PET methodology in rat models of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases worldwide. The use of animal, especially rodent, models is of utmost importance to expand our understanding of the pathological features and treatments for the disease. Research in PD patients and rodent disease models has indicated that several neurotransmitter systems and inflammatory processes are involved in the brain of PD patients. A common method for the assessment of physiological processes in vivo is positron emission tomography (PET). Radiolabelled compounds specific for a certain biological process are administered to a subject and subsequently their distribution through the body, or brain is followed over time using a PET camera. The distribution and kinetics of the radiolabelled compound can be used to quantify the physiological process of interest using mathematical models. In this thesis, methodological aspects for the quantification of markers of the cholinergic neurotransmitter system using PET imaging were evaluated. The optimal quantification methods for the PET radiotracers [11C]-PMP, an acetylcholinesterase substrate, and [18F]-FEOBV, a ligand of the vesicular acetylcholine transporter, were determined in rats. Furthermore, the newly characterized as well as established radiotracers were applied to quantify changes in cholinergic activity, dopaminergic innervation, and neuroinflammation in rat models of PD. In the first study in a striatal 6-OHDA model of PD, no increase in cholinergic activity was found up to one month after the 6-OHDA injection. Additionally, no effect of exercise on cholinergic activity was seen. In the second study, a rat model carrying one of the most common genetic mutations in PD patients (LRRK2 p.G2019S) was subjected to a peripheral inflammatory trigger and followed over several months. Ten months after the inflammatory trigger no change in dopaminergic innervation but increased neuroinflammation in brain regions related to other neurotransmitters was found.