Synopsis

Keywords: Parkinson's Disease, Neurodegeneration, neuromelanin

The bilateral neuromelanin degeneration pattern in substantia nigra in normal aging and underlying mechanisms of asymmetric motor symptoms in early Parkinson’s disease (PD) are still unknown. Here we examined the neuromelanin hemispheric asymmetry in normal elderly people and early PD patients with motor symptoms laterality by short-echo-time magnitude images derived from QSM. We demonstrated hemispheric asymmetry of neuromelanin in normal aging, as well as a left-hemispheric preferential nigral dysfunction in early-stage PDR, but a different spatial neuromelanin loss pattern in PDL. This template-based neuromelanin measurement might help to detect aging-related change and deepen our understanding of PD with motor laterality.

Introduction

Parkinson’s disease (PD) is a progressive neurodegeneration disorder, and its cardinal motor symptoms are bradykinesia, rigidity, resting tremor, and postural instability¹, which often present unilaterally^2-5. The asymmetric feature of motor symptoms implied the possibility of lateralized dysfunction of the nigrostriatal circuit.
However, laterality of dopaminergic neurons in the substantia nigra (SN) has yet been fully investigated. Several MRI markers are able to detect underlying neuroanatomic, functional and pathophysiologic alterations in SN⁶. Neuromelanin (NM)-sensitive MRI⁷ could visualize the hyperintensity areas containing neuromelanin, a by-product of dopamine and noradrenaline metabolism. One study reported the concordance between motor asymmetry and NM changes of SNc was 61.36%⁴. Another study revealed lower nigral pigmentation in the clinically-defined most affected side, and relationships between nigral pigmentation and striatal dopamine transporter binding were only observed in the severity side⁸. Notably, PD with right-side dominance (PDR) was associated with a faster disease progression⁵ and more medication-related motor fluctuations9, while PDL was associated with longer disease duration9 and more impairment of non-motor symptoms^10-12. It is necessary to explore similarities and differences of nigral dysfunction in PDR and PDL, as well as bilateral degeneration pattern in normal aging.
In this study, we aimed to investigate the neuromelanin hemispheric asymmetry in normal elderly people and early-PD patients with motor symptoms laterality by short-echo-time magnitude (setMag) images derived from QSM¹³. Primarily, we focused on both hemisphere effect and group effect, then compared the neuromelanin loss ratio between the most and the least affected side in PDR and PDL.

Methods

Ethical approval was obtained from our hospital (No. KY2018-226). Informed consent was obtained from each participant. 52 patients with PD and 34 healthy controls (HC) were recruited in this study. In PD group, H&Y scale¹⁴ was evaluated and only early-stage patients with HY stage 1 and 2 were included. The severity of motor dysfunction was assessed based on the MDS-UPDRS Part III¹⁵, and we calculated the sub-score of rigidity, bradykinesia and tremor¹⁶. Only patients with definite motor asymmetry (at least 2 points difference) were included.
MR examinations were performed on a 3.0-T MR scanner (Signa HDxt; GE Healthcare, Milwaukee, WI). QSM images were acquired with a 3D multi-echo GRE sequence (TR/TE = 41.6/3.2:2.4:38.5 ms; flip angle = 12°; FOV = 256 × 256 mm; matrix = 256 × 256; thickness = 1 mm). NM-sensitive setMag images were reconstructed from QSM data following the procedure published previously¹³.
We firstly constructed a setMag template based on the symmetric group-wise normalization (SyGN) method using advanced normalization tools (ANTs)^17,18. Bilateral hyperintensity of SNc areas were manually outlined on the setMag template using ITK-SNAP¹⁹, and then segmented into three ROIs: posterolateral sensorimotor, anteromedial associative, and posteromedial limbic regions^16,20,21. Bilateral cerebral peduncle (CP) masks were also defined as a reference region. Subsequently, these masks were applied to each participant’s setMag image (Figure 1). The neuromelanin contrast ratio (CR) was calculated as follows⁷: $$CR = (SN_CROI/CP_ROI)-1$$
where SN_CROI and CP_ROI indicate signal intensity in SNc and CP, respectively. Neuromelanin loss ratio (LR) was calculated as follows: $$LR = (1-CR_PD/CR_HC)*100%$$
where CR_PD and CR_HC indicate contrast ratio in PD and the mean contrast ratio in HC on the bilateral territories of SNc, respectively.
Comparisons of demographic information and clinical characteristics were conducted using one-way ANOVA, independent t-test, and Chi-square test among groups. To assess hemispheric asymmetry differences of CR, a mixed ANOVA was conducted with group as between-subjects factors, hemisphere as within-subject factors, and age, gender as covariates. Paired-t test was conducted to compare LR differences between the most and least affected side.

Results

The clinical and demographic data are shown in Table 1. All groups were matched for age, sex and the clinical indexes.
Mixed ANOVA showed a hemispheric asymmetry of CR in HC and PDR groups (Figure 2), while not in PDL group, where only a tendency of lower CR in the left sensorimotor territory was found (p = 0.055). Mixed ANOVA showed a significant group difference of CR in right and left hemispheres among three groups (Figure 3). In comparison to HCs, PDR patients showed significant reduced CR in the sensorimotor, associative and limbic subregions of SNc on both hemispheres. For PDL patients, CR were significantly reduced in the sensorimotor, associative and limbic subregions of right SNc, and only sensorimotor subregion of left SNc. For the comparison between PDR and PDL groups, CR was reduced in PDR patients in the left limbic subregion, while no differences were found in the right SNc.
In PDR patients, the LR were significantly higher in the most affected side compared to the least affected side in the sensorimotor and associative subregions of SNc, and had a lower tendency in the limbic subregion (Table 2). However, in PDL patients, the most affected side showed more NM loss in the associative and limbic subregions of SNc.

Conclusion

In conclusion, the current study demonstrates hemispheric asymmetry of neuromelanin in normal aging, as well as a left-hemispheric preferential nigral dysfunction in PDR, but a different spatial neuromelanin loss pattern in PDL. This template-based neuromelanin measurement might help to detect aging-related change and deepen our understanding of PD with motor laterality.

References

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