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

Abstract

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.

Relative fundamental frequency during vocal onset and offset in older speakers with and without Parkinson's disease

“…Disease duration and OFF medication UPDRS scores were statistically significantly (p ¼ 0.003) but weakly (R 2 ¼ 0.25) correlated. This finding is not surprising given the uncertainty associated with PD diagnosis due to its long preclinical period and the non-linear progression of the disease (Hilker et al, 2005).…”

Imaging in Parkinson's Disease

“…Loss of cortical AChE activity as measured by [ 11 C]PMP correlated with worse performance in working memory and attention tests in PD patients (Bohnen et al, 2006). Moreover, in PDD patients, decreased striatal [ 18 F]dopa uptake correlated with cortical [ 11 C]MPA reduction, suggesting that cognitive decline in PD occurs when the disease spreads from nigral neurons to the cortex, leading to a cholinergic dysfunction in this region (Hilker, Schweitzer, et al, 2005;Hilker, Thomas, et al, 2005). Postsynaptic nAChR loss, as measured by [ 18 F]2FA PET, also correlated with depression and cognitive decline (Meyer et al, 2009).…”

“…[ 18 F]dopa PET has shown that early-stage PD patients displayed a rapid progression of dopaminergic denervation in the putamen with a posterior-to-anterior gradient and a side-to-side asymmetry between the less and more affected striatal structures (Hilker, Schweitzer, et al, 2005;Hilker, Thomas, et al, 2005;Nandhagopal et al, 2009). In advanced stages, dopaminergic degeneration becomes slower, and although the gradient is maintained, the degree of asymmetry diminishes (Hilker, Schweitzer, et al, 2005;Hilker, Thomas, et al, 2005;Nandhagopal et al, 2009). The mean annual decline in [ 18 F]dopa uptake ranges from 8% to 12% in the putamen and from 4% to 6% in the caudate and it is considerably more than the decline typical of aging (Nurmi et al, 2001;Pavese, Rivero-Bosch, Lewis, Whone, & Brooks, 2011).…”

“…The mean annual decline in [ 18 F]dopa uptake ranges from 8% to 12% in the putamen and from 4% to 6% in the caudate and it is considerably more than the decline typical of aging (Nurmi et al, 2001;Pavese, Rivero-Bosch, Lewis, Whone, & Brooks, 2011). Moreover, presynaptic dopaminergic PET imaging has been used to estimate the duration of preclinical PD and it has shown 30%-55% loss of putamen dopaminergic function at the time of symptom onset (de la Fuente-Fernández et al, 2011;Hilker, Schweitzer, et al, 2005;Hilker, Thomas, et al, 2005;Lee, 2000). [ 11 C]DTBZ PET imaging estimated a preclinical state lasting up to 17 years, and [ 11 C]MP PET has shown a period of up to 13 years in patients with PD who were diagnosed at just over 50 years of age.…”

“…PET studies using [ 11 C]MP4A and [ 11 C]PMP have shown 20%-30% decreases in cortical AChE activity in PD with dementia (PDD) and dementia Lewy body (DLB) patients (Bohnen et al, 2006;Hilker, Schweitzer, et al, 2005;Hilker, Thomas, et al, 2005;Klein et al, 2010). Loss of cortical AChE activity as measured by [ 11 C]PMP correlated with worse performance in working memory and attention tests in PD patients (Bohnen et al, 2006).…”