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

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, [beta-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 [beta-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 [beta-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.

• Authors: Yuji Nagai, Shigeru Obayashi, Kiyoshi Ando, Motoki Inaji, Jun Maeda, Takashi Okauchi, Hiroshi Ito, Tetsuya Suhara
• Journal: Synapse (New York, N.Y.) (Synapse) Vol. 61 Issue 10 Pg. 809-19 (Oct 2007) ISSN: 0887-4476 [Print] United States
• PMID: 17598150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2007 Wiley-Liss, Inc.

Chemical References

• Dopamine Agents
• N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane
• Nortropanes
• Radioisotopes
• Raclopride
• Dihydroxyphenylalanine
• Dopamine

Topics

• Analysis of Variance
• Animals
• Behavior, Animal (drug effects, physiology)
• Brain (diagnostic imaging, drug effects, pathology)
• Dihydroxyphenylalanine (pharmacokinetics)
• Disease Models, Animal
• Dopamine (metabolism)
• Dopamine Agents (pharmacokinetics)
• MPTP Poisoning (diagnostic imaging, pathology, physiopathology)
• Macaca fascicularis
• Male
• Neurons (drug effects, pathology)
• Nortropanes (pharmacokinetics)
• Positron-Emission Tomography
• Raclopride (pharmacokinetics)
• Radioisotopes (pharmacokinetics)
• Wakefulness (drug effects, physiology)