Inflammation-Induced Brain Changes in Breast Cancer Patients Studied with MRS

 描述（由申请人提供）：乳腺癌是影响美国女性的最常见癌症之一。抑郁和疲劳等行为症状是接受化疗的乳腺癌患者的常见症状，并且在治疗停止后可能持续很长时间。行为症状的潜在机制尚不清楚，但以前的工作已经证明了外周炎症与持续的行为和认知症状之间的关系。例如，由于化疗激活免疫系统而释放的炎性细胞因子可以靶向并与已知控制行为，情绪和认知的多个大脑区域相互作用。虽然已经提出了炎症诱导的行为变化的几种机制，但强有力的证据支持谷氨酸（主要兴奋性神经递质）作为外周炎症和行为变化之间的联系。最近的工作表明，免疫系统激活后，管理的促炎细胞因子，干扰素-α，导致增加中枢神经系统（CNS）谷氨酸浓度测量磁共振波谱（MRS），进一步支持谷氨酸失调的作用，炎症和行为变化之间的介质。该提案的工作假设是，暴露于化疗的乳腺癌患者将在CNS中显示出更高的谷氨酸浓度，这将与炎症标志物和行为症状（包括抑郁和疲劳）呈正相关。为了检验这一假设，将使用多体素MRS测量接受过化疗的乳腺癌患者、未接受化疗的乳腺癌患者和未患乳腺癌的健康对照者的双侧基底神经节、背侧前扣带皮层和皮层下白色物质中的谷氨酸浓度。为了实现谷氨酰胺和谷胱甘肽（由谷氨酸合成的神经保护代谢物）的光谱分辨率，将实施新的2D MRS技术。将对行为评估数据和来自抽血的血浆炎症标志物进行二次分析。这项研究的结果将提供重要的洞察炎症，谷氨酸和相关代谢物之间的关联，以及接受化疗治疗的乳腺癌患者的行为症状。此外，拟议的研究计划将为研究人员提供MRS技术和应用方面的培训，介绍埃默里大学将使用的第一种体内2D MRS技术，并帮助研究人员开发一种独立的调查路线，以研究MRS在癌症及其治疗的神经行为研究中的应用。

 DESCRIPTION (provided by applicant): Breast cancer is one of the most common cancers affecting women in the U.S. Behavioral symptoms such as depression and fatigue are common symptoms among breast cancer patients receiving chemotherapy treatment and can persist long after treatment cessation. The underlying mechanism for the behavioral symptoms is unknown, however previous work has demonstrated a relationship between peripheral inflammation and persisting behavioral and cognitive symptoms. For example, inflammatory cytokines released as a result of immune system activation by chemotherapy treatment can target and interact with multiple brain regions known to control behavior, mood, and cognition. While several mechanisms for inflammation-induced behavioral changes have been proposed, strong evidence supports the role of glutamate, the primary excitatory neurotransmitter, as the link between peripheral inflammation and behavioral changes. Recent work has shown that immune system activation following administration of the proinflammatory cytokine, interferon-alpha, resulted in increased central nervous system (CNS) glutamate concentrations measured with magnetic resonance spectroscopy (MRS), further supporting the role of glutamate dysregulation as a mediator between inflammation and behavioral changes. The working hypothesis of this proposal is that breast cancer patients exposed to chemotherapy will show higher glutamate concentrations in the CNS that will be associated positively with inflammatory markers and behavioral symptoms including depression and fatigue. To test this hypothesis, multi-voxel MRS will be used to measure glutamate concentrations in the bilateral basal ganglia, dorsal anterior cingulate cortex, and subcortical white matter in patients with breast cancer who have undergone chemotherapy treatment, breast cancer patients who have not undergone chemotherapy, and healthy controls without breast cancer. To enable spectral resolution of glutamine and glutathione, neuroprotective metabolites synthesized from glutamate, a new 2D MRS technique will be implemented. Secondary analysis will be performed on behavioral assessment data and plasma inflammatory markers from blood draws. The results of this research will provide important insight into the association between inflammation, glutamate and related metabolites, and behavioral symptoms in breast cancer patients undergoing chemotherapy treatment. Additionally, the proposed research plan will provide training for the investigator in MRS techniques and applications, introduce the first in vivo 2D MRS technique to be used at Emory University, and aid the investigator in developing an independent line of inquiry into applications of MRS for neurobehavioral studies of cancer and its treatment.