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

 描述(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，并可在停止治疗后持续很长时间。行为症状的潜在机制尚不清楚，但先前的工作已证明外周炎症与持续性的行为和认知症状之间存在关系。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。虽然已经提出了几种炎症诱导的行为改变的机制，但强有力的证据支持谷氨酸作为主要的兴奋性神经递质，作为外周炎症和行为改变之间的联系。最近的研究表明，注射促炎症细胞因子干扰素-α后的免疫系统激活导致磁共振波谱(MRS)测量的中枢神经系统(CNS)谷氨酸浓度增加，进一步支持谷氨酸调节失调作为炎症和行为变化之间的中介的作用。这项提议的工作假设是，接受化疗的乳腺癌患者中枢神经系统中的谷氨酸浓度会更高，这将与炎症标志物和行为症状(包括抑郁和疲劳)呈正相关。为了验证这一假设，多体素MRS将用于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组的双侧基底节、扣带回皮质背侧前皮质和皮质下白质中的谷氨酸浓度。为了能够对谷氨酸合成的神经保护代谢物谷氨酰胺和谷胱甘肽进行光谱分辨，将实施一种新的2D MRS技术。二次分析将对行为评估数据和抽血所得的血浆炎症标志物进行。这项研究的结果将为了解接受化疗的乳腺癌患者的炎症、谷氨酸和相关代谢物与行为症状之间的关系提供重要的见解。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，介绍埃默里大学使用的第一个在体2D MRS技术，并帮助研究人员开发独立的MRS应用于癌症神经行为研究及其治疗。

 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.