Abstract
Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF) that may influence secondary injury cascades associated with traumatic brain injury (TBI) and predict outcome. We investigated concurrent CSF BDNF and cortisol relationships in 117 patients sampled days 0–6 after severe TBI while accounting for BDNF genetics and age. We also determined associations between CSF BDNF and cortisol with 6-month mortality. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to previously published hypothesized risk for mortality in “younger patients” (<48 years) and hypothesized BDNF production/secretion capacity with these variants. Group based trajectory analysis (TRAJ) was used to create two cortisol groups (high and low trajectories). A Bayesian estimation approach informed the mediation models. Results show CSF BDNF predicted patient cortisol TRAJ group (P = 0.001). Also, GRS moderated BDNF associations with cortisol TRAJ group. Additionally, cortisol TRAJ predicted 6-month mortality (P = 0.001). In a mediation analysis, BDNF predicted mortality, with cortisol acting as the mediator (P = 0.011), yielding a mediation percentage of 29.92%. Mediation effects increased to 45.45% among younger patients. A BDNF*GRS interaction predicted mortality in younger patients (P = 0.004). Thus, we conclude 6-month mortality after severe TBI can be predicted through a mediation model with CSF cortisol and BDNF, suggesting a regulatory role for cortisol with BDNF's contribution to TBI pathophysiology and mortality, particularly among younger individuals with severe TBI. Based on the literature, cortisol modulated BDNF effects on mortality after TBI may be related to known hormone and neurotrophin relationships to neurological injury severity and autonomic nervous system imbalance.
Highlights
Death rates have decreased over time, ∼2.5 million Americans experience traumatic brain injury (TBI) yearly, with more than 50,000 associated fatalities (Centers for Disease Control Prevention, 2016)
TBI results in several acute secondary injury cascades, that include aseptic inflammation (Kumar et al, 2015, 2016), excitotoxicity (Wagner et al, 2005), monaminergic dysfunction (Wagner et al, 2007), neurotrophin abnormalities (Failla et al, 2016), and stress induced steroidogenesis (Wagner et al, 2011a; Santarsieri et al, 2014) that result in blood brain barrier disruption and CNS damage (Wagner et al, 2011b; Goyal et al, 2013); representative biomarkers for each of these pathways have been identified in CSF and serum for clinical populations with moderate/severe TBI
Cortisol and Brain derived neurotrophic factor (BDNF) are crucial biomarkers to characterize in the context of TBI, as they can have both potentially useful and harmful effects in the brain
Summary
Death rates have decreased over time, ∼2.5 million Americans experience traumatic brain injury (TBI) yearly, with more than 50,000 associated fatalities (Centers for Disease Control Prevention, 2016). Cortisol in humans and corticosterone in animals, can be neuroprotective, anti-inflammatory, and anticonvulsive, in order to restore homeostasis after injury, as the end product of the stressactivated HPA axis (McEwan, 1999; Jeanneteau et al, 2008; Joëls, 2008). Based on this premise, the Corticosteroid Randomization after Significant Head Injury (CRASH) trial administered the glucocorticoid methylprednisolone acutely after TBI. Our previous work shows endogenous CSF cortisol levels are markedly increased after TBI, and we showed that sustained elevations in CSF cortisol profiles are associated with poorer outcomes (Santarsieri et al, 2014)
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