Intrathecal catheter implantation decreases cerebrospinal fluid dynamics in cynomolgus monkeys

• Type of Material: Article
• Authors: Mohammadreza Khani, University of Idaho; Audrey Q. Fu, University of Idaho; Joshua Pluid, University of Idaho; Christina P. Gibbs, University of Idaho; John Oshinski, Emory University; Tao Xing, University of Idaho; Gregory R. Stewart, Voyager Therapeutics; Jillynne R. Zeller, Northern Biomedical Research; Bryn A. Martin, University of Idaho
• Language: English
• Date: 2020-12-30
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Khani et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0244090
• Title of Journal or Parent Work: PLOS ONE
• Volume: 15
• Issue: 12
• Start Page: e0244090
• End Page: e0244090
• Grant/Funding Information: This work was supported by Voyager Therapeutics, National Institutes of Health, National Institute of General Medical Sciences grant P20GM103408 and 4U54GM104944-04 and the University of Idaho, Vandal Ideas Project. Publication of this article was funded by the University of Idaho Open Access Publishing Fund. The funders had no role in study data collection and analysis, decision to publish, or preparation of the manuscript. Voyager Therapeutics had a role in the study design. Authors BAM and GRS are employed by Alcyone Therapeutics. GRS was employed by Voyager Therapeutics during the course of this study. Alcyone Therapeutics provided support in the form of salary for authors BAM and GRS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Voyager Therapeutics provided support in the form of salary for author GRS. Author JRZ is employed by Northern Biomedical Research. Northern Biomedical Research provided support in the form of salary for author JRZ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
• Keywords: Multidisciplinary Sciences; MOVEMENT; RESPIRATION; SYSTEM; MOTION; Science & Technology; FLOW; MAGNETIC-RESONANCE; ARTERIAL PULSATION; VALUES; Science & Technology - Other Topics
• Research Categories: Education, Technology; Health Sciences, Medicine and Surgery

Abstract

A detailed understanding of the CSF dynamics is needed for design and optimization of intrathecal drug delivery devices, drugs, and protocols. Preclinical research using large-animal models is important to help define drug pharmacokinetics-pharmacodynamics and safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there was a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with cervical implantation compared to lumbar implantation. CSF flow rate decreased up to 55% with the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation in Cynomolgus monkeys.