Computed tomography (CT) is the current standard for time-critical decision-making in stroke patients, informing decisions on thrombolytic therapy with tissue plasminogen activator (tPA), which has a narrow therapeutic index. We aimed to develop a CT-based method to directly visualize cerebrovascular thrombi and guide thrombolytic therapy. Glycol-chitosan-coated gold nanoparticles (GC-AuNPs) were synthesized and conjugated to fibrin-targeting peptides, forming fib-GC-AuNP. This targeted imaging agent and non-targeted control agent were characterized in vitro and in vivo in C57Bl/6 mice (n = 107) with FeCl3-induced carotid thrombosis and/or embolic ischemic stroke. Fibrin-binding capacity was superior with fib-GC-AuNPs compared to GC-AuNPs, with thrombi visualized as high density on microCT (mCT). mCT imaging using fib-GC-AuNP allowed the prompt detection and quantification of cerebral thrombi, and monitoring of tPA-mediated thrombolytic effect, which reflected histological stroke outcome. Furthermore, recurrent thrombosis could be diagnosed by mCT without further nanoparticle administration for up to 3 weeks. fib-GC-AuNP-based direct cerebral thrombus imaging greatly enhance the value and information obtainable by regular CT, has multiple uses in basic / translational vascular research, and will likely allow personalized thrombolytic therapy in clinic by a) optimizing tPA-dosing to match thrombus burden, b) enabling the rational triage of patients to more radical therapies such as endovascular clot-retrieval, and c) potentially serving as a theranostic platform for targeted delivery of concurrent thrombolysis.

IMPORTANCE Cerebral vascular territories are of key clinical importance in patients with stroke, but available maps are highly variable and based on prior studies with small sample sizes. OBJECTIVE To update and improve the state of knowledge on the supratentorial vascular supply to the brain by using the natural experiment of large artery infarcts and to map out the variable anatomy of the anterior, middle, and posterior cerebral artery (ACA, MCA, and PCA) territories. DESIGN, SETTING, AND PARTICIPANTS In this cross-sectional study, digital maps of supratentorial infarcts were generated using diffusion-weighted magnetic resonance imaging (MRI) of 1160 patients with acute (<1-week) stroke recruited (May 2011 to February 2013) consecutively from 11 Korean stroke centers. All had supratentorial infarction associated with significant stenosis or occlusion of 1 of 3 large supratentorial cerebral arteries but with patent intracranial or extracranial carotid arteries. Data were analyzed between February 2016 and August 2017. MAIN OUTCOMES AND MEASURES The 3 vascular territories were mapped individually by affected vessel, generating 3 data sets for which infarct frequency is defined for each voxel in the data set. By mapping these 3 vascular territories collectively, we generated data sets showing the Certainty Index (CI) to reflect the likelihood of a voxel being a member of a specific vascular territory, calculated as either ACA, MCA, or PCA infarct frequency divided by total infarct frequency in that voxel. RESULTS Of the 1160 patients (mean [SD] age, 67.0 [13.3] years old), 623 were men (53.7%). When the cutoff CI was set as 90%, the volume of the MCA territory (approximately 54% of the supratentorial parenchymal brain volume) was about 4-fold bigger than the volumes of the ACA and PCA territories (each approximately 13%). Quantitative studies showed that the medial frontal gyrus, superior frontal gyrus, and anterior cingulate were involved mostly in ACA infarcts, whereas the middle frontal gyrus and caudate were involved mostly by MCA infarcts. The PCA infarct territory was smaller and narrower than traditionally shown. Border-zone maps could be defined by using either relative infarct frequencies or CI differences. CONCLUSIONS AND RELEVANCE We have generated statistically rigorous maps to delineate territorial border zones and lines. The new topographic brain atlas can be used in clinical care and in research to objectively define the supratentorial arterial territories and their borders.

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This is the first report on a hyperacute direct thrombus imaging technique using thrombus-seeking AuNPs and computed tomography. When translated into stroke practice, the thrombus imaging may allow us to advance to personalized thrombolytic therapy by demonstrating thrombus burden, distribution, and character in a prompt and quantitative manner. Further study into this area is indicated.