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.

PUBLIC HEALTH RELEVANCE: Behavioral symptoms such as depression and fatigue are among the most common side effects in patients treated for breast cancer, possibly due to increased peripheral inflammation resulting from treatments such as chemotherapy. Recent evidence supports the hypothesis that dysregulation of the neurotransmitter glutamate is responsible for mediating the association between increased inflammation and behavioral symptoms. The proposed research will explore the relationship between chemotherapy-induced inflammation, changes in glutamate and related metabolites, and behavioral symptoms in patients with breast cancer using multi-voxel magnetic resonance spectroscopy.