Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques

Objective: Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. Methods: Presynaptic PET tracers 6-[¹⁸F]- fluorodopa (FD), [¹¹C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [¹¹C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration. Results: We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R² = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (r_s = -0.77, -0.71, respectively, p < 0.001), but FD uptake did not. Interpretation: Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function.