Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans

Abstract

Previous work has found that serum G-CSF was acutely elevated in mice 24h but not one week after controlled cortical impact (CCI). The purpose of this study was to investigate whether blood G-CSF correlates with the elevated brain cytokines in mice after CCI and also if it correlates with traumatic brain injury (TBI) in humans. Here, we found in mice undergoing CCI, a procedure that induces direct injury to the brain, that serum G-CSF correlated directly or indirectly with several brain cytokines, indicating it is a useful marker for the neuroinflammation of TBI. A pilot study in humans (phase I, n=19) confirmed that plasma G-CSF is acutely elevated on day 1 (p<0.001) of TBI and has returned to baseline by one week. In a second human sample (phase II) (n=80), we found plasma G-CSF peaks about 12h after arriving in the emergency department (41.6+/-5.4 pg/ml). Aging was weakly associated (p<0.05) with a less robust elevation in serum G-CSF, but there was no difference with gender. ISS, a measure of total severity of injury, correlated with the degree of elevation in serum G-CSF (r=.419; p<0.05), but severity of head injury (via AIS) did not. The latter may have been because of the statistically narrow range of head injuries among our cases and the high number of cases diagnosed with closed head injury (a non-codable diagnosis). In conclusion, plasma G-CSF may be a useful biomarker of TBI, correlating with neuroinflammation in the animal model and in the human studies with time since injury and total severity of injury. As such, it may be useful in determining whether TBI has occurred within the last 24h.

Keywords: Biomarker; Blood–brain barrier; G-CSF; Neuroinflammation; Traumatic brain injury.

Fig. 1

Path analysis of relation of serum G-CSF to brain cytokines in a mouse model of TBI. Results show that serum G-CSF was most directly correlated with brain G-CSF levels and so was related to several other brain cytokines.

Fig. 2

Phase I study: levels of plasma G-CSF in ten patients followed serially with blood taken immediately, one week, and one month after TBI and compared to nine control patients. Plasma G-CSF was elevated immediately after TBI, but not later. The n per group is shown in parentheses.

Fig. 3

Phase II study: upper panel: plasma G-CSF was elevated in a cohort of 39 control and 41 TBI patients. Lower panel: histogram for plasma G-CSF levels in controls and TBI patients. These Phase II study patients were the cohort further evaluated in Figs. 4–6.

Fig. 4

Interval between arriving in the emergency room and blood drawing vs plasma G-CSF levels. Upper panel: levels of G-CSF peaked in blood samples drawn 6–12 h after arriving in the emergency room. Lower panel: a statistically significant correlation existed between plasma G-CSF levels and interval for the first 12 h.

Fig. 5

Age and plasma G-CSF levels. Upper panel: younger patients, but not older patients showed an increase in G-CSF after TBI. Young and older controls showed no differences. Lower panel: a trend (p = 0.054) between age and plasma G-CSF occurred among those who had suffered TBI.

Fig. 6

Severity of injury and plasmaG-CSF levels. Upper panel: no correlation existed between the measure of severity of head injury and G-CSF levels. Lower panel: a significant correlation existed between the measure of total injury severity and G-CSF levels.

Fig. 7

Receiver operator characteristics (ROC) curve. Data used was from the validation study. The curve had an AUC of 0.748 and a predictive value of 15 pg/ml.