Cerebrospinal Fluid Cortisol Mediates Brain-Derived Neurotrophic Factor Relationships to Mortality after Severe TBI: A Prospective Cohort Study

Figure 1. Diagram depicting how the cohort was derived for analysis. The cohort was restricted to self-reported White individuals with complete demographic, clinical, genetics and biomarker data. There were a total of 216 White severe TBI subjects with CSF Cortisol and BDNF. Of these, 185 and 155 subjects had CSF BDNF and cortisol, respectively. A total of 131 subjects had both CSF cortisol and BDNF. A total of 14 subjects were removed for missing BDNF genetics or GCS or mortality data, leaving a final cohort of 117. 1Used for estimating prior distributions in the mediation analysis path for BDNF-mortality (total effect). 2Used for estimating prior distributions in the mediation analysis path of BDNF-cortisol, cortisol-mortality, and BDNF-mortality (direct effect). 3Used to generate CSF cortisol trajectories in the most inclusive cohort with CSF cortisol.

Figure 2. Daily mean CSF cortisol levels for CSF cortisol TRAJ groups (N = 117). Daily mean CSF cortisol levels for the cortisol TRAJ groups. Error bars indicate standard error of the mean. There was a significant difference in CSF cortisol levels between the two groups on days 1–6 (p < 0.01). CSF cortisol values are provided for N = 13 healthy controls as a reference.

Figure 3. (A) Acute CSF Cortisol by Survival Status (N = 117). The open circles indicate survivors and closed circles are non-survivors. Data for CSF Cortisol (ng/mL) were averaged within survival category each day. Error bars indicate standard error of the mean. On days 2–4, CSF Cortisol levels were significantly (p < 0.05) elevated among non-survivors compared to survivors. (B) Acute CSF BDNF by Survival Status (N = 117). The open circles indicate survivors and closed circles are non-survivors. Data for CSF BDNF (ng/mL) were averaged within survival category each day. Error bars indicate standard error of the mean. On days 3 and 5, CSF BDNF levels were significantly (p < 0.05) elevated among non-survivors compared to survivors. There was a trend toward significant difference in levels on day 0 (p = 0.078); there were no significant differences in CSF BDNF levels for any other day.

Figure 4. Acute CSF BDNF by Cortisol Trajectory Group by GRS. Weekly average CSF BDNF (ng/mL) is reported. Error bars indicate standard error of the mean. White, gray, and black corresponds to GRS scores of 0, 1, and 2, respectively. Results are stratified among the high (n = 44) and low (n = 73) cortisol TRAJ groups. Among individuals with GRS = 1, those in the high cortisol TRAJ group had significantly elevated BDNF levels compared to those in the low cortisol TRAJ group p = 0.011. There were no significant differences in BDNF levels by cortisol TRAJ group for individuals with GRS of 0 or 2.

Figure 5. (A) Acute CSF BDNF by Mortality Status by GRS. Weekly average CSF BDNF (ng/mL) is reported. Error bars indicate standard error of the mean. White, gray, and black corresponds to GRS scores of 0, 1, and 2, respectively. Results are stratified among survivors (n = 91) and non-survivors (n = 26). Among non-survivors, there is a significant difference in BDNF levels by GRS, such that higher GRS scores have lowest BDNF levels (p = 0.015). There is no difference in BDNF levels by GRS in survivors-only. Only among individuals with GRS scores of 0 is there a significant difference in BDNF levels in survivors compared to non-survivors (p = 0.007). (B) Acute CSF BDNF by Mortality Status by GRS among age below 48. Weekly average CSF BDNF (ng/mL) in reported after restricting population to only individuals below age 48. Error bars indicate standard error of the mean. White, gray, and black corresponds to GRS scores of 0, 1, and 2, respectively. Results are stratified among survivors (n = 78) and non-survivors (n = 12). Among non-survivors, there is a significant difference in BDNF levels by GRS, such that higher GRS scores have lowest BDNF levels (p = 0.032). There is no difference in BDNF…

Figure 6. Conceptual figure capturing biomarker relationships among younger individuals (≤48 years. Old, N = 90): (1) cortisol has a significant regulatory (mediating) effect on BDNF's influence on mortality, accounting for ~45% of BDNF's mortality effects; (2) the association between BDNF above/below the 75th percentile and high cortisol TRAJ is only significant among individuals with low BDNF secretion genotypes; and (3) the direct association between BDNF above/below the 75th percentile and mortality risk is stronger among individuals with the high BDNF secretion genotype (GRS = 0) compared to the low secretion genotypes. Taken together, the data support a conceptual model for younger individuals with TBI wherein high BDNF levels among those with high BDNF secretion phenotypes directly increases mortality risk, while mortality risk for those with high BDNF levels paired with low BDNF secretion genotypes is regulated (mediated) by cortisol.