Volume 54, Issue 4 pp. 1098-1106

Original Research

Serum Ceruloplasmin Depletion is Associated With Magnetic Resonance Evidence of Widespread Accumulation of Brain Iron in Parkinson's Disease

Xiaojun Guan PhD,

Xiaojun Guan PhD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

These authors contributed equally to this paper.

Search for more papers by this author

Xueqin Bai MD,

Xueqin Bai MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

These authors contributed equally to this paper.

Search for more papers by this author

Cheng Zhou MD,

Cheng Zhou MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Tao Guo MD,

Tao Guo MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Jingjing Wu MD,

Jingjing Wu MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Luyan Gu MD,

Luyan Gu MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Ting Gao MD,

Ting Gao MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Xuchu Wang PhD,

Xuchu Wang PhD

Department of Laboratory Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Hongjiang Wei PhD,

Hongjiang Wei PhD

orcid.org/0000-0002-9060-4152

Institute for Medical Imaging Technology, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

Search for more papers by this author

Yuyao Zhang PhD,

Yuyao Zhang PhD

School of Information Science and Technology, ShanghaiTech University, Shanghai, China

Search for more papers by this author

Min Xuan PhD,

Min Xuan PhD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Quanquan Gu PhD,

Quanquan Gu PhD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Peiyu Huang PhD,

Peiyu Huang PhD

orcid.org/0000-0003-4226-9369

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Chunlei Liu Ph.D.,

Chunlei Liu Ph.D.

Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, USA

Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA

Search for more papers by this author

Baorong Zhang MD, PhD,

Baorong Zhang MD, PhD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Jiali Pu PhD,

Jiali Pu PhD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Zhe Song MD,

Zhe Song MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Yaping Yan MD,

Yaping Yan MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Xiaojun Xu MD,

Xiaojun Xu MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Minming Zhang MD, PhD,

Corresponding Author

Minming Zhang MD, PhD

[email protected]

orcid.org/0000-0003-0145-7558

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Address reprint requests to: M.Z., No.88 Jiefang Road, Shangcheng District, Hangzhou, China, 31009. E-mail: [email protected]

Search for more papers by this author

Xiaojun Guan PhD,

Xiaojun Guan PhD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

These authors contributed equally to this paper.

Search for more papers by this author

Xueqin Bai MD,

Xueqin Bai MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

These authors contributed equally to this paper.

Search for more papers by this author

Cheng Zhou MD,

Cheng Zhou MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Tao Guo MD,

Tao Guo MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Jingjing Wu MD,

Jingjing Wu MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Luyan Gu MD,

Luyan Gu MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Ting Gao MD,

Ting Gao MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Xuchu Wang PhD,

Xuchu Wang PhD

Department of Laboratory Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Hongjiang Wei PhD,

Hongjiang Wei PhD

orcid.org/0000-0002-9060-4152

Institute for Medical Imaging Technology, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

Search for more papers by this author

Yuyao Zhang PhD,

Yuyao Zhang PhD

School of Information Science and Technology, ShanghaiTech University, Shanghai, China

Search for more papers by this author

Min Xuan PhD,

Min Xuan PhD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Quanquan Gu PhD,

Quanquan Gu PhD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Peiyu Huang PhD,

Peiyu Huang PhD

orcid.org/0000-0003-4226-9369

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Chunlei Liu Ph.D.,

Chunlei Liu Ph.D.

Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California, USA

Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA

Search for more papers by this author

Baorong Zhang MD, PhD,

Baorong Zhang MD, PhD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Jiali Pu PhD,

Jiali Pu PhD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Zhe Song MD,

Zhe Song MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Yaping Yan MD,

Yaping Yan MD

Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Xiaojun Xu MD,

Xiaojun Xu MD

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Search for more papers by this author

Minming Zhang MD, PhD,

Corresponding Author

Minming Zhang MD, PhD

[email protected]

orcid.org/0000-0003-0145-7558

Department of Radiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Address reprint requests to: M.Z., No.88 Jiefang Road, Shangcheng District, Hangzhou, China, 31009. E-mail: [email protected]

Search for more papers by this author

First published: 05 May 2021

https://doi.org/10.1002/jmri.27680

Citations: 5

Share a link

Email
Wechat
Bluesky

Abstract

Background

Excessive iron accumulation is one of the main pathogeneses of Parkinson's disease (PD). Ceruloplasmin plays an important role in keeping the iron homoeostasis.

