Project Summary – Project 3 (Rettenmeier) Nonalcoholic fatty liver disease (NAFLD) has emerged as a major health concern in the world and is fueled by the growing pandemic of obesity and insulin resistance as a consequence of overnutrition and a more sedentary lifestyle. Thus, improving dietary habits is crucial to reduce the risk of disease onset and progression. However, the drivers for disease progression are not fully understood, and reliable noninvasive tools to monitor and characterize hepatic changes are urgently needed to improve risk assessment and interventions. NAFLD is characterized by fat accumulation in the liver and encompasses simple nonalcoholic fatty liver and the more progressive nonalcoholic steatohepatitis (NASH). NASH is strongly associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. The differentiation between benign NAFLD and NASH using current noninvasive diagnostic tools remains challenging and biopsy is often needed for a definitive diagnosis. The key histological features of NASH include the degree of steatosis, necroinflammation and fibrosis and is often associated with iron overload. Among them, the stage of fibrosis has been shown to be the most reliable predictor of liver-related mortality and presents a prominent target for the development of new imaging techniques. Magnetic resonance elastography (MRE) is considered the imaging gold standard which targets the increase in extracellular matrix in fibrotic liver tissue based on stiffness measurements. Recently, multiparametric MRI (mp- MRI) approaches have evolved that use MR relaxometry to assess the increase of extracellular fluid (ECF) volume as a measure of fibrosis. These methods use T2* mapping to account for iron deposition which presents a major confounding factor in the assessment of ECF volumes. Both, MRE and MRI techniques have shown promising results, however, improvements in specificity and accuracy are still needed. Our long-term goal is to develop a novel QSM based multiparametric MRI approach (QSMmp-MRI) that addresses shortcomings of previous mp-MRI techniques by incorporating quantitative susceptibility mapping (QSM) into the method. QSM has high specificity towards magnetically active iron compounds such as ferritin and hemosiderin and could improve the quantification of iron load in NASH patients and thereby indirectly enhance the accuracy of the corresponding ECF volume measurements in liver tissue. Overall, this new technique will enable the assessment of hepatic tissue parameters such as fibrosis, inflammation, steatosis, and iron load. The objective of this proposal is to implement the QSMmp-MRI sequences and to perform initial testing in a pilot study that uses noninvasive MRE as reference. In Aim 1, we will develop a set of MR sequences to quantify T1, T2*, magnetic susceptibility, and proton density fat fraction maps based on motion-robust radial sampling. Different acquisition modes will be tested, and perfor...