Elsevier

Parkinsonism & Related Disorders

Volume 55, October 2018, Pages 117-121
Parkinsonism & Related Disorders

Association of metals with the risk and clinical characteristics of Parkinson's disease

https://doi.org/10.1016/j.parkreldis.2018.05.022Get rights and content

Highlights

  • Clinical evidence on the implication of metal in Parkinson's disease (PD) is rare.

  • Higher copper level in serum is associated with a decreased PD risk.

  • Higher copper or lower iron is associated with levodopa-induced dyskinesia in women.

  • Serum copper level is negatively correlated with MMSE scores in PD patients.

  • There are associations between serum metals and PD risk or clinical presentation.

Abstract

Introduction

While metals have been implicated in the pathophysiology of Parkinson's disease (PD), the clinical evidence is scarce. Further, the contribution of metals for the risk or clinical presentation of PD remains to be explored.

Methods

To investigate the associations between the level of metals in blood serum and PD risk or clinical presentation, including sex-related differences, we studied 325 PD patients and age- and sex-matched 304 controls. We collected clinical data of the PD patients, including age at onset, PD duration, levodopa-equivalent dose (LED), Hoehn and Yahr stage (H-Y stage), presence of motor fluctuation, levodopa-induced dyskinesia (LID), freezing of gait, hallucination, and Mini-Mental State Examination (MMSE) score. Iron, copper, and zinc levels in serum were assayed by inductively coupled plasma mass spectrometry. Statistical analyses were performed to determine the sex-related differences in metal levels.

Results

Among the three metal elements tested, serum copper levels showed significant correlations with PD risk or clinical presentation. Higher copper levels were associated with a decreased PD risk. Higher copper or lower iron levels were associated with the risk of LID in women. Serum copper levels were negatively correlated with MMSE scores in PD patients.

Conclusions

This clinical study suggests significant associations between serum metal levels and PD risk or essential clinical features, demonstrating the possible roles of metals in PD pathogenesis or symptom development.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disease and has increased in prevalence in developed countries. The main pathological features of PD are progressive dopaminergic neuronal loss in the pars compacta of the substantia nigra (SNpc) and deposition of intracellular Lewy bodies.

Metals have been implicated in PD pathophysiology. Iron is the most extensively studied metal in the PD brain, and its elevation in SN of PD patients has been consistently reported [1]. The ferroxidase activity of ceruloplasmin that facilitates iron export from cells, was reduced in SN of PD brain, a probable mechanism for iron accumulation in the same region [2]. Iron accumulation in SNpc causes oxidative stress-induced damage to dopaminergic neurons, in turn leading to Parkinsonism [3]. Copper acts as a cofactor in many key enzymes, including cytochrome c oxidase, copper/zinc superoxide dismutase, dopamine β-hydroxylase, and ceruloplasmin, which are crucial for neurological development and function [4]. Reduced copper in SNpc accompanies elevated nigral iron [2]. Such alterations of iron and copper levels could promote toxic redox cycling by catalyzing the formation of reactive oxygen species [5]. In addition, both metals interact with the pathogenic α-synuclein (αSyn) protein to inhibit formation of αSyn filaments with concomitant accumulation of toxic αSyn oligomers [6]. Zinc is present within synaptic vesicles and has a prime role in synaptic transmission by serving as an endogenous neuromodulator. Zinc, as a constituent of copper/zinc superoxide dismutase, helps to protect cells from superoxide radical damage [7]. Recent studies have showed that PARK9/ATP13A2, one of the causative genes for familial PD, regulates cellular level of zinc and promotes αSyn externalization via exosomes, and its deficiency causes zinc dyshomeostasis and mitochondrial dysfunction [8,9].

Previous studies have demonstrated changes in levels of metals in blood, urine, and the cerebrospinal fluid (CSF) in PD patients, but the results have been inconsistent among the studies [[10], [11], [12]]. Moreover, the contribution of metals for specific clinical or symptomatic characteristics of PD patients remains to be elucidated. Thus, this population study investigated the associations of serum metals (iron, copper, and zinc) with PD risk and specific clinical characteristics of PD patients, including sex-related differences.

