Steven Warach - US grants
Affiliations: | National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States |
Area:
Brain Imaging, Stroke Diagnostics and TherapeuticsWebsite:
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According to our matching algorithm, Steven Warach is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2007 — 2012 | Warach, Steven | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Clinical Trial Protocols For Acute Ischemic Stroke @ Neurological Disorders and Stroke Toward the goal in improving reperfusion and clinical outcomes in patients treated with standard iv tPA we have been conducting the Combination Anti-platelet and Anti-coagulation Treatment After Lysis of Ischemic Stroke Trial (CATALIST). This is a clinical trial to determine an acceptable dose of eptifibatide in combination with aspirin, tinzaparin (a low molecular weight heparin) in patients receiving standard iv TPA therapy. Patients may be treated with these adjunctive medicines up to 6 hours from stroke symptom onset. We completed enrollment of the first level (aspirin plus tinzaparin), enrolling 18 patients. In comparison with matched historical controls of tPA-treated patients in our database, the evidence in this small sample with early use of anti-platelet and anti-coagulant after standard rt-PA therapy is that it appears safe and without excessive systemic or intracranial bleeding complications. We have stopped CATALIST enrollment and are bifurcating it into two other studies. We will study the effects of tPA plus eptifibitide as a site in the NINDS SPOTRIAS clinical trial CLEAR-ER, with a planned substudy to We are investigating the potential of interferon beta-1a to protect the blood brain barrier in acute ischemic stroke and prevent hemorrhagic complications of thrombolytic therapy. The first clinical trial in this series, Recombinant human interferon beta-1a in acute ischemic stroke: a dose escalation and safety study, completed enrollment this year. The purpose of this randomized double-blind placebo-controlled sequential dose escalation, phase 1 study is to investigate the safety of IFN-beta-1a in patients with acute ischemic stroke 3-24 hours from onset and to determine the maximum tolerated dose of administration in this setting. Five dose cohorts of 5 patients (4:1 active: placebo) at 11 mcg, 22 mcg, 44 mcg, 66 mcg and 88 mcg were planned. Patients receive interferon beta 1a or placebo once daily for 7 days (dose 1 is given intravenously;doses 2-7 are injected subcutaneously). Dose escalation is continuous unless drug-related toxicity reaches a predetermined level of one dose-limiting adverse event (1 of 4 treated) within a dose cohort, in which case a second cohort of 5 patients (4:1) will be treated at that dose. The study is to be terminated at a dose level at which 2 of 4 or 3 of 8 patients on active treatment have a severe dose limiting toxicity or when all planned dose cohorts are completed. This stopping rule was reached at the 44mcg dose. Blinded data verification and analysis, including pharmacokinetic and plasma MMP-9 concentrations, are ongoing. Upon unblinding, the results will be reviewed with the DSMB. Data analysis is on-going. We have completed the design of a new protocol toward the long term goal of expanding the indications for thrombolytic therapy for ischemic stroke. The study name is MR Witness: A Phase IIa Safety Study of Intravenous Thrombolysis with Alteplase in MRI-Selected Patients. The objectives of this study are to: 1) determine the safety of intravenous alteplase (tPA) in subjects with unwitnessed stroke onset, last known well less than 24 hours before, and MRI evidence of early stroke (less than 6 hours from onset), 2) validate novel MRI profiles to improve the sensitivity while maintaining high specificity for detecting subjects with acute stroke, and 3) explore the clinical efficacy of using imaging surrogates in subjects with unwitnessed stroke onset who are treated with thrombolysis. Eighty adult male and female subjects with acute ischemic stroke who present within 24 hours since the time they were last known well and are outside the standard tPA time window, but have an MRI suggestive of early stroke treatable with thrombolysis. This is an open-label, Phase IIa safety study to determine if it is safe to extend intravenous thrombolytic treatment to subjects who are evaluated within 24 hours from last known well and eligible to receive thrombolytic treatment within 4.5 hours from symptom discovery with the assistance of an MRI-based witness when no human witness of stroke onset is available. The study is designed to investigate the safety in using standard diagnostic MRI in selecting patients for thrombolytic therapy when the last known well time places the patient beyond the current IV