Brain structural changes in cynomolgus monkeys administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A longitudinal voxel-based morphometry and diffusion tensor imaging study.

Hyeonseok S Jeong,Jooyeon J Im,Eun Namgung,Yong-An Chung,Sejung Yang,Jiyoung Ma,Jieun E Kim,Soo Mee Lim,In Kyoon Lyoo,Sang-Rae Lee,Sujung Yoon,Ilhyang Kang,Saerom Jeon,Kyu-Tae Chang,Bom Sahn Kim,Bobby Thomas

doi:10.1371/journal.pone.0189804

Abstract

In animal models of Parkinson's disease (PD), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most widely used agents that damages the nigrostriatal dopaminergic pathway. However, brain structural changes in response to MPTP remain unclear. This study aimed to investigate in vivo longitudinal changes in gray matter (GM) volume and white matter (WM) microstructure in primate models administered with MPTP. In six cynomolgus monkeys, high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) scans were acquired 7 times over 32 weeks, and assessments of motor symptoms were conducted over 15 months, before and after the MPTP injection. Changes in GM volume and WM microstructure were estimated on a voxel-by-voxel basis. Mixed-effects regression models were used to examine the trajectories of these structural changes. GM volume initially increased after the MPTP injection and gradually decreased in the striatum, midbrain, and other dopaminergic areas. The cerebellar volume temporarily decreased and returned to its baseline level. The rate of midbrain volume increase was positively correlated with the increase rate of motor symptom severity (Spearman rho = 0.93, p = 0.008). Mean, axial, and radial diffusivity in the striatum and frontal areas demonstrated initial increases and subsequent decreases. The current multi-modal imaging study of MPTP-administered monkeys revealed widespread and dynamic structural changes not only in the nigrostriatal pathway but also in other cortical, subcortical, and cerebellar areas. Our findings may suggest the need to further investigate the roles of inflammatory reactions and glial activation as potential underlying mechanisms of these structural changes.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is primarily characterized by progressive loss of dopaminergic neurons in the substantia nigra (SN), decreased levels of striatal dopamine, and consequent development of motor symptoms [1].The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been most widely used as a potent agent to investigate the pathophysiology of PD in animal models
Considering partial recovery of clinical symptoms in later stages of MPTP-induced PD [15], we examined whether the increases in mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values of the nigrostriatal white matter (WM) tracts are alleviated in the long term
In this longitudinal in vivo multi-modal neuroimaging study of cynomolgus monkeys, we investigated MPTP-induced changes in brain structures and their associations with motor symptoms

Summary

Introduction

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been most widely used as a potent agent to investigate the pathophysiology of PD in animal models. In vivo brain structural changes in response to MPTP remain unclear in spite of a growing number of functional and molecular imaging studies. Voxel-based morphometry (VBM) analysis of structural magnetic resonance imaging (MRI) data allows reliable quantification of regional gray matter (GM) volumes in an unbiased way [2]. Diffusion tensor imaging (DTI) is a promising imaging modality for mapping three-dimensional diffusion of water in biologic tissues and characterizing microstructural changes in white matter (WM).

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