White matter alterations in Parkinson's disease with levodopa-induced dyskinesia

Takashi Ogawa,Taku Hatano,Koji Kamagata,Christina Andica,Haruka Takeshige-Amano,Wataru Uchida,Yuya Saito,Yasushi Shimo,Genko Oyama,Atsushi Umemura,Hirokazu Iwamuro,Masanobu Ito,Masaaki Hori,Shigeki Aoki,Nobutaka Hattori

doi:10.1016/j.parkreldis.2021.07.021

Abstract

IntroductionLevodopa-induced dyskinesia is a complication of levodopa therapy and negatively impacts the quality of life of patients. We aimed to elucidate white matter alterations in Parkinson's disease with levodopa-induced dyskinesia using advanced diffusion magnetic resonance imaging techniques. MethodsThe enrolled subjects included 26 clinically confirmed Parkinson's disease patients without levodopa-induced dyskinesia, 25 Parkinson's disease patients with levodopa-induced dyskinesia, and 23 healthy controls. Subjects were imaged using a 3-T magnetic resonance scanner. Diffusion tensor imaging, diffusion kurtosis imaging, and neurite orientation dispersion and density imaging findings were compared between groups with a group-wise whole brain approach and a region-of-interest analysis for each white matter tract. Additionally, logistic regression analysis was used to calculate odds ratios for levodopa-induced dyskinesia. ResultsGroup-wise tract-based spatial statistical analysis revealed significant white matter differences in isotropic diffusion, complexity, or heterogeneity, and neurite density between healthy controls and Parkinson's disease patients without levodopa-induced dyskinesia and between patients with and without levodopa-induced dyskinesia. Region-of-interest analysis revealed similar alterations using a group-wise whole-brain approach in the external capsule, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus. These tracts had an odds ratio of approximately 2.3 for the presence of levodopa-induced dyskinesia. ConclusionsOur findings suggest that Parkinson's disease with levodopa-induced dyskinesia produces less white matter microstructural disruption, especially in temporal lobe fibers, than Parkinson's disease without levodopa-induced dyskinesia. These fibers has a more than 2-fold odds ratio for the presence of levodopa-induced dyskinesia and might be associated with the pathogenesis of the sequela.

Highlights

Levodopa-induced dyskinesia is a complication of levodopa therapy and negatively impacts the quality of life of patients
tract-based spatial statistics (TBSS) analysis revealed that differences of all diffusion tensor imaging (DTI) and diffusional kurtosis imaging (DKI) parameters, as well as the Intracellular volume fraction (ICVF) on neurite orientation dispersion and density imaging (NODDI) were observed in the diffuse white matter areas in Parkinson’s disease (PD)-nLID patients compared with healthy controls (HCs) (Fig. 1A–1, Supplementary Table 1), whereas there were no differences in axial diffusivity (AD) on DTI, all parameters of DKI, and ICVF on NODDI between PD-Levodopa-induced dyskinesia (LID) patients and HCs
We found reduced effects in the external capsule (EC), inferior fronto-occipital fasciculus (IFOF), and uncinate fasciculus (UF) in PD with LID (PD-LID) patients and axonal loss or reduced neurite density in PD-nLID patients, which supports the importance of cortico-striatal pro jections in LID pathogenesis

Summary

Introduction

Levodopa-induced dyskinesia is a complication of levodopa therapy and negatively impacts the quality of life of patients. Region-of-interest analysis revealed similar alterations using a group-wise whole-brain approach in the external capsule, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus These tracts had an odds ratio of approximately 2.3 for the presence of levodopa-induced dyskinesia. Previous microstructural studies have reported striatal dendritic or dendritic spine alterations and electrophysiological changes related to the cortico-striatal-thalamic loop in LID models [4], and imaging studies have reported changes associated with LID in the frontal cortex and striatum[6,7,8] Given these changes, white matter structures serving as pathways connecting the cortex and basal ganglia may be involved in LID pathophysiology. NODDI enables estimation of the density and orientation of neurites (axons and dendrites) based on a multicompartmental (intracellular, extracellular, and cerebrospinal fluid) diffusion model The advantages of these methods for evaluating alterations in white matter microstructures in PD and related neurodegenerative disorders have been demonstrated by previous studies[14,15]

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