Search

Distinct regulatory signaling mechanisms exist between cortisol and brain derived neurotrophic factor (BDNF), and both acute cerebral spinal fluid (CSF) cortisol and BDNF can predict TBI outcome. We investigated concurrent CSF BDNF relationships with CSF cortisol in 92 patients week-1 after severe traumatic brain injury (sTBI). BDNF genetics and age were assessed for relationships with 6-month mortality. We hypothesized cortisol would mediate BDNF effects on 6-month mortality when also considering age and BDNF genetics. We also hypothesized BDNF genetics would moderate relationships between CSF BDNF and cortisol levels. BDNF variants, rs6265 and rs7124442, were used to create a gene risk score (GRS) in reference to "younger patients" ( < 48 years old). GRS = 0 was hypothesized as the no-risk group (Val/Val, T/T), GRS = 1 included carriers for one risk-allele (Val/Val, C-carrier or T/T, Met-carrier), and GRS = 2 included carriers of both risk-alleles (Met-carrier, C-carrier). Group based trajectory analysis was used to create patient cortisol groupings, and spline analysis was used to identify the 80th percentile as an appropriate cut-point for high vs. low BDNF levels. CSF BDNF predicted patient cortisol trajectory grouping (p = 0.041) when controlling for age and injury severity. Additionally, cortisol grouping predicted 6-month mortality (p = 0.020), when controlling for age, injury severity and genetics. In mediation analysis, the direct effect of BDNF predicting mortality, when controlling for cortisol trajectory grouping, was not significant. However, the total BDNF effect predicting mortality, with cortisol acting as the mediator, was significant (p = 0.040), yielding a mediation percentage of 20.30%. Also, BDNF was associated with cortisol trajectory grouping among patients with a BDNF GRS = 1 or GRS = 2 (p = 0.026). A BDNF*GRS interaction predicted mortality in younger subjects when controlling for cortisol trajectory grouping, GCS, and GRS (p = 0.018). Thus, we conclude that 6-month mortality after sTBI can be predicted through a mediation model with CSF cortisol and BDNF while also considering age and BDNF genetics. [ABSTRACT FROM AUTHOR]

Previous work has linked the Val158Met polymorphism within the COMT gene to behavioral dysfunction among those dealing with depression following traumatic brain injury (TBI). In TBI and other populations, Met-homozygotes, (i.e. having higher synaptic DA levels), have more behavioral dysfunction. Since the biological rationale for this relationship is unclear, further efforts are needed to elucidate how Val158Met may influence behavior and depression. The literature suggests a link between Val158Met status and the hypothalamicpituitary-adrenal (HPA) axis, proposing that Val158Met status may confer a differential response to stress sensitivity, wherein carrying the Met-allele increases sensitivity to environmental and/or behavioral stressors, increasing the HPA axis response. To examine this relationship withinTBI, cortisolmeasurements weremade using ELISAwith samples collected from individuals post-injury who also had COMT genetic data and depression status available for analysis. To examine temporal relationships between cortisol levels byVal158Met group, we first examined general trends within our entire cortisol study population. Overall, serum cortisol levels were significantly elevated for individuals with TBI (n = 251) versus controls (n = 17) initially after injury (220.01+ / - 97.81 ng/ml vs. 154.12 + / - 54.44 n/mL; p = 0.0065), but cortisol trended downward significantly over time for all subjects (n = 50) by 3 months (p = 0.001) to conrol levels. At 6-months post-TBI (n = 60), individualswhowereMet-homozygotes (n = 17) had significantly higher cortisol levels (169.11 + / - 66.16 ng/ml) versus Val/Met-heterozygotes (123.08 + / - 63.02 ng/ml) (n = 29; p = 0.018) or Val-homozygotes (111.21 + / - 31.72 ng/ml) (n = 17; p = 0.008). Suggesting increased sensitivity for Met-homozygotes to post-acute stressors. These findings may help to elucidate previously observed relationships between Val158Met and behavior through the lens of HPA axis response. [ABSTRACT FROM AUTHOR]