Vol 54, No 1 (2020)
Review Article
Published online: 2020-01-31
In search of Parkinson’s disease biomarkers — is the answer in our mouths? A systematic review of the literature on salivary biomarkers of Parkinson’s disease
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Abstract
The identification of reliable biomarkers of Parkinson’s disease (PD) is a pivotal step in the introduction of causal therapies. Saliva is a biofluid which may be involved in synuclein pathology in PD. We have reviewed current studies on salivary proteins and compounds in PD patients and healthy controls, and their potential application as biomarkers. A systematic literature search of the Pubmed and Scopus databases was performed. A total of 198 studies were screened, of which 20 were included in our qualitative analysis. We conclude that the oligomeric form of salivary alpha synuclein is higher in PD patients, and that this may serve as a potential biomarker of PD. Salivary DJ-1 concentrations fail to differentiate PD patients from controls. Other enzymes and substances (heme oxygenase-1, nitric oxide, acetylcholinesterase) have been assessed in single studies. Salivary cortisol levels are higher in PD than in healthy subjects. Further validation of these findings is needed.
Saliva may be a promising source of biomarkers in PD.
Keywords: Parkinson’s diseasesalivabiomarkerneurodegeneration
References
- Lau Lde, Breteler M. Epidemiology of Parkinson's disease. The Lancet Neurology. 2006; 5(6): 525–535.
- Parkinson J. An Essay on the Shaking Palsy: Sherwood, Neely, and Jones. ; 1817.
- Potulska A, Friedman A, Królicki L, et al. [Swallowing disorders in Parkinson's disease]. Neurol Neurochir Pol. 2002; 36(3): 449–456.
- Proulx M, de Courval FP, Wiseman MA, et al. Salivary production in Parkinson's disease. Mov Disord. 2005; 20(2): 204–207.
- Cersósimo MG, Tumilasci OR, Raina GB, et al. Hyposialorrhea as an early manifestation of Parkinson disease. Auton Neurosci. 2009; 150(1-2): 150–151.
- Karakoc M, Yon MI, Cakmakli GY, et al. Pathophysiology underlying drooling in Parkinson's disease: oropharyngeal bradykinesia. Neurol Sci. 2016; 37(12