Characterization of a novel murine model for spontaneous hemorrhagic stroke using in vivo PET and MR multiparametric imaging

Salvador Castaneda Vega; Christine Weinl; Carsten Calaminus; Lisa Wang; Maren Harant; Walter Ehrlichmann; Dennis Thiele; Ursula Kohlhofer; Gerald Reischl; Johann-Martin Hempel; Ulrike Ernemann; Leticia Quintanilla Martinez; Alfred Nordheim; Bernd J Pichler

doi:10.1016/j.neuroimage.2017.04.071

Characterization of a novel murine model for spontaneous hemorrhagic stroke using in vivo PET and MR multiparametric imaging

Neuroimage. 2017 Jul 15:155:245-256. doi: 10.1016/j.neuroimage.2017.04.071. Epub 2017 May 1.

Affiliations

¹ Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tuebingen, Tuebingen, Germany.
² Department of Molecular Biology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
³ Institute of Clinical Epidemiology and Applied Biostatistics, University Hospital Tuebingen, Tuebingen, Germany.
⁴ Institute of Pathology, Eberhard Karls University and Comprehensive Cancer Center, University Clinic Tuebingen, Tuebingen, Germany.
⁵ Department of Diagnostic and Interventional Neuroradiology, University Clinic Tuebingen, Tuebingen, Germany.
⁶ Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tuebingen, Tuebingen, Germany. Electronic address: Bernd.Pichler@med.uni-tuebingen.de.

PMID: 28473286
DOI: 10.1016/j.neuroimage.2017.04.071

Abstract

The clinical use of Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) has proven to be a strong diagnostic tool in the field of neurology. The reliability of these methods to confirm clinical diagnoses has guided preclinical research to utilize these techniques for the characterization of animal disease models. Previously, we demonstrated that an endothelial cell-specific ablation of the murine Serum Response Factor (Srf^iECKO) results in blood brain barrier (BBB) breakdown and hemorrhagic stroke. Taking advantage of this mouse model we here perform a comprehensive longitudinal, multiparametric and in vivo imaging approach to reveal pathophysiological processes occurring before and during the appearance of cerebral microbleeds using combined PET and MRI. We complement our imaging results with data regarding animal behavior and immunohistochemistry. Our results demonstrate diffusion abnormalities in the cortical brain tissue prior to the onset of cerebral microbleeds. Diffusion reductions were accompanied by significant increments of [¹⁸F]FAZA uptake before the onset of the lesions in T2WI. The Open Field behavioral tests revealed reduced activity of Srf^iECKO animals, whereas histology confirmed the presence of hemorrhages in cortical regions of the mouse brain and iron deposition at lesion sites with increased hypoxia inducible factor 1α, CD31 and glial fibrillary acidic protein expression. For the first time, we performed a thorough evaluation of the prodromal period before the occurrence of spontaneous cerebral microbleeds. Using in vivo PET and MRI, we show the pathological tissue changes that occur previous to gross blood brain barrier (BBB) disruption and breakage. In addition, our results show that apparent diffusion coefficient (ADC) reduction may be an early biomarker of BBB disruption proposing an alternate clinical interpretation. Furthermore, our findings remark the usefulness of this novel Srf^iECKO mouse model to study underlying mechanisms of hemorrhagic stroke.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier / diagnostic imaging*
Cerebral Cortex / diagnostic imaging*
Disease Models, Animal
Intracranial Hemorrhages / diagnostic imaging*
Magnetic Resonance Imaging / methods*
Male
Mice
Mice, Transgenic
Positron-Emission Tomography / methods*
Prodromal Symptoms*
Stroke / diagnosis*