Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.
This report describes a method to assess, in vivo, the turnover of dopamine (DA) and describes its application to the evaluation of DA function in normal monkeys and monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions of the DA nigro-striatal pathway. Using positron emission tomography with the tracer of presynaptic DA function, 6-[18F]fluoro-L-DOPA (FDOPA), and an extension of the graphical method of analysis, we measured the striatal FDOPA uptake rate constant, Ki, and the rate of reversibility of FDOPA trapping k(loss) in normal and MPTP-treated monkeys, either neurologically normal or displaying a parkinsonian symptomatology. An index of effective DA turnover was defined as the ratio of k(loss)/Ki. Compared to normal controls, Ki was decreased and k(loss) was increased in the MPTP-lesioned monkeys. The index of DA turnover was significantly increased in the monkeys displaying a parkinsonian symptomatology as compared to the controls and the neurologically normal MPTP-treated monkeys. The DA turnover index was also significantly increased in the neurologically normal MPTP-lesioned animals compared to normals. This suggests that an increase in DA turnover develops early in the disease process and may be one of the compensatory mechanisms partly responsible for the delay in the development of the clinical manifestations in Parkinson's disease.
The effectiveness of 6-[18F]fluoro-L-m-tyrosine (6FMT) to evaluate dopamine presynaptic integrity was compared to that of 6-[18F]fluoro-L-dopa (6FDOPA) in vivo by positron emission tomography (PET). Six normal and six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys received 6FDOPA and 6FMT PET scans on separate occasions with identical scanning protocols. Four measures, the rate of uptake of tracer into striatum using either the arterial input function (Ki) or the activity in the occipital cortex as the input function (Kc), the rate of loss of striatal radioactivity (k(loss)), and an index of "effective turnover" of dopamine (k(loss)/Ki), were obtained for both tracers during extended PET studies. 6-[18F]Fluoro-L-m-tyrosine was as effective as 6FDOPA in separating normals from MPTP-lesioned subjects on the basis of the uptake rate constants Ki and Kc. However, in contrast to 6FDOPA, it was not possible to differentiate the normal from the lesioned animal using k(loss) or k(loss)/Ki for 6FMT. Thus, FMT appears to be a reasonable, highly specific tracer for studying the activity of aromatic dopa decarboxylase enzyme as an index of presynaptic integrity. However, if one is interested in investigating further the metabolic pathway and obtaining an in vivo estimate of the effective turnover of dopamine (after pharmacologic manipulation, for example), 6FDOPA remains the tracer of choice.
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