thrombolytic time window. We will apply the following definition of treatable stroke as diffusion-positive, FLAIR-negative approach (DPFN) shown by us and several other centers to be indicative of early stage stroke. During the study course we will also consider comparable MRI models. A posttreatment safety evaluation using non-contrast CT will be performed for all treated subjects, consistent with standards of care after treatment with IV tPA. The maximum total number of subjects treat with tPA will be 80. A DSMB will independently monitor for safety, and stopping rules are defined to stop the study early if excessive symptomatic intracranial hemorrhage (sICH) rates occur. The stopping boundary for the trial is a hybrid of two conditions such that if an unacceptably high hemorrhage rate is detected by either condition, the trial will be terminated for safety concerns. The two conditions are the lower 95% confidence bound for the true hemorrhage rate is >5.3% or the absolute number of sICH exceeds 6. The primary outcome variable is sICH. Symptomatic hemorrhage is defined as any hemorrhage with neurological deterioration with an NIHSS score that increased by 4 or more points over baseline value or the lowest value in the first 7 days or any hemorrhage leading to death. The primary hypothesis is the rate of sICH will not exceed that observed in ECASS 3, a clinical trial that demonstrated the clinical efficacy of rt-PA up to 4.5 hours from last known well (5.3%, 95% exact Confidence Interval: 3.3% to 7.9%). Secondary outcomes will be clinical outcomes and other imaging features of ischemic stroke, e.g., brain edema, lesion volume growth. At 3 months from treatment, clinical outcome will be evaluated by modified Rankin Scale scores and compared to historical controls for both non-tPA and standard tPA treated patients. The clinical trial was designed and will be conducted in collaboration with colleagues from Massachusetts General Hospital in Boston. MR Witness was initiated in 2011, and 5 patients have been enrolled to date, with no sICH events. |
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2007 — 2011 | Warach, Steven | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Clinical, Imaging, and Experimental Core Support of Acute Stroke Research @ Neurological Disorders and Stroke The foundation of an acute stroke research program is an acute stroke clinical service that will assure maximum patient referral and allow rapid identification, screening and recruitment of potential research subjects in the timely fashion needed to study the early events in cerebral ischemia and enroll patients in acute stroke research protocols. Absence of an emergency department and the time constraints on screening and recruitment of acute stroke patients as research subjects has precluded the NIH Clinical Center as the main site of our research projects. Thus, we have needed to establish and maintain the clinical, imaging and research infrastructure required to support such a program at local hospitals, Suburban Hospital (SH) in Bethesda, Maryland, and Washington Hospital Center (WHC) in DC. The major elements of this infrastructure include the NIH Stroke Service, a combination of NIH and contractor clinicians stroke neurologists, nurses, clinical fellows, on-site research/nurse coordinators, MRI scanners NIH 3T MRI at WHC, shared 1,5 T scanner at SH and MRI technologists, NIH computer network placed and maintained at each hospital, hospital office space for program needs. In addition, we maintain our own PACS for images obtained on the WHC and SH MRI scanners, and developed and maintain a database for clinical and research patient data. In FY2008 up to September 15, 2008, we screened 1234 patients and enrolled 303 in one of our research protocols at our two clinical research sites.[unreadable] [unreadable] On the NIH campus, we provide experimental stroke models at the NMR center to support our clinical research efforts. For example, in the past year we developed an experimental model of symptomatic intracranial hemorrhage in ischemic reperfusion using multimodal MRI. Symptomatic hemorrhagic transformation is the most important complicating factor following treatment of ischemic stroke with thrombolytics. Space occupying hemorrhage with mass effect (Type 2 parenchymal hematoma) is the hemorrhage type associated with the most severe adverse clinical effects. After 30 minutes of suture occlusion followed by reperfusion 46% of experimental animals developed parenchymal hematoma (15% Type 2). This model will be used to test novel therapeutics targeting blood-brain barrier integrity and the reduction of intracerebral hemorrhages and the leading candidates will be brought to clinical trial. |
