Region-specific disturbed iron distribution in early idiopathic Parkinson's disease measured by quantitative susceptibility mapping

Abstract

In Parkinson's disease (PD), iron elevation in specific brain regions as well as selective loss of dopaminergic neurons is a major pathologic feature. A reliable quantitative measure of iron deposition is a potential biomarker for PD and may contribute to the investigation of iron-mediated PD. The primary purpose of this study is to assess iron variations in multiple deep grey matter nuclei in early PD with a novel MRI technique, quantitative susceptibility mapping (QSM). The inter-group differences of susceptibility and R2* value in deep grey matter nuclei, namely head of caudate nucleus (CN), putamen (PUT), global pallidus (GP), substantia nigra (SN), and red nucleus (RN), and the correlations between regional iron deposition and the clinical features were explored in forty-four early PD patients and 35 gender and age-matched healthy controls. Susceptibility values were found to be elevated within bilateral SN and RN contralateral to the most affected limb in early PD compared with healthy controls (HCs). The finding of increased susceptibility in bilateral SN is consistent with work on a subgroup of patients at the earliest clinical detectable state (Hoehn and Yahr [1967]: Neurology 17:427-442; Stage I). However, increased R2* values were only seen within SN contralateral to the most affected limb in the PD group when compared with controls. Furthermore, bilateral SN magnetic susceptibility positively correlated with disease duration and UPDRS-III scores in early PD. This finding supports the potential value of QSM as a non-invasive quantitative biomarker of early PD.

Keywords: deep grey matter nuclei; early Parkinson's disease; iron deposition; magnetic resonance imaging; quantitative susceptibility mapping.

Figure 1

The correlation between bilateral mean susceptibility values in controls and iron content in the normal adult brain as published by Hallgren and Sourander [1958]. Error bar of the graph showed two standard errors from the mean: x‐axis, mean ± SD iron concentration (mg/10 g fresh weight) was determined postmortem in each ROI [Hallgren and Sourander, 1958]; y‐axis, mean ± SD QSM (ppm) in all 35 normal controls. CN, the head of caudate nucleus; PUT, putamen; GP, globus pallidus; SN, substantia nigra; RN, red nucleus.

Figure 2

A typical susceptibility map from one single patient with early‐stage PD illustrates the regions of interest (A–B). (C–F) show the exact positions of SN. To minimize the possibility of including the subthalamic nucleus, the segmentation of the SN was started either at the level of the red nucleus showing the largest radius or one slice lower, depending on the slice in which the SN appeared most prominently, and a total of three to four slices (6–8 mm in height) were used. CN, the head of caudate nucleus; PUT, putamen; GP, globus pallidus; SN, substantia nigra; RN, red nucleus.

Figure 3

Comparison of susceptibility values between ipsilateral or contralateral subcortical nuclei in PD and pertinent mean values in bilateral sides of controls using covariance (ANCOVA) analysis, adjusted for age, and Bonferroni correction was used for comparison between multiple groups. Significant differences between PD and control subjects are represented as: ^* P < 0.005, ^** P < 0.001. CN, the head of caudate nucleus; PUT, putamen; GP, globus pallidus; SN, substantia nigra; RN, red nucleus.

Figure 4

Comparison of R2^* values between ipsilateral or contralateral subcortical nuclei in PD and pertinent mean values in bilateral sides of controls using covariance (ANCOVA) analysis, adjusted for age, and Bonferroni correction was used for comparison between multiple groups. Significant differences between PD and control subjects are represented as: ^* P<0.005. CN, the head of caudate nucleus; PUT, putamen; GP, globus pallidus; SN, substantia nigra; RN, red nucleus.

Figure 5

Scatter plots and regression lines show the significant relationship between susceptibility values in bilateral SN and clinical measures in early‐stage PD. Correlations are partialed for age. The susceptibility value of ipsilateral SN is positively correlated with disease duration (upper‐left: r = 0.391, P = 0.0094) and UPDRS‐III score (bottom‐left: r = 0.386, P = 0.0105) in PD. The susceptibility value in SN contralateral to the most affected side in PD patients is positively correlated with disease duration (upper‐right: r = 0.347, P = 0.0226) and UPDRS‐III score (bottom‐right: r = 0.368, P = 0.0152). SN, substantia nigra.

Figure 6

Comparison of SN anatomy in healthy controls and PD subjects on both magnitude maps and susceptibility maps. Example magnitude maps (left) and susceptibility maps (right) of a healthy control (A–D, 69 years old) and a patient with early‐stage Parkinson's disease (E and F, 65 years old). Nigrosome 1 is observable in the control subject (A–D, arrow head), which is not observable in the patient with early‐stage PD. The nigrosome 1 is hyperintense on magnitude maps and hypointense on susceptibility maps due to its low iron content.