Plasma Alpha Synuclein as a Potent Biomarker of Diseases with Synucleinopathies
DOI:
https://doi.org/10.33192/smj.v75i12.265475Keywords:
alpha synuclein, biomarker, plasma, Parkinson's disease dementia, lewy body dementia, alzheimer's diseaseAbstract
Objective: We explored whether plasma α-syn be used as a potential biomarker for synucleinopathies.
Materials and Methods: α-syn levels in plasma from 54 Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) patents, 31 Alzheimer’s disease dementia (AD), and 29 controls were measured by enzymelinked immunosorbent assay (ELISA).
Results: The mean age of the synucleinopathies group, the AD group, and the normal controls was 72.70, 74.26, and 62 years old. The median plasma α-syn levels in the synucleinopathies group, AD group and controls were 9.72 (4.41-25.30), 16.78 (7.68-51.41) and 16.65 (10.37-32.72) ng/ml, respectively (Independent-Samples Kruskal-Wallis test, p = 0.026). The α-syn levels in the synucleinopathies group were lower than those of AD and controls. There was a fair correlation between plasma α-syn levels and the sum of the Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 (spearman correlation coefficient r = -0.261, p = 0.021) but not with cognition measured by Thai Mental Status Examination (TMSE). The area under the receiver operating characteristic curve (ROC) was 0.710 between the PDD and DLB vs non synucleinopathies group (AD and normal controls) (SE = 0.052, p ≤ 0.001). At the cut-off levels of 11.4 ng/ml indicated a sensitivity of 58% (95% CI 43.21-71.81%), specificity of 84.78% (95% CI 71.13-93.66%), positive predictive value (PPV) of 80.56%, a negative predictive value (NPV) of 65% and a precision of 70.83%.
Conclusion: The present results suggest that plasma α-syn could be a potential biomarker to differentiate synucleinopathies from Alzheimer’s disease and the elderly with normal cognition.
References
Martı´ MJ, Tolosa E, Campdelacreu J. Clinical Overview of the Synucleinopathies. Mov Disord. 2003;18 Suppl 6:S21-7. DOI: https://doi.org/10.1002/mds.10559
Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001;2:492-501. DOI: https://doi.org/10.1038/35081564
Eller M, Williams DR. α-Synuclein in Parkinson Disease and other neurodegenerative disorders. Clin Chem Lab Med. 2011;49(3):403-8. DOI: https://doi.org/10.1515/CCLM.2011.077
Kasuga K, Nishizawa M, Ikeuchi T. α-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies. Int J Alzheimers Dis. 2012;2012:437025. DOI: https://doi.org/10.1155/2012/437025
Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T, et al. Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology. 2010;75:1766-70. DOI: https://doi.org/10.1212/WNL.0b013e3181fd613b
Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, Galasko D, et al. DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain. 2010;133:713-26. DOI: https://doi.org/10.1093/brain/awq008
Lee PH, Lee G, Park HJ, Bang OY, Joo IS, Huh K. The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy. J Neural Transm (Vienna). 2006;113(10):1435-9. DOI: https://doi.org/10.1007/s00702-005-0427-9
Lin CH, Yang SY, Horng HE, Yang CC, Chieh JJ, Chen HH, et al. Plasma α-synuclein predicts cognitive decline in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2017;88:818-24. DOI: https://doi.org/10.1136/jnnp-2016-314857
Kim JY, Illigens BM, McCormick MP, Wang N, Gibbons CH. Alpha-Synuclein in Skin Nerve Fibers as a Biomarker for Alpha-Synucleinopathies. J Clin Neurol. 2019; 15(2):135-42. DOI: https://doi.org/10.3988/jcn.2019.15.2.135
