Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity

Background: The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD). Objective: To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET). Design: Longitudinal prospective cohort study with a follow-up period of 64.5 +/- 22.6 months (mean +/- SD). Setting: University hospital Patients: A consecutive sample of patients with PD (N = 31; age at symptom onset, 53.6 +/- 11.3 years) with a wide range of symptom duration and severity at the time of study entry. Interventions: Investigation by serial fluorodopa F 18 ([F-18] fluorodopa) PET as a marker for striatal dopaminergic function. Main Outcome Measures: Changes in caudate and putaminal [F-18] fluorodopa influx constant (K-i) values. Results: In patients with PD, the decline rate of putaminal [F-18] fluorodopa Ki correlated inversely with disease duration before study inclusion (r=-0.46, P=.01) and positively with baseline Ki values (r=0.44, P=.01),indicating a negative exponential loss of dopamine neurons. Annual disease progression rates ranged from 4.4% in the caudate nucleus to 6.3% in the putamen. A mean preclinical period of 5.6 +/- 3.2 years was calculated with symptom onset at a putaminal Ki threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [F-18] fluorodopa PET was found to increase strongly with the preceding symptom duration of study subjects. Conclusion: These data suggest that the neurodegenerative process in PD follows a negative exponential course and slows down with increasing symptom duration, contradicting the long-latency hypothesis of PD.