Collateral blood flow plays a central role during acute ischemic stroke, and the presence of good collaterals has been linked to improved clinical and radiologi- cal outcome measures both with and without successful recanalization. Despite this, the only method to assess adequacy of collaterals currently is in- vasive and expensive, digital subtraction cerebral angiography (DSA). It would be tremendously beneficial if collaterals could be visualized using a tomo- graphic, non-invasive imaging based modality, so that early treatment deci- sions could incorporate this critical information.
AIMS AND METHODS The overall goal of the imaging the Collaterals in Acute Stroke (iCAS) study, is to identify and quantify cerebral blood flow (CBF) delivered via collateral routes using arterial spin labeling (ASL), a non-contrast MRI technique, and to determine its impact on ischemic lesion growth and patient outcome. We will perform a prospective, multi-center study of 180 acute stroke patients imaged in the 4.5-12 hr time window with large vessel occlusive stroke who are under consideration for endovascular thrombolytic therapy. We will add two ASL sequences to our rapid stroke protocol: pseudocontinuous ASL (pcASL, 2.5 min) for identifying collaterals and velocity-selective ASL (VS-ASL, 2.5 min) for measuring quantitative CBF independent of arterial arrival delay.
In Aim 1, we will demonstrate equivalence between DSA and pcASL for collateral assessment, and determine the relationship between collateral and quantitative CBF using VS-ASL. Then, in Aim 2, we will determine whether ASL might be used to supplement or replace conventional bolus contrast PWI, determine the predictive ability of collateral assessment upon ischemic lesion growth, and evaluate how to incorporate collateral measurements into patient selection algorithms for endovascular therapy by examining the relationship between collaterals, revascularization, and patient outcome. SIGNIFICANCE We believe successful attainment of these aims will markedly improve acute stroke care by validating a non-invasive MRI-based method to assess both the presence of collaterals and the amount of CBF they deliver. iCAS will be the first prospective, multi-center study of ASL, a promising new non-contrast perfusion method, in acute stroke. In particular, the use of VS-ASL to obtain quantitative CBF measurements at serial timepoints in acute stroke will yield invaluable information on this critica hemodynamic parameter. It will provide a framework for incorporating collateral status into treatment decision-making, specifically by answering the question of whether patients with either very good or very poor collaterals benefit from recanalization. This study will lead to bettr understanding of the benefit of ASL measurements in patients with severe cerebrovascular disease and enhance the already significant diagnostic power of MRI in acute ischemic stroke.

Public Health Relevance

The ultimate severity of a large vessel occlusive stroke, which affects over 200,000 patients per year in the USA, is largely determined by the ability of collateral flow networks to supply blood to ischemic tissue via circuitous routes that bypass the proximal clot. Robust collateral flow improves the chance of good outcome in endovascular stroke therapy and decreases the risk of intracranial bleeding. Despite this, there has yet to be a prospective study of collateral flow in acute stroke patients. The goal of the imaging of Collaterals in Acute Stroke (iCAS) study is to determine how to incorporate MRI-based collateral perfusion assessment using a non-contrast perfusion method, arterial spin labeling (ASL), into patient-selection algorithms for endovascular stroke therapy. In our prior funding cycle, we successfully showed that ASL can effectively detect collaterals and determine the cerebral blood flow (CBF) they provide in patients with Moyamoya disease, a vasculopathy of young people who develop extensive collateral networks. Based on this, we are ready to apply these techniques to the larger population of acute stroke patients. We will build on the recently completed, successful DEFUSE-2 trial by adding two short ASL sequences to the acute stroke assessment, one to assess collaterals (pseudocontinuous ASL) and the other to measure quantitative CBF (velocity-selective ASL). To this end, we will perform the first multi-center ASL trial in 180 acute stroke patients, who will undergo serial MR imaging and clinical follow-up. Our aims address (1) the accuracy of ASL methods for assessing collaterals and (2) the ability of early ASL collateral imaging to predict infarct lesion growth and good clinical outcome. We will specifically determine how to integrate information about collaterals into patient triage strategie to obtain the best possible outcomes. Such information will have importance beyond endovascular therapy, and could impact decision- making on the use of intravenous tPA both within and beyond current standard time windows. Successful completion of the iCAS study will lead to better understanding of the role of collaterals in acute stroke patients. Furthermore, imaging quantitative CBF at multiple time points will better elucidate the physiology underlying tissue infarction in patients with both successful and unsuccessful stroke therapy. In summary, the findings from this study will markedly enhance our understanding of collaterals and their physiological impact in the ischemic brain, and enhance already significant diagnostic power of MRI in acute ischemic stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Guo, Jia; Holdsworth, Samantha J; Fan, Audrey P et al. (2018) Comparing accuracy and reproducibility of sequential and Hadamard-encoded multidelay pseudocontinuous arterial spin labeling for measuring cerebral blood flow and arterial transit time in healthy subjects: A simulation and in vivo study. J Magn Reson Imaging 47:1119-1132
Ni, Wendy W; Christen, Thomas; Zaharchuk, Greg (2017) Benchmarking transverse spin relaxation based oxygenation measurements in the brain during hypercapnia and hypoxia. J Magn Reson Imaging 46:704-714
Kroll, Hannes; Zaharchuk, Greg; Christen, Thomas et al. (2017) Resting-State BOLD MRI for Perfusion and Ischemia. Top Magn Reson Imaging 26:91-96
Chen, Jingyuan E; Jahanian, Hesamoddin; Glover, Gary H (2017) Nuisance Regression of High-Frequency Functional Magnetic Resonance Imaging Data: Denoising Can Be Noisy. Brain Connect 7:13-24
Antonucci, Michael U; Burns, Terrence C; Pulling, T Michael et al. (2016) Acute Preoperative Infarcts and Poor Cerebrovascular Reserve Are Independent Risk Factors for Severe Ischemic Complications following Direct Extracranial-Intracranial Bypass for Moyamoya Disease. AJNR Am J Neuroradiol 37:228-235
Christen, Thomas; Jahanian, Hesamoddin; Ni, Wendy W et al. (2015) Noncontrast mapping of arterial delay and functional connectivity using resting-state functional MRI: a study in Moyamoya patients. J Magn Reson Imaging 41:424-30
Ni, Wendy; Christen, Thomas; Zun, Zungho et al. (2015) Comparison of R2' measurement methods in the normal brain at 3 Tesla. Magn Reson Med 73:1228-36
Alsop, David C; Detre, John A; Golay, Xavier et al. (2015) Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia. Magn Reson Med 73:102-16
Zun, Zungho; Shankaranarayanan, Ajit; Zaharchuk, Greg (2014) Pseudocontinuous arterial spin labeling with prospective motion correction (PCASL-PROMO). Magn Reson Med 72:1049-56
Zun, Zungho; Hargreaves, Brian A; Pauly, John et al. (2014) Near-contiguous spin echo imaging using matched-phase RF and its application in velocity-selective arterial spin labeling. Magn Reson Med 71:2043-50

Showing the most recent 10 out of 37 publications