title: Extravasation into brain and subsequent spread beyond the ischemic core of a magnetic resonance contrast agent following a step-down infusion protocol in acute cerebral ischemia.
abstract: BACKGROUND
  Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion (SDI) protocols.
  
  
  METHODS
  Male Wistar rats underwent middle cerebral artery (MCA) occlusion for 3 h followed by reperfusion. Perfusion-diffusion mismatched regions indicating the extent of spread were identified by measuring cerebral blood flow (CBF) deficits by arterial spin-labeled magnetic resonance imaging and the extent of the ischemic core by mapping the apparent diffusion coefficient (ADC) of water with diffusion-weighted imaging. Vascular injury was assessed via MRCA, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) penetration, by Look-Locker T1-weighted MR imaging after either a bolus injection (n = 8) or SDI (n = 6). Spatial and temporal expansion of the MRCA front during a 25 min imaging period was measured from images obtained at 2.5 min intervals.
  
  
  RESULTS
  The mean ADC lesion was 20 ± 7% of the hemispheric area whereas the CBF deficit area was 60 ± 16%, with the difference between the areas suggesting the possible presence of a penumbra. The bolus injection led to MRCA enhancement with an area that initially spread into the ischemic core and then diminished over time. The SDI produced a gradual increase in the area of MRCA enhancement that slowly enlarged to occupy the core, eventually expanded beyond it into the surrounding tissue and then plateaued. The integrated area from SDI extravasation was significantly larger than that for the bolus (p = 0.03). The total number of pixels covered by the SDI at its maximum was significantly larger than the pixels covered by bolus maximum (p = 0.05).
  
  
  CONCLUSIONS
  These results demonstrate that the SDI protocol resulted in a spread of the MRCA beyond the ischemic core. Whether plasma-borne acute stroke therapeutics can be delivered to the ischemic penumbra in a similar way needs to be investigated.
authors.affiliation: Department of Anesthesiology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689, USA.
authors.forename: Tavarekere N
authors.initials: TN
authors.lastname: Nagaraja
authors.affiliation: Department of Anesthesiology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Keenan
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA ; Present address: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Madhava P
authors.initials: MP
authors.lastname: Aryal
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA ; Department of Physics, Oakland University, Rochester, MI, USA ; Department of Neurology, Wayne State University, Detroit, MI, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Ewing
authors.affiliation: Department of Anesthesiology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689, USA.
authors.forename: Saarang
authors.initials: S
authors.lastname: Gopinath
authors.affiliation: Department of Anesthesiology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689, USA.
authors.forename: Varun S
authors.initials: VS
authors.lastname: Nadig
authors.affiliation: Department of Anesthesiology, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689, USA.
authors.forename: Sukruth
authors.initials: S
authors.lastname: Shashikumar
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA ; Department of Physics, Oakland University, Rochester, MI, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Knight
keywords: Blood–brain barrier; Brain drug delivery; Penumbra; Perfusion-diffusion mismatch; Stroke