Publications & Posters

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


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

DOI: 10.1089/neu.2020.7317


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.