-chemotherapy-treated breast cancer patients, 30 of these women will be treated with surgery and chemotherapy and 30 with surgery alone. 30 healthy women without breast cancer will serve as controls. These data will be the first to examine whether CNS glutamate is an important mediator of effects of inflammation on the brain and behavior, while providing preliminary indication that glutamate may be a therapeutic target for treatment of behavioral and cognitive changes in women with breast cancer.