Assignment of molecular origins of NOE signal at −3.5 ppm in the brain

Purpose Nuclear Overhauser enhancemen mediated saturation transfer effect, termed NOE (−3.5 ppm), is a major source of CEST MRI contrasts at 3.5 ppm in the brain. Previous phantom experiments have demonstrated that both proteins and lipids, two major components in tissues, have substantial contributions to NOE (−3.5 ppm) signals. Their relative contributions in tissues are informative for the interpretation of NOE (−3.5 ppm) contrasts that could provide potential imaging biomarkers for relevant diseases, which remain incompletely understood. Methods Experiments on homogenates and supernatants of brain tissues collected from healthy rats, that could isolate proteins from lipids, were performed to evaluate the relative contribution of lipids to NOE (−3.5 ppm) signals. On the other hand, experiments on ghost membranes with varied pH, and reconstituted phospholipids with different chemical compositions were conducted to study the dependence of NOE (−3.5 ppm) on physiological conditions. Besides, CEST imaging on rat brains bearing 9 L tumors and healthy rat brains was performed to analyze the causes of the NOE (−3.5 ppm) contrast variations between tumors and normal tissues, and between gray matter and white matter. Results Our experiments reveal that lipids have dominant contributions to the NOE (−3.5 ppm) signals. Further analysis suggests that decreased NOE (−3.5 ppm) signals in tumors and higher NOE (−3.5 ppm) signals in white matter than in gray matter are mainly explained by changes in membrane lipids, rather than proteins. Conclusion NOE (−3.5 ppm) could be exploited as a highly sensitive MRI contrast for imaging membrane lipids in the brain.