title: Validation of in vivo magnetic resonance imaging blood-brain barrier permeability measurements by comparison with gold standard histology.
abstract: OBJECTIVE
  We sought to validate the blood-brain barrier permeability measurements extracted from perfusion-weighted MRI through a relatively simple and frequently applied model, the Patlak model, by comparison with gold standard histology in a rat model of ischemic stroke.
  
  
  METHODS
  Eleven spontaneously hypertensive rats and 11 Wistar rats with unilateral 2-hour filament occlusion of the right middle cerebral artery underwent imaging during occlusion at 4 hours and 24 hours after reperfusion. Blood-brain barrier permeability was imaged by gradient echo imaging after the first pass of the contrast agent bolus and quantified by a Patlak analysis. Blood-brain barrier permeability was shown on histology by the extravasation of Evans blue on fluorescence microscopy sections matching location and orientation of MR images. Cresyl-violet staining was used to detect and characterize hemorrhage. Landmark-based elastic image registration allowed a region-by-region comparison of permeability imaging at 24 hours with Evans blue extravasation and hemorrhage as detected on histological slides obtained immediately after the 24-hour image set.
  
  
  RESULTS
  Permeability values in the nonischemic tissue (marginal mean ± SE: 0.15 ± 0.019 mL/min 100 g) were significantly lower compared to all permeability values in regions of Evans blue extravasation or hemorrhage. Permeability values in regions of weak Evans blue extravasation (0.23 ± 0.016 mL/min 100 g) were significantly lower compared to permeability values of in regions of strong Evans blue extravasation (0.29 ± 0.020 mL/min 100 g) and macroscopic hemorrhage (0.35 ± 0.049 mL/min 100 g). Permeability values in regions of microscopic hemorrhage (0.26 ± 0.024 mL/min 100 g) only differed significantly from values in regions of nonischemic tissue (0.15 ± 0.019 mL/min 100 g).
  
  
  CONCLUSIONS
  Areas of increased permeability measured in vivo by imaging coincide with blood-brain barrier disruption and hemorrhage observed on gold standard histology.
authors.affiliation: University of Virginia, Department of Radiology, Neuroradiology Division, Charlottesville, VA 22908, USA.
authors.forename: Angelika
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Bredno
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wendland
authors.forename: Nikita
authors.initials: N
authors.lastname: Derugin
authors.forename: Jason
authors.initials: J
authors.lastname: Hom
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.forename: Hua
authors.initials: H
authors.lastname: Su
authors.forename: Peter T
authors.initials: PT
authors.lastname: Ohara
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.forename: Max
authors.initials: M
authors.lastname: Wintermark
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D002545:Brain Ischemia / Q000473:pathology*; D004195:Disease Models, Animal; D005070:Evans Blue / Q000494:pharmacology; D006470:Hemorrhage / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D010539:Permeability; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D020521:Stroke / Q000473:pathology*
chemical_list: D005070:Evans Blue