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Theranostics 2018; 8(6):1706-1722. doi:10.7150/thno.21685 This issue Cite

Research Paper

Perfluorocarbon Enhanced Glasgow Oxygen Level Dependent (GOLD) Magnetic Resonance Metabolic Imaging Identifies the Penumbra Following Acute Ischemic Stroke

Graeme A Deuchar^1,3✉, David Brennan^2,3, William M Holmes¹, Martin Shaw⁴, I Mhairi Macrae¹, Celestine Santosh^2,3

1. Glasgow Experimental MRI Centre, Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow
2. Department of Neuroradiology, Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK
3. Aurum Biosciences Ltd, 20-23 Woodside Place, Glasgow, G3 7QL
4. Clinical Physics, University of Glasgow, Western Infirmary, Glasgow, United Kingdom

✉ Corresponding author: Dr Graeme Deuchar, Aurum Biosciences Ltd, 20-23 Woodside Place, Glasgow, G3 7QL, Scotland, UK. Tel: +44 141 582 1212; Email: gdeucharcom

Abstract

The ability to identify metabolically active and potentially salvageable ischaemic penumbra is crucial for improving treatment decisions in acute stroke patients. Our solution involves two complementary novel MRI techniques (Glasgow Oxygen Level Dependant (GOLD) Metabolic Imaging), which when combined with a perfluorocarbon (PFC) based oxygen carrier and hyperoxia can identify penumbra due to dynamic changes related to continued metabolism within this tissue compartment. Our aims were (i) to investigate whether PFC offers similar enhancement of the second technique (Lactate Change) as previously demonstrated for the T₂*OC technique (ii) to demonstrate both GOLD metabolic imaging techniques working concurrently to identify penumbra, following administration of Oxycyte^® (O-PFC) with hyperoxia.

Methods: An established rat stroke model was utilised. Part-1: Following either saline or PFC, magnetic resonance spectroscopy was applied to investigate the effect of hyperoxia on lactate change in presumed penumbra. Part-2; rats received O-PFC prior to T₂*OC (technique 1) and MR spectroscopic imaging, which was used to identify regions of tissue lactate change (technique 2) in response to hyperoxia. In order to validate the techniques, imaging was followed by [¹⁴C]2-deoxyglucose autoradiography to correlate tissue metabolic status to areas identified as penumbra.

Results: Part-1: PFC+hyperoxia resulted in an enhanced reduction of lactate in the penumbra when compared to saline+hyperoxia. Part-2: Regions of brain tissue identified as potential penumbra by both GOLD metabolic imaging techniques utilising O-PFC, demonstrated maintained glucose metabolism as compared to adjacent core tissue.

Conclusion: For the first time in vivo, enhancement of both GOLD metabolic imaging techniques has been demonstrated following intravenous O-PFC+hyperoxia to identify ischaemic penumbra. We have also presented preliminary evidence of the potential therapeutic benefit offered by O-PFC. These unique theranostic applications would enable treatment based on metabolic status of the brain tissue, independent of time from stroke onset, leading to increased uptake and safer use of currently available treatment options.

Keywords: Acute Ischaemic Stroke, perfluorocarbon, penumbra, GOLD metabolic imaging, MRI

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