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 substantia nigra neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in SNCA, 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 SNCA gene. SNCA(G51D/+) and SNCA(G51D/G51D) rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-(18)F-fluorophenylalanine ((18)F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCA(G51D/+) and SNCA(G51D/G51D) rats were characterized over the course of ageing (5, 11, and 16 months old) using (18)F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (K(i)) and effective distribution volume ratio (EDVR) of (18)F-DOPA in the striatum relative to the cerebellum in WT, SNCA(G51D/+) and SNCA(G51D/G51D) rats. A significant reduction in EDVR was observed in SNCA(G51D/G51D) rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCA(G51D/G51D) rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCA(G51D/G51D) rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. SNCA(G51D) rats represent a novel genetic model of PD, and kinetic modelling of (18)F-DOPA PET data has identified a highly relevant early disease phenotype.