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Original Article

Validation of nigrostriatal positron emission tomography measures: Critical limits

  1. Morvarid Karimi MD1,
  2. LinLin Tian PhD1,
  3. Christopher A. Brown BA1,
  4. Hubert P. Flores MS1,
  5. Susan K. Loftin BA1,
  6. Tom O. Videen PhD1,2,
  7. Stephen M. Moerlein PhD2,3,
  8. Joel S. Perlmutter MD1,2,4,5,6,*

Article first published online: 19 FEB 2013

DOI: 10.1002/ana.23798

Issue

Annals of Neurology

Annals of Neurology

Volume 73, Issue 3, pages 390–396, March 2013

Additional Information

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

Author Information

  1. 1

    Departments of Neurology, Washington University, St Louis, MO

  2. 2

    Departments of Radiology, Washington University, St Louis, MO

  3. 3

    Departments of Biochemistry and Molecular Biophysics, Washington University, St Louis, MO

  4. 4

    Departments of Neurobiology, Washington University, St Louis, MO

  5. 5

    Departments of Occupational Therapy, Washington University, St Louis, MO

  6. 6

    Departments of Physical Therapy, Washington University, St Louis, MO

*Address correspondence to Dr Perlmutter, 660 S. Euclid, Campus Box 8111, St Louis, MO 63110-1093. E-mail: joel@npg.wustl.edu

Publication History

  1. Issue published online: 17 APR 2013
  2. Article first published online: 19 FEB 2013
  3. Accepted manuscript online: 9 NOV 2012 12:58PM EST
  4. Manuscript Accepted: 29 OCT 2012
  5. Manuscript Revised: 28 SEP 2012
  6. Manuscript Received: 9 MAY 2012

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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 (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.

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;73:390–396

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