Wang Z, Becker K, Donadio V, Siedlak S, Yuan J, Rezaee M, et al. Skin α-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease. JAMA Neurol. 2021;78(1):30-40. DOI: https://doi.org/10.1001/jamaneurol.2020.3311
Kasuga K, Tokutake T, Ishikawa A, Uchiyama T, Tokuda T, Onodera O, et al. Differential levels of alpha-synuclein, beta-amyloid42 and tau in CSF between patients with dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2010;81:608-10. DOI: https://doi.org/10.1136/jnnp.2009.197483
Tateno F, Sakakibara R, Kawai T, Kishi M, Murano T. Alpha-synuclein in the Cerebrospinal Fluid Differentiates Synucleinopathies (Parkinson Disease, Dementia with Lewy Bodies, Multiple System Atrophy) From Alzheimer Disease. Alzheimer Dis Assoc Disord. 2011;26(3):213-6. DOI: https://doi.org/10.1097/WAD.0b013e31823899cc
Foulds PG, Diggle P, Mitchell JD, Parker A, Hasegawa M, Masuda-Suzukake M, et al. A longitudinal study on α-synuclein in blood plasma as a biomarker for Parkinson’s disease. Sci Rep. 2013;3:2540. DOI: https://doi.org/10.1038/srep02540
Koehler NK, Stransky E, Meyer M, Gaertner S, Shing M, Schnaidt M, et al. Alpha-Synuclein Levels in Blood Plasma Decline with Healthy Aging. PLoS One. 2015; 10(4):e0123444. DOI: https://doi.org/10.1371/journal.pone.0123444
Chang CW, Yang SY, Yang CC, Chang CW, Wu YR. Plasma and Serum Alpha-Synuclein as a Biomarker of Diagnosis in Patients With Parkinson’s Disease. Front Neurol. 2020;10:1388. DOI: https://doi.org/10.3389/fneur.2019.01388
Bougea A, Stefanis L, Paraskevas GP, Emmanouilidou E, Vekrelis K, Kapaki E. Plasma alpha-synuclein levels in patients with Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci. 2019;40:929-38. DOI: https://doi.org/10.1007/s10072-019-03738-1
Duran R, Berrero FJ, Morales B, Luna JD, Ramirez M, Vives F. Plasma alpha-synuclein in patients with Parkinson’s disease with and without treatment. Mov Disord. 2010;25(4):489-93. DOI: https://doi.org/10.1002/mds.22928
Li QX, Mok SS, Laughton KM, McLean CA, Cappai R, Masters CL, et al. Plasma alpha-synuclein is decreased in subjects with Parkinson’s disease. Exp Neurol. 2007; 204(2):583-8. DOI: https://doi.org/10.1016/j.expneurol.2006.12.006
Gorostidi A, Bergareche A, Ruiz-Martinez J, Martí-Massó JF, Cruz M, Varghese S, et al. Alpha-synuclein levels in blood plasma from LRRK2 mutation carriers. PLoS One. 2012;7(12):e52312. DOI: https://doi.org/10.1371/journal.pone.0052312
Caranci G, Piscopo P, Rivabene R, Traficante A, Riozzi B, Castellano AE, et al. Gender differences in Parkinson’s disease: focus on plasma α-synuclein. J Neural Transm (Vienna). 2013;120(8):1209-15. DOI: https://doi.org/10.1007/s00702-013-0972-6
Park MJ, Cheon SM, Bae HR, Kim SH, Kim JW. Elevated levels of alpha-synuclein oligomer in the cerebrospinal fluid of drug-naïve patients with Parkinson’s disease. J Clin Neurol. 2011;7(4):215-22. DOI: https://doi.org/10.3988/jcn.2011.7.4.215
Mata IF, Shi M, Agarwal P, Chung KA, Edwards KL, Factor SA, et al. SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol. 2010;67(11):1350-6. DOI: https://doi.org/10.1001/archneurol.2010.279
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591-601. DOI: https://doi.org/10.1002/mds.26424
Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22(16):2314-24. DOI: https://doi.org/10.1002/mds.21844
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88. DOI: https://doi.org/10.1212/WNL.0000000000004058