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2007 — 2012 | Warach, Steven | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Developing Innovative Stroke Trial Designs @ Neurological Disorders and Stroke The ROSIE clinical trial was the first application of a Bayesian dose escalation design to balance efficacy-toxicity trade offs. The performance of this design was successful and particularly well suited for stroke thrombolytic trials because early efficacy (reperfusion) and toxicity (intracranial hemorrhage) outcomes are attainable. The model performed appropriately in that it escalated the dose when insufficient rates of reperfusion were achieved and de-escalated the dose when toxicity occurred. The model statistically eliminated abciximab with no reteplase as an acceptable dosing regimen because of insufficient efficacy after only 36 patients, whereas approximately 1200 patients were required to reach the same conclusion in Phase II and Phase III trials using conventional trial methodology. Our results demonstrate the value and efficiency of this approach to making the correct decisions about dose finding. From post-hoc exploratory analyses of the ROSIE trial data we have further refined the MRI inclusion criteria and reperfusion response that better approximates a dose-response relationship on reperfusion for a 24 hour window thrombolytic trial. This includes requiring an estimated volume of baseline perfusion defect of at least 5cc, and a definition of clinically meaningful reperfusion response as a 67% or greater reduction in ischemic volume by 24 hours (previously complete reperfusion was required). Our reperfusion half-life study described under Project 1 Z01 NS003043-01 modeled the time to reperfusion in tPA-treated and untreated patients and derived the half-life value that defines reperfusion rates in these populations. Future lytic trials will obtain sufficient serial MRI scans to model reperfusion rates against these two benchmarks.[unreadable] [unreadable] Lesion volume measurements by MRI are used as an objective outcome measure ischemic stroke studies, yet some fundamental questions about these measurements had not previously been addressed. We have completed studies quantifying the intra- and inter-reader lesion volume measurements using a standard semi-automated planimetric method on lesions acquired with diffusion weighted (DWI), mean transit time (MTT) perfusion and Fluid Attenuated Inversion Recovery (FLAIR) MRI at acute and chronic time points in 68 patients. Across in image types and time points the test-retest correlations for both intra- and interreader variability were excellent, ranging between .83 and .99 (intra-reader with higher), with test-retest volume differences of < 5% or < 2cc.[unreadable] [unreadable] We also studied whether there was a difference in final infarct volumes measured at 30 and 90 days after stroke onset. Although 90 day is standard for assessing final clinical outcome, if 90 day lesion volume can be estimated at day 30 then the follow-up period for imaging outcome stroke studies could be shorter. We performed a retrospective study of 18 patients that had lesions scanned with DWI acutely and with FLAIR at both 30 and 90 days. Mean (SD) volumes for 30, and 90 day images were 18.6 (14.0), and 15.9 (13.8) mL respectively linear regression analysis revealed a strong relationship, r=0.96 (p<0.001), between lesion volumes at 30 and 90 days. Although there is a small difference between the volumes measured and 30 and 90 days, the 30 day measured is a good estimate of 90 day lesion volume and may be acceptable as a final infarct volume outcome.[unreadable] [unreadable] The unrelenting failure of neuroprotective stroke trials to demonstrate clinical benefits brings to light shortcomings in the development of neuroprotective drugs for stroke. No compound that has reached late Phase II or Phase III trials, has ever been demonstrated to have (1) reached the target brain tissue, the ischemic penumbra, in adequate concentrations, (2) produced a pharmacological effect in the ischemic region know to occur in animal models or (3) caused an attenuation of infarct volume. It is our objective to develop novel methods to directly measure neuroprotective effects in the stroke patient. Studies of infarct volume have been previously described under this and other projects. We are conducting several other investigations toward that end. The optimal experimental setting for a test of neuroprotection in stroke would be to begin administration of the neuroprotective drug prior to the ischemic event. While that is not possible for spontaneous stroke presenting to the hospital emergency department, we propose that patients undergoing open heart surgery may be such a clinical model. Although disabling stroke is an infrequent adverse consequence of this surgery (< 5% of cases), published work has indicated that the occurrence of new ischemic lesions, most not overtly symptomatic, occurs at a much higher rate. In this year we have nearly completed enrollment in our study to identify pre-operative factors associated with the highest rates peri-operative ischemic lesions. If we find at least a 30% risk of new lesions, then a proof of principle pretreatment neuroprotective trial to modify the rate and volume of ischemic lesions would be feasible. Preliminary analysis of the data suggest that new lesions may occur in greater than 50% of patients, if this result is confirmed, then this approach can be taken to the next stage.