in vivo MR characterization of pathological changes in liver microstructures - in vivo MR characterization of pathological changes in liver microstructures Summary Liver biopsy is currently the gold standard for diagnosing and evaluating the extent of most liver diseases, but it is an invasive procedure that carries risks such as sampling errors, rare complications, intra/inter-observer variability, and significant patient anxiety. Noninvasive tests and imaging techniques for the diagnosis and management of liver diseases have gained significant interest due to the limitations of liver biopsy, particularly for identifying nonalcoholic steatohepatitis (NASH), the most severe form of Nonalcoholic fatty liver disease (NAFLD). Due to the obesity pandemic and type 2 diabetes, an increased number of NASH patients (~ 27 million NASH patients by 2030 in the US alone) is expected in the near future. The ability to differentiate NASH from simple steatosis is critically important for the clinical management of NAFLD patients. Currently, NASH is exclusively diagnosed invasively through liver biopsy to assess steatosis, inflammation, ballooning and fibrosis. While MRI-based PDFF and elastography have been shown to reliably quantify steatosis and fibrosis, respectively, the lack of a non-invasive tool to assess inflammation in NASH remains a significant gap in the daily clinical care of this common disease. Our lab has developed a novel concept that cell size and cell density could serve as indicators of hepatic inflammation and has developed a multi-compartment diffusion MRI-based method called in vivo quantitative Temporal Diffusion Spectroscopy (qTDS), which quantifies cell size and cell density by fitting multi-b value- multi-diffusion time fat-suppressed diffusion-weighted MRI signals to a three-compartment (blood, intra and extracellular water) signal model. Recently, qTDS has shown promising results in in vivo NASH patients and ex vivo human liver specimens with different pathologies, including normal liver tissues, cirrhosis, steatosis, and cirrhotic regenerative nodules (CRN). This grant proposal aims to establish the relationship between qTDS-derived parameters and histology values in a mouse model of NASH, optimize a clinical qTDS protocol for reliable in vivo quantification of cell size and cell density in human livers within a short period (less than 12 minutes), and demonstrate the efficacy of qTDS in characterizing hepatic inflammation, a key diagnostic component for differentiating NASH from simple steatosis. Successful completion of these aims will provide a solid foundation for a large-scale clinical trial to develop a noninvasive diagnostic metric for NASH, offer a standard qTDS imaging protocol that can be implemented on clinical 3T MR scanners, and provide a qTDS data processing toolbox that can be downloaded online. These outcomes will advance the use of noninvasive microstructure imaging in the diagnosis and management of liver diseases.
