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Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques

Authors

  • Christopher A. Brown BS, BA,

    1. Department of Neurology, Washington University of Medicine, St Louis, MO
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  • Morvarid K. Karimi MD,

    1. Department of Neurology, Washington University of Medicine, St Louis, MO
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  • LinLin Tian MD, PhD,

    1. Department of Neurology, Washington University of Medicine, St Louis, MO
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  • Hugh Flores MD, MS,

    1. Department of Neurology, Washington University of Medicine, St Louis, MO
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  • Yi Su PhD,

    1. Department of Radiology, Washington University of Medicine, St Louis, MO
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  • Samer D. Tabbal MD,

    1. Department of Neurology, American University of Beirut, Beirut, Lebanon
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  • Susan K. Loftin BA,

    1. Department of Neurology, Washington University of Medicine, St Louis, MO
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  • Stephen M. Moerlein PhD,

    1. Department of Radiology, Washington University of Medicine, St Louis, MO
    2. Department of Biochemistry and Molecular Biophysics, Washington University of Medicine, St Louis, MO
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  • Joel S. Perlmutter MD

    Corresponding author
    1. Department of Neurology, Washington University of Medicine, St Louis, MO
    2. Department of Radiology, Washington University of Medicine, St Louis, MO
    3. Department of Neurobiology, Washington University of Medicine, St Louis, MO
    4. Department of Occupational Therapy, Washington University of Medicine, St Louis, MO
    5. Department of Physical Therapy, Washington University of Medicine, St Louis, MO
    • Address correspondence to Dr Perlmutter, Washington University School of Medicine, 660 South Euclid, Campus Box 8111, St Louis, MO 63110. E-mail: joel@npg.wustl.edu

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Abstract

Objective

Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates.

Methods

Presynaptic PET tracers 6-[18F]-fluorodopa (FD), [11C]-2β-methoxy-3β-4-fluorophenyltropane (CFT), and [11C]-dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration.

Results

We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R2 = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = −0.77, −0.71, respectively, p < 0.001), but FD uptake did not.

Interpretation

Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function. Ann Neurol 2013;74:602–610

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