期刊
JOURNAL OF NEUROTRAUMA
卷 38, 期 13, 页码 1870-1878出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/neu.2020.7317
关键词
biomarkers; cyclosporine; diffusion tensor imaging; traumatic brain injury
资金
- Department of Anesthesiology and Critical Care Medicine at The Children's Hospital of Philadelphia
- Department of Anesthesiology and Critical Care Medicine Endowed Chair Funds at The Children's Hospital of Philadelphia
- Children's Hospital of Philadelphia Research Institute Resuscitation Science Center of Emphasis
- Mary Jane Raymond Foundation
- Abliva AB
All phase III trials evaluating medical treatments for traumatic brain injury have failed, highlighting the need for novel outcome metrics. This study found that diffusion tensor imaging and biofluid-based biomarkers may be feasible as efficacy outcome metrics in evaluating neuroprotective drugs for TBI. The findings suggest that these measures could bridge pre-clinical and clinical trials for future success in TBI treatment.
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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