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

MRS 研究乳腺癌患者炎症引起的大脑变化

• 批准号: 9263681
• 负责人: Candace C. Fleischer
• 金额: $ 2.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263681
• 关键词: Adverse effects; Affect; Aftercare; Anterior; Antidepressive Agents; Basal Ganglia; Behavior Control; Behavior assessment; Behavioral; Behavioral Mechanisms; Behavioral Symptoms; Bilateral; Blood; Brain; Brain region; Breast Cancer Patient; Breast Cancer Treatment; Chemical Shift Imaging; Chronic; Clinical; Cognition; Complement; Data; Diagnosis; Dorsal; Exhibits; Fatigue; Glutamate Metabolism Pathway; Glutamates; Glutamine; Glutathione; Goals; Immune system; In Vitro; Inflammation; Inflammatory; Interferon-alpha; Link; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Mental Depression; Moods; Motivation; Necrosis; Neuraxis; Neurobehavioral Manifestations; Neurotransmitters; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Proteins; Recruitment Activity; Reproducibility; Research; Research Personnel; Research Training; Resolution; Role; Spectrum Analysis; Symptoms; Techniques; Testing; Universities; Validation; Withholding Treatment; Woman; Work; anticancer research; base; chemotherapy; cingulate cortex; cognitive function; common symptom; cytokine; design; experience; improved; in vivo; inflammatory marker; insight; interest; investigator training; malignant breast neoplasm; mood regulation; neurobehavioral; neuropsychiatric disorder; neurotransmission; novel; public health relevance; receptor; secondary analysis; tumor; white matter

 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.

 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。行为症状尚不清楚，但之前的工作已经证明了周围炎症与持续的行为和认知症状之间的关系，例如，化疗治疗激活免疫系统而释放的炎症细胞因子可以靶向已知控制的多个大脑区域并与之相互作用。虽然已经提出了炎症引起的行为变化的几种机制，但强有力的证据支持谷氨酸（主要的兴奋性神经递质）的作用，因为最近的研究表明免疫系统与外周炎症和行为变化之间存在联系。给予促炎细胞因子干扰素-α后的激活导致中枢神经系统（CNS）谷氨酸浓度增加，通过磁共振波谱（MRS）测量，进一步支持谷氨酸失调作为介导的作用该提案的工作假设是，接受化疗的乳腺癌患者的中枢神经系统中谷氨酸浓度较高，这与炎症标志物和行为症状（包括抑郁和疲劳）呈正相关。体素MRS将用于测量接受化疗的乳腺癌患者、未接受化疗的乳腺癌患者以及未接受化疗的健康对照者的双侧基底神经节、背侧前扣带皮层和皮质下白质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，将对抽血的行为评估数据和血浆炎症标记物进行二次分析。深入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此外，拟议的研究计划将为研究者提供 MRS 技术和应用方面的培训，介绍。这是埃默里大学使用的第一个体内 2D MRS 技术，并帮助研究人员开发一条独立的调查线，研究 MRS 在癌症及其治疗的神经行为研究中的应用。