Mapping alteration of dopaminergic neurons in a rat model of Parkinson Disease through the comparison of the presynaptic PET tracers

NECTAR 2018 Parkinson’s Disease (PD) is characterized by dopaminergic neuronal loss in the substantia nigra (SN) resulting in a dopamine deficiency in the striatum.1 We developed a pathologically relevant rat model of PD using viral vectors to overexpress mutant alpha-synuclein.2 Our aims were to evaluate the dopaminergic changes and neuronal loss at different time-points in this model with two different presynaptic PET tracers, and relate imaging results with behavioural and histological changes. Therefor rats were unilaterally injected in the SN with AAV2/6 viral vector coding for mutated (A53T) human alpha-synuclein, and were studied at 6 or 12 weeks post-injection (wpi). PET imaging was performed using 6-[18F]fluoro-L-m-tyrosine3 (FMT), a substrate for AADC and [18F]-LBT9994 (LBT), a radioligand for dopamine transporter (DAT). Quantitative uptake images were calculated using Logan and Patlak graphical methods, with a cerebellar reference. At 6wpi we did not observe any asymmetry in the striatum; neither with FMT (n=5;p=0.421) nor LBT (n=6;p=0.310). At 12wpi we observed an asymmetry with LBT (n=4;p=0.003), but not with FMT (n=2;p=0.336). Histological evaluation showed 28% loss of TH-positive cells in the SN at 12wpi (n=8;p=0.031), but not at 6wpi (n=6;ns). A motor deficit was observed with the cylinder test at both time-points (n=7/8;pin vivo in a rat model characterized by progressive and mild neurodegeneration of the nigro-striatal pathway. This PET tracer may be of particular interest to test neuroprotective or neuro-restorative therapeutic strategies in future studies using our PD rat model. References: 1. [10.1016/S0896-6273(03)00568-3] 2. Cresto et al. [2017], Neurodegener Dis 2017;17(suppl 1):8-590 – Page 448. 3. [10.1111/jnc.14016] 4. [10.1016/j.nucmedbio.2013.09.007] Acknowledgements: This project has been funded by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Skłodowska-Curie Innovative Training Network and Grant Agreement No.676408.
This project has been funded by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Skłodowska-Curie Innovative Training Network and Grant Agreement No.676408.