Nonlinear Progression of Parkinson Disease as Determined by Serial Positron Emission Tomographic Imaging of Striatal Fluorodopa F 18 Activity

University of Cologne, Köln, North Rhine-Westphalia, Germany
JAMA Neurology (Impact Factor: 7.01). 04/2005; 62(3):378-82. DOI: 10.1001/archneur.62.3.378
Source: PubMed

ABSTRACT The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD).
To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET).
Longitudinal prospective cohort study with a follow-up period of 64.5 +/- 22.6 months (mean +/- SD).
University hospital.
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.
Investigation by serial fluorodopa F 18 ([(18)F]fluorodopa) PET as a marker for striatal dopaminergic function.
Changes in caudate and putaminal [(18)F]fluorodopa influx constant (K(i)) values.
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.
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.

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    • "These lines of evidence hint that synaptic í µí»¼-synuclein pathology could initiate and determine the onset of motor symptoms in PD. Indeed, clinical manifestations of the disease appear when dopamine levels in the striatum are reduced to 80% of normal levels, as measured by a decrease in [ 18 F] fluoro-DOPA PET binding, a consequence of dopamine neuron loss in substantia nigra [15] [32] [33]. Of note, this initial symptomatic phase is characterized by a significant worsening of putaminal presynaptic deficiency, with a marked reduction in dopamine presynaptic storage, transporter binding , and release [34] [35]. "
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    • "Furthermore, a hypothetical model of functional changes in the cerebellum accompanying the progression of PD has been described in their study [55]. To be specific, pathological impairments should be more severe as disease progresses due to gradually development of the dopaminergic degeneration [56]. The compensatory effect, by contrast, strengthens at a relatively early stage, but may diminish or eventually fail as pathological damages become more severe at the advanced stage [57]. "
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