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263. DOI: https://doi.org/10.1016/j.jalz.2011.03.005
Wennstrӧm M, Surova Y, Hall S, Nilsson C, Minthon L, Boström F, et al. Low CSF levels of both α-synuclein and the α-synuclein cleaving enzyme neurosin in patients with synucleinopathy. PLoS One. 2013;8(1):e53250. DOI: https://doi.org/10.1371/journal.pone.0053250
Senanarong V, Harnphadungkit K, Prayoonwiwat N, Poungvarin N, Sivasariyanonds N, Printarakul T, et al. A new measurement of activities of daily living for Thai elderly with dementia. Int Psychogeriatr. 2003;15(2):135-48. DOI: https://doi.org/10.1017/S1041610203008822
Saeed U, Lang AE, Masellis M. Neuroimaging Advances in Parkinson’s Disease and Atypical Parkinsonian Syndromes. Front Neurol. 2020;11:572976. DOI: https://doi.org/10.3389/fneur.2020.572976
Gao L, Tang H, Nei K, Wang L, Zhao J, Gan R, et al. Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson’s disease diagnosis: a systematic review and meta-analysis. Int J Neurosci. 2015;125(9):645-54. DOI: https://doi.org/10.3109/00207454.2014.961454
van Steenoven I, Majbour NK, Vaikath NN, Berendse HW, van der Flier WM, van de Berg WDJ, et al. α-Synuclein species as potential cerebrospinal fluid biomarkers for dementia with lewy bodies. Mov Disord. 2018;33(11):1724-33. DOI: https://doi.org/10.1002/mds.111
Ashton NJ, Hye A, Rajkumar AP, Leuzy A, Snowden S, Suárez-Calvet M, et al. An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders. Nat Rev Neurol. 2020;16(5):265-84. DOI: https://doi.org/10.1038/s41582-020-0348-0
Leuzy A, Mattsson-Carlgren N, Palmqvist S, Janelidze S, Dage JL, Hansson O. Blood-based biomarkers for Alzheimer’s disease. EMBO Mol Med. 2022;14(1): e14408. DOI: https://doi.org/10.15252/emmm.202114408
Teunissen CE, Verberk IMW, Thijssen EH, Vermunt L, Hansson O, Zetterberg H, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol. 2022;21(1):66-77. DOI: https://doi.org/10.1016/S1474-4422(21)00361-6
Chiu MJ, Leu LF, Sabbagh MN, Chen TF, Chen HH, Yang SY. Long-Term Storage Effects on Stability of Aβ1-40, Aβ1-42, and Total Tau Proteins in Human Plasma Samples Measured with Immunomagnetic Reduction Assays. Dement Geriatr Cogn Dis Extra. 2019;9(1):77-86. DOI: https://doi.org/10.1159/000496099
Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, et al. Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis. 2008;5:55-59. DOI: https://doi.org/10.1159/000112832
Ding J, Zhang J, Wang X, Zhang L, Jiang S, Yuan Y, et al. Relationship between the plasma levels of neurodegenerative proteins and motor subtypes of Parkinson’s disease. J Neural Transm (Vienna). 2017;124(3):353-60. DOI: https://doi.org/10.1007/s00702-016-1650-2
Malec-Litwinowicz M, Plewka A, Plewka D, Bogunia E, Morek M, Szczudlik A, et al. The relation between plasma alpha-synuclein level and clinical symptoms or signs of Parkinson’s disease. Neurol Neurochir Pol. 2018;52(2):243-51. DOI: https://doi.org/10.1016/j.pjnns.2017.11.009
Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D, et al. Dementia with Lewybodies: an update and outlook. Mol Neurodegeneration. 2019;14:5. DOI: https://doi.org/10.1186/s13024-019-0306-8
Campese N, Fanciulli A, Stefanova N, Haybaeck J, Kiechl S, Wenning GK. J Neural Transm. 2021;128:1481-94. DOI: https://doi.org/10.1007/s00702-021-02383-3
Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW. Mol Neurodegeneration. 2021;16:83. DOI: https://doi.org/10.1186/s13024-021-00501-z
