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

University of British Columbia/TRIUMF, University of British Columbia, Vancouver, Canada.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 03/2002; 22(2):232-9. DOI: 10.1097/00004647-200202000-00011
Source: PubMed


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.

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    • "Although a vesicular storage defect would be expected to accelerate the loss of F-DOPA-derived radioactivity, this does not necessarily mean that the finding of accelerated loss indicates a vesicular storage defect. An alternative explanation is increased release coupled with decreased reuptake [27]. The current data about Fractional Loss, considered in isolation, are consistent with but does not necessarily imply decreased vesicular storage. "
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    ABSTRACT: Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson's disease (PD) is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are lost has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity caused by catecholamine metabolites. Since vesicular sequestration limits the buildup of toxic products of enzymatic and spontaneous oxidation of catecholamines, a vesicular storage defect could play a pathogenic role in the death of catecholaminergic neurons in a variety of neurodegenerative diseases. In putamen, deficient vesicular storage is revealed in vivo by accelerated loss of (18)F-DOPA-derived radioactivity and post-mortem by decreased tissue dopamine (DA):DOPA ratios; in myocardium in vivo by accelerated loss of (18)F-dopamine-derived radioactivity and post-mortem by increased 3,4-dihydroxyphenylglycol:norepinephrine (DHPG:NE) ratios; and in sympathetic noradrenergic nerves overall in vivo by increased plasma F-dihydroxyphenylacetic acid (F-DOPAC):DHPG ratios. We retrospectively analyzed data from 20 conditions with decreased or intact catecholaminergic innervation, involving different etiologies, pathogenetic mechanisms, and lesion locations. All conditions involving parkinsonism had accelerated loss of putamen (18)F-DOPA-derived radioactivity; in those with post-mortem data there were also decreased putamen DA:DOPA ratios. All conditions involving cardiac sympathetic denervation had accelerated loss of myocardial (18)F-dopamine-derived radioactivity; in those with post-mortem data there were increased myocardial DHPG:NE ratios. All conditions involving localized loss of catecholaminergic innervation had evidence of decreased vesicular storage specifically in the denervated regions. Thus, across neurodegenerative diseases, loss of catecholaminergic neurons seems to be associated with decreased vesicular storage in the residual neurons.
    Parkinsonism & Related Disorders 07/2015; 21(9). DOI:10.1016/j.parkreldis.2015.07.009 · 3.97 Impact Factor
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    • "turnover in the striatum may be a more sensitive indicator of disease involvement than the uptake rate constant (Sossi et al. 2002). Therefore, increased dopamine turnover in this anterior cingulate cortex may also be an early sign of pathologic involvement. "
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    ABSTRACT: Subtle cognitive and behavioral changes are common in early Parkinson's disease. The cause of these symptoms is probably multifactorial but may in part be related to extra-striatal dopamine levels. 6-[(18) F]-Fluoro-L-dopa (FDOPA) positron emission tomography has been widely used to quantify dopamine metabolism in the brain; the most frequently measured kinetic parameter is the tissue uptake rate constant, Ki. However, estimates of dopamine turnover, which also account for the small rate of FDOPA loss from areas of specific trapping, may be more sensitive than Ki for early disease-related changes in dopamine biosynthesis. The purpose of the present study was to compare effective distribution volume ratio (eDVR), a metric for dopamine turnover, to cognitive and behavioral measures in Parkinson's patients. We chose to focus the investigation on anterior cingulate cortex, which shows highest FDOPA uptake within frontal regions and has known roles in executive function. Fifteen non-demented early-stage PD patients were pretreated with carbidopa and tolcapone, a central catechol-O-methyl transferase (COMT) inhibitor, and then underwent extended imaging with FDOPA PET. Anterior cingulate eDVR was compared with composite scores for language, memory, and executive function measured by neuropsychological testing, and behavior change measured using two informant-based questionnaires, the Cambridge Behavioral Inventory and the Behavior Rating Inventory of Executive Function-Adult Version. Lower mean eDVR (thus higher dopamine turnover) in anterior cingulate cortex was related to lower (more impaired) behavior scores. We conclude that subtle changes in anterior cingulate dopamine metabolism may contribute to dysexecutive behaviors in Parkinson's disease.
    Brain Imaging and Behavior 12/2014; DOI:10.1007/s11682-014-9338-4 · 4.60 Impact Factor
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    • "These alterations in the ipsilateral striatum of the untreated lesioned rats were reversed after SEMU treatments. An increase in DA turnover has been assumed to occur early in Parkinson's disease, as a compensatory mechanism for dopaminergic neuronal loss [36]. Earlier studies [37] have shown that a relatively slower decrease in dopamine synthesis and a relatively faster increase in turnover in early disease probably act as compensatory mechanisms, and that the clinical onset of PD reflects a global failure of dopaminergic compensatory mechanisms. "
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    ABSTRACT: Myracrodruon urundeuva Fr. All. (Anacardiaceae) is a Brazilian medicinal species, which is common to the Northeastern Brazilian semiarid region, whose stem-bark is widely used in folk medicine. It is an endangered species, presenting as main bioactive components tannins and chalcones. In this work, we studied the neuroprotective effects of a standardized extract from cultivated M. urundeuva (SEMU), in a model of Parkinson's disease. Thus, a unilateral injection of 6-OHDA was done into the rat right stratum. The animals were submitted to stereotaxic surgery, then treated with SEMU (5, 10, 20, or 40 mg/kg, p.o.) for 2 weeks, subjected to behavioral tests, and euthanized for striata dissections and neurochemical, histological, and immunohistochemical analyses. We showed, for the first time, that SEMU reverted behavioral alterations seen in the 6-OHDA-lesioned group and partially blocked the decrease in DA and DOPAC contents. The numbers of viable neurons and TH immunopositive cells were increased by SEMU. In addition, the SEMU-treated 6-OHDA groups showed lower numbers of GFAP and OX-42 immunopositive cells. The neuroprotective action of SEMU is possibly related to the antioxidant and anti-inflammatory properties of M. urundeuva, pointing out to its potential use in the prevention or treatment of neurodegenerative conditions, such as Parkinson's disease.
    Parkinson's Disease 06/2014; 2014:519615. DOI:10.1155/2014/519615 · 2.01 Impact Factor
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