REFERENCES
1. Uversky VN. Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 2007;103:17-37.
2. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, et al. Alpha-synuclein in Lewy bodies. Nature 1997;388:839-40.
3. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997;276:2045-7.
4. Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55:164-73.
5. Proukakis C, Houlden H, Schapira AH. Somatic alpha-synuclein mutations in Parkinson’s disease: hypothesis and preliminary data. Mov Disord 2013;28:705-12.
6. Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, et al. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 2013;136:385-91.
7. Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 2004;364:1167-9.
8. Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson’s disease: progress and therapeutic implications. Mov Disord 2013;28:14-23.
9. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet 2009;41:1303-7.
10. Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009;41:1308-12.
11. Emamzadeh FN, Surguchov A. Parkinson’s disease: biomarkers, treatment, and risk factors. Front Neurosci 2018;12:612.
12. Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, et al. alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 2002;4:160-4.
13. Paleologou KE, Kragh CL, Mann DM, Salem SA, Al-Shami R, et al. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 2009;132:1093-101.
14. Surguchov A. Parkinson’s disease: assay of phosphorylated alpha-synuclein in skin biopsy for early diagnosis and association with melanoma. Brain Sci 2016;6.
15. Mollenhauer B, Bowman FD, Drake D, Duong J, Blennow K, et al. Antibody-based methods for the measurement of α-synuclein concentration in human cerebrospinal fluid - method comparison and round robin study. J Neurochem 2019;149:126-38.
16. Magdalinou N, Lees AJ, Zetterberg H. Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions. J Neurol Neurosurg Psychiatry 2014;85:1065-75.
17. Eusebi P, Hansson O, Paciotti S, Orso M, Chiasserini D, et al. Cerebrospinal fluid biomarkers for the diagnosis and prognosis of Parkinson’s disease: protocol for a systematic review and individual participant data meta-analysis. BMJ Open 2017;7:e018177.
18. Mollenhauer B, Caspell-Garcia CJ, Coffey CS, Taylor P, Singleton A, et al. Longitudinal analyses of cerebrospinal fluid α-Synuclein in prodromal and early Parkinson’s disease. Mov Disord 2019;34:1354-64.
19. Hong Z, Shi M, Chung KA, Quinn JF, Peskind ER, et al. DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain 2010;133:713-26.
20. Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro TF, et al. Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol 2008;213:315-25.
21. van Dijk KD, Bidinosti M, Weiss A, Raijmakers P, Berendse HW, et al. Reduced α-synuclein levels in cerebrospinal fluid in Parkinson’s disease are unrelated to clinical and imaging measures of disease severity. Eur J Neurol 2014;21:388-94.
22. Kruse N, Mollenhauer B. Quantification of alpha-synuclein in biological fluids by electrochemiluminescence-based detection. Methods Mol Biol 2019;1948:59-68.
23. Borghi R, Marchese R, Negro A, Marinelli L, Forloni G, et al. Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci Lett 2000;287:65-7.
24. Saijo E, Groveman BR, Kraus A, Metrick M, Orrù CD, et al. Ultrasensitive RT-QuIC seed amplification assays for disease-associated tau, α-synuclein, and prion aggregates. Methods Mol Biol 2019;1873:19-37.
25. Shahnawaz M, Mukherjee A, Pritzkow S, Mendez N, Rabadia P, et al. Discriminating alpha-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature 2020;578:273-7.
26. Shahnawaz M, Tokuda T, Waragai M, Mendez N, Ishii R, et al. Development of a biochemical diagnosis of Parkinson disease by detection of α-synuclein misfolded aggregates in cerebrospinal fluid. JAMA Neurol 2017;74:163-72.
27. Park MJ, Cheon SM, Bae HR, Kim SH, Kim JW. Elevated levels of α-synuclein oligomer in the cerebrospinal fluid of drug-naïve patients with Parkinson’s disease. J Clin Neurol 2011;7:215-22.
28. Ohrfelt A, Grognet P, Andreasen N, Wallin A, Vanmechelen E, et al. Cerebrospinal fluid alpha-synuclein in neurodegenerative disorders-a marker of synapse loss. Neurosci Lett 2009;450:332-5.
29. Aerts MB, Esselink RA, Abdo WF, Bloem BR, Verbeek MM. CSF α-synuclein does not differentiate between parkinsonian disorders. Neurobiol Aging 2012;33:430.e1-3.
30. García-Ayllón MS, Monge-Argilés JA, Monge-García V, Navarrete F, Cortés-Gómez MA, et al. Measurement of CSF α-synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer’s disease. J Neurochem 2019;150:218-30.
