A Reversible Tracer Analysis Approach to the Study of Effective Dopamine Turnover

University of British Columbia/TRIUMF, Vancouver, British Columbia, Canada.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 05/2001; 21(4). DOI: 10.1097/00004647-200104000-00015
Source: OAI


Changes in dopamine turnover resulting from disease states such as Parkinson's disease may be reflected in corresponding changes in the kinetics of the positron emission tomographic tracer [(18)F]fluorodopa. The authors had previously refined the conventional irreversible-tracer graphical approach to determine both the uptake rate constant K(i) and the rate constant kloss that describes the slow loss of the trapped kinetic component. Because these parameters change in the opposite sense with disease, their ratios may be more powerfully discriminating than either one alone. The ratio k(loss)/K(i) is indicative of effective dopamine turnover. Its inverse, K(i)/k(loss), can be interpreted as the effective distribution volume (EDV) of the specific uptake compartment referred to the fluorodopa concentration in plasma. Here the authors present a new approach to the estimation of EDV based on reversible-tracer graphical methods. When implemented with a plasma input function, the method evaluates EDV directly. When implemented with a tissue input function, the outcome is proportional to the ratio of the distribution volumes of the specific uptake and precursor compartments. Comparison of the new and previous approaches strongly validates this alternative approach to the study of effective dopamine turnover.

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Available from: James E Holden, Mar 12, 2014
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    • "In addition to the uptake rate constant, Ki, the extended method estimates K loss , a rate constant that quantifies the slow egress of trapped radiotracer due to neurotransmission. The ratio K i /K loss is effective distribution volume (eDV), the inverse of which is dopamine turnover (Doudet et al. 1998; Sossi et al. 2001). "
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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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    • "[18 F]FDOPA was similarly analyzed using the Logan plot, with the modification that the time-activity curve (TAC) from the reference region was subtracted from the striatal TAC prior to running the analysis [6]. The estimated slope equals the effective distribution volume ratio (EDVR), which informs on the distribution volume of the striatal 6-[18 F]fluorodopamine (FDA) compartment as compared to the reference region. "
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    ABSTRACT: [18 F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [18 F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques. [18 F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [11C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity. The different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BPND; r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BPND) but not with the contralateral PET measures. EDVR and BPND in the contralateral striatum were not different from controls and were not correlated with the denervation severity. The demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [18 F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control.
    EJNMMI Research 10/2013; 3(1):69. DOI:10.1186/2191-219X-3-69
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    • "Following this mathematical subtraction of brain OMFD, FDOPA kinetics in brain simplifies to an “inlet-outlet” model [17], , comprising the intrinsic blood-brain clearance rate of FDOPA (K, ml g−1 min−1), and the fractional rate constant for the process of elimination of [18F]fluorodopamine together with its deaminated metabolites from brain (kloss, min−1). The ratio (K/kloss) is analogous to an effective distribution volume (EDV ml g−1), as defined in [15]. In the method used here, the steady-state total tracer distribution volume in brain (Vd, ml g−1) equals the sum of the FDOPA plasma volume (V0, ml g−1), the distribution volume of unmetabolized FDOPA in brain (Vf, ml g−1), and the decarboxylated metabolite pool, consisting of [18F]fluorodopamine and its deaminated metabolites (K/kloss ml g−1; see [19], Fig. 2C). "
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    ABSTRACT: A previous study of the DOPA decarboxylase substrate 6-[(18)F]fluoro-L-DOPA (FDOPA) with positron emission tomography (PET) detected no difference of the net blood-brain transfer rate (Kin (app) ) between detoxified alcoholic patients and healthy controls. Instead, the study revealed an inverse correlation between Kin (app) in left ventral striatum and alcohol craving scores. To resolve the influx and efflux phases of radiolabeled molecules, we independently estimated the unidirectional blood-brain FDOPA clearance rate (K) and the washout rate of [(18)F]fluorodopamine and its deaminated metabolites (k loss), and we also calculated the total distribution volume of decarboxylated metabolites and unmetabolized FDOPA as a steady-state index of the dopamine storage capacity (Vd ) in brain. The craving scores in the 12 alcoholics correlated positively with the rate of loss (kloss ) in the left ventral striatum. We conclude that craving is most pronounced in the individuals with relatively rapid dopamine turnover in the left ventral striatum. The blood-brain clearance rate (K), corrected for subsequent loss of radiolabeled molecules from brain, was completely normal throughout the brain of the alcoholics, in whom the volume of distribution (Vd ) was found to be significantly lower in the left caudate nucleus. The magnitude of Vd in the left caudate head was reduced by 43% relative to the 16 controls, consistent with a 58% increase of kloss . We interpret the findings as indicating that a trait for rapid dopamine turnover in the ventral striatum subserves craving and reward-dependence, leading to an acquired state of increased dopamine turnover in the dorsal striatum of detoxified alcoholic patients.
    PLoS ONE 09/2013; 8(9):e73903. DOI:10.1371/journal.pone.0073903 · 3.23 Impact Factor
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