Validation of nigrostriatal positron emission tomography measures: Critical limits
Article first published online: 19 FEB 2013
Copyright © 2013 American Neurological Association
Annals of Neurology
Volume 73, Issue 3, pages 390–396, March 2013
How to Cite
Karimi, M., Tian, L., Brown, C. A., Flores, H. P., Loftin, S. K., Videen, T. O., Moerlein, S. M. and Perlmutter, J. S. (2013), Validation of nigrostriatal positron emission tomography measures: Critical limits. Ann Neurol., 73: 390–396. doi: 10.1002/ana.23798
- Issue published online: 17 APR 2013
- Article first published online: 19 FEB 2013
- Accepted manuscript online: 9 NOV 2012 12:58PM EST
- Manuscript Accepted: 29 OCT 2012
- Manuscript Revised: 28 SEP 2012
- Manuscript Received: 9 MAY 2012
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.
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 (0–0.31mg/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 hydroxylase–stained nigral cells.
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).
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;73:390–396