Accuracy of head computed tomography scoring systems in predicting outcomes for patients with moderate to severe traumatic brain injury: A ProTECT III ancillary study.

BACKGROUND: Several types of head CT classification systems have been developed to prognosticate and stratify TBI patients. OBJECTIVE: The purpose of our study was to compare the predictive value and accuracy of the different CT scoring systems, including the Marshall, Rotterdam, Stockholm, Helsinki, and NIRIS systems, to inform specific patient management actions, using the ProTECT III population of patients with moderate to severe acute traumatic brain injury (TBI). METHODS: We used the data collected in the patients with moderate to severe (GCS score of 4-12) TBI enrolled in the ProTECT III clinical trial. ProTECT III was a NIH-funded, prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial designed to determine the efficacy of early administration of IV progesterone. The CT scoring systems listed above were applied to the baseline CT scans obtained in the trial. We assessed the predictive accuracy of these scoring systems with respect to Glasgow Outcome Scale-Extended at 6 months, disability rating scale score, and mortality. RESULTS: A total of 882 subjects were enrolled in ProTECT III. Worse scores for each head CT scoring systems were highly correlated with unfavorable outcome, disability outcome, and mortality. The NIRIS classification was more strongly correlated than the Stockholm and Rotterdam CT scores, followed by the Helsinki and Marshall CT classification. The highest correlation was observed between NIRIS and mortality (estimated odds ratios of 4.83). CONCLUSION: All scores were highly associated with 6-month unfavorable, disability and mortality outcomes. NIRIS was also accurate in predicting TBI patients' management and disposition.

Exposure of cyclosporin A in whole blood, cerebral spinal fluid, and brain extracellular fluid dialysate in adults with traumatic brain injury.

Cyclosporin A (CsA), an immunosuppressive medication traditionally used in the prevention of post-transplant rejection, is a promising neuroprotective agent for traumatic brain injury (TBI). Preliminary studies in animals and humans describe the efficacy and safety of CsA when administered following neurotrauma. The objective of this study is to describe CsA exposure in adults with severe TBI by assessing concentrations in whole blood, cerebrospinal fluid (CSF), and brain extracellular fluid (ECF) dialysate as measured by brain microdialysis. Severe TBI patients were enrolled in a randomized controlled trial following the written informed consent of their legal guardians. Patients received either CsA 5 mg/kg as a continuous infusion over 24 h, or matching placebo. Noncompartmental exposure analyses were performed using CsA concentrations in whole blood, CSF, and ECF dialysate. There were 37 patients randomized to the CsA arm of the trial and included in this exposure analysis. CsA was detected in the ECF dialysate and CSF at a fraction of the whole blood concentration. Mean CsA maximum concentrations were achieved at 24 and 30 h from the start of the 24 h infusion, in the CSF and ECF dialysate, respectively. A correlation was found between ECF dialysate and CSF concentrations. CsA was detected in the blood, CSF, and brain ECF dialysate. CsA exposure characteristic differences exist for whole blood, CSF, and ECF dialysate in severe TBI patients when administered as a continuous intravenous infusion. These exposure characteristics should be used for safer CsA dose optimization to achieve target CsA concentrations for neuroprotection in future TBI studies.

Age-related intraneuronal elevation of αII-spectrin breakdown product SBDP120 in rodent forebrain accelerates in 3×Tg-AD mice.

Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs) of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer's disease (AD), although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (3×Tg-AD) relative to non-transgenic controls. SBDP120 immunoreactivity (IR) was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 3×Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP) expression, ß-amyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an αII-spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice.