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.
Depression, fatigue and cognitive dysfunction are debilitating symptoms that can affect up to 30% of women with breast cancer months to years after therapy. Our data suggest that inflammation secondary to chemotherapy may play an important role in these symptoms, and one mechanism by which inflammation may alter behavior is through increases in brain glutamate, a neurotransmitter that is toxic to neurons in high concentrations. In the proposed study, we will examine the relationship among inflammation, brain glutamate and behavior, thereby potentially revealing glutamate as a novel therapeutic target for the management of chemotherapy-induced symptoms while at the same time identifying inflammatory biomarkers of risk.
| Haroon, Ebrahim; Miller, Andrew H; Sanacora, Gerard (2017) Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology 42:193-215 |
