title: Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion.
abstract: OBJECTIVE
  Intrinsic disease processes of the brainstem (gliomas, neurodegenerative disease, and others) have remained difficult or impossible to treat effectively because of limited drug penetration across the blood-brainstem barrier with conventional delivery methods. The authors used convection-enhanced delivery (CED) of a macromolecular tracer visible on magnetic resonance (MR) imaging to examine the utility of CED for safe perfusion of the brainstem.
  
  
  METHODS
  Three primates (Macaca mulatta) underwent CED of various volumes of infusion ([Vis]; 85, 110, and 120 microl) of Gd-bound albumin (72 kD) in the pontine region of the brainstem during serial MR imaging. Infusate volume of distribution (Vd), homogeneity, and anatomical distribution were visualized and quantified using MR imaging. Neurological function was observed and recorded up to 35 days postinfusion. Histological analysis was performed in all animals. Large regions of the pons and midbrain were successfully and safely perfused with the macromolecular protein. The Vd was linearly proportional to the Vi (R2 = 0.94), with a Vd/Vi ratio of 8.7 +/- 1.2 (mean +/- standard deviation). Furthermore, the concentration across the perfused region was homogeneous. The Vd increased slightly at 24 hours after completion of the infusion, and remained larger until the intensity of infusion faded (by Day 7). No animal exhibited a neurological deficit after infusion. Histological analysis revealed normal tissue architecture and minimal gliosis that was limited to the region immediately surrounding the cannula track.
  
  
  CONCLUSIONS
  First, CED can be used to perfuse the brainstem safely and effectively with macromolecules. Second, a large-molecular-weight imaging tracer can be used successfully to deliver, monitor in vivo, and control the distribution of small- and large-molecular-weight putative therapeutic agents for treatment of intrinsic brainstem processes.
authors.affiliation: Surgical Neurology Branch and Biomedical Engineering and Instrumentation Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. lonserr@ninds.nih.gov
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.forename: Stuart
authors.initials: S
authors.lastname: Walbridge
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Walters
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.forename: Paul F
authors.initials: PF
authors.lastname: Morrison
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
mesh_terms: D000418:Albumins / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001812:Blood-Brain Barrier; D001933:Brain Stem / Q000098:blood supply*; D003287:Contrast Media / Q000493:pharmacokinetics* / Q000633:toxicity; D018481:Convection; D005682:Gadolinium / Q000493:pharmacokinetics* / Q000633:toxicity; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000418:Albumins; D003287:Contrast Media; D005682:Gadolinium