Novel Insights Into Cerebral Ischemic Pathophysiology In Humans

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Through our Natural History of Stroke study (Clinicaltrials.gov No. NCT00009243) we have studied over 3100 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 microRNA in peripheral blood, next generation sequencing has been used to identify and characterize the biological systems relevant to the imaging phenotype. 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 found that change in lesion volume from pre-treatment diffusion-weighted imaging 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. As part of a broader NINDS effort to address health care disparities, there growing interest in social determinants of health, and the potential for mobile MRI, deployed to communities with marginal health care access, may have at increasing accessiblity. Through collaboration with a new mobile MRI core within NINDS, we have started to co-enroll patients to image at ultralow field and gain experience with the modality. During this past fiscal year, our efforts have largely been focused as follows: Minor stoke (TIMES): Patients often present to the emergency department with very mild and potentially non-disabling or fluctuating symptoms. These may lead to delayed diagnosis and/or withholding of treatment. We are prospectively studying the use of MRI in identifying those patients who would most likely benefit from intervention. Enrollment has been paused and data analysis is ongoing. Secondary damage post mechanical embolectomy (GUARDS): In patients with large vessel occlusion, one of the most severe categories of stroke, removal of the clot by mechanical means has proven to be efficacious. However, many patients go on to poor outcome despite successful mechanical intervention. We are using MRI to study and classify the kind of injury that occurs following recanalization of the large vessel. Progress has been made in our prospective observational study to identify markers of blood-brain barrier disruption, paradoxical increased blood flow, edema, and hemorrhage. We have nearly reached our target enrolment and plan to halt enrollent, focus on data analysis, and publish results. Focusing on Interesting Neuroimaging Diagnoses (FIND): We have identified a couple, potentially novel, imaging markers in both the GUARDS and TIMES2 populations that need further exploration. They may provide some differentiation between patients who successfully recover. While the findings are preliminary, we plan to further target these markers in a population of patient selected in the acute setting, and followed out to one year at our hospitals, or at the NIH Clinical Center. This is the mechanism which we will use to bring patients to NIH for optional ultra-low field MRI.