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Evaluation of Diffusion Tensor Imaging and Fluid Based Biomarkers in a Large Animal Trial of Cyclosporine in Focal Traumatic Brain Injury

Karlsson, Michael LU ; Yang, Zhihui ; Chawla, Sanjeev ; Delso, Nile ; Pukenas, Bryan ; Elmér, Eskil LU orcid ; Hugerth, Matilda ; Margulies, Susan S. ; Ehinger, Johannes LU orcid and Hansson, Magnus J. LU orcid , et al. (2021) In Journal of Neurotrauma 38(13). p.1870-1878
Abstract

All phase III trials evaluating medical treatments for traumatic brain injury (TBI), performed to date, have failed. To facilitate future success there is a need for novel outcome metrics that can bridge pre-clinical studies to clinical proof of concept trials. Our objective was to assess diffusion tensor imaging (DTI) and biofluid-based biomarkers as efficacy outcome metrics in a large animal study evaluating the efficacy of cyclosporine in TBI. This work builds on our previously published study that demonstrated a reduced volume of injury by 35% with cyclosporine treatment based on magnetic resonance imaging (MRI) results. A focal contusion injury was induced in piglets using a controlled cortical impact (CCI) device. Cyclosporine in... (More)

All phase III trials evaluating medical treatments for traumatic brain injury (TBI), performed to date, have failed. To facilitate future success there is a need for novel outcome metrics that can bridge pre-clinical studies to clinical proof of concept trials. Our objective was to assess diffusion tensor imaging (DTI) and biofluid-based biomarkers as efficacy outcome metrics in a large animal study evaluating the efficacy of cyclosporine in TBI. This work builds on our previously published study that demonstrated a reduced volume of injury by 35% with cyclosporine treatment based on magnetic resonance imaging (MRI) results. A focal contusion injury was induced in piglets using a controlled cortical impact (CCI) device. Cyclosporine in a novel Cremophor/Kolliphor EL-free lipid emulsion, NeuroSTAT, was administered by continuous intravenous infusion for 5 days. The animals underwent DTI on day 5. Glial fibrillary acidic protein (GFAP), as a measure of astroglia injury, and neurofilament light (NF-L), as a measure of axonal injury, were measured in blood on days 1, 2, and 5, and in cerebrospinal fluid (CSF) on day 5 post-injury. Normalized fractional anisotropy (FA) was significantly (p = 0.027) higher in in the treatment group, indicating preserved tissue integrity with treatment. For the biomarkers, we observed a statistical trend of a decreased level of NF-L in CSF (p = 0.051), in the treatment group relative to placebo, indicating less axonal injury. Our findings suggest that DTI, and possibly CSF NF-L, may be feasible as translational end-points assessing neuroprotective drugs in TBI.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biomarkers, cyclosporine, diffusion tensor imaging, traumatic brain injury
in
Journal of Neurotrauma
volume
38
issue
13
pages
9 pages
publisher
Mary Ann Liebert, Inc.
external identifiers
  • pmid:33191835
  • scopus:85108330360
ISSN
0897-7151
DOI
10.1089/neu.2020.7317
language
English
LU publication?
yes
id
79ef5c8a-b0e1-4d71-ba6d-27cc3e00a042
date added to LUP
2021-07-16 10:43:52
date last changed
2024-06-16 16:10:07
@article{79ef5c8a-b0e1-4d71-ba6d-27cc3e00a042,
  abstract     = {{<p>All phase III trials evaluating medical treatments for traumatic brain injury (TBI), performed to date, have failed. To facilitate future success there is a need for novel outcome metrics that can bridge pre-clinical studies to clinical proof of concept trials. Our objective was to assess diffusion tensor imaging (DTI) and biofluid-based biomarkers as efficacy outcome metrics in a large animal study evaluating the efficacy of cyclosporine in TBI. This work builds on our previously published study that demonstrated a reduced volume of injury by 35% with cyclosporine treatment based on magnetic resonance imaging (MRI) results. A focal contusion injury was induced in piglets using a controlled cortical impact (CCI) device. Cyclosporine in a novel Cremophor/Kolliphor EL-free lipid emulsion, NeuroSTAT, was administered by continuous intravenous infusion for 5 days. The animals underwent DTI on day 5. Glial fibrillary acidic protein (GFAP), as a measure of astroglia injury, and neurofilament light (NF-L), as a measure of axonal injury, were measured in blood on days 1, 2, and 5, and in cerebrospinal fluid (CSF) on day 5 post-injury. Normalized fractional anisotropy (FA) was significantly (p = 0.027) higher in in the treatment group, indicating preserved tissue integrity with treatment. For the biomarkers, we observed a statistical trend of a decreased level of NF-L in CSF (p = 0.051), in the treatment group relative to placebo, indicating less axonal injury. Our findings suggest that DTI, and possibly CSF NF-L, may be feasible as translational end-points assessing neuroprotective drugs in TBI.</p>}},
  author       = {{Karlsson, Michael and Yang, Zhihui and Chawla, Sanjeev and Delso, Nile and Pukenas, Bryan and Elmér, Eskil and Hugerth, Matilda and Margulies, Susan S. and Ehinger, Johannes and Hansson, Magnus J. and Wang, Kevin K.W. and Kilbaugh, Todd J.}},
  issn         = {{0897-7151}},
  keywords     = {{biomarkers; cyclosporine; diffusion tensor imaging; traumatic brain injury}},
  language     = {{eng}},
  number       = {{13}},
  pages        = {{1870--1878}},
  publisher    = {{Mary Ann Liebert, Inc.}},
  series       = {{Journal of Neurotrauma}},
  title        = {{Evaluation of Diffusion Tensor Imaging and Fluid Based Biomarkers in a Large Animal Trial of Cyclosporine in Focal Traumatic Brain Injury}},
  url          = {{http://dx.doi.org/10.1089/neu.2020.7317}},
  doi          = {{10.1089/neu.2020.7317}},
  volume       = {{38}},
  year         = {{2021}},
}