Measuring Glial Metabolism in Repetitive Brain Trauma and Alzheimer s Disease
Abstract
Glutamate is a key compound in cellular metabolism with its most important role as a neurotransmitter with which the brain utilizes 80% of energy consumption to maintain this important cycle. Elevated levels of glutamate have been shown to be predictive of outcome in severe traumatic brain injury, and our preliminary data from existing studies have shown that glutamate remains elevated in the chronic stages of repetitive brain trauma as well. This is important given that high glutamate levels have been shown to be excitotoxic, which means that they start damaging brain cells. However, it is unclear what levels can cause the damage and more importantly which pathways are not functioning properly that may lead to the long-term effects of head trauma. Current methods of measure brain glutamate using proton spectroscopy are not specific to different cell types or the dynamic changes that undergo metabolism. We have developed a novel, non-invasive, quantitative method of measuring the dynamic rates of glutamate using 13C-labeled glucose. Unlike FDG-PET, the 13C label is nonionizing and more importantly, it is metabolized by the brain and can be tracked through the tricarboxylic acid cycle using 13C magnetic resonance spectroscopy. The rate at which glucose enriches glutamate through the glutamate-glutamine cycle has been found to be directly correlated with glutamate neurotransmission rates, thus allowing for a non-invasive window into direct metabolic pathways of this process. Previously published work in patients suffering from Alzheimer s disease demonstrated reduced levels of glutamate neurotransmission in astrocytes using this method. Furthermore, a recent study from our co-investigator has demonstrated that by using 13C-labeled acetate, the primary fuel for glial cells, will allow us to target specifically glial cells. Thus, our goal is to utilize infusion of 13C-labeled acetate in our existing cohort of retired National Football League (NFL) athletes with and without increased glutamate, subjects with Alzheimer s disease, military Veterans with a history of traumatic brain injury, and age-matched controls to measure the effect of repetitive brain trauma upon glutamate metabolism. Our hypothesis is that increased glutamate found in these players will be reflected in upregulation of glial pathways. The result of the study would be to identify the dysfunctional pathways that underlie glutamate excitotoxicity in sports-related brain trauma. These dysfunctions will provide precise targets for existing glutamate medications that are known to modulate specific pathways. Therefore, we anticipate not only providing a better understanding of the metabolic mechanisms of sports-related head injury but also to provide data that will be useful for the development of much needed treatments for this devastating disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510412
Entities
People
- Alexander Lin
Organizations
- United States Army