Increase in Dopamine Turnover Occurs Early in Parkinson's Disease: Evidence from a New Modeling Approach to PET ¹⁸F-Fluorodopa Data

Abstract

An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.

PET Studies of Net Blood—Brain Clearance of FDOPA to Human Brain: Age-Dependent Decline of [18F]Fluorodopamine Storage Capacity

“…Consistent with the present results, the magnitude of k loss has been found to be elevated two-three-fold in the striatum of monkeys with MPTP-induced parkinsonism Sossi et al, 2001;Cumming et al, 2001), and in patients with idiopathic Parkinson's disease (Sossi et al, 2002). The present estimates of the magnitude of k loss predict that the half-life for [ 18 F]fluorodopamine formed in the caudate and putamen declines from 7 h in the healthy young to 3 h in the healthy elderly, and only 75 mins in patients with early Parkinson's disease (Hoehn and Yahr II).…”

“…The magnitude of K in app is reduced by the eventual catabolism of [ 18 F]fluorodopamine to metabolites that diffuse from the brain (k loss ), especially when calculated from dynamic emission recordings of long duration Doudet et al, 1998;Cumming et al, 2001;Sossi et al, 2001Sossi et al, , 2002Sossi et al, , 2003. The effective distribution volume, an index of the specific binding capacity for FDOPA metabolites in the brain, has been defined as the ratio K in app /k loss (EDV 1 ; Sossi et al, 2001Sossi et al, , 2002, and in the present study as the ratio K/k loss (EDV 2 ).…”

“…The effective distribution volume, an index of the specific binding capacity for FDOPA metabolites in the brain, has been defined as the ratio K in app /k loss (EDV 1 ; Sossi et al, 2001Sossi et al, , 2002, and in the present study as the ratio K/k loss (EDV 2 ). We hypothesized that subtraction of the reference tissue radioactivity obscures the negative deviation of influx plots already present during the first two hours of FDOPA circulation, and also obscures declines in the magnitudes of k loss and effective distribution volume (TACs) as a function of normal aging or Parkinson's disease.…”

Dopamine Storage Capacity in Caudate and Putamen of Patients with Early Parkinson's Disease: Correlation with Asymmetry of Motor Symptoms

“…As in an earlier compartmental analysis (Rousset et al, 2000), the magnitude of k loss was increased 50% in the caudate and two-fold in the putamen of early PD patients. Similar two-fold increases in k loss have been reported in the whole striatum of monkeys with MPTP-induced parkinsonism Sossi et al, 2001;Cumming et al, 2001), and in the putamen of patients with early PD (Sossi et al, 2002). We have earlier attributed a decreased capacity to retain [ 18 F]fluorodopamine in the brain to a specific loss of vesicular storage in PD patients (Kumakura et al, 2005).…”

“…This approach provides the basis for calculating the EDV of FDOPA in the brain, EDV 1 , defined as the ratio K in app /k loss , which is an index of the dopamine storage capacity in the brain. The magnitude of EDV 1 was substantially reduced in the striatum of MPTP-treated monkeys (Sossi et al, 2001) and patients with early PD (Sossi et al, 2002), indicating an impaired capacity to retain [ 18 F]fluorodopamine within the brain. The magnitude of EDV 1 was reduced by 84% in the striatum of monkeys with severe MPTP lesions compared with healthy monkeys, whereas the magnitude of K in app declined by Dopamine storage capacity in caudate and putamen in patients with PD Y Kumakura et al only 66% ).…”