[unreadable] [unreadable] We have begun to use MR spectroscopy applications to investigate in stroke patients altered brain metabolism and drug pharmacokinetics and pharmacodynamics. Spectroscopy has had limited application to acute stroke patients because of excessive long acquisition times. Using the stroke dedicated 3 Tesla MRI scanner at our Washington Hospital research site, we have been modifying and optimizing pulse sequences for this purpose. Chemical Shift Imaging (CSI) can provide muti-voxel images of proton metabolites such as NAA, creatine, choline, and lactate. We found a 2D PRESS to be optimal for this purpose. Using this protocol, 2D CSI spectra with matrix size of 12x10, slice thickness 15 mm can be obtained within five minutes. In addition, fat contamination of the spectra is greatly reduced because of the spatial localization by PRESS. This is important for detecting the lactate peak which overlaps with the lipid peaks. [unreadable] [unreadable] A metabolite more specific to stroke and neuroprotective stroke therapy is glutathione. Glutathione (GSH) is one the major intracellular anti-oxidants that has neuroprotective effects in ischemic stroke models. Preserved or increased tissue concentrations of glutathione may be evidence of antioxidant neuroprotective response. Glutathione (GSH) is difficult to measure in vivo due to its low concentration (0.8 to 3 mM) and overlapping of its peak with more intense peaks from other metabolites, such as creatine. There has been one prior report of a GSH spectrum in human brain at 4 Tesla with an acquisition time of 39 minutes. We developed a MEGA-PRESS sequence for the 3T Philips scanners at the NIH NMR Center and Washington Hospital Center. After theoretical simulations and hundreds of phantom scans, as well as in vivo scans, we found that TE of 131 ms is optimal. Using a voxel size of 50 x 30 x 30 mm-cubed to further improve signal strength, we consistently get a good quality GSH spectrum in 9 minutes. A novel post-processing algorithm and computer program were also developed to process the data and generate spectra. Frequency and phase changes caused by system instability and small patient motions are corrected by registering each spectrum to a target spectrum. This target spectrum is generated from the original spectra by a fitting and selection process. The whole post-processing program is fully automatic and gives reliable results consistently without any manual adjustment. GSH measurements in stroke patients will permit us to assess antioxidant effects of putative neuroprotective therapies. |
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2007 | Warach, Steven | Z01Activity Code Description: Undocumented code - click on the grant title for more information. |
Improving the Diagnosis of Acute Stroke @ Neurological Disorders and Stroke Patients diagnosed with acute ischemic stroke are offered interventions of proven clinical benefit (e.g., thrombolysis, in-patient stroke units, secondary prevention medicines), therefore greater diagnostic accuracy would lead to increased utilization of these treatments and improve the overall outcomes of patients with stroke compared to their misdiagnosed counterparts. Several years ago we initiated an investigation, the primary objective of which was to compare the diagnostic information contained in non-contrast CT with that of non-contrast MRI in the full range of patients with stroke-like symptoms presenting to a community hospital emergency department (Suburban Hospital, Bethesda, MD) to test the hypothesis that magnetic resonance imaging (MRI) was superior to computed tomography (CT) in acute stroke diagnosis. Free from the selection bias of other studies on the subject, our study was designed to give the definitive comparison of MRI to CT in this real world sample and scenario of the emergency diagnosis of potential stroke. In the past year we completed and published the results of the study in The Lancet. MRI is increasingly used for the diagnosis of acute stroke, but its superiority to CT in the emergency setting has not been established. This was a prospective blind comparison