title: In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke.
abstract: OBJECTIVE
  In vivo imaging of inflammatory processes is a valuable tool in stroke research. We here investigated the combination of two imaging modalities in the chronic phase after cerebral ischemia: magnetic resonance imaging (MRI) using intravenously applied ultra small supraparamagnetic iron oxide particles (USPIO), and positron emission tomography (PET) with the tracer [(11)C]PK11195.
  
  
  METHODS
  Rats were subjected to permanent middle cerebral artery occlusion (pMCAO) by the macrosphere model and monitored by MRI and PET for 28 or 56 days, followed by immunohistochemical endpoint analysis. To our knowledge, this is the first study providing USPIO-MRI data in the chronic phase up to 8 weeks after stroke.
  
  
  RESULTS
  Phagocytes with internalized USPIOs induced MRI-T2(∗) signal alterations in the brain. Combined analysis with [(11)C]PK11195-PET allowed quantification of phagocytic activity and other neuroinflammatory processes. From 4 weeks after induction of ischemia, inflammation was dominated by phagocytes. Immunohistochemistry revealed colocalization of Iba1+ microglia with [(11)C]PK11195 and ED1/CD68 with USPIOs. USPIO-related iron was distinguished from alternatively deposited iron by assessing MRI before and after USPIO application. Tissue affected by non-phagocytic inflammation during the first week mostly remained in a viably vital but remodeled state after 4 or 8 weeks, while phagocytic activity was associated with severe injury and necrosis accordingly.
  
  
  CONCLUSIONS
  We conclude that the combined approach of USPIO-MRI and [(11)C]PK11195-PET allows to observe post-stroke inflammatory processes in the living animal in an intraindividual and longitudinal fashion, predicting long-term tissue fate. The non-invasive imaging methods do not affect the immune system and have been applied to human subjects before. Translation into clinical applications is therefore feasible.
authors.affiliation: Department of Neurology, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany. Electronic address: helene.walter@uk-koeln.de.
authors.forename: H L
authors.initials: HL
authors.lastname: Walter
authors.affiliation: Department of Neurology, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Walberer
authors.affiliation: Department of Neurology, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Rueger
authors.affiliation: Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Backes
authors.affiliation: Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Wiedermann
authors.affiliation: Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany; Department of Radiology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Hoehn
authors.affiliation: Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Neumaier
authors.affiliation: Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Graf
authors.affiliation: Department of Neurology, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Institute of Neuroscience and Medicine (INM-3), Cognitive Neuroscience, Research Centre Jülich, 52425 Jülich, Germany.
authors.forename: G R
authors.initials: GR
authors.lastname: Fink
authors.affiliation: Department of Neurology, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; Max-Planck-Institute for Neurological Research, Gleueler Straße 50, 50931 Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schroeter
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D002908:Chronic Disease; D004195:Disease Models, Animal; D005290:Ferric Compounds; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery; D007546:Isoquinolines; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology / Q000502:physiology; D010587:Phagocytosis / Q000502:physiology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D017208:Rats, Wistar; D020521:Stroke / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002135:Calcium-Binding Proteins; D002250:Carbon Radioisotopes; D005290:Ferric Compounds; D007546:Isoquinolines; D008840:Microfilament Proteins; D019275:Radiopharmaceuticals; C100745:Aif1 protein, rat; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C000499:ferric oxide; C037850:PK 11195
keywords: MRI; PET; chronic post-stroke phase; in vivo imaging; phagocytic activity; regional tissue fate