Parnetti L, Chiasserini D, Bellomo G, Giannandrea D, De Carlo C, Qureshi MM, et al. Cerebrospinal fluid Tau/α-synuclein ratio in Parkinson’s disease and degenerative dementias. Mov Disord. 2011;26(8):1428-35. DOI: https://doi.org/10.1002/mds.23670
Kang JH, Irwin DJ, Chen-Plotkin AS, Siderowf A, Caspell C, Coffey CS, et al. Association of cerebrospinal fluid β-aymloid 1-42, T-tau, P-tau 181, and α-synuclein levels with clinical features of drug-naïve patients with early Parkinson disease. JAMA Neurol. 2013;70(10):1277-87. DOI: https://doi.org/10.1001/jamaneurol.2013.3861
Hanchcliffe C. Blood and cerebrospinal fluid markers in Parkinson’s disease: current biomarker findings. Current Biomarker Findings. 2015;5:1-11. DOI: https://doi.org/10.2147/CBF.S50424
Lin CH, Yang SY, Horng HE, Yang CC, Chieh JJ, Chen HH, et al. Plasma Biomarkers Differentiate Parkinson’s Disease From Atypical Parkinsonism Syndromes. Front Aging Neurosci. 2018;10:123. DOI: https://doi.org/10.3389/fnagi.2018.00123
Chen NC, Chen HL, Li SH, Chang YH, Chen MH, Tsai NW, et al. Plasma Levels of α-Synuclein, Aβ-40 and T-tau as Biomarkers to Predict Cognitive Impairment in Parkinson’s Disease. Front Aging Neurosci. 2020;12:112. DOI: https://doi.org/10.3389/fnagi.2020.00112
Ren J, Pan C, Wang Y, Xue C, Lin H, Xu J, et al. Plasma α-synuclein and phosphorylated tau 181 as a diagnostic biomarker panel for de novo Parkinson’s disease. J Neurochem. 2022;161(1):506-15. DOI: https://doi.org/10.1111/jnc.15601
Li Q, Li Z, Han X, Shen X, Wang F, Bai L, et al. A Panel of Plasma Biomarkers for Differential Diagnosis of Parkinsonian Syndromes. Front Neurosci. 2022;16:805953. DOI: https://doi.org/10.3389/fnins.2022.805953
Ratanamart V, Senanarong V, Chulakadabba S, Chiewvit P. SPECT as An Aid for Clinicians in the Diagnosis of Alzheimer’s Disease: A case report and review of current diagnostic approaches and the need for early accurate diagnosis to optimize treatment. Siriraj Med J. 2003;55(1):31-41.
Ferrando R, Damian A. Brain SPECT as a Biomarker of Neurodegeneration in Dementia in the Era of Molecular Imaging: Still a Valid Option? Front Neurol. 2021;12:629442. DOI: https://doi.org/10.3389/fneur.2021.629442
Fabiani G, Camargo CHF, Filho RM, Froehner GS, Teive HAG. Evaluation of Brain SPECT with 99mTc-TRODAT-1 in the Differential Diagnosis of Parkinsonism. Parkinsons Dis. 2022;2022:1746540. DOI: https://doi.org/10.1155/2022/1746540
Hung GU, Chiu PY. The Value of 99mTc-Trodat-1 SPECT for Discriminating Dementia with Lewy Bodies and Alzheimer’s disease. J Nucl Med. 2017;58 (Suppl 1):1279.
Published
How to Cite
License
Copyright (c) 2023 Siriraj Medical Journal

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Authors who publish with this journal agree to the following conditions:
Copyright Transfer
In submitting a manuscript, the authors acknowledge that the work will become the copyrighted property of Siriraj Medical Journal upon publication.
License
Articles are licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). This license allows for the sharing of the work for non-commercial purposes with proper attribution to the authors and the journal. However, it does not permit modifications or the creation of derivative works.
Sharing and Access
Authors are encouraged to share their article on their personal or institutional websites and through other non-commercial platforms. Doing so can increase readership and citations.