31. Twohig D, Rodriguez-Vieitez E, Sando SB, Berge G, Lauridsen C, et al. The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease. Acta Neuropathol Commun 2018;6:130.
32. Oeckl P, Metzger F, Nagl M, von Arnim CA, Halbgebauer S, et al. Alpha-, beta-, and gamma-synuclein quantification in cerebrospinal fluid by multiple reaction monitoring reveals increased concentrations in Alzheimer’s and Creutzfeldt-Jakob disease but no alteration in synucleinopathies. Mol Cell Proteomics 2016;15:3126-38.
33. Katayama T, Sawada J, Kikuchi-Takeguchi S, Kano K, Takahashi K, et al. Cerebrospinal fluid levels of alpha-synuclein, amyloid β, tau, phosphorylated tau, and neuron-specific enolase in patients with Parkinson’s disease, dementia with Lewy bodies or other neurological disorders: their relationships with cognition and nuclear medicine imaging findings. Neurosci Lett 2019;715:134564.
34. Bougea A, Stefanis L, Paraskevas GP, Emmanouilidou E, Efthymiopoulou E, et al. Neuropsychiatric symptoms and α-Synuclein profile of patients with Parkinson’s disease dementia, dementia with Lewy bodies and Alzheimer’s disease. J Neurol 2018;265:2295-301.
35. Bongianni M, Ladogana A, Capaldi S, Klotz S, Baiardi S, et al. α-Synuclein RT-QuIC assay in cerebrospinal fluid of patients with dementia with Lewy bodies. Ann Clin Transl Neurol 2019;6:2120-6.
36. Lerche S, Wurster I, Roeben B, Zimmermann M, Riebenbauer B, et al. Parkinson’s disease: glucocerebrosidase 1 mutation severity is associated with CSF alpha-synuclein profiles. Mov Disord 2020;35:495-9.
37. Viodé A, Epelbaum S, Benyounes I, Verny M, Dubois B, et al. Simultaneous quantification of tau and α-synuclein in cerebrospinal fluid by high-resolution mass spectrometry for differentiation of Lewy Body Dementia from Alzheimer’s disease and controls. Analyst 2019;144:6342-51.
38. Shi M, Tang L, Toledo JB, Ginghina C, Wang H, et al. Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer’s disease. Alzheimers Dement 2018;14:1052-62.
39. Chen XQ, Niu JP, Peng RQ, Song YH, Xu N, et al. The early diagnosis of Parkinson’s disease through combined biomarkers. Acta Neurol Scand 2019;140:268-73.
40. Duran R, Barrero FJ, Morales B, Luna JD, Ramirez M, et al. Plasma alpha-synuclein in patients with Parkinson’s disease with and without treatment. Mov Disord 2010;25:489-93.
41. Lee PH, Lee G, Park HJ, Bang OY, Joo IS, et al. The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy. J Neural Transm 2006;113:1435-9.
42. 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 2019;10:1388.
43. Ng ASL, Tan YJ, Lu Z, Ng EYL, Ng SYE, et al. Plasma alpha-synuclein detected by single molecule array is increased in PD. Ann Clin Transl Neurol 2019;6:615-9.
44. Lin CH, Liu HC, Yang SY, Yang KC, Wu CC, et al. Plasma pS129-alpha-synuclein is a surrogate biofluid marker of motor severity and progression in Parkinson’s disease. J Clin Med 2019;8.
45. Lin CH, Yang SY, Horng HE, Yang CC, Chieh JJ, et al. Plasma biomarkers differentiate Parkinson’s disease from atypical parkinsonism syndromes. Front Aging Neurosci 2018;10:123.
46. Lin CH, Yang SY, Horng HE, Yang CC, Chieh JJ, et al. Plasma alpha-synuclein predicts cognitive decline in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2017;88:818-24.
47. Shi M, Zabetian CP, Hancock AM, Ginghina C, Hong Z, et al. Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease. Neurosci Lett 2010;480:78-82.
48. Mata IF, Shi M, Agarwal P, Chung KA, Edwards KL, et al. SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol 2010;67:1350-6.
49. Li QX, Mok SS, Laughton KM, McLean CA, Cappai R, et al. Plasma alpha-synuclein is decreased in subjects with Parkinson’s disease. Exp Neurol 2007;204:583-8.
50. Cariulo C, Martufi P, Verani M, Azzollini L, Bruni G, et al. Phospho-S129 alpha-synuclein is present in human plasma but not in cerebrospinal fluid as determined by an ultrasensitive immunoassay. Front Neurosci 2019;13:889.
