Comparing Brain and Blood Lipidome Changes following Single and Repetitive Mild Traumatic Brain Injury in Rats

Abstract

Traumatic brain injury (TBI) is a major health concern in the United States and globally, contributing to disability and long-term neurological problems. Lipid dysregulation after TBI is underexplored, and a better understanding of lipid turnover and degradation could point to novel biomarker candidates and therapeutic targets. Here, we investigated overlapping lipidome changes in the brain and blood using a data-driven discovery approach to understand lipid alterations in the brain and serum compartments acutely following mild TBI (mTBI) and the potential efflux of brain lipids to peripheral blood. The cortices and sera from male and female Sprague−Dawley rats were analyzed via ultra-high performance liquid chromatography−mass spectrometry (UHPLC-MS) in both positive and negative ion modes following single and repetitive closed head impacts. The overlapping lipids in the data sets were identified with an in-house data dictionary for investigating lipid class changes. MS-based lipid profiling revealed overall increased changes in the serum compartment, while the brain lipids primarily showed decreased changes. Interestingly, there were prominent alterations in the sphingolipid class in the brain and blood compartments after single and repetitive injury, which may suggest efflux of brain sphingolipids into the blood after TBI. Genetic algorithms were used for predictive panel selection to classify injured and control samples with high sensitivity and specificity. These overlapping lipid panels primarily mapped to the glycerophospholipid metabolism pathway with Benjamini−Hochberg adjusted q-values less than 0.05. Collectively, these results detail overlapping lipidome changes following mTBI in the brain and blood compartments, increasing our understanding of TBIrelated lipid dysregulation while identifying novel biomarker candidates.

Integrative Analysis of Cytokine and Lipidomics Datasets Following Mild Traumatic Brain Injury in Rats

“…There were 609 tentatively annotated lipids in the dataset at an MSI level 2 [ 43 ] ( Figure 5 ). The isotopic features were summed [ 22 ] and resulting features were divided into subclasses. These included lipids from the carnitine (Car) and free fatty acids (FFAs) subclasses (fatty acid class), diacylglycerols (DG), phosphatic acid (PA), phosphatidylglycerols (PG), and triacylglycerols (TG) subclasses (glycerolipid class), cardiolipin (CL), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidylserine (PS) (phospholipid class), and ceramides (Cer), hexosylceramides (HexCer), sulfoglycolipids (SGL), sphingomyelins (SM), and sphingoid bases (sphingolipid class) ( Figure 5 A).…”

“…Samples were randomized and analyzed over a range of 150–2000 m/z . Detailed UPLC-MS methods were previously described [ 22 , 41 ].…”

“…With the opportunity of multi-dimensional analyses, there are many challenges, including the identification of molecules, determining meaningful interactions, managing the absence of key molecules and unknown systemic influences, and temporal alignment of relevant molecular events. A previous study from our lab compared changes in the brain and serum after mTBI where there were different temporal profiles between each compartment 24 h post TBI [ 22 ]. The lipids decreased in the cortices and increased in the serum relative to sham control, possibly due to an examination of a single time point and missing information.…”

Valproic Acid Treatment after Traumatic Brain Injury in Mice Alleviates Neuronal Death and Inflammation in Association with Increased Plasma Lysophosphatidylcholines

“…These findings suggest that VPA-evoked metabolic changes are complex-positive and negative depending on the source and context-and contribute in part to its effects on the brain. We have recently shown that abnormal behavior following TBI in mice is associated with long-lasting alterations of brain lipids, mainly low phosphatidylethanolamines and high triglycerides [31], while others showed lipidome changes within 24 h after TBI in rats [32,33]. In addition, clinical studies found differential phospholipid profiles in cerebrospinal fluid during the acute phase of TBI between surviving and deceased patients [34], and recently, a large human study revealed an inverse correlation between plasma levels of LPCs and TBI severity, suggesting that LPCs in this context provided protective effects or were a marker for favorable metabolic changes [35].…”