Section snippets

Study subjects

The institutional review board of Asan Medical Center (Seoul, Korea) approved this study, and all subjects provided informed consent in accordance with the institutional review board regulations. The study subjects consisted of 325 patients with PD (175 men and 150 women) and 304 controls (141 men and 163 women), who were recruited through the movement disorders clinic at Asan Medical Center and differentiated on the basis of the clinical diagnosis criteria of the United Kingdom Parkinson's

Results

The demographic and clinical characteristics of PD patients and controls are summarized in Table 1. There were no significant differences in age and sex between the PD patients and controls. MMSE scores were significantly lower in the PD patients than in the controls.

Discussion

In this study, we found that serum metal levels were associated with PD risk and specific clinical features of PD. The associations of metals with some clinical features of PD were dependent on the sex of the PD patients. In particular, the most interesting finding is that the level of copper was strongly correlated with PD risk or specific clinical features among the metal elements analyzed. Higher serum copper levels were associated with decreased PD risk. In women with PD, higher serum

Conclusion

This study firstly found significant associations between serum metals and PD risk or essential clinical features of PD. Above all, copper levels in serum were strongly associated with the risk or incidence of PD-related clinical features or dementia, allowing evaluation of the influence of the metal on PD pathogenesis.

Authors' contributions

MJK, AIB, J-YL, and SJC conceived, designed and organized the study. MJK, S-BO, JK, KK, H-SR, MSK, SA, J-YL, and SJC performed the experiments and the data analysis. MJK, SA, AIB, J-YL, and SJC wrote the manuscript. All authors reviewed and approved the final draft of the manuscript.

Disclosures

All authors have no conflict of interest to declare, but Dr. Bush AI is a shareholder in Prana Biotechnology Ltd, Cogstate Ltd, Mesoblast Ltd, NextVet Ltd, Brighton Biotech LLC and Cogstate Ltd, and a consultant for Collaborative Medicinal Development Pty Ltd.

Acknowledgement and funding

This study was supported by a grant of the Korea Healthcare Technology R & D Project, Ministry of Health & Welfare, Republic of Korea (HI17C0328) and a grant (2013-0416) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

References (30)

  • K. Markopoulou et al.

    Does alpha-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease?

    Park. Relat. Disord.

    (2014)
  • S. Ayton et al.

    Nigral iron elevation is an invariable feature of Parkinson's disease and is a sufficient cause of neurodegeneration

    BioMed Res. Int.

    (2014)
  • S. Ayton et al.

    Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease

    Ann. Neurol.

    (2013)
  • K.M. Davies et al.

    Copper dyshomoeostasis in Parkinson's disease: implications for pathogenesis and indications for novel therapeutics

    Clin. Sci. (Lond)

    (2016)
  • K. Jomova et al.

    Metals, oxidative stress and neurodegenerative disorders

    Mol. Cell. Biochem.

    (2010)
  • Cited by (33)

    • Naked-eye chemosensor with high absolute fluorescence quantum yield for selective detection of Cu(II) and cell imaging

      2022, Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy
      Citation Excerpt :

      Maintaining a healthy balance of copper ions, which are the key structural components of many proteins, is important for various physiological and pathological processes [1]. Many serious neurodegenerative, genetic, and metabolic diseases, such as liver and kidney damage [2], neurotoxicity [3], Parkinson’s disease [4], Alzheimer’s disease [5], Wilson’s disease [6], Menkes disease [7], obesity, and diabetes [8], have been associated with the misregulation of copper in the body. Furthermore, excess copper waste produced by the mining and smelting industries is a significant cause of environmental pollution [9].

    • Shared perturbations in the metallome and metabolome of Alzheimer's, Parkinson's, Huntington's, and dementia with Lewy bodies: A systematic review

      2020, Ageing Research Reviews
      Citation Excerpt :

      CSF copper was largely reported to be unchanged (Ahmed and Santosh, 2010; Alimonti et al., 2007; Bocca et al., 2006; Karpenko et al., 2018) although there were two reports of increases (Boll et al., 2008; Pall et al., 1987) and one of decreases (Sanyal et al., 2016). Investigations of copper in the blood were conflicting, with four reports of increases (Bocca et al., 2006; Fukushima et al., 2013; Hegde et al., 2004; Kumudini et al., 2014), six of decreases (Bharucha et al., 2008; Bocca et al., 2006; Kim et al., 2018; Sanyal et al., 2016; Younes-Mhenni et al., 2013; Zhao et al., 2013) and one finding of no change (Ling and Bhidayasiri, 2011). As such, biofluid findings aren’t conclusive enough to suggest viability of blood copper as a biomarker in PD.

    View all citing articles on Scopus
    View full text