alphaII-Spectrin breakdown product cerebrospinal fluid exposure metrics suggest differences in cellular injury mechanisms after severe traumatic brain injury

Abstract

Traumatic brain injury (TBI) produces alphaII-spectrin breakdown products (SBDPs) that are potential biomarkers for TBI. To further understand these biomarkers, the present study examined (1) the exposure and kinetic characteristics of SBDPs in cerebrospinal fluid (CSF) of adults with severe TBI, and (2) the relationship between these exposure and kinetic metrics and severity of injury. This clinical database study analyzed CSF concentrations of 150-, 145-, and 120-kDa SBDPs in 38 severe TBI patients. Area under the curve (AUC), mean residence time (MRT), maximum concentration (C(max)), time to maximum concentration (T(max)), and half-life (t(1/2)) were determined for each SBDP. Markers of calpain proteolysis (SBDP150 and SBDP145) had a greater median AUC and C(max) and a shorter MRT than SBDP120, produced by caspase-3 proteolysis in the CSF in TBI patients ( p < 0.001). AUC and MRT for SBDP150 and SBDP15 were significantly greater in patients with worse Glasgow Coma Scale (GCS) scores at 24 h after injury compared to those whose GCS scores improved (AUC p=0.013, MRT p=0.001; AUC p=0.009, MRT p=0.021, respectively). A positive correlation was found between patients with longer elevations in intracranial pressure (ICP) measurements of 25mmHg or higher and those with a greater AUC and MRT for all three biomarkers. This is the first study to show that the biomarkers of proteolysis differentially associated with calpain and caspase-3 activity have distinct CSF exposure profiles following TBI that suggest a prominent role for calpain activity. Further studies are being conducted to determine if exposure and kinetic metrics for biofluid-based biomarkers can predict clinical outcome.

FIG. 1.

Comparison of levels of SBDPs in patients with TBI versus controls at all time points up to 5 days post-injury. Levels of SBDP150 and SBDP145 were predominantly elevated in the first 24–72 h post-injury, while SBDP120 levels were significantly elevated at all time points except 24 h post-injury in TBI patients compared to controls (n = 22–47 for each time point; ^*, #, &p < 0.05 compared to controls). Values represent arbitrary densitometry units means ± SEM. Reproduction of authors' work (Pineda et al., 2007).

FIG. 2.

Comparison of median area under the curve (AUC) for SBDP150, SBDP145, and SBDP120. The differences in AUC were statistically significant between SBDP150 and SBDP120 (p < 0.001), and also between SBDP145 and SBDP120 (p < 0.001). There was no significant difference between SBDP150 and SBDP145. AUC is expressed in arbitrary densitometric units (adu)^*min. The line in the box indicates the median value of the data, the upper edge of the box indicates the 75th percentile of the data set, and the lower edge indicates the 25th percentile. The ends of the vertical lines indicate the minimum and maximum data values (#p < 0.05 compared to SBDP120).

FIG. 3.

Comparison of maximum concentrations (C_max) for SBDP150, SBDP145, and SBDP120. The differences in median C_max were significant between SBDP150 and SBDP120 (p < 0.001), and also between SBDP145 and SBDP120 (p <0.001). There was no significant difference between SBDP150 and SBDP145. C_max is expressed in arbitrary densitometric units (adu). The line in the box indicates the median value of the data, the upper edge of the box indicates the 75th percentile of the data set, and the lower edge indicates the 25th percentile. The ends of the vertical lines indicate the minimum and maximum data values (#p < 0.05 compared to SBDP120).

FIG. 4.

Comparison of area under the curve (AUC) and changes in GCS scores from post-resuscitation to day 1. There was a statistically significant difference in median AUC for SBDP150 (p = 0.013) and SBDP145 (p = 0.009), but not SBDP120 (p = 0.322), between patients who had no improvement or worsening GCS (n = 22), compared to those who improved (n = 13) during this time period. AUC is expressed in arbitrary densitometric units (adu)^*min. The line in the box indicates the median value of the data, the upper edge of the box indicates the 75th percentile of the data set, and the lower edge indicates the 25th percentile. The ends of the vertical lines indicate the minimum and maximum data values (&p < 0.05 compared to SBDP150 in the improved group; #p < 0.05 compared to SBDP145 in the improved group).

FIG. 5.

Correlation between the number of hours ICP elevations were 25 mm Hg or higher and area under the curve (AUC) for SBDP150. This figure shows the positive correlation between the number of hours ICP was 25 mm Hg or higher and AUC (n = 33) for SBDP150 [correlation coefficient 0.5; p = 0.003]. AUC is expressed in arbitrary densitometric units (adu)*min.