51. Foulds PG, Diggle P, Mitchell JD, Parker A, Hasegawa M, et al. A longitudinal study on alpha-synuclein in blood plasma as a biomarker for Parkinson’s disease. Sci Rep 2013;3:2540.
52. Barbour R, Kling K, Anderson JP, Banducci K, Cole T, et al. Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 2008;5:55-9.
53. Tian C, Liu G, Gao L, Soltys D, Pan C, et al. Erythrocytic alpha-Synuclein as a potential biomarker for Parkinson’s disease. Transl Neurodegener 2019;8:15.
54. Adler CH, Serrano GE, Zhang N, Hinni ML, Lott DG, et al. Feasibility of repeat and bilateral submandibular gland needle biopsies in Parkinson’s disease. Parkinsonism Relat Disord 2019;68:69-72.
55. Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol 2010;119:703-13.
56. Kang W, Chen W, Yang Q, Zhang L, Zhang L, et al. Salivary total alpha-synuclein, oligomeric alpha-synuclein and SNCA variants in Parkinson’s disease patients. Sci Rep 2016;6:28143.
57. Vivacqua G, Suppa A, Mancinelli R, Belvisi D, Fabbrini A, et al. Salivary alpha-synuclein in the diagnosis of Parkinson’s disease and Progressive Supranuclear Palsy. Park Relat Disord 2019;63:143-8.
58. Al-Nimer MSM, Mshatat SF, Abdulla HI. Saliva alpha-synuclein and a high extinction coefficient protein: a novel approach in assessment biomarkers of Parkinson’s disease. N Am J Med Sci 2014;6:633-7.
59. Devic I, Hwang H, Edgar JS, Izutsu K, Presland R, et al. Salivary alpha-synuclein and DJ-1: potential biomarkers for Parkinson’s disease. Brain 2011;134:178.
60. Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J Neurosci 2005;25:6016-24.
61. Recasens A, Dehay B. Alpha-synuclein spreading in Parkinson’s disease. Front Neuroanat 2014;8:159.
62. Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 2011;42:360-7.
63. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, et al. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 2010;30:6838-51.
64. Von Bartheld CS, Altick AL. Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol 2011;93:313-40.
65. Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, et al. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 2012;7:42.
66. Bellingham SA, Guo BB, Coleman BM, Hill AF. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases. Front Physiol 2012;3:124.
67. Chang C, Lang H, Geng N, Wang J, Li N, et al. Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. Neurosci Lett 2013;548:190-5.
68. Zhao ZH, Chen ZT, Zhou RL, Zhang X, Ye QY, et al. Increased DJ-1 and α-synuclein in plasma neural-derived exosomes as potential markers for Parkinson’s disease. Front Aging Neurosci 2018;10:438.
69. Stuendl A, Kunadt M, Kruse N, Bartels C, Moebius W, et al. Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies. Brain 2016;139:481-94.
70. Shi M, Liu C, Cook TJ, Bullock KM, Zhao Y, et al. Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol 2014;128:639-50.
71. Shi M, Kovac A, Korff A, Cook TJ, Ginghina C, et al. CNS tau efflux via exosomes is likely increased in Parkinson’s disease but not in Alzheimer’s disease. Alzheimers Dement 2016;12:1125-31.
72. Tomlinson PR, Zheng Y, Fischer R, Heidasch R, Gardiner C, et al. Identification of distinct circulating exosomes in Parkinson’s disease. Ann Clin Transl Neurol 2015;2:353-61.
73. Papadopoulos VE, Nikolopoulou G, Antoniadou I, Karachaliou A, Arianoglou G, et al. Modulation of β-glucocerebrosidase increases α-synuclein secretion and exosome release in mouse models of Parkinson’s disease. Hum Mol Genet 2018;27:1696-710.
74. Parnetti L, Paciotti S, Eusebi P, Dardis A, Zampieri S, et al. Cerebrospinal fluid β-glucocerebrosidase activity is reduced in parkinson’s disease patients. Mov Disord 2017;32:1423-31.
75. Cerri S, Ghezzi C, Sampieri M, Siani F, Avenali M, et al. The exosomal/total α-synuclein ratio in plasma is associated with glucocerebrosidase activity and correlates with measures of disease severity in PD patients. Front Cell Neurosci 2018;12:125.
76. Gui YX, Liu H, Zhang LS, Lv W, Hu XY. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 2015;6:37043-53.
77. Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, et al. alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 2015;522:340-4.