of non-contrast CT and MRI (with diffusion-weighted DWI and susceptibility-weighted images) in a consecutive series of patients referred for emergency evaluation of suspected acute stroke. Patients were included without regard to time from onset, symptom severity or ultimate clinical diagnosis. The scans were independently interpreted by four experts, blinded to clinical information, MRI-CT pairings, and follow-up imaging. The sample consisted of 356 patients, 217 of whom had a final clinical diagnosis of acute stroke. MRI was superior to CT for the detection of any acute stroke (ischemic or hemorrhagic), acute ischemic stroke, and chronic hemorrhage (p <0.0001, for all comparisons). MRI was comparable to CT for the detection of acute intracranial hemorrhage. MRI detected acute ischemic stroke in 164 of 356 patients, 46% (95% CI 41-51%); CT in 35 of 356 patients, 10% (7-14%). In the subset of patients scanned within 3 hours from symptom onset, MRI detected acute ischemic stroke in 41 of 90, 46% (95% CI 35-56%); CT in 6 of 90, 7% (3-14%). Relative to the final clinical diagnosis, emergency brain imaging had a sensitivity of 83% (181 of 217; 95% CI 78-88%) for MRI and 26% (56 of 217; 95% CI 20 - 32%) for CT in the diagnosis of any acute stroke. The MRI superiority was greatest for the type of strokes most difficult to accurately diagnose on purely clinical criteria the milder, smaller strokes. The superiority of MRI for the detection of acute ischemia coupled with its ability to detect acute and chronic hemorrhage make it the preferred test for accurate diagnosis of patients with suspected acute stroke. Because the patient sample studied covered the spectrum of disease likely to be encountered when evaluating emergent cases of suspected stroke, these results are directly applicable to clinical practice. [unreadable] [unreadable] In the above-mentioned study we identified clinical circumstances in which even MRI gave false negative results on DWI as early, milder and brainstem strokes, i.e., small lesions with less contrast. To further improve the diagnostic yield of DWI we performed an analysis of DWI sensitivity using a DWI sequence of higher spatial resolution. Ischemic lesion conspicuity on routine diffusion-weighted imaging (DWI 7 mm thick, 3 directions, 30 seconds acquisition) was compared with an improved sequence (high-resolution DWI 2.5 mm thick DWI-HR, 13 directions, 256 seconds, acquisition) having increased spatial resolution and signal to noise and decreased eddy current artifact in patients with acute ischemic stroke. We hypothesized that improving image quality by increasing spatial resolution and signal to noise ratio will allow for a more accurate lesion detection, and an improved lesion pattern characterization. We studied a total of 69 patients imaged within 6 hours of symptom onset, with both standard diffusion weighted imaging DWI (7mm thick, 3 gradient directions, 28s) and high resolution DWI (DWI-HR) (2.5 mm thick, 13 gradient directions, 246s). A greater number of lesions (194 vs 98) lesions were identified on DWI-HR and DWI, respectively (p<0.05). Among the lesions identified on DWI-HR, 101 (50%) were not seen on DWI, whereas only 5 lesions were unique to DWI. Lesions unique to DWI-HR were predominantly found in the cortical gray matter. Overall, the level of confidence in lesion identification rose from an average of 82% on DWI to 91% on DWI-HR. A total of 19 patients (28%) had lesions on DWI-HR in vascular territories that were not affected on DWI; 9 patients (13%) had multiple vascular territories affected while a single vascular territory was involved on DWI, and 10 patients (15%) had lesions on DWI-HR while DWI was considered negative. From this study we could conclude that increased lesion conspicuity resulted from higher resolution DWI, however an unexpected result was the identification of lesions previously missed by DWI. Those lesions were primarily located in the cortical gray matter and white matter, affected vascular territories that were seen as unaffected on DWI and caused a change in lesion pattern in a subset of patients. Higher resolution DWI may hence be a powerful tool in helping institute the most appropriate management in acute stroke patients based on the pattern and distribution of acute ischemic injury.[unreadable] [unreadable] Having discovered several clinically important features and biomarkers of ischemic stroke pathology by performing exploratory studies of repeated scans in the acute period using advanced MRI, we have adapted this strategy to the study acute intracerebral hemorrhage. In the past year, as part of our Evaluation, Pathogenesis, and Treatment of Patients with or at Risk for Cerebrovascular Disease (Protocol 01-N-0007), we began a study at our two acute stroke translational research sites (Suburban Hospital and Washington Hospital Center) of serial MRI scans in patients with acute supratentorial intracerebral hematoma at the time of presentation, and perform follow-up scans at 6 hours, 24 hours, 72 hours, and 5-7 days later. These scan time points are accompanied by collection of stroke clinical severity scales and blood biomarker samples. This ongoing study will be of several years duration and ongoing data analyses are expected to generate testable hypotheses regarding the evolution and treatment of primary brain hemorrhage. |
