Successful and safe perfusion of the primate brainstem: In vivo magnetic resonance imaging of macromolecular distribution during infusion

Russell R. Lonser, Stuart Walbridge, Kayhan Garmestani, John A. Butman, Hugh A. Walters, Alexander Vortmeyer, Paul F. Morrison, Martin W. Brechbiel, Edward H. Oldfield

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Object. 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 μl) 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 (R 2 = 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.

Original languageEnglish (US)
Pages (from-to)905-913
Number of pages9
JournalJournal of neurosurgery
Volume97
Issue number4
DOIs
StatePublished - Oct 1 2002
Externally publishedYes

Fingerprint

Primates
Brain Stem
Convection
Perfusion
Magnetic Resonance Imaging
Molecular Weight
Molecular Imaging
Gliosis
Pons
Mesencephalon
Macaca mulatta
Glioma
Neurodegenerative Diseases
Albumins
Pharmaceutical Preparations
Proteins

Keywords

  • Brainstem
  • Convection-enhanced delivery
  • Macaca mulatta
  • Magnetic resonance imaging
  • Rat

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Successful and safe perfusion of the primate brainstem : In vivo magnetic resonance imaging of macromolecular distribution during infusion. / Lonser, Russell R.; Walbridge, Stuart; Garmestani, Kayhan; Butman, John A.; Walters, Hugh A.; Vortmeyer, Alexander; Morrison, Paul F.; Brechbiel, Martin W.; Oldfield, Edward H.

In: Journal of neurosurgery, Vol. 97, No. 4, 01.10.2002, p. 905-913.

Research output: Contribution to journalArticle

Lonser, RR, Walbridge, S, Garmestani, K, Butman, JA, Walters, HA, Vortmeyer, A, Morrison, PF, Brechbiel, MW & Oldfield, EH 2002, 'Successful and safe perfusion of the primate brainstem: In vivo magnetic resonance imaging of macromolecular distribution during infusion', Journal of neurosurgery, vol. 97, no. 4, pp. 905-913. https://doi.org/10.3171/jns.2002.97.4.0905
Lonser, Russell R. ; Walbridge, Stuart ; Garmestani, Kayhan ; Butman, John A. ; Walters, Hugh A. ; Vortmeyer, Alexander ; Morrison, Paul F. ; Brechbiel, Martin W. ; Oldfield, Edward H. / Successful and safe perfusion of the primate brainstem : In vivo magnetic resonance imaging of macromolecular distribution during infusion. In: Journal of neurosurgery. 2002 ; Vol. 97, No. 4. pp. 905-913.
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T2 - In vivo magnetic resonance imaging of macromolecular distribution during infusion

AU - Lonser, Russell R.

AU - Walbridge, Stuart

AU - Garmestani, Kayhan

AU - Butman, John A.

AU - Walters, Hugh A.

AU - Vortmeyer, Alexander

AU - Morrison, Paul F.

AU - Brechbiel, Martin W.

AU - Oldfield, Edward H.

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N2 - Object. 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 μl) 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 (R 2 = 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.

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