Serguei Liachenko , Jaivijay Ramu , Merle G. Paule , Joseph Hanig
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Abstract
The assessment of the sensitivity and specificity of any potential biomarker against the gold standard is an important step in the process of its qualification by regulatory authorities. Such qualification is an important step towards incorporating the biomarker into the panel of tools available for drug development. In the current study we analyzed the sensitivity and specificity of T2 MRI relaxometry to detect trimethyltin-induced neurotoxicity in rats. Seventy-five male Sprague-Dawley rats were injected with a single intraperitoneal dose of either TMT (8, 10, 11, or 12 mg/kg) or saline (2 ml/kg) and imaged with 7 T MRI before and 3, 7, 14, and 21 days after injection using a quantitative T2 mapping. Neurohistopathology (the gold standard in the case of neurotoxicity) was performed at the end of the observation and used as an outcome qualifier in receiver-operator characteristic (ROC) curve analysis of T2 changes as a predictor of neurotoxicity. TMT treatment led to a significant increase in T2 values in many brain areas. The biggest changes in T2 values were seen around the lateral ventricles, which was interpreted as ventricular dilation. The area under the ROC curve for the volume of the lateral ventricles was 0.878 with the optimal sensitivity/specificity of 0.805/0.933, respectively. T2 MRI is a promising method for generating a non-invasive biomarkers of neurotoxicity, which shows the dose-response behavior with substantial sensitivity and specificity. While its performance was strong in the TMT model, further characterization of the sensitivity and specificity of T2 MRI with other neurotoxicants is warranted.
期刊介绍：
Neurotoxicology and Teratology provides a forum for publishing new information regarding the effects of chemical and physical agents on the developing, adult or aging nervous system. In this context, the fields of neurotoxicology and teratology include studies of agent-induced alterations of nervous system function, with a focus on behavioral outcomes and their underlying physiological and neurochemical mechanisms. The Journal publishes original, peer-reviewed Research Reports of experimental, clinical, and epidemiological studies that address the neurotoxicity and/or functional teratology of pesticides, solvents, heavy metals, nanomaterials, organometals, industrial compounds, mixtures, drugs of abuse, pharmaceuticals, animal and plant toxins, atmospheric reaction products, and physical agents such as radiation and noise. These reports include traditional mammalian neurotoxicology experiments, human studies, studies using non-mammalian animal models, and mechanistic studies in vivo or in vitro. Special Issues, Reviews, Commentaries, Meeting Reports, and Symposium Papers provide timely updates on areas that have reached a critical point of synthesis, on aspects of a scientific field undergoing rapid change, or on areas that present special methodological or interpretive problems. Theoretical Articles address concepts and potential mechanisms underlying actions of agents of interest in the nervous system. The Journal also publishes Brief Communications that concisely describe a new method, technique, apparatus, or experimental result.
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