Biological parameter estimation for longitudinal imaging in the rodent brain

Abstract

The thesis investigates kinetic modelling and parameter estimation techniques for longitudinal imaging studies in pre-clinical PET (positron emission tomography) of the rodent brain. Pre-clinical PET imaging is useful for investigating animal models of disease, and it is possible to follow evolution toward pathology with longitudinal imaging studies. Longitudinal studies require experimental methods that avoid blood sampling. It's also necessary to have methods that will allow the generation of parametric maps and give statistically robust and accurate parameter estimates. The work presented in this thesis aimed to develop, explore and validate parameter estimation methods for longitudinal studies using extensive kinetic modelling and simulation based approaches. Two biological targets were investigated, the D2 dopamine system, and the translocator protein (TSPO), useful for PET imaging as an indicator of neuroinflammation. The first part of the work achieved a robust and accurate data driven method for following changes in parameter estimates or creating parametric maps of the D2 dopamine system with 11C-raclopride. The method was validated for estimating Bavail and appKD in a broad range of experimental conditions. The second part of the thesis focused on the characterisation of TSPO ligands. The binding properties of two lead radiotracers (18F-PBR111 and 18F-PBR102) were compared in a well validated model of neuroinflammation, and found to be similar. The binding parameters of 18F-PBR111 were further characterised in an animal model of epileptogenesis. The studies presented in this thesis explored, developed and validated extensive kinetic modelling techniques and image processing tools for longitudinal imaging studies. The techniques will reliably estimate stable and accurate kinetic parameters, create parametric maps, and be able to detect small changes locally. This will allow researchers to study the progression through all stages of neurodegenerative diseases.