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

Abstract

Conventional methods for the graphical analysis of 6-[ 18 F]fluorodopa (FDOPA)/positron emission tomography (PET) recordings (K in app ) may be prone to negative bias because of oversubtraction of the precursor pool in the region of interest, and because of diffusion of decarboxylated FDOPA metabolites from the brain. These effects may reduce the sensitivity of FDOPA/PET for the detection of age-related changes in dopamine innervations. To test for these biasing effects, we have used a constrained compartmental analysis to calculate the brain concentrations of the plasma metabolite 3-O-methyl-FDOPA (OMFD) during 120 mins of FDOPA circulation in healthy young, healthy elderly, and Parkinson's disease subjects. Calculated brain OMFD concentrations were subtracted frame-byframe from the dynamic PET recordings, and maps of the FDOPA net influx to brain were calculated assuming irreversible trapping (K app ). Comparison of K in app and K app maps revealed a global negative bias in the conventional estimates of FDOPA clearance. The present OMFD subtraction method revealed curvature in plots of K app at early times, making possible the calculation of the corrected net influx (K) and also the rate constant for diffusion of decarboxylated metabolites from the brain (k loss ). The effective distribution volume (EDV 2 ; K/k loss ) for FDOPA, an index of dopamine storage capacity in brain, was reduced by 85% in putamen of patients with Parkinson's disease, and by 58% in the healthy elderly relative to the healthy young control subjects. Results of the present study support claims that storage capacity for dopamine in both caudate and putamen is more profoundly impaired in patients with Parkinson's disease than is the capacity for DOPA utilization, calculated by conventional FDOPA net influx plots. The present results furthermore constitute the first demonstration of an abnormality in the cerebral utilization of FDOPA in caudate and putamen as a function of normal aging, which we attribute to loss of vesicular storage capacity.

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

“…However, a practical limitation of the EDV 1 method is imposed by the requirement of 4-h long emission recordings for this analysis. We have shown earlier that the present procedure for the mathematical subtraction of the calculated brain OMFD allows the stable estimation EDV 2 (the magnitude of the ratio K/k loss ) in VOIs using dynamic emission recordings of only 2-h duration (Kumakura et al, 2005). We have argued furthermore that the calculation of EDV 1 may be biased because of oversubtraction of the precursor pool in the brain.…”

“…We have argued furthermore that the calculation of EDV 1 may be biased because of oversubtraction of the precursor pool in the brain. The present OMFD subtraction procedure unmasks the curvature in influx plots already present during the interval 60 to 120 mins after FDOPA injection (Kumakura et al, 2005), which is obscured in conventional K in app plots by the incorrect subtraction of the total mass of FDOPA and OMFD measured in the reference tissue; in effect, the assumptions underlying the method of Sossi and Holden become progressively less violated because of the eventual depletion of FDOPA throughout the brain during 4 h of tracer circulation.…”

Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

“…18 F]fluorodopamine results in underestimation of the true rate of FDOPA consumption in brain (Huang et al, 1991;Kuwabara et al, 1993;Cumming and Gjedde, 1998;Cumming et al, 2001;Kumakura et al, 2005). No compartmental PET model can accommodate the entire complexity of the catecholamine pathway; of necessity, the […”

Influence of O-Methylated Metabolite Penetrating the Blood–Brain Barrier to Estimation of Dopamine Synthesis Capacity in Human L-[β-11C]DOPA PET

“…16 to TACs acquired from 10 healthy volunteers. The difference of net dopamine synthesis rate (K i ) estimated by Gjedde-Patlak graph plot analysis [21][22][23][24] between without and with metabolite correction was examined.…”

“…C]OMD in the total radioactivity in each brain region was calculated mathematically by the compartment model analysis proposed by Kumakura et al 16 With the assumption of the uniform distribution of OMD around the brain, 12,34 the reference region in which decarboxylation and further metabolism of L-[b-…”