Novel observations with FDOPA‐PET imaging after early nigrostriatal damage

Abstract

Striatal 6-[18F]fluoro-L-DOPA (FDOPA) kinetic rate constants were measured by positron emission tomography (PET) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated squirrel monkeys. After scanning, stereological counts of dopaminergic neurons were done in substantia nigra, and dopamine (DA) and metabolite concentrations were determined in the caudate, putamen, and substantia nigra. Graded doses of MPTP produced animals with mild to moderate reductions (10-35%) in dopaminergic neurons, where the percent of cell loss was proportional to the amount of MPTP given. Striatal DA and metabolite concentrations were relatively unchanged in animals given 1.0 and 1.5 mg/kg of MPTP, but were significantly reduced after 2.0 mg/kg of MPTP. All animals injected with a single dose of MPTP showed no overt signs of parkinsonism. In contrast, DA and metabolite concentrations in the substantia nigra were significantly reduced for all MPTP-treated animals. Reduction of dopaminergic indices in the substantia nigra did not parallel reductions in the striatum, indicating differential sensitivity of the nigrostriatal pathway to the neurotoxic effects of MPTP. The percent change in FDOPA uptake (Ki) and decarboyxlation (k3) after MPTP showed significant positive correlations to striatal DA levels, but not to the number of dopaminergic neurons. This suggests that FDOPA is a good index of striatal DA levels.

Imaging end points for monitoring neuroprotection in Parkinson's disease

“…18 Yee and colleagues also found a correlation between striatal Ki values and striatal and nigral dopamine levels and dopa decarboxylase activity, although in vivo estimations of the latter were 10-fold lower than in vitro measurements probably reflecting an influence of transport restrictions. 19,20 There was poor correlation with nigral cell counts, but this may have been because their animals were only mildly lesioned compared with the study by Pate. 18 There was only a 10 to 35% nigral cell loss and no overt parkinsonism was evident.…”

PET Studies of Cerebral Levodopa Metabolism: A Review of Clinical Findings and Modeling Approaches

“…In severely MPTP-poisoned baboons, there remained only 67,000 dopamine neurons, which imparted an FDOPA k 3 S of only 0.001 min -1 (Poyot and others 2001). In monkeys with less severe MPTPpoisoning, reduced FDOPA utilization correlated better with striatal dopamine concentration measured postmortem (Yee and others 2001), and with striatal activity of AAADC in vitro (Yee and others 2000), than with numerical loss of dopamine neurons. Relative preservation of FDOPA k 3 S as a function of the severity of idiopathic Parkinson's disease suggests the occurrence of compensatory up-regulation of AAADC in residual dopamine terminals (Lee and others 2000).…”

Serotonin 1A receptors in the living brain of Alzheimer's disease patients

“…Clearly, more work with subjects with mild AD and MCI, and subjects at risk (apolipoprotein E 4 carriers), is needed to fully understand the relationship between decreases in 5-HT 1A receptors, particularly in hippocampus, pathology deposition, neuronal degeneration, and the clinical variables of disease progression. By analogy with other neurodegenerative diseases (e.g., Parkinson's disease), plasticity mechanisms may be at play to tolerate significant and measurable functional neuronal damage to occur before significant clinical symptoms could develop (27). Perhaps not surprisingly, reduction of 5-HT 1A densities in the hippocampus seems to precede clinical symptoms and to offer a powerful avenue for understanding the mechanism of disease progression and a potentially sensitive tool for early diagnosis.…”