In vivo 18 F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation

Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in , encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat gene. and rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. -3,4-dihydroxy-6- F-fluorophenylalanine ( F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), and rats were characterized over the course of ageing (5, 11, and 16 months old) using F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant ( ) and effective distribution volume ratio ( ) of F-DOPA in the striatum relative to the cerebellum in WT, and rats. A significant reduction in was observed in rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in between the left and right striatum in aged rats. The increased and asymmetric dopamine turnover observed in the striatum of aged rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. rats represent a novel genetic model of PD, and kinetic modelling of F-DOPA PET data has identified a highly relevant early disease phenotype.