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2007 — 2012 | Warach, Steven | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Novel Insights Into Cerebral Ischemic Pathophysiology in Humans @ Neurological Disorders and Stroke As the proximate pathologic cause of ischemic stroke, focal deficits of cerebral blood flow are central to understanding stroke evolution and developing therapies for its treatment. Over the several years of this project we performed serial perfusion MRI studies in ischemic stroke patients. We previously reported that reduction of the volume of ischemia by at least 30% within 2 hours from the start of tPA therapy predicted good clinical outcome. From a further analysis of serial perfusion scans, we developed the pharmacodynamic concept of reperfusion half-life as a measure of thrombolytic drug activity. We modeled the time-reperfusion relationship for untreated and IV tPA-treated ischemic stroke patients to quantify the reperfusion rate characteristic of each condition. We hypothesized that the probability of reperfusion relates to time according to an exponential decay function, analogous to plasma concentration half-life, and that reperfusion half-life following IV tPA therapy would indicate more rapid rates of reperfusion than those in the untreated condition of spontaneous reperfusion. Blinded to clinical and treatment status, we evaluated serial perfusion MRI scans for evidence of reperfusion in 148 patients. We analyzed IV tPA-treated (n=45) and untreated (n=103) patients separately, and used Kaplan-Meier survival analysis to calculate the cumulative probability of reperfusion. We then fit the data with exponential decay functions. The reperfusion half-life (t), the rate at which 50% of the sample reperfuses, was the parameter used to compare the groups. In untreated patients (spontaneous reperfusion), a monoexponential decay function described the data well (R-squared = 0.95) with t = 29.1 hours. In tPA-treated patients, a biexponential decay function, with fast and slow components, was required to describe the data (R-squared = 0.99). The slow component was similar to that of the untreated condition; t=29.21 hours. The fast reperfusion component, attributable to tPA therapy, had t=0.7 hours. By approximately 3.5 hours after start of treatment, the effect of tPA on the probability of reperfusion was negligible. Our data show that modeling reperfusion as an exponential decay function distinguishes spontaneous from tPA-associated reperfusion and provides a measure of the speed and duration of thrombolytic activity. The probability of spontaneous reperfusion over time is a mono-exponential function with a half-life of approximately 29 hours. Treatment with tPA adds a fast reperfusion component with a half-life of 0.7 hours. Determination of reperfusion half-life is a promising approach to evaluate the relative potency and reperfusion effects of different thrombolytic regimens. A paper describing these results has been submitted to a medical journal. Prospective clinical and pre-clinical studies are planned to further study the utility of reperfusion half-life in identifying single or combination thrombolytic therapy that may [unreadable] [unreadable] In 2004, we published the our discovery of an imaging marker of early blood brain barrier in ischemic stroke and its hypothesized relationship to reperfusion, hemorrhagic transformation, thrombolytic therapy, and worse clinical outcome from a sample of 214 stroke patients. For simplicity of reference we described the observation by the acronym HARM (Hyperintense Acute Reperfusion injury Marker). Several follow-up studies to further elucidate the mechanism and features of HARM have completed enrollment the during current year; data analysis and study report preparations are in progress and we expect to publish these results in the upcoming year. Preliminary results confirm that the localization of HARM is in the CSF space rather than in the parenchyma, prove an association of HARM with serum concentrations of matrix metalloproteinase-9, and demonstrate that HARM can be detected on immediate post-contrast, prior to treatment with tPA. The ability to detect of BBB disruption prior thrombolytic therapy may aid in the development of new therapies to protect the barrier and minimize the potential risks of thrombolytic therapy.