NOVEL INSIGHTS INTO CEREBRAL ISCHEMIC PATHOPHYSIOLOGY IN HUMANS

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Through our Natural History of Stroke study (Protocol No. 01-N-0007; Clinicaltrials.gov No. NCT00009243) we have studied greater than 2,700 participants in order to learn more about stroke and obtain information that may serve as the basis for future investigations. This protocol has allowed us to 1) establish a registry of patients with cerebrovascular disease (stroke); 2) characterize the natural history of acute stroke and transient ischemic attacks (TIA) an interruption of blood flow to the brain that causes stroke symptoms for a short period of time); and 3) evaluate the data to generate ideas for future studies. MRI has improved our ability to diagnose and stratify patients with acute stroke by providing highly sensitive and specific markers of the disease. Imaging based phenotypes of stroke increase objectivity, however they remain a gross oversimplification of the complex biological system set in motion by a stroke. Next generation sequencing, with unprecedented improvement in throughput and speed, provides an opportunity to probe the complex biological response to stroke in patients stratified using acute MRI. Based on the premise that the biology responsible for the imaging abnormalities will be reflected in differential gene expression and micro RNA in peripheral blood, next generation sequencing will be used to identify and characterize the biological systems relevant to the imaging phenotype. A systems biology approach will be developed to better describe stroke, and hopefully, better differentiate those patients in who we can expect a favorable response to an intervention, from those at risk of further deterioration. Through collaboration with NINR, we are developing an approach to sequencing single monocytes in the blood to better characterize the acute immune response and factors that may contributed to outcome. 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. We found that change in lesion volume from pre-treatment DWI to post-treatment FLAIR can discriminate between patients destined for good and poor outcomes when treated with effective acute stroke therapy, i.e., intravenous tPA. Thus, lesion volume change may be a useful marker of clinical response in the stroke therapy development. Following multiple positive trials of mechanical embolectomy to treat large vessel occlusion stroke, a significant increase in the population of patients receiving this therapy at our centers has occurred. Using MRI, we have observed injury secondary to embolectomy that may be a form of reperfusion injury that could possibly be prevented. We are currently studying the imaging markers using data collected in this project through a prospective sub-study termed GUARDS. The goal of this effort is to prospectively study an imaging marker of secondary injury to develop a trial to protect the brain prior to embolectomy and for patients in whom embolectomy can not be accomplished. Through collaboration with the McGavern lab, we have identified a strategy to reduce secondary injury to tissue caused by a massive influx of water secondary to myeloid cell infiltration. We have characterized the degree of edema associated with post-embolectomy reperfusion and hamorrhagic transformation. The McGavern team has discovered an anti-adhesion molecule therapeutic approach. We are currently in the early phase of designing a trial to treat patients post embolectomy. Over the past five years, the rate of thrombolytic therapy has also increased dramatically at our center, we believe owing in part to a higher level of surveillance made possible by the NINDS Stroke Team and MRI diagnostic approach. Approximately 1 in 2 patients treated may be categorized as minor stroke, and 1 in 4 have symptoms that may not be disabling. Retrospective analysis suggests that imaging targets for thrombolytic therapy do not differ between those with and without disabling deficits. The recent failure of a clinical trial for minor stroke has created controversy in the field, with some practitioners arguing little is to be gained, and much to be risked, by treating minor (non-disabling) stroke with tPA. We believe MRI may be the best way to select those patients who could benefit. The trend toward equipoise in the program and field argues for a trial to test a thrombolytic in minor stroke selected using MRI. We have prospectively collected data on minor stroke to support the design of a trial and are in the process of analysis. The work with NINR on single cell drop seq of circulating monocytes provides some insight into the biological mechanisms relevant to recovery or worsening in minor stroke. As part of the Stroke Branch, there is significant interested in vascular cognitive impairment and white matter disease, originally initiated but the Neuro Vascular Brain Imaging Unit (NVBI). Investigators continue to access data and images to study white matter disease and BBB disruption. A new protocol was initiated for this purpose (PI Clinton Wright), however the pandemic caused a pause in all study related activity. Work continues to study the impact of stroke on white matter disease and cognitive impairment through data collected as part of this project.