Purpose

To explore the association between serum ceruloplasmin depletion and subcortical iron distribution in PD.

Study type

Prospective.

Population

One hundred and twenty-one normal controls, 34 PD patients with low serum ceruloplasmin (PD-LC), and 28 patients with normal serum ceruloplasmin (PD-NC).

Sequence

Enhanced susceptibility-weighted angiography (ESWAN) on a 3 T scanner.

Assessment

Quantitative susceptibility mapping was employed to quantify the regional iron content by using a semi-automatic method. Serum ceruloplasmin concentration was measured from peripheral blood sample. Clinical assessments were conducted by a neurologist.

Statistical Tests

General linear model was used to compare the intergroup difference of region iron distribution among groups, and the statistics was adjusted by Bonferroni method (P < 0.01). Partial correlation analysis was used to detect the association between regional iron distribution and serum ceruloplasmin concentration (P < 0.05).

Results

Compared with normal controls, significant iron accumulation in substantia nigra, putamen, and red nucleus was observed in PD-LC, while the only region showing significant iron accumulation was SN in PD-NC. Between PD-NC and PD-LC, the iron accumulation in putamen remained significantly different, which had a negative correlation with serum ceruloplasmin in whole PD patients (r = −0.338, P = 0.008).

Data Conclusion

Nigral iron accumulation characterizes PD patients without significant association with serum ceruloplasmin. Differentially, when PD patients appear with reduced serum ceruloplasmin, more widespread iron accumulation would be expected with additionally involving putamen and red nucleus. All these findings provide insightful evidence for the abnormal iron metabolism behind the ceruloplasmin depletion in PD.

