Abstract
Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (TBI). However, their relationship with diffuse histopathology remains unclear. Additionally, translatability is a focus of neurotrauma research, however, studies using translational animal models are limited. Here, we evaluated associations between circulating biomarkers and acute thalamic histopathology in a translational micro pig model of mTBI. Serum samples were collected pre-injury, and 1 min-6 h following mTBI. Markers of neuronal injury (Ubiquitin Carboxy-terminal Hydrolase L1 [UCH-L1]), microglial/macrophage activation (Ionized calcium binding adaptor molecule-1 [Iba-1]) and interleukin-6 [IL-6]) and astrogliosis/astrocyte damage (glial fibrillary acidic protein [GFAP]) were measured. Axonal injury and histological features of neurons and glia were also investigated using immunofluorescent labeling and correlated to serum levels of the associated biomarkers. Consistent with prior experimental and human studies, GFAP, was highest at 6 h post-injury, while no substantial changes were observed in UCH-L1, Iba-1 or IL-6 over 6 h. This study also found promising associations between thalamic glial histological signatures and ensuing release of Iba-1 and GFAP into the circulation. Our findings suggest that in diffuse injury, monitoring serum Iba-1 and GFAP levels can provide clinically relevant insight into the underlying acute pathophysiology and biomarker release kinetics following mTBI, providing previously underappreciated diagnostic capability.
Highlights
Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (TBI)
Within the unique Operation Brain Trauma Therapy (OBTT) multi-center, multi-species, pre-clinical therapy and serum biomarker screening consortium framework[8,10], we have demonstrated that certain biomarkers, namely glial fibrillary acidic protein [GFAP], can be considered as a surrogate endpoint of gross pathology and strongly predicts behavioral morbidity and response to therapies across multiple experimental rodent models of T BI8,11
Unlike GFAP, there was no evidence of longitudinal changes in Ubiquitin Carboxy-terminal Hydrolase L1 (UCH-L1) (Fig. 2), Ionized calcium binding adaptor molecule 1 (Iba-1) (Fig. 3) or interleukin 6 (IL-6) (Fig. 4) serum levels over the first 6 h following central fluid percussion injury (cFPI) and no substantial change in the levels of UCH-L1, Iba-1 or IL-6, in post-injury samples compared with baseline samples
Summary
Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (TBI). Within the unique OBTT multi-center, multi-species, pre-clinical therapy and serum biomarker screening consortium framework[8,10], we have demonstrated that certain biomarkers, namely glial fibrillary acidic protein [GFAP], can be considered as a surrogate endpoint of gross pathology and strongly predicts behavioral morbidity and response to therapies across multiple experimental rodent models of T BI8,11. We detected acute microglia/macrophage activation in the thalamus following mild TBI in micro pigs, suggesting a role for inflammation following mTBI in this model[29,30] These pathophysiological changes were observed in the absence of cell death or parenchymal micro bleeds within the thalamic domain[29], indicating that this micro pig model is ideal for assessing potential diffuse mTBI-induced thalamic patholphysiology
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