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.
Highlights
Parkinson’s disease (PD) is a major neurodegenerative disease in the elderly affecting 10 million patients worldwide
Connectivity matrices at 3 weeks showed increased functional connectivity (FC) in the 6-OHDA group compared to the sham group (Fig 2)
At 3 weeks, significant increases of FC were found between ipsilateral globus pallidus (GP) and ipsilateral STR (p
Summary
Parkinson’s disease (PD) is a major neurodegenerative disease in the elderly affecting 10 million patients worldwide (according to the Parkinson’s Disease Foundation). PD is characterized by massive degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNc), leading to clinical symptoms such as tremor, bradykinesia, and rigidity (according to the Parkinson’s Disease Foundation). Non-invasive imaging biomarkers may be used for early diagnosis and monitoring of drug effect and for the development of more efficient treatments against the disease. To date, histological validation of these markers is still lacking. In this regard, animal models play a critical role for the evaluation of biomarkers that can monitor disease progression and the effects of new treatments
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