Evaluation of Diffusion Tensor Imaging and Fluid Based Biomarkers in a Large Animal Trial of Cyclosporine in Focal Traumatic Brain Injury
JOURNAL OF NEUROTRAUMA | NOVEMBER 15, 2020
Karlsson M, Yang Z, Chawla S, Delso N, Pukenas B, Elmér E, Hugerth M, Margulies S, Ehinger JK, Hansson MJ, Wang KKW and Kilbaugh TJ.
J Neurotrauma. 2020 Nov 15
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 preclinical 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 upon 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 day 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 endpoints assessing neuroprotective drugs in TBI.