Human striatal L-dopa decarboxylase activity estimated in vivo using 6-[18F]fluoro-dopa and positron emission tomography: error analysis and application to normal subjects.
DOPA decarboxylase is the enzyme directly responsible for the synthesis of the neurotransmitters dopamine and serotonin, and indirectly of noradrenaline, in brain. We used the decarboxylation coefficient (k3D) of 6-[18F]fluoro-DOPA (FDOPA) to denote the relative activity of L-DOPA decarboxylase in vivo in the human brain. To determine the relative enzyme activity with positron emission tomography (PET), we evaluated the model that separates the metabolism into compartments of nondiffusible and diffusible (i.e., transient) tracer metabolites. Error analysis indicated that the least-squares optimization alone was not sufficient to yield accurate estimates of k3D in the presence of the inherent error of PET. To improve the accuracy of the k3D estimates by optimizing the number of parameters, we introduced biological constraints which included a tracer partition volume (Ve) common to frontal cortex and striatum, and a fixed ratio (q) between the blood-brain barrier transport coefficients of O-methyl-[18F]fluoro-DOPA and FDOPA, the two sources of radioactivity in plasma. We found that a two-step analysis yielded sufficiently accurate estimates of k3D. The two steps include the initial estimation of the partition volume in frontal cortex and the subsequent use of this value to determine k3D in striatum and other structures. We studied twelve healthy controls (age 45 +/- 15 years). The average k3D value was 0.081 +/- 0.024 min-1 (coefficient of variation (COV) 30%) for caudate nucleus, 0.074 +/- 0.013 min-1 (COV 18%) for putamen, and 0.010 +/- 0.005 min-1 (COV 50%) for cerebral cortex.
Kuwabara
H
H
Positron Imaging Laboratories, McConnell Brain Imaging Center, Montreal Neurological Institute, Quebec, Canada.
Cumming
P
P
Reith
J
J
Léger
G
G
Diksic
M
M
Evans
A C
AC
Gjedde
A
A
D000328:Adult; D000465:Algorithms; D001923:Brain Chemistry; D003342:Corpus Striatum / Q000201:enzymology*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004296:Dopa Decarboxylase / Q000378:metabolism* / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D012016:Reference Values; D014055:Tomography, Emission-Computed
D005462:Fluorine Radioisotopes; C054651:2-fluorodopa; D004295:Dihydroxyphenylalanine; D004296:Dopa Decarboxylase