Progressive changes of pre- and post-synaptic dopaminergic biomarkers in conscious MPTP-treated cynomolgus monkeys measured by positronemission tomography

Authors

  • Yuji Nagai,

    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
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  • Shigeru Obayashi,

    Corresponding author
    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
    • Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba 263-8555, Japan
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  • Kiyoshi Ando,

    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
    2. Nonhuman Primate Laboratory, Central Institute for Experimental Animals, Miyamae-ku, Kawasaki 216-0001, Japan
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  • Motoki Inaji,

    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
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  • Jun Maeda,

    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
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  • Takashi Okauchi,

    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
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  • Hiroshi Ito,

    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
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  • Tetsuya Suhara

    1. Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan
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Abstract

Positron emission tomography (PET) is a useful technique for the consecutive investigation of the relationship between changes in neurotransmission biomarkers and behavioral signs in animal models of Parkinson's disease (PD). In this study, we aimed to investigate the threshold of dopamine (DA) neuron damage for the appearance of tremor by observing the longitudinal changes of pre- and post-synaptic DA biomarkers in awake monkeys using PET with multiple tracers. Three cynomolgus monkeys were treated with MPTP every 3–6 weeks until tremor was observed. Brain uptake of [11C]PE2I, [β-11C]DOPA, and [11C]raclopride for DA transporter (DAT), DOPA utilization, and DA D2 receptor were measured using PET as a single set in awake condition. Sets of PET scans were repeated in parallel with continuous behavioral estimation. The pre-synaptic biomarkers of DA neuron in the striatum decreased [11C]PE2I binding and [β-11C]DOPA uptake in an MPTP dose-dependent manner. Tremor was not observed until striatal [11C]PE2I binding was reduced to about 15% of the pretreatment level and [β-11C]DOPA uptake was reduced to about 34%. DA D2 receptor measured by [11C]raclopride was not significantly changed throughout the experiment. Our results revealed that it is possible to quantitatively define the threshold of the onset of behavioral PD signs by monitoring spontaneous motor activity, and in vivo PET with DAT marker can be a biomarker for early diagnosis at the presymptomatic stage of PD and for high-risk groups. Synapse 61:809–819, 2007. © 2007 Wiley-Liss, Inc.

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