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

University of Wisconsin–Madison, Madison, Wisconsin, United States
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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    • "As it will be demonstrated later, the accuracy of the two Patlak models depends on the ratio of k K / i loss . Sossi et al (2001) in particular also studied, in the case of region-based 18 F-fluorodopa brain PET tracer kinetic analysis for Parkinson's disease evaluations, the effect of this ratio, which they term as 'effective dopamine turnover' (EDT). The standard Patlak model assumes a 2-tissue compartment model involving 3 parameter rate constants (K 1 , k 2 and k 3 ) with the second compartment considered irreversible, i.e. "
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    ABSTRACT: We recently developed a dynamic multi-bed PET data acquisition framework to translate the quantitative benefits of Patlak voxel-wise analysis to the domain of routine clinical whole-body (WB) imaging. The standard Patlak (sPatlak) linear graphical analysis assumes irreversible PET tracer uptake, ignoring the effect of FDG dephosphorylation, which has been suggested by a number of PET studies. In this work: (i) a non-linear generalized Patlak (gPatlak) model is utilized, including a net efflux rate constant kloss, and (ii) a hybrid (s/g)Patlak (hPatlak) imaging technique is introduced to enhance contrast to noise ratios (CNRs) of uptake rate Ki images. Representative set of kinetic parameter values and the XCAT phantom were employed to generate realistic 4D simulation PET data, and the proposed methods were additionally evaluated on 11 WB dynamic PET patient studies. Quantitative analysis on the simulated Ki images over 2 groups of regions-of-interest (ROIs), with low (ROI A) or high (ROI B) true kloss relative to Ki, suggested superior accuracy for gPatlak. Bias of sPatlak was found to be 16-18% and 20-40% poorer than gPatlak for ROIs A and B, respectively. By contrast, gPatlak exhibited, on average, 10% higher noise than sPatlak. Meanwhile, the bias and noise levels for hPatlak always ranged between the other two methods. In general, hPatlak was seen to outperform all methods in terms of target-to-background ratio (TBR) and CNR for all ROIs. Validation on patient datasets demonstrated clinical feasibility for all Patlak methods, while TBR and CNR evaluations confirmed our simulation findings, and suggested presence of non-negligible kloss reversibility in clinical data. As such, we recommend gPatlak for highly quantitative imaging tasks, while, for tasks emphasizing lesion detectability (e.g. TBR, CNR) over quantification, or for high levels of noise, hPatlak is instead preferred. Finally, gPatlak and hPatlak CNR was systematically higher compared to routine SUV values.
    Full-text · Article · Oct 2015 · Physics in Medicine and Biology
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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.
    Full-text · Article · Dec 2014 · Brain Imaging and Behavior
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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.
    Full-text · Article · Oct 2013 · EJNMMI Research
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