Differential Expression of Circulating Inflammatory Proteins Following Sport-Related Traumatic Brain Injury

Abstract

Sport-related traumatic brain injury (TBI) elicits a multifaceted inflammatory response leading to brain injury and morbidity. This response could be a predictive tool for the progression of TBI and to stratify the injury of which mild TBI is most prevalent. Therefore, we examined the differential expression of serum inflammatory markers overtime and identified novel markers in repetitively concussed athletes. Neuropsychological assessment by Wechsler Adult Intelligence Scale (WAIS) and Immediate Post Concussion Assessment and Cognitive Test (ImPACT) was performed on rugby players and serum was taken from healthy, concussed and repetitively concussed athletes. Serum was also obtained <1 week and >1 week after trauma and analyzed for 92 inflammatory protein markers. Fibroblast growth factor 21 (FGF21) and interleukin-7 (IL-7) differentiated repetitively concussed athletes. Macrophage chemotactic protein-1 (MCP-1), tumor necrosis factor superfamily member 14 (TNFSF14) were significantly reduced >1 week and chemokine (C-X3-C motif) ligand 1 (CX3CL1) upregulated <1 week after injury. FGF21 and MCP-1 negatively correlated with symptoms and their severity. We have identified dynamic changes in the inflammatory response overtime and in different classes of concussion correlating with disease progression. This data supports the use of inflammatory biomarkers as predictors of symptom development due to secondary complications of sport-related mTBI. mTBI can be defined as head trauma resulting in either memory loss or altered neurological function up to a day following the traumatic ictus or loss of consciousness for under 30 min [5]. A large proportion of mTBI consists of sport-related concussive (SRC) injury with up to 3.8 million cases reported in the United States annually [6]. There is also a greater risk of these athletes experiencing repetitive concussions which has been associated with the development of neurodegenerative diseases such as Parkinson's, Alzheimer's, and chronic traumatic encephalopathy (CTE) [6][7][8][9][10][11][12][13][14][15]. Neurocognitive tests have been developed to diagnose concussion. However, these assessments are expensive, subject to bias due to lack of appropriate baselines and have not yet demonstrated efficacy as prognostic tools [16][17][18].Difficulties in developing tools for the prediction of progressive pathology in TBI are confounded by the variability in the anatomical location, extent of the mechanical injury to the brain, as well as the multitude of biological response mechanisms involved. TBI is broadly characterized by 2 phases [19,20]. Immediately after impact, the primary phase is associated with shearing and tearing of neural and vascular brain structures and enhanced permeability of the blood-brain barrier. Within minutes start the secondary phase, where danger-associated molecular pattern (DAMPs) molecules are released from damaged cells which stimulate the Toll-like receptor (TLR) [21]. Cytokines and chemokines are also released leading to the recruitment of microglia a...

Analysis of Cerebrospinal Fluid Extracellular Vesicles by Proximity Extension Assay: A Comparative Study of Four Isolation Kits

“…PEA has been applied to EVs derived from various cell cultures, breast milk, and seminal plasma [ 16 ]. Further, PEA has been used for biomarker discovery related to sports-related brain trauma [ 17 ], chronic mild traumatic brain injury [ 18 ], and Duchenne muscular dystrophy [ 19 ], and could also distinguish patients with Parkinson’s disease from patients with atypical parkinsonisms [ 20 ].…”

Biomarkers of Neuroinflammation in Traumatic Brain Injury

“…Fibroblast growth factor 21 (FGF21) is a growth factor that enhances metabolic activity and promotes cell growth. Begum et al (2020) found that FGF21 was significantly downregulated in repeatedly concussed patients. Along with MCP-1, FGF21 was found to be negatively correlated with symptoms (e.g., higher protein expression of FGF21 was associated with fewer symptoms).…”

“…For example, TBI induces cytokine changes, and thus changes in levels of IL-6 (pro-inflammatory) and IL-10 (anti-inflammatory), among others, may be indicative of depressive symptoms and can be useful in depressive symptom research (Bodnar et al, 2018; Sheikh-Wu et al, 2022). Begum et al (2020) measured FGF21 and MCP-1 among concussed athletes and found that increased serum concentrations of FGF21 and MCP-1 correlated greater likelihood for reporting headache and fatigue. Biomarkers can also provide insight into the effects of the injury and subsequent neuroinflammatory response in the development or improvement in functional outcomes in TBI patients.…”

“…In the brain, MCP-1 is expressed and released by astrocytes (Deshmane et al, 2009). Begum et al (2020) found that reduced MCP-1 expression was associated with frequency and severity of symptoms experienced among those with mild TBI, including symptoms such as feeling foggy and poor balance.…”

Increased level of LIGHT/TNFSF14 is associated with survival in aneurysmal subarachnoid hemorrhage

“…The decrease in serum levels of LIGHT/TNFSF14 by natalizumab treatment in MS patients suggests that LIGHT/TNFSF14 decreases when inflammation is reduced by disease‐modifying treatment. LIGHT/TNFSF14 was found to be significantly reduced in concussed patients when compared with healthy individuals 21 . LIGHT/TNFSF14 engages two cellular signaling receptors, lymphotoxin receptor (LTR) and HVEM, and is inactivated by Decoy receptor‐3 (DcR3) 22 .…”