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

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 characte...

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Veröffentlicht in:NeuroImage (Orlando, Fla.) Fla.), 2017-07, Vol.155, p.245-256
Hauptverfasser: Castaneda Vega, Salvador, Weinl, Christine, Calaminus, Carsten, Wang, Lisa, Harant, Maren, Ehrlichmann, Walter, Thiele, Dennis, Kohlhofer, Ursula, Reischl, Gerald, Hempel, Johann-Martin, Ernemann, Ulrike, Quintanilla Martinez, Leticia, Nordheim, Alfred, Pichler, Bernd J.
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container_start_page 245
container_title NeuroImage (Orlando, Fla.)
container_volume 155
creator Castaneda Vega, Salvador
Weinl, Christine
Calaminus, Carsten
Wang, Lisa
Harant, Maren
Ehrlichmann, Walter
Thiele, Dennis
Kohlhofer, Ursula
Reischl, Gerald
Hempel, Johann-Martin
Ernemann, Ulrike
Quintanilla Martinez, Leticia
Nordheim, Alfred
Pichler, Bernd J.
description 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 (SrfiECKO) 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 SrfiECKO 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 SrfiECKO mouse model to study underlying mechanisms of hemorrhagic stroke. •PET-MRI characterization of an endogenous spontaneous stroke model•BBB breakage courses with reductions in water diffusion•Evolution of microangiopathies not associated to amyloid plaque deposition.
doi_str_mv 10.1016/j.neuroimage.2017.04.071
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Weinl, Christine ; Calaminus, Carsten ; Wang, Lisa ; Harant, Maren ; Ehrlichmann, Walter ; Thiele, Dennis ; Kohlhofer, Ursula ; Reischl, Gerald ; Hempel, Johann-Martin ; Ernemann, Ulrike ; Quintanilla Martinez, Leticia ; Nordheim, Alfred ; Pichler, Bernd J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-2f5a603bce8e8128db8a178e9fbb72185144a20d9100f8cd3634e310e9197ac53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Ablation</topic><topic>Age</topic><topic>Animal diseases</topic><topic>Animal models</topic><topic>Animals</topic><topic>Aquaporins</topic><topic>Bioindicators</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - diagnostic imaging</topic><topic>Brain</topic><topic>Cerebral Cortex - diagnostic imaging</topic><topic>Cortex</topic><topic>Dementia</topic><topic>Diagnostic software</topic><topic>Diffusion coefficient</topic><topic>Disease Models, Animal</topic><topic>Disruption</topic><topic>Glial fibrillary acidic protein</topic><topic>Glucose</topic><topic>Hemorrhage</topic><topic>Histology</topic><topic>Hypoxia</topic><topic>Immunohistochemistry</topic><topic>Intracranial Hemorrhages - diagnostic imaging</topic><topic>Iron</topic><topic>Lesions</topic><topic>Magnetic resonance imaging</topic><topic>Magnetic Resonance Imaging - methods</topic><topic>Male</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neuroimaging</topic><topic>Neurology</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Permeability</topic><topic>Pets</topic><topic>Positron emission tomography</topic><topic>Positron-Emission Tomography - methods</topic><topic>Prodromal Symptoms</topic><topic>Rodents</topic><topic>Serum response factor</topic><topic>Stem cells</topic><topic>Stroke</topic><topic>Stroke - diagnosis</topic><topic>Tomography</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Castaneda Vega, Salvador</creatorcontrib><creatorcontrib>Weinl, Christine</creatorcontrib><creatorcontrib>Calaminus, Carsten</creatorcontrib><creatorcontrib>Wang, Lisa</creatorcontrib><creatorcontrib>Harant, Maren</creatorcontrib><creatorcontrib>Ehrlichmann, Walter</creatorcontrib><creatorcontrib>Thiele, Dennis</creatorcontrib><creatorcontrib>Kohlhofer, Ursula</creatorcontrib><creatorcontrib>Reischl, Gerald</creatorcontrib><creatorcontrib>Hempel, Johann-Martin</creatorcontrib><creatorcontrib>Ernemann, Ulrike</creatorcontrib><creatorcontrib>Quintanilla Martinez, Leticia</creatorcontrib><creatorcontrib>Nordheim, Alfred</creatorcontrib><creatorcontrib>Pichler, Bernd J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health &amp; 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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 (SrfiECKO) 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 SrfiECKO 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 SrfiECKO mouse model to study underlying mechanisms of hemorrhagic stroke. •PET-MRI characterization of an endogenous spontaneous stroke model•BBB breakage courses with reductions in water diffusion•Evolution of microangiopathies not associated to amyloid plaque deposition.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28473286</pmid><doi>10.1016/j.neuroimage.2017.04.071</doi><tpages>12</tpages></addata></record>
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source MEDLINE; Elsevier ScienceDirect Journals; ProQuest Central UK/Ireland
subjects Ablation
Age
Animal diseases
Animal models
Animals
Aquaporins
Bioindicators
Blood-brain barrier
Blood-Brain Barrier - diagnostic imaging
Brain
Cerebral Cortex - diagnostic imaging
Cortex
Dementia
Diagnostic software
Diffusion coefficient
Disease Models, Animal
Disruption
Glial fibrillary acidic protein
Glucose
Hemorrhage
Histology
Hypoxia
Immunohistochemistry
Intracranial Hemorrhages - diagnostic imaging
Iron
Lesions
Magnetic resonance imaging
Magnetic Resonance Imaging - methods
Male
Metabolism
Mice
Mice, Transgenic
Neuroimaging
Neurology
NMR
Nuclear magnetic resonance
Permeability
Pets
Positron emission tomography
Positron-Emission Tomography - methods
Prodromal Symptoms
Rodents
Serum response factor
Stem cells
Stroke
Stroke - diagnosis
Tomography
Transcription factors
title Characterization of a novel murine model for spontaneous hemorrhagic stroke using in vivo PET and MR multiparametric imaging
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