The candidate is a fellowship-trained academic vascular neurologist with a long-term goal of becoming an independent clinical stroke researcher focused on understanding factors which influence the development and progression of intracranial atherosclerosis and influence the risk of recurrent stroke. This application proposes a comprehensive training plan which includes i.) didactic training in clinical research methodology, ii.) training in MRI imaging and vascular biology, and iii.) hands-on experience in clinical research by participating in a supervised leadership role in an NIH-funded clinical trial and completion of a mentored research project. The goal of this mentored research project is to develop a validated approach to characterize intracranial atherosclerotic plaque components using HR MRI which will be used as both a.) a clinical tool for risk stratification and a marker for disease activity and b.) a research tool to further study atherosclerotic plaque development and progression. Intracranial atherosclerosis is a leading cause of stroke, but little is known about the composition of the intracranial atherosclerotic lesion and how intracranial plaque morphology is related to the risk of stroke. There is no established in vivo model for characterizing intracranial plaque components, but the use of high resolution magnetic resonance imaging (HR MRI) in patients with extracranial carotid atherosclerosis has shown this technique can identify histologically-defined plaque components (i.e. intraplaque hemorrhage, fibrous cap, and lipid core) with high inter-rater agreement and that these plaque components are predictors of recurrent stroke. The candidate's pilot data has demonstrated that features of atherosclerotic plaque can be visualized in the intracranial arteries using HR MRI. This study aims to refine a HR MRI imaging protocol by systematically altering sequence parameters in a step-wise fashion in 36 patients in order to define a protocol that will consistently visualize intracranial atherosclerotic plaque components (Part 1 of this proposal). This will be followed by a prospective observational study of 90 patients, which aims to demonstrate high inter-rater agreement for identifying intracranial plaque components on HR MRI, determine the frequency of these components in symptomatic vs. asymptomatic plaques, and estimate the 1 year rate of stroke in the territory of high risk plaque components (Part 2 of this proposal). Additionally, a comparison of HR MRI-defined plaque components and post-mortem vascular histology will be performed in patients who die of acute stroke from intracranial stenosis. After establishing the reliability and validity of these measures, the candidate will submit an R01 grant application to determine the prevalence and prognosis of intracranial atherosclerotic plaque components in a multicenter study using the HR MRI protocol defined in the K23. These studies will lead to new understanding of the pathophysiological mechanisms of cerebral ischemia in patients with atherosclerotic intracranial stenosis, improvements in risk stratification, and potentially to new treatments of this common and serious disease.

Public Health Relevance

Project Narrative This project will evaluate the use of high-resolution (HR) MRI for identifying atherosclerotic plaque components in patients with intracranial atherosclerosis. Establishing that HR MRI is a useful in-vivo tool for determining intracranial plaque composition could lead to new understanding of the pathophysiological mechanisms of cerebral ischemia in patients with atherosclerotic intracranial stenosis as well as improvements in risk stratification and treatment of this common disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-2 Subcommittee (NST)
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Moy, Claudia S
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Medical University of South Carolina
Schools of Medicine
United States
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Turan, Tanya N; Smock, Alison; Cotsonis, George et al. (2017) Is There Benefit from Stenting on Cognitive Function in Intracranial Atherosclerosis? Cerebrovasc Dis 43:31-35
Kwon, Hyung-Min; Lynn, Michael J; Turan, Tanya N et al. (2016) Frequency, Risk Factors, and Outcome of Coexistent Small Vessel Disease and Intracranial Arterial Stenosis: Results From the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial. JAMA Neurol 73:36-42
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Lutsep, Helmi L; Lynn, Michael J; Cotsonis, George A et al. (2015) Does the Stenting Versus Aggressive Medical Therapy Trial Support Stenting for Subgroups With Intracranial Stenosis? Stroke 46:3282-4
Chaturvedi, Seemant; Turan, Tanya N; Lynn, Michael J et al. (2015) Do Patient Characteristics Explain the Differences in Outcome Between Medically Treated Patients in SAMMPRIS and WASID? Stroke 46:2562-7
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Derdeyn, Colin P; Chimowitz, Marc I; Lynn, Michael J et al. (2014) Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet 383:333-41
López-Cancio, Elena; Matheus, Maria Gisele; Romano, Jose G et al. (2014) Infarct patterns, collaterals and likely causative mechanisms of stroke in symptomatic intracranial atherosclerosis. Cerebrovasc Dis 37:417-22
Turan, Tanya N; Cotsonis, George; Lynn, Michael J et al. (2014) Intracranial stenosis: impact of randomized trials on treatment preferences of US neurologists and neurointerventionists. Cerebrovasc Dis 37:203-11

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