Magnetic Resonance Imaging Features of the Nigrostriatal System: Biomarkers of Parkinson's Disease Stages?

Abstract

Introduction: Magnetic resonance imaging (MRI) can be used to identify biomarkers in Parkinson's disease (PD); R2* values reflect iron content related to high levels of oxidative stress, whereas volume and/or shape changes reflect neuronal death. We sought to assess iron overload in the nigrostriatal system and characterize its relationship with focal and overall atrophy of the striatum in the pivotal stages of PD.

Methods: Twenty controls and 70 PD patients at different disease stages (untreated de novo patients, treated early-stage patients and advanced-stage patients with L-dopa-related motor complications) were included in the study. We determined the R2* values in the substantia nigra, putamen and caudate nucleus, together with striatal volume and shape analysis. We also measured R2* in an acute MPTP mouse model and in a longitudinal follow-up two years later in the early-stage PD patients.

Results: The R2* values in the substantia nigra, putamen and caudate nucleus were significantly higher in de novo PD patients than in controls. Early-stage patients displayed significantly higher R2* values in the substantia nigra (with changes in striatal shape), relative to de novo patients. Measurements after a two-year follow-up in early-stage patients and characterization of the acute MPTP mouse model confirmed that R2* changed rapidly with disease progression. Advanced-stage patients displayed significant atrophy of striatum, relative to earlier disease stages.

Conclusion: Each pivotal stage in PD appears to be characterized by putative nigrostriatal MRI biomarkers: iron overload at the de novo stage, striatal shape changes at early-stage disease and generalized striatal atrophy at advanced disease.

Fig 1. The study flowchart.

MRI = Magnetic resonance imaging. PD = Parkinson’s disease. SN = Substantia nigra. MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Delimitation of Region of interest (ROI) by a semi-automatic segmentation (A), extraction of ROI 3D mask to calculate the volume, achieve shape analysis (C), and registration on the T2* map sequence (D) and obtain mean R2* value of the ROI.

Fig 2

(A): R2* values in the nigrostriatal system at different stages of PD; Fig (B): Striatal volumes at different stages of PD; (C): Shape analysis of caudate nucleus and putamen at different stages of PD relative to controls. In blue no statistical difference p>0.05, from yellow to read decrease of p value from p<0.05 (p value of read surface< pvalue of yellow surface<0.05). Yellow and read surface correspond to surface contraction and thus atrophy; (D): Iron overload in the MPTP mouse model of PD. Mice were treated with MPTP (or not; n = 10 per group). Data are presented as the mean and SEM. Immunohistochemistry of tyrosine hydroxylase (TH) stained sections of the right substantia nigra (SN), illustrating the level of degeneration after MPTP intoxication. TH+ cell counts of both sides of the SN. *: Wilcoxon test: p<0.0001. Total iron levels in the SN, as measured by atomic absorption spectrometry. *: p = 0.035. R2* multiple-echo spin echo value (7 T MRI) in the SN (MRI performed in vivo prior to sacrifice and spectrometry measurements) (R2* = 1/T2*(ms-1) x 103) *: p = 0.001. Motor handicap scores (measured in a 10-minute actimetry test). Number of rearings *: p = 0.004. Maximum speed: *: p = 0.03.