期刊
ANNALS OF NEUROLOGY
卷 73, 期 3, 页码 390-396出版社
WILEY-BLACKWELL
DOI: 10.1002/ana.23798
关键词
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资金
- NIH NINDS [NS069746, NS058714, NS41509, NS075321]
- Michael J. Fox Foundation
- Murphy Fund
- American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University
- Greater St Louis Chapter of the APDA
- McDonnell Center for Higher Brain Function
- Hartke Fund
- Barnes-Jewish Hospital Foundation
- Howard Hughes Medical Institute
Objective Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Methods Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (00.31mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylasestained nigral cells. Results Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss <50% (r2 = 0.84, r2 = 0.86, r2 = 0.87, p < 0.001 respectively; n = 10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2 = 0.95, r2 = 0.94, r2 = 0.94, p < 0.001; n = 16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2 = 0.98, p < 0.001). Interpretation Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury. ANN NEUROL 2013;73:390396
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