The overall aims of this research program are 1. Create and maintain state-of-the-art stroke centers in the metro DC area as the foundation of and source of clinical material for the intramural translational research program in acute stroke. 2. Develop and validate imaging diagnostics and markers for acute stroke. 3. Investigate the early pathophysiological processes in evolving cerebral ischemic injury and the effects of thrombolytic and other therapies in modifying these events. 4. Develop predictive maps of ischemic injury with multiparametric advanced MRI. 5. Conduct innovative clinical trials of novel therapeutic strategies for stroke. In 2000, we established a stroke research and care center at Suburban Hospital, a private community hospital in Bethesda, Maryland, consisting of an emergency response team and inpatient service staffed by neurologists, nurses, and researchers specializing in stroke and a research infrastructure centered around a state-of-the-art MRI facility. We demonstrated that establishment of a primary stroke center at a community hospital resulted in a nearly 10-fold increase in the proportion of patients receiving thrombolytic therapy for ischemic stroke. In the past year, we replicated our stroke program at the Washington Hospital Center in Washington, DC, which admits approximately 800 acute strokes per year and serves a primarily minority population. The activities at Washington Hospital Center were launched in October, 2004 and in May, 2005 we opened a stroke-dedicated 3T MRI facility located adjacent to the emergency department. In the last year we completed and published two studies to determine whether MRI is as sensitive to acute intracranial hemorrhage as CT, the current standard, and whether MRI prior to thrombolytic therapy is feasible and safe. To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms, a prospective study was performed. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. We concluded that MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage. MRI screening for thrombolytic therapy may improve patient selection. We compared the results of 120 consecutive patients treated with intravenous tissue plasminogen activator (tPA) within 3 hours of onset at our center with those of the 2 largest multicenter post-marketing registries of tPA use. In addition to standard criteria, MRI specific eligibility criteria were applied in 97 patients. Times to treatment (median door-to-needle time 81.5 minutes; median onset-to-needle time 135 minutes) were shorter and outcomes (mRS 0 to 1, 40.8%; mRS 0 to 2, 47.5%) were not inferior to those of the typical clinical practice. Outcomes were not different between MRI screening and CT screening. These data demonstrated that MRI screening before tPA therapy is feasible, identified patients who would not have been treated if only CT screening was used and was not associated with unacceptable times to treatment or outcomes. We published the second in a series of studies assessing the risk of silent strokes, seen only on diffusion weighted MRI (DWI), for developing subsequent strokes. We hypothesized that that early lesion recurrence within the first week after a symptomatic stroke is associated with late lesion recurrence. Late lesion recurrence occurred in 26% of patients, more frequently observed on 30-day MRI than 90-day MRI (p = 0.016). Early lesion recurrence was independently associated with late lesion recurrence. Studies are on-going to investigate whether MRI-defined ischemic lesion recurrences predict subsequent clinical recurrence and thus may be a potential surrogate endpoint in stroke secondary prevention trials. In the past year we published our discovery of a novel MRI marker of early blood-brain barrier (BBB) disruption in acute focal brain ischemia and tested its associations with reperfusion, hemorrhagic transformation (HT), and poor outcome (modified Rankin score >2). Loss of integrity of the (BBB) resulting from ischemia and reperfusion is a hypothesized precursor to HT and worse clinical outcome than would be expected from the beneficial effects of reperfusion. The BBB disruption was evident as delayed gadolinium enhancement of cerebrospinal fluid space on fluid-attenuated inversion recovery (FLAIR) images and, for convenience, has been termed hyperintense acute reperfusion marker (HARM). HARM was found in 47 of 144 (33%) ischemic stroke patients. Reperfusion was found to be the strongest independent predictor of early BBB disruption (P=0.018) in multivariate analysis. HARM was associated with HT and worse clinical outcome (after adjustment for initial severity). It was also associated with more severe strokes at onset, greater age, and thromblytic therapy. Because the timing of the disruption was early enough (median estimate 3.8 hours from onset) to make it relevant to acute thrombolytic therapy, early BBB disruption as defined by HARM may be a promising target for adjunctive therapy to reduce the complications associated with thrombolytic therapy, broaden the therapeutic window, and improve clinical outcome. Ongoing prospective studies aim to confirm these observations and better characterize this early BBB opening and its association with adverse effects of thrombolytic therapy. Toward that end we are investigating interferon beta-1a as a potential stroke therapy, based on its inhibition of matrix metalloproteinase-9, inflammatory cytokines, and BBB opening. A phase I, dose escalation and safety trial of interferon beta-1a is in progress. Other on-going studies include further investigations of the temporal progression of complementary aspects of ischemic injury measurable by MRI ? perfusion, diffusion coefficients, BBB opening, HT ? to predict tissue infarction and clinical outcome in tPA treated and untreated patients. The results of these analyses constitute our historical controls for our Phase II clinical trials. Furthest along of our Phase II clinical trials is ROSIE - ReoPro Retavase Reperfusion of Stroke Safety study - Imaging Evaluation, which investigates the combination of the thrombolytic, reteplase, and the platelet GP IIbIIIa antibody, abciximab, up to 24 hours from stroke onset, selecting patients based on MRI as well as standard criteria. This dose finding study uses a novel Bayesian model for dose selection, is currently treating at the 5th of 5 dose levels and is likely to find an acceptable dose combination, which will be taken forward to a subsequent placebo controlled trial. The acceptable combination will show re-perfusion rates at least twice that of historical controls while maintaining serious adverse event rates no worse than positive thrombolytic trials.
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