[unreadable] [unreadable] Imaging based predictors of stroke outcome and response to therapy are necessary for the utility and validation of imaging biomarkers in drug development. Useful models are those that can distinguish patients destined for good outcomes versus poor outcomes, those who received effective therapy from those who did not, and treatment responders from non-responders. We are investigating several predictive models. These prediction models may be useful for the development, selection and use of acute therapies.[unreadable] [unreadable] A change in acute-to-chronic lesion volume has been proposed as a biomarker for stroke therapies. We determined the magnitude of lesion volume change in 53 patients treated with standard tPA and determined specific volume change thresholds that discriminated clinical responders from non-responders. The mean acute-to-chronic lesion volume increase was 11.7 (7.7) cm-c. In 23 patients, the chronic lesion was smaller than the baseline lesion. At 3 months, 32 patients had an excellent clinical outcome. Dichotomous volume change variables associated with outcome include decrease in volume 30% (p=0.004) and volume increase 5 cm3 (p=0.002). We conclude that change in lesion volume can discriminate between patients destined for good and poor outcomes when treated with effective acute stroke therapy. Thus, lesion volume change may be a useful marker of clinical response in the stroke therapy development.[unreadable] [unreadable] The more accurate prediction of final infarct volume was investigated by combining clinical and imaging variables in a generalized regression neural network model. The model was trained with data from 99 patients that presented with stroke symptoms within 3 hours of onset, underwent acute MRI scans, and were treated with IV tPA therapy using the following variables: sex, age, National Institutes of Health Stroke Scale (NIHSS), stroke onset time to MRI scan time and baseline lesion volume, baseline ischemia volume. The model was then tested in 13 tPA-treated and 30 untreated stroke patients to assess whether the model could differentiate treated from untreated patients. The measured values for final lesion volume did not significantly differ from the predicted values for the tPA-treated patients, but did differ for the untreated patients, indicating that this model, indicating that neural net modeling of infarct volume can discriminate between patients receiving clinically effective stroke therapies and those who do not.[unreadable] [unreadable] We have taken a lead role in developing an international consortium of stroke imaging researchers and image archive - the STroke Image Repository (STIR). The overall purpose is to create an international consortium of investigators and a repository of source MRI and CT images toward the objectives of standardization and validation of acquisition, analytic, and clinical research methods of image-based stroke research. STIR is hosted in NINDS intramural and the first version of the STIR repository and software was released in September 2008. |
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2010 — 2012 | Warach, Steven | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Eval, Pathogenesis, Outcome of Subjects With or Suspected Traumatic Brain Injury @ Neurological Disorders and Stroke Each year, at least 1.4 million people sustain TBI, with over 1.1 million treated and released from the emergency department (ED). Approximately 125,000 patients with TBI, typically those more severely injured, experience permanent disability as a result of damage to the brain. On the other hand, mild TBI, accounting for at least 75% of all TBI, results in more subtle functional and cognitive deficits that often go undetected in the acute setting. These patients can experience drastic changes in their quality of life, have difficulties returning to daily activities and may be unable to return to work for weeks or months. It is estimated that mild TBI alone costs the United States in excess of $17 billon per year in long-term care and lost productivity. Lack of objective criteria for diagnosing and classifying acute TBI presents a significant impediment to developing therapies and to providing uniform quality of care. Patients with a history of head injury often receive a screening brain scan using computed tomography (CT) in the ED despite a low sensitivity for detecting mild injury. Logistic issues coupled with expense have contributed to a lack of evidence to support the use of head MRI over non-contrast CT in the ED evaluation of patients with acute mild TBI. The majority of patients discharged directly from the ED are