Quantitative PET analysis of subregional striatal dopaminergic neurodegeneration in the MPTP primate model of Parkinson’s disease

Objectives: Previous studies indicated that subregions of the striatum with distinctive dopaminergic neurodegradation is related to different pathogeneses in Parkinson’s disease (PD). MPTP is a neurotoxin with high specificity for the dopamine (DA) neurons of the nigrostriatal pathway of humans and non-human primates. In the present study, we performed quantitative PET studies using ¹⁸F-N-3-fluoropropyl-2-b-carboxymethoxy-3-b-(4-iodophenyl)nortropane ([¹⁸F]FP-CIT) in an attempt to characterize DA-ergic neurodegradation in a MPTP primate model of PD.

Methods: Total five male cynomolgus monkeys underwent repeatedly 90-min dynamic [¹⁸F]FP-CIT PET scans before and one month after systemic intramuscular MPTP injection resulting in bilateral effects. Time-activity curves (TAC) of the [¹⁸F]FP-CIT distribution in subregions of the striatum (anterior, posterior and ventral putamen, and anterior and posterior caudate), midbrain and the cerebellum were generated using spatially normalized PET images. The net influx rate constant (K_i [min^-1]) of the radiotracer was estimated with Patlak graphical analysis method for those TACs. The cerebellum was used as the reference tissue. Changes (%) in K_i beforeand 1-month after the MPTP treatment were calculated and statistically tested using repeated measure ANOVA. Finally, correlation analysis was performed between level of inter-individual K_i changes in the subregions of the striatum and those in the midbrain.

Results: Subregional striatal DA-ergic neuronal degradation or decreased K_i by systemic intramuscular MPTP injection were substantial (F(1, 24) = 177.1, P < 0.05), while the level of the changes in K_i were distinctive between subregions of striatum (F(4, 20) = 9.542, P < 0.05). Interestingly, level of decreased K_i in the midbrain was relatively marginal, possibly due to underestimated K_i by partial volume effects. The ventral putamen showed the greatest changes ([mean ± SEM] = -85.4 ± 6.8%change), followed by posterior putamen, anterior putamen, anterior caudate and posterior caudate. Level of changes in midbrain K_i was significantly correlated with those of the anterior and posterior putamen (Pearson’s r = 0.960 and 0.954, respectively), and anterior caudate (Pearson’s r = 0.904).

Conclusion: Results demonstrated distinctive subregional striatal DA-ergic neurodegradation by systemic intramuscular MPTP injection in non-human primate model of PD. Further study investigating time-course of K_i changes should help understanding pathophysiologic details of this PD model. Research Support: This research was supported by grant from the National Research Foundation (2012M3A9B6055379) of South Korea