Evidence Level

Technical Efficacy

References

1Lees AJ, Hardy J, Revesz T. Parkinson's disease. Lancet 2009; 373(9680): 2055-2066.
10.1016/S0140-6736(09)60492-X
CAS PubMed Web of Science® Google Scholar
2Braak H, Del TK, Rub U, de Vos RA, Jansen SE, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003; 24(2): 197-211.
10.1016/S0197-4580(02)00065-9
PubMed Web of Science® Google Scholar
3Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 2014; 13(10): 1045-1060.
10.1016/S1474-4422(14)70117-6
CAS PubMed Web of Science® Google Scholar
4Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al. Pathophysiology of the basal ganglia in Parkinson's disease. Trends Neurosci 2000; 23(10 Suppl): S8-S19.
10.1016/S1471-1931(00)00028-8
CAS PubMed Web of Science® Google Scholar
5Hare DJ, Double KL. Iron and dopamine: A toxic couple. Brain 2016; 139(Pt 4): 1026-1035.
10.1093/brain/aww022
PubMed Web of Science® Google Scholar
6Hill JM. Iron concentration reduced in ventral pallidum, globus pallidus, and substantia nigra by GABA-transaminase inhibitor, gamma-vinyl GABA. Brain Res 1985; 342(1): 18-25.
10.1016/0006-8993(85)91348-4
CAS PubMed Web of Science® Google Scholar
7Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid Redox Signal 2014; 21(2): 195-210.
10.1089/ars.2013.5593
CAS PubMed Web of Science® Google Scholar
8Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B. The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 2000; 20(16): 6048-6054.
10.1523/JNEUROSCI.20-16-06048.2000
CAS PubMed Web of Science® Google Scholar
9Jellinger K, Paulus W, Grundke-Iqbal I, Riederer P, Youdim MB. Brain iron and ferritin in Parkinson's and Alzheimer's diseases. J Neural Transm Park Dis Dement Sect 1990; 2(4): 327-340.
10.1007/BF02252926
CAS PubMed Web of Science® Google Scholar
10Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annu Rev Nutr 2002; 22: 439-458.
10.1146/annurev.nutr.22.012502.114457
CAS PubMed Web of Science® Google Scholar
11Lee GR, Nacht S, Lukens JN, Cartwright GE. Iron metabolism in copper-deficient swine. J Clin Invest 1968; 47(9): 2058-2069.
10.1172/JCI105891
CAS PubMed Web of Science® Google Scholar
12Ayton S, Lei P, Duce JA, et al. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 2013; 73(4): 554-559.
10.1002/ana.23817
CAS PubMed Web of Science® Google Scholar
13Jin L, Wang J, Zhao L, et al. Decreased serum ceruloplasmin levels characteristically aggravate nigral iron deposition in Parkinson's disease. Brain 2011; 134(Pt 1): 50-58.
10.1093/brain/awq319
PubMed Web of Science® Google Scholar
14Torsdottir G, Kristinsson J, Sveinbjornsdottir S, Snaedal J, Johannesson T. Copper, ceruloplasmin, superoxide dismutase and iron parameters in Parkinson's disease. Pharmacol Toxicol 1999; 85(5): 239-243.
10.1111/j.1600-0773.1999.tb02015.x
CAS PubMed Google Scholar
15Grolez G, Moreau C, Sablonniere B, et al. Ceruloplasmin activity and iron chelation treatment of patients with Parkinson's disease. BMC Neurol 2015; 15: 74.
10.1186/s12883-015-0331-3
PubMed Web of Science® Google Scholar
16Liu C, Li W, Tong KA, Yeom KW, Kuzminski S. Susceptibility-weighted imaging and quantitative susceptibility mapping in the brain. J Magn Reson Imaging 2015; 42(1): 23-41.
10.1002/jmri.24768
PubMed Web of Science® Google Scholar
17Jin L, Wang J, Jin H, et al. Nigral iron deposition occurs across motor phenotypes of Parkinson's disease. Eur J Neurol 2012; 19(7): 969-976.
10.1111/j.1468-1331.2011.03658.x
CAS PubMed Web of Science® Google Scholar
18Wei H, Dibb R, Zhou Y, et al. Streaking artifact reduction for quantitative susceptibility mapping of sources with large dynamic range. NMR Biomed 2015; 28(10): 1294-1303.
10.1002/nbm.3383
PubMed Web of Science® Google Scholar
19Guan X, Zhang Y, Wei H, et al. Iron-related nigral degeneration influences functional topology mediated by striatal dysfunction in Parkinson's disease. Neurobiol Aging 2019; 75: 83-97.
10.1016/j.neurobiolaging.2018.11.013
CAS PubMed Web of Science® Google Scholar
20Guan X, Xuan M, Gu Q, et al. Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping. NMR Biomed 2017; 30(4):e3489.
10.1002/nbm.3489
Web of Science® Google Scholar
21He N, Ling H, Ding B, et al. Region-specific disturbed iron distribution in early idiopathic Parkinson's disease measured by quantitative susceptibility mapping. Hum Brain Mapp 2015; 36(11): 4407-4420.
10.1002/hbm.22928
PubMed Web of Science® Google Scholar
22Langkammer C, Pirpamer L, Seiler S, et al. Quantitative susceptibility mapping in Parkinson's disease. PLOS One 2016; 11(9):e162460.
10.1371/journal.pone.0162460
PubMed Web of Science® Google Scholar
23Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55(3): 181-184.
10.1136/jnnp.55.3.181
CAS PubMed Web of Science® Google Scholar
24Li W, Avram AV, Wu B, Xiao X, Liu C. Integrated Laplacian-based phase unwrapping and background phase removal for quantitative susceptibility mapping. NMR Biomed 2014; 27(2): 219-227.
10.1002/nbm.3056
PubMed Web of Science® Google Scholar
25Wu B, Li W, Guidon A, Liu C. Whole brain susceptibility mapping using compressed sensing. Magn Reson Med 2012; 67(1): 137-147.
10.1002/mrm.23000
CAS PubMed Web of Science® Google Scholar
26Guan X, Guo T, Zhou C, et al. Asymmetrical nigral iron accumulation in Parkinson's disease with motor asymmetry: An explorative, longitudinal and test-retest study. Aging (Albany NY) 2020; 12(18): 18622-18634.
10.18632/aging.103870
CAS PubMed Google Scholar
27Avants BB, Epstein CL, Grossman M, Gee JC. Symmetric diffeomorphic image registration with cross-correlation: Evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 2008; 12(1): 26-41.
10.1016/j.media.2007.06.004
CAS PubMed Web of Science® Google Scholar
28Zhang Y, Wei H, Cronin MJ, He N, Yan F, Liu C. Longitudinal atlas for normative human brain development and aging over the lifespan using quantitative susceptibility mapping. Neuroimage 2018; 171: 176-189.
10.1016/j.neuroimage.2018.01.008
PubMed Web of Science® Google Scholar
29Sofic E, Paulus W, Jellinger K, Riederer P, Youdim MB. Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem 1991; 56(3): 978-982.
10.1111/j.1471-4159.1991.tb02017.x
CAS PubMed Web of Science® Google Scholar
30Sofic E, Riederer P, Heinsen H, et al. Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 1988; 74(3): 199-205.
10.1007/BF01244786
CAS PubMed Web of Science® Google Scholar
31Hare DJ, Adlard PA, Doble PA, Finkelstein DI. Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Metallomics 2013; 5(2): 91-109.
10.1039/c2mt20164j
CAS PubMed Web of Science® Google Scholar
32Guan X, Xuan M, Gu Q, et al. Influence of regional iron on the motor impairments of Parkinson's disease: A quantitative susceptibility mapping study. J Magn Reson Imaging 2017; 45(5): 1335-1342.
10.1002/jmri.25434
CAS PubMed Web of Science® Google Scholar
33Xuan M, Guan X, Gu Q, et al. Different iron deposition patterns in early- and middle-late-onset Parkinson's disease. Parkinsonism Relat Disord 2017; 44: 23-27.
10.1016/j.parkreldis.2017.08.013
PubMed Web of Science® Google Scholar
34Chen Q, Chen Y, Zhang Y, et al. Iron deposition in Parkinson's disease by quantitative susceptibility mapping. BMC Neurosci 2019; 20(1): 23.
10.1186/s12868-019-0505-9
PubMed Web of Science® Google Scholar
35Graham JM, Paley MN, Grunewald RA, Hoggard N, Griffiths PD. Brain iron deposition in Parkinson's disease imaged using the PRIME magnetic resonance sequence. Brain 2000; 123(Pt 12): 2423-2431.
10.1093/brain/123.12.2423
PubMed Web of Science® Google Scholar
36Ryvlin P, Broussolle E, Piollet H, Viallet F, Khalfallah Y, Chazot G. Magnetic resonance imaging evidence of decreased putamenal iron content in idiopathic Parkinson's disease. Arch Neurol 1995; 52(6): 583-588.
10.1001/archneur.1995.00540300057013
CAS PubMed Web of Science® Google Scholar
37Guan X, Xu X, Zhang M. Region-specific iron measured by MRI as a biomarker for Parkinson's disease. Neurosci Bull 2017; 33(5): 561-567.
10.1007/s12264-017-0138-x
CAS PubMed Web of Science® Google Scholar
38Kish SJ, Rajput A, Gilbert J, et al. Elevated gamma-aminobutyric acid level in striatal but not extrastriatal brain regions in Parkinson's disease: Correlation with striatal dopamine loss. Ann Neurol 1986; 20(1): 26-31.
10.1002/ana.410200106
CAS PubMed Web of Science® Google Scholar
39Philippens I, Wubben JA, Franke SK, Hofman S, Langermans J. Involvement of the red nucleus in the compensation of parkinsonism may explain why primates can develop stable Parkinson's disease. Sci Rep 2019; 9(1): 880.
10.1038/s41598-018-37381-1
PubMed Web of Science® Google Scholar
40Xu X, Guan X, Guo T, et al. Brain atrophy and reorganization of structural network in Parkinson's disease with hemiparkinsonism. Front Hum Neurosci 2018; 12: 117.
10.3389/fnhum.2018.00117
PubMed Web of Science® Google Scholar

Citing Literature

Volume54, Issue4

October 2021

Pages 1098-1106

Serum Ceruloplasmin Depletion is Associated With Magnetic Resonance Evidence of Widespread Accumulation of Brain Iron in Parkinson's Disease

Abstract

Background

Purpose

Study type

Population

Sequence

Assessment

Statistical Tests

Results

Data Conclusion

Evidence Level

Technical Efficacy

References

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Serum Ceruloplasmin Depletion is Associated With Magnetic Resonance Evidence of Widespread Accumulation of Brain Iron in Parkinson's Disease

Abstract

Background

Purpose

Study type

Population

Sequence

Assessment

Statistical Tests

Results

Data Conclusion

Evidence Level

Technical Efficacy

References

Citing Literature

References

Related

Information