Scaled traumatic brain injury results in unique metabolomic signatures between gray matter, white matter, and serum in a piglet model

Abstract

Traumatic brain injury (TBI) is a leading cause of death and long-term disability in the United States. The heterogeneity of the disease coupled with the lack of comprehensive, standardized scales to adequately characterize multiple types of TBI remain to be major challenges facing effective therapeutic development. A systems level approach to TBI diagnosis through the use of metabolomics could lead to a better understanding of cellular changes post-TBI and potential therapeutic targets. In the current study, we utilize a GC-MS untargeted metabolomics approach to demonstrate altered metabolism in response to TBI in a translational pig model, which possesses many neuroanatomical and pathophysiologic similarities to humans. TBI was produced by controlled cortical impact (CCI) in Landrace piglets with impact velocity and depth of depression set to 2m/s;6mm, 4m/s;6mm, 4m/s;12mm, or 4m/s;15mm resulting in graded neural injury. Serum samples were collected pre-TBI, 24 hours post-TBI, and 7 days post-TBI. Partial least squares discriminant analysis (PLS-DA) revealed that each impact parameter uniquely influenced the metabolomic profile after TBI, and gray and white matter responds differently to TBI on the biochemical level with evidence of white matter displaying greater metabolic change. Furthermore, pathway analysis revealed unique metabolic signatures that were dependent on injury severity and brain tissue type. Metabolomic signatures were also detected in serum samples which potentially captures both time after injury and injury severity. These findings provide a platform for the development of a more accurate TBI classification scale based unique metabolomic signatures.

Serum metabolome associated with severity of acute traumatic brain injury

“…Serine, on the other hand, has been suggested to play an essential role in the function of the central nervous system 55 and disruption in the metabolism of glycine, serine and threonine might affect neuroprotection and normal function of the nervous system 56 . In a piglet model of TBI, similar changes in amino acid levels were observed in brain tissue, with different responses occurring in gray and white matter across all injury severities 57 . It is also plausible that decreased amino acid concentrations may reflect both increased protein catabolism associated with acute illness 58 , and increased use of these metabolites for energy substrates in the body.…”

Lipid profiling of brain tissue and blood after traumatic brain injury

“…Plasma PC was not altered 1 hour after lateral fluid percussion in rats, although changes in brain PC were identified [70]. In a pig TBI model, serum PL metabolism was altered 24 hours post-CCI, but no longer at 7 days [71].…”

Traumatic brain injury induces region-specific glutamate metabolism changes as measured by multiple mass spectrometry methods

“…Previous studies have presented changes in the levels of various metabolites within the damaged hemispheres of experimental TBI animals ( Baker et al., 2018 ; Chitturi et al., 2018 ; Harris et al., 2012 ; McGuire et al., 2019 ). In this study, we observed changes in the levels of a sufficient number of metabolites to suggest how normal metabolic pathways have been disturbed and result in alternative metabolic pathways not previously described within the context of TBI.…”