Covariance analysis of L-[1-11C]leucine PET: methodological considerations

Protein biosynthesis in the central nervous system (CNS) is essential for physiological maintenance and neural circuitry function, thus serving as a translational biomarker for behavioral, adaptive and cognitive processes. The L-[1-11C]leucine PET method has emerged as a relevant tool for the in vivo quantification of regional cerebral protein synthesis rates (rCPS) in human subjects. In this thesis I apply a covariance analysis-based approach to investigate rCPS patterns across designated regions of interest (ROIs), in both human and rat models. By establishing an interspecies framework, I aim to evaluate the translatability of leucine-based imaging methodologies, emphasizing the importance of molecular connectivity as an emerging transformative platform. The first section of this study focuses on the L-[1-11C]leucine PET sensitivity analysis, examining the influence of varying experimental variables on human rCPS data, including estimation approaches, scan duration and PET quantification methods. The second section shifts the focus on L-[1-14C]leucine autoradiographic data from rat models, assessing the effects of environmental enrichment, dietary restrictions, and stress-controlled conditions on rCPS patterns. In this context, I further introduce a framework for constructing individualized connectomes revealing individual molecular abnormalities in CPS pathways in rat models. While the L-[1-11C]leucine PET method shows a responsiveness to different estimation approaches, it generates stable and consistent rCPS patterns even with varying scanning intervals and quantification methods. Chronic stress does not significantly impact on the rCPS patterns in rat models, whereas an active lifestyle substantially affects the rCPS patterns in rats, thus improving the brain’s neuronal capacity.