assigned the vague diagnosis of concussion and left to their own accord to seek further medical support, despite a persistent and complex post concussive syndrome that includes complaints of headaches, dizziness, impaired attention, trouble concentrating, poor memory, and emotional problems. The identification of imaging and other markers obtained upon acute presentation could help in the diagnosis and classification of TBI, the homogenization of populations for clinical trials, and the prognosis of clinical, functional, and cognitive outcome. It is therefore important to improve our understanding of the nature of acute TBI in order to better design future studies to address specific research and clinical gaps. The objective of this project is to generate natural history data for cohort-based comparisons to serve as the basis for future hypothesis-driven protocols and to contribute to the clinical and physiological understanding of traumatic brain injury (TBI) through the description of manifestations of the injury and the relationship among radiological, hematological, clinical variables and standard functional/cognitive outcome measures. Three hundred male and female adult subjects with history of recent head injury with or suspected non-penetrating acute TBI, will be enrolled. Subjects having varying degrees of TBI severity will be recruited from the collaborative programs between NIH and non-NIH hospitals. We anticipate approximately 80% of subjects will be classified as mild TBI, concussion, or no injury, with approximately two thirds of those subjects enrolled being discharged directly from the emergency department. This is a prospective cohort study of subjects with known and suspected non-penetrating acute traumatic brain injury. Subjects presenting to the emergency department or trauma service at participating hospitals with a history of recent head injury will be studied during the course of their hospital stay and after discharge using radiological, hematological, clinical and functional/cognitive outcome measures. Subjects will be stratified according to findings into cohorts for comparison. The design is intentionally broad in scope to allow acquisition of initial data for the development of future hypothesis-driven protocols. Research performed under this protocol will not interfere with standard of care and subjects will not be treated with experimental therapies as part of the research study. Data collected under this research study may be shared without personal identifiers with other researchers if subjects approve this option on the informed consent. A variety of outcome measures will be used including diagnosis, evidence of injury on magnetic resonance imaging (MRI), functional and cognitive impairment, and quality of life (QOL) assessments. The initial research questions will focus on a positive diagnosis of brain injury and monitoring the natural history. Statistical analysis plans will be developed as specific research questions and hypotheses are generated. |
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2012 | Warach, Steven | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Clinical and Imaging Core Support of Acute Stroke Research @ Neurological Disorders and Stroke The foundation of an acute stroke translational research program is an acute stroke clinical service that will assure maximum patient referral and allow rapid identification, screening and recruitment of potential research subjects in the timely fashion needed to study the early events in cerebral ischemia and enroll patients in acute stroke research protocols. Absence of an emergency department and the time constraints on screening and recruitment of acute stroke patients as research subjects has precluded the NIH Clinical Center as the main site of our research projects. Thus, we have needed to establish and maintain the clinical, imaging and research infrastructure required to support such a program at local hospitals, Suburban Hospital (SH) in Bethesda, Maryland, and Washington Hospital Center (WHC) in DC. The major elements of this infrastructure include the NIH Stroke Service, a combination of NIH and contractor clinicians stroke neurologists, nurses, clinical fellows, on-site research/nurse coordinators, MRI scanners NIH 3T MRI at WHC, shared 1.5 T scanner at SH and MRI technologists, NIH computer network placed and maintained at each hospital, hospital office space for program needs. In addition, we maintain our own PACS for images obtained on the WHC and SH MRI scanners, and developed and maintain a registry for clinical and research patient data. Every year we screen approximately 1200 patients and enroll approximately 100 patients into one of our clinical research protocols. |
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