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 ([(18)F]fluorodopa) PET as a marker for striatal dopaminergic function. MAIN OUTCOME MEASURES Changes in caudate and putaminal [(18)F]fluorodopa influx constant (K(i)) values. RESULTS In patients with PD, the decline rate of putaminal [(18)F]fluorodopa K(i) correlated inversely with disease duration before study inclusion (r = -0.46, P = .01) and positively with baseline K(i) 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 K(i) threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [(18)F]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.