Performance of the prospective T2 MRI biomarker of neurotoxicity in a trimethyltin model in rats at 7 T

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.