Development of an ultra-high sensitive immunoassay with plasma biomarker for differentiating Parkinson disease dementia from Parkinson disease using antibody functionalized magnetic nanoparticles

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Abstract

Background

It is difficult to discriminate healthy subjects and patients with Parkinson disease (PD) or Parkinson disease dementia (PDD) by assaying plasma α-synuclein because the concentrations of circulating α-synuclein in the blood are almost the same as the low-detection limit using current immunoassays, such as enzyme-linked immunosorbent assay. In this work, an ultra-sensitive immunoassay utilizing immunomagnetic reduction (IMR) is developed. The reagent for IMR consists of magnetic nanoparticles functionalized with antibodies against α-synuclein and dispersed in pH-7.2 phosphate-buffered saline. A high-T _c superconducting-quantum-interference-device (SQUID) alternative-current magnetosusceptometer is used to measure the IMR signal of the reagent due to the association between magnetic nanoparticles and α-synuclein molecules.

Results

According to the experimental α-synuclein concentration dependent IMR signal, the low-detection limit is 0.3 fg/ml and the dynamic range is 310 pg/ml. The preliminary results show the plasma α-synuclein for PD patients distributes from 6 to 30 fg/ml. For PDD patients, the concentration of plasma α-synuclein varies from 0.1 to 100 pg/ml. Whereas the concentration of plasma α-synuclein for healthy subjects is significantly lower than that of PD patients.

Conclusions

The ultra-sensitive IMR by utilizing antibody-functionalized magnetic nanoparticles and high-T _c SQUID magnetometer is promising as a method to assay plasma α-synuclein, which is a potential biomarker for discriminating patients with PD or PDD.

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Most cited references 20

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Phosphorylated α-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson's disease.

David Mann, David Allsop, Tracey Turner … (2011)

Parkinson's disease (PD) is characterized by the presence of Lewy bodies containing phosphorylated and aggregated α-synuclein (α-syn). α-Syn is present in human body fluids, including blood plasma, and is a potential biomarker for PD. Immunoassays for total and oligomeric forms of both normal and phosphorylated (at Ser-129) α-syn have been used to assay plasma samples from a longitudinal cohort of 32 patients with PD (sampled at mo 0, 1, 2, 3), as well as single plasma samples from a group of 30 healthy control participants. The levels of α-syn in plasma varied greatly between individuals, but were remarkably consistent over time within the same individual with PD. The mean level of phospho-α-syn was found to be higher (P=0.053) in the PD samples than the controls, whereas this was not the case for total α-syn (P=0.244), oligo-α-syn (P=0.221), or oligo-phospho-α-syn (P=0.181). Immunoblots of plasma revealed bands (at 21, 24, and 50-60 kDa) corresponding to phosphorylated α-syn. Thus, phosphorylated α-syn can be detected in blood plasma and shows more promise as a diagnostic marker than the nonphosphorylated protein. Longitudinal studies undertaken over a more extended time period will be required to determine whether α-syn can act as a marker of disease progression.

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Plasma tau as a window to the brain-negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer's disease.

Ming-Jang Chiu, Ya-Fang Chen, Ta-Fu Chen … (2013)

Neurofibrillary tangles are associated with cognitive dysfunction, and hippocampal atrophy with increased CSF tau markers. However, the plasma tau levels of Alzheimer's disease (AD) have not been well studied. We investigated plasma tau by using an immunomagnetic reduction assay in 20 patients with mild cognitive impairment (MCI) due to AD, 10 early AD dementia, and 30 healthy elders (HE). All received a 3D-brain MRI scan and a set of cognitive function test. We explored their relationships with both brain structure and cognitive functions. Images were analyzed to determine the brain volumes and gray matter densities. Patients with MCI or early AD had significantly increased plasma tau levels compared with HE. Plasma tau levels were negatively associated with the performance of logical memory, visual reproduction, and verbal fluency; also negatively associated with volume of total gray matter, hippocampus, amygdala; and gray matter densities of various regions. Regression analyses indicated that logical memory explained 0.394 and hippocampus volume predicted .608 of the variance of plasma tau levels, both P < 0.001. Education years were negatively associated with the gray matter densities of the supramarginal (r = -0.407), middle temporal gyrus (r = -0.40) and precuneus (r = -0.377; all P < 0.05) in HE; and negatively associated with plasma tau levels in patients (r = -0.626). We propose that plasma tau may serve as a window to both structure and function of the brain. Higher education is a protective factor against AD and is associated with lower plasma tau levels in patients.

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alpha-Synuclein gene duplication is present in sporadic Parkinson disease.

Y Min, David Ahn, B. C. Jeon … (2008)

alpha-Synuclein gene (SNCA) multiplication was found in familial Parkinson disease (PD). We examined SNCA multiplication in patients with familial and sporadic PD and multiple system atrophy (MSA). We screened 1,106 patients with parkinsonism (PD = 906, MSA = 200) for SNCA multiplication by multiplex PCR. Fluorescent in situ hybridization was done to confirm the multiplication. [(123)I]N-omega-Fluoropropyl-2 beta-carbomethoxy-3beta-(4-iodophenyl)-tropane ([(123)I]FP-CIT) SPECT was done in the patients with SNCA multiplication and their family members. Three patients were identified as having SNCA duplication. One patient had a positive family history, and two patients were sporadic. Each patient had asymptomatic carriers in their families. The familial case had early onset parkinsonism with rapidly progressive course, cognitive impairment, and dysautonomia. Sporadic cases were more typical of PD. [(123)I]FP-CIT SPECT was abnormal in the patients and normal in the asymptomatic carriers. SNCA multiplication is present in sporadic Parkinson disease (PD) and needs to be screened. Low penetrance, clinical heterogeneity, and normal dopamine transporter imaging in asymptomatic carriers may suggest the presence of other genetic modifiers or environmental triggers that play a role in the pathogenesis of PD due to SNCA duplication.

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Author and article information

Contributors

Shieh-Yueh Yang: syyang@magqu.com

Ming-Jang Chiu: mjchiu@ntu.edu.tw

Chin-Hsien Lin: chlin@ntu.edu.tw

Herng-Er Horng: phyfv001@ntnu.edu.tw

Che-Chuan Yang: elvis.yang@magqu.com

Jen-Jie Chieh: jjchieh@ntnu.edu.tw

Hsin-Hsien Chen: joseph.chen@magqu.com

Bing-Hsien Liu: fresh.liu@magqu.com

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 8 June 2016

Publication date PMC-release: 8 June 2016

Publication date Collection: 2016

Volume: 14

Electronic Location Identifier: 41

Affiliations

[ ]MagQu Co., Ltd., Xindian District, New Taipei City, 231 Taiwan

[ ]Institute of Electro-optical Science and Technology, National Taiwan Normal University, Taipei, 116 Taiwan

[ ]Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, 100 Taiwan

[ ]Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 100 Taiwan

[ ]Department of Psychology, National Taiwan University, Taipei, 100 Taiwan

[ ]Graduate Institute of Biomedical Engineering and Bioinformatics, National Taiwan University, Taipei, 116 Taiwan

Article

Publisher ID: 198

DOI: 10.1186/s12951-016-0198-5

PMC ID: 4898388

PubMed ID: 27278241

SO-VID: 53f417a1-e376-480e-a4c7-85eaebbfc12e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 December 2015

Date accepted : 24 May 2016

Funding

Funded by: New Taipei City Goverment

Award ID: 101-EC-17-A-17-I1-0074

Award Recipient : Bing-Hsien Liu

Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;

Award ID: 104-2745-B-003 -002

Award Recipient : Herng-Er Horng

Funded by: Ministry of Economic Affairs, Republic of Taiwan (TW)

Award ID: 101-EC-17-A-17-I1-0074

Award Recipient : Che-Chuan Yang

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ScienceOpen disciplines: Biotechnology

Keywords: α-synuclein,parkinson disease,immunomagnetic reduction

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ScienceOpen disciplines: Biotechnology

Keywords: α-synuclein, parkinson disease, immunomagnetic reduction

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Development of an ultra-high sensitive immunoassay with plasma biomarker for differentiating Parkinson disease dementia from Parkinson disease using antibody functionalized magnetic nanoparticles

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Abstract

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Most cited references 20

Phosphorylated α-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson's disease.

Plasma tau as a window to the brain-negative associations with brain volume and memory function in mild cognitive impairment and early Alzheimer's disease.

alpha-Synuclein gene duplication is present in sporadic Parkinson disease.

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