Diagnostic Accuracy of Glial Fibrillary Acidic Protein and Ubiquitin Carboxy-Terminal Hydrolase-L1 Serum Concentrations for Differentiating Acute Intracerebral Hemorrhage from Ischemic Stroke.

BACKGROUND: Biomarkers indicative of intracerebral hemorrhage (ICH) may help triage acute stroke patients in the pre-hospital phase. We hypothesized that serum concentration of glial fibrillary acidic protein (GFAP) in combination with ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), measured by a rapid bio-assay, could be used to distinguish ICH from ischemic stroke. METHODS: This prospective two-center study recruited patients with a clinical diagnosis of acute stroke both in the pre-hospital phase and at hospital admission (within 4 and 6 h after symptom onset, respectively). Blood samples were analyzed for concentrations of GFAP and UCH-L1 using ELISA techniques. The reference standard was the diagnosis of ICH, ischemic stroke, or stroke mimicking condition achieved after clinical workup including brain imaging. RESULTS: A total of 251 patients were included (mean age [± SD] 72 ± 15 years; 5 ICH, 23 ischemic strokes and 14 stroke mimics in the pre-hospital part; and 59 ICH, 148 ischemic strokes and 2 stroke mimics in the in-hospital part). Mean delay (± SD) from symptom onset to blood withdrawal was 130 ± 79 min for the pre-hospital patients and 136 ± 86 min for the in-hospital patients. Both GFAP and UCH-L1 serum concentrations were higher in patients having ICH as compared to other diagnoses (GFAP: median 330 ng/L [interquartile range 64-7060, range 8-56,100] vs. 27.5 ng/L [14-57.25, 0-781], p < 0.001; UCH-L1: 401 ng/L [265-764, 133-1812] vs. 338 ng/L [213-549.5, 0-2950], p = 0.025). Area-under-the-curve values were 0.866 (95% CI 0.809-0.924, p < 0.001) for GFAP, and 0.590 (0.511-0.670, p = 0.033) for UCH-L1. Regarding overall diagnostic accuracy, UCH-L1 did not add significantly to the performance of GFAP. CONCLUSIONS: GFAP may differentiate ICH from ischemic stroke and stroke mimics. A point-of-care test to distinguish between ischemic and hemorrhagic strokes might facilitate triage to different treatment pathways or locations, or be used to select patients for trials of ultra-early interventions.

Synthesis of Findings, Current Investigations, and Future Directions: Operation Brain Trauma Therapy.

Operation Brain Trauma Therapy (OBTT) is a fully operational, rigorous, and productive multicenter, pre-clinical drug and circulating biomarker screening consortium for the field of traumatic brain injury (TBI). In this article, we synthesize the findings from the first five therapies tested by OBTT and discuss both the current work that is ongoing and potential future directions. Based on the results generated from the first five therapies tested within the exacting approach used by OBTT, four (nicotinamide, erythropoietin, cyclosporine A, and simvastatin) performed below or well below what was expected based on the published literature. OBTT has identified, however, the early post-TBI administration of levetiracetam as a promising agent and has advanced it to a gyrencephalic large animal model--fluid percussion injury in micropigs. The sixth and seventh therapies have just completed testing (glibenclamide and Kollidon VA 64), and an eighth drug (AER 271) is in testing. Incorporation of circulating brain injury biomarker assessments into these pre-clinical studies suggests considerable potential for diagnostic and theranostic utility of glial fibrillary acidic protein in pre-clinical studies. Given the failures in clinical translation of therapies in TBI, rigorous multicenter, pre-clinical approaches to therapeutic screening such as OBTT may be important for the ultimate translation of therapies to the human condition.

Insight into Pre-Clinical Models of Traumatic Brain Injury Using Circulating Brain Damage Biomarkers: Operation Brain Trauma Therapy.

Operation Brain Trauma Therapy (OBTT) is a multicenter pre-clinical drug screening consortium testing promising therapies for traumatic brain injury (TBI) in three well-established models of TBI in rats--namely, parasagittal fluid percussion injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like brain injury (PBBI). This article presents unique characterization of these models using histological and behavioral outcomes and novel candidate biomarkers from the first three treatment trials of OBTT. Adult rats underwent CCI, FPI, or PBBI and were treated with vehicle (VEH). Shams underwent all manipulations except trauma. The glial marker glial fibrillary acidic protein (GFAP) and the neuronal marker ubiquitin C-terminal hydrolase (UCH-L1) were measured by enzyme-linked immunosorbent assay in blood at 4 and 24 h, and their delta 24-4 h was calculated for each marker. Comparing sham groups across experiments, no differences were found in the same model. Similarly, comparing TBI + VEH groups across experiments, no differences were found in the same model. GFAP was acutely increased in injured rats in each model, with significant differences in levels and temporal patterns mirrored by significant differences in delta 24-4 h GFAP levels and neuropathological and behavioral outcomes. Circulating GFAP levels at 4 and 24 h were powerful predictors of 21 day contusion volume and tissue loss. UCH-L1 showed similar tendencies, albeit with less robust differences between sham and injury groups. Significant differences were also found comparing shams across the models. Our findings (1) demonstrate that TBI models display specific biomarker profiles, functional deficits, and pathological consequence; (2) support the concept that there are different cellular, molecular, and pathophysiological responses to TBI in each model; and (3) advance our understanding of TBI, providing opportunities for a successful translation and holding promise for theranostic applications. Based on our findings, additional studies in pre-clinical models should pursue assessment of GFAP as a surrogate histological and/or theranostic end-point.

Transcranial laser therapy in acute stroke treatment: results of neurothera effectiveness and safety trial 3, a phase III clinical end point device trial.

BACKGROUND AND PURPOSE: On the basis of phase II trials, we considered that transcranial laser therapy could have neuroprotective effects in patients with acute ischemic stroke. METHODS: We studied transcranial laser therapy in a double-blind, sham-controlled randomized clinical trial intended to enroll 1000 patients with acute ischemic stroke treated ≤24 hours after stroke onset and who did not undergo thrombolytic therapy. The primary efficacy measure was the 90-day functional outcome as assessed by the modified Rankin Scale, with hierarchical Bayesian analysis incorporating relevant previous data. Interim analyses were planned after 300 and 600 patients included. RESULTS: The study was terminated on recommendation by the Data Monitoring Committee after a futility analysis of 566 completed patients found no difference in the primary end point (transcranial laser therapy 140/282 [49.6%] versus sham 140/284 [49.3%] for good functional outcome; modified Rankin Scale, 0-2). The results remained stable after inclusion of all 630 randomized patients (adjusted odds ratio, 1.024; 95% confidence interval, 0.705-1.488). CONCLUSIONS: Once the results of the interim futility analysis became available, all study support was immediately withdrawn by the capital firms behind PhotoThera, and the company was dissolved. Proper termination of the trial was difficult but was finally achieved through special efforts by former employees of PhotoThera, the CRO Parexel and members of the steering and the safety committees. We conclude that transcranial laser therapy does not have a measurable neuroprotective effect in patients with acute ischemic stroke when applied within 24 hours after stroke onset. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01120301.

Long-term safety of single and multiple infrared transcranial laser treatments in Sprague-Dawley rats.

BACKGROUND AND OBJECTIVE: Growing interest exists in the use of near-infrared laser therapies for the treatment of numerous neurologic conditions, including acute ischemic stroke, traumatic brain injury, Parkinson's disease, and Alzheimer's disease. In consideration of these trends, the objective of this study was to evaluate the long-term safety of transcranial laser therapy with continuous-wave (CW) near-infrared laser light (wavelength, 808 ± 10 nm, 2-mm diameter) with a nominal radiant power of 70 mW; power density, 2,230 mW/cm(2), and energy density, 268 J/cm(2) at the scalp (10 mW/cm(2) and 1.2 J/cm(2) at the cerebral cortical surface) in healthy Sprague-Dawley rats. MATERIALS AND METHODS: In this study, 120 anesthetized rats received sequential transcranial laser treatments to the right and left parietal areas of the head on the same day (minimum of 5 min between irradiation of each side), on either Day 1 or on each of Days 1, 3, and 5. Sixty anesthetized rats served as sham controls. Rats were evaluated 1 year after treatment for abnormalities in clinical hematology and brain and pituitary gland histopathology. RESULTS: No toxicologically important differences were found in the clinical hematology results between sham-control and laser-treated rats for any hematologic parameters examined. All values fell within historic control reference ranges for aged Sprague-Dawley rats. Similarly, brain and pituitary gland histopathology showed no treatment-related abnormalities or induced neoplasia. CONCLUSIONS: Single and multiple applications of transcranial laser therapy with 808-nm CW laser light at a nominal power density of 10 mW/cm(2) at the surface of the cerebral cortex appears to be safe in Sprague-Dawley rats 1 year after treatment.