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Radiology. 2018 Dec 4:181051. doi: 10.1148/radiol.2018181051. [Epub ahead of print]

MRI of Iron Oxide Nanoparticles and Myeloperoxidase Activity Links Inflammation to Brain Edema in Experimental Cerebral Malaria.

Author information

1
From the Department of Neuroradiology (A.H., J.J., X.H., S.H., M.B., M.O.B.), Centre for Infectious Diseases, Parasitology Unit (J.P., A.K.M.), and Center for Childhood and Adolescent Medicine, General Pediatrics (J.P.), University Hospital Heidelberg, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; German Centre for Infection Research (DZIF), Heidelberg, Germany (J.P., A.K.M.); DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany (K.D., M.P., M.O.B.); NeuroImaging Centre Research, Department of Neuroscience, Ruhr-University Bochum, Bochum, Germany (X.H.); Center for Systems Biology and Institute for Innovation in Imaging (C.W., J.W.C.) and Division of Neuroradiology, Department of Radiology (J.W.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; and Neurology Clinic, University Hospital Mannheim, Mannheim, Germany (M.P.).

Abstract

Purpose To investigate the association of inflammation and brain edema in a cerebral malaria (CM) mouse model with a combination of bis-5-hydroxy-tryptamide-diethylenetriaminepentaacetate gadolinium, referred to as MPO-Gd, and cross-linked iron oxide nanoparticle (CLIO-NP) imaging. Materials and Methods Female wild-type (n = 23) and myeloperoxidase (MPO) knock-out (n = 5) mice were infected with the Plasmodium berghei ANKA strain from May 2016 to July 2018. Seven healthy mice served as control animals. At a Rapid Murine Coma and Behavioral Scale (RMCBS) score of less than 15, mice underwent MRI at 9.4 T and received gadodiamide, MPO-Gd, or CLIO-NPs. T1-weighted MRI was used to assess MPO activity, and T2*-weighted MRI was used to track CLIO-NPs. Immunofluorescent staining and flow cytometric analyses characterized CLIO-NPs, MPO, endothelial cells, and leukocytes. An unpaired, two-tailed Student t test was used to compare groups; Spearman correlation analysis was used to determine the relationship of imaging parameters to clinical severity. Results MPO-Gd enhancement occurred in inflammatory CM hotspots (olfactory bulb > rostral migratory stream > brainstem > cortex, P < .05 for all regions compared with control mice; mean olfactory bulb signal intensity ratio: 1.40 ± 0.07 vs 0.96 ± 0.01, P < .01). The enhancement was reduced in MPO knockout mice (mean signal intensity ratio at 60 minutes: 1.13 ± 0.04 vs 1.40 ± 0.07 in CM, P < .05). Blood-brain barrier compromise was suggested by parenchymal gadolinium enhancement, leukocyte recruitment, and endothelial activation. CLIO-NPs accumulated mainly intravascularly and at the vascular endothelium. CLIO-NPs were also found in the choroid plexus, indicating inflammation of the ventricular system. Blood-cerebrospinal fluid barrier breakdown showed correlation with brain swelling (r2: 0.55, P < .01) and RMCBS score (r2: 0.75, P < .001). Conclusion Iron oxide nanoparticle imaging showed strong inflammatory involvement of the microvasculature in a murine model of cerebral malaria. Furthermore, bis-5-hydroxy-tryptamide-diethylenetriaminepentaacetate gadolinium imaging depicted parenchymal and intraventricular inflammation. This combined molecular imaging approach links vascular inflammation to breakdown of the blood-brain barrier and blood-cerebrospinal fluid barrier that correlate with global brain edema and disease severity. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Kiessling in this issue.

PMID:
30615566
DOI:
10.1148/radiol.2018181051

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