Vol. 3 No. 2 - June 2017

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Hyperpolarized 13 C Magnetic Resonance Imaging Can Detect Metabolic Changes Characteristic of Penumbra in Ischemic Stroke Yafang Xu, Steffen Ringgaard, Christian Østergaard Mariager, Lotte Bonde Bertelsen, Marie Schroeder, Haiyun Qi, Christoffer Laustsen, and Hans Stødkilde-Jørgensen Department of Clinical Medicine, MR Research Centre, Aarhus University, Aarhus, Denmark Corresponding Author: Hans Stødkilde-Jørgensen, MD, DMSc Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark; E-mail: Key Words: MRI, hyperpolarized 13C, cerebral stroke, endothelin-1 Abbreviations: Magnetic resonance imaging (MRI), adenosine triphosphate (ATP), magnetic resonance (MR), endothelin-1 (ET-1), blood– brain barrier (BBB), lactate dehydrogenase (LDH), monocarboxylate transporters (MCT) Magnetic resonance imaging (MRI) is increasingly the method of choice for rapid stroke assessment in pa- tients and for guiding patient selection in clinical trials. The underlying metabolic status during stroke and following treatment is recognized as an important prognostic factor; thus, new methods are required to moni- tor local biochemistry following cerebral infarction, rapidly and in vivo. Hyperpolarized MRI with the tracer [1- 13 C]pyruvate enables rapid detection of localized [1- 13 C]lactate production, which has recently been shown in patients, supporting its translation to assess clinical stroke. Here we show the ability of hyperpolar- ized 13 C MRI to detect the metabolic alterations characteristic of endothelin-1-induced ischemic stroke in ro- dents. In the region of penumbra, determined via T2-weighted 1 H MRI, both [1- 13 C]pyruvate delivery and [1- 13 C]pyruvate cellular uptake independently increased. Furthermore, we observed a 33% increase in abso- lute [1- 13 C]lactate signal in the penumbra, and we determined that half of this increase was due to increased intracellular [1- 13 C]pyruvate supply and half was mediated by enhanced lactate dehydrogenase-mediated [1- 13 C]lactate production. Future work to characterize the kinetics of delivery, uptake, and enzymatic conversions of hyperpolarized tracers following ischemic stroke could position hyperpolarized 13 C MRI as an ideal technology for rapid assessment of the penumbra during the critical time window following ischemic stroke in patients. INTRODUCTION Stroke is the third leading cause of death worldwide and the leading cause of disability among adults. In total, 80% of strokes are ischemic, resulting from occlusion of a cerebral artery that deprives the tissue perfused by that artery of metabolic substrates and oxygen it requires to sustain function (1). The only Food and Drug Administration-approved therapy for ischemic stroke in- volves reperfusion by thrombolysis induced by intravenous in- jection of recombinant tissue plasminogen activator within 4.5 hours of ischemia onset (2). Mechanical clot retrieval has been shown to extend the treatment window to 6 hours in patients with stroke (3). There remains an urgent need to both develop new neuroprotective strategies that preserve tissue viability following ischemic stroke and further lengthen the treatment window during which patients can hope to receive successful treatment (4). Experimental work on the flow thresholds of brain tissue showed the existence of the following 2 critical levels of de- creased perfusion (5, 6): a level representing the flow threshold for reversible neuronal failure and a lower threshold below which irreversible morphological damage, adenosine triphosphate (ATP) depletion, and ultimately necrotic cell death occur. The tissue experiencing perfusion at rates between these limits is called the "ischemic penumbra," and it is characterized by the potential for functional recovery without morphological damage, provided that local blood flow can be reestablished within a certain time window (6). Biochemically, the penumbra is defined by high rates of glucose extraction and anaerobic glycolysis (7, 8), which generate lactate and small amounts of ATP that enable basic neuronal "housekeeping" functions temporarily (such as axonal transport, biosynthetic processes, and other functions not directly related to action potentials). The penumbra progressively experi- ences irreversible damage at a rate inversely proportional to resid- ual blood flow, and within ;8 –24 hours, it will be converted into a necrotic core unless reperfusion therapy is performed (6). Therapy for a patient with ischemic stroke critically depends on the presence of a penumbra, as the penumbra is the only damaged tissue with potential to be rescued to restore cerebral function. Neuroimaging techniques that can be applied in the clinic to rapidly assess the penumbra are essential to guide treat- ment decisions and develop new therapies (6, 9). The combination of perfusion and diffusion-weighted magnetic resonance imaging (MRI) has emerged as one candidate (10); however, the MRI perfu- ADVANCES IN BRIEF ABSTRACT © 2017 The Authors. Published by Grapho Publications, LLC This is an open access article under the CC BY-NC-ND license ( ISSN 2379-1381 TOMOGRAPHY.ORG | VOLUME 3 NUMBER 2 | JUNE 2017 67

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