Spectroscopic Investigation of a Novel Traumatic Brain Injury Biomarker and Analysis of Neurometabolic Changes in Youth American Football Athletes

Recent advances in Magnetic Resonance Imaging (MRI), a noninvasive imaging technique, have spurred the exploration of poorly understood physiological phenomena in vivo. Applications of MRI vary greatly, from anatomical evaluation to complex functional analysis. The body of this dissertation presents four applications of MRI: 1) investigation of a novel traumatic brain injury (TBI) biomarker, 2) analysis of position-specific head acceleration events on neurometabolic profiles in high school football athletes, 3) the first reporting of neurometabolic changes in middle school football athletes, and 4) a novel application of diffusion-weighted imaging (DWI) to characterize implantable drug-delivery depots (Appendix A).

Magnetic resonance spectroscopy (MRS) is an MRI method used to evaluate the metabolic profiles of tissues. Certain brain metabolites (N-acetyl aspartate, myo-inositol, choline, creatine, and glutamate/glutamine) offer unique information regarding brain homeostasis following TBI. When coupled with additional metrics, such as head acceleration events recorded during collision-sport participation, the mechanisms of neurophysiological changes can be further elucidated. Here, player position-specific neurometabolic changes were evaluated in high school and middle school football athletes. Striking differences were noted between linemen and non-linemen as well as high school and middle school athletes.

However, in most clinical cases of TBI, information regarding head acceleration events is unknown and baseline scans are not available.Therefore, it is critical to evaluate candidate biomarkers which increase solely in response to injury. Acrolein, a toxic reactive oxygen species, has been shown to increase following injury to the central nervous system in animal models. Hence, acrolein is a prime TBI biomarker candidate and has been investigated using nuclear magnetic resonance and MRS at 7 Tesla.

Applications of MRI are not limited to the brain, or even tissues. Studies have reported that up to 50% of patients fail to take their medications correctly - resulting in disease progression and medication waste. In situ forming implants (ISFIs) offer an alternative to oral dosage regimens but have not been validated in vivo. Using DWI, ISFIs can be characterized noninvasively and their design can be refined, ultimately improving patient outcomes.

Taken together, MRI is powerful tool that can be used to investigate a wide range of physiological questions. Chapters 2-4 will emphasize efforts to improve TBI diagnostics and better understand neurometabolic changes in youth football athletes. Appendix A offers insights into the DWI-guided characterization of in situ forming implants.