Alterations of the nigrostriatal pathway in a 6-OHDA rat model of Parkinson's disease evaluated with multimodal MRI

PLoS One. 2018 Sep 6;13(9):e0202597. doi: 10.1371/journal.pone.0202597. eCollection 2018.

Abstract

Parkinson's disease is characterized by neurodegeneration of the dopaminergic neurons in the substantia nigra pars compacta. The 6-hydroxydopamine (6-OHDA) rat model has been used to study neurodegeneration in the nigro-striatal dopaminergic system. The goal of this study was to evaluate the reliability of diffusion MRI and resting-state functional MRI biomarkers in monitoring neurodegeneration in the 6-OHDA rat model assessed by quantitative histology. We performed a unilateral injection of 6-OHDA in the striatum of Sprague Dawley rats to produce retrograde degeneration of the dopamine neurons in the substantia nigra pars compacta. We carried out a longitudinal study with a multi-modal approach combining structural and functional MRI together with quantitative histological validation to follow the effects of the lesion. Functional and structural connectivity were assessed in the brain of 6-OHDA rats and sham rats (NaCl injection) at 3 and 6 weeks post-lesioning using resting-state functional MRI and diffusion-weighted. Our results showed (i) increased functional connectivity in ipsi- and contra-lesioned regions of the cortico-basal ganglia network pathway including the motor cortex, the globus pallidus, and the striatum regions at 3 weeks; (ii) increased fractional anisotropy (FA) in the ipsi- and contralateral striatum of the 6-OHDA group at 3 weeks, and increased axial diffusivity (AD) and mean diffusivity in the ipsilateral striatum at 6 weeks; (iii) a trend for increased FA in both substantia nigra of the 6-OHDA group at 3 weeks. Optical density measurements of tyrosine-hydroxylase (TH) staining of the striatum showed good correlations with the FA and AD measurements in the striatum. No correlations were found between the number of TH-stained dopaminergic neurons and MRI measurements in the substantia nigra. This study suggested that (i) FA and AD were reliable biomarkers to evaluate neurodegeneration in the cortico-basal ganglia network of the 6-OHDA model, (ii) diffusion MRI and resting-state functional MRI (rsfMRI) were not sensitive enough to detect changes in the substantia nigra in this model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anisotropy
  • Case-Control Studies
  • Corpus Striatum / diagnostic imaging
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiopathology*
  • Disease Models, Animal
  • Magnetic Resonance Imaging / methods*
  • Male
  • Multimodal Imaging
  • Oxidopamine / adverse effects*
  • Parkinson Disease / diagnostic imaging*
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Sensitivity and Specificity
  • Substantia Nigra / diagnostic imaging
  • Substantia Nigra / metabolism
  • Substantia Nigra / physiopathology*
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Oxidopamine
  • Tyrosine 3-Monooxygenase

Grants and funding

The research leading to these results received funding from the France Parkinson Association, and from the programs “Institut des Neurosciences Translationnelles” ANR-10-IAIHU-06 and “Infrastructure d’Avenir en Biologie Santé” ANR-11-INBS-0006. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.