Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study.
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.BDNFvariants, 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.
Department of Physical Medicine and Rehabilitation, University of PittsburghPittsburgh, PA, USA; Department of Biological Sciences, Carnegie Mellon UniversityPittsburgh, PA, USA.
Miranda J
MJ
Munoz
Department of Physical Medicine and Rehabilitation, University of PittsburghPittsburgh, PA, USA; Department of Epidemiology, University of PittsburghPittsburgh, PA, USA.
Raj G
RG
Kumar
Department of Physical Medicine and Rehabilitation, University of PittsburghPittsburgh, PA, USA; Department of Rehabilitation Medicine, Seoul National University HospitalSeoul, South Korea.
Byung-Mo
BM
Oh
Department of Physical Medicine and Rehabilitation, University of PittsburghPittsburgh, PA, USA; Department of Epidemiology, University of PittsburghPittsburgh, PA, USA.
Yvette P
YP
Conley
Department of Nursing, University of PittsburghPittsburgh, PA, USA; Safar Center for Resuscitation Research, University of PittsburghPittsburgh, PA, USA.
Zhensheng
Z
Wang
Department of Psychiatry, Vanderbilt University Medical Center Nashville, TN, USA.
Michelle D
MD
Failla
Department of Physical Medicine and Rehabilitation, University of PittsburghPittsburgh, PA, USA; Safar Center for Resuscitation Research, University of PittsburghPittsburgh, PA, USA; Department of Neuroscience, University of PittsburghPittsburgh, PA, USA; Center for Neuroscience, University of PittsburghPittsburgh, PA, USA.
Amy K
AK
Wagner
BDNF; TBI; biomarkers; cerebrospinal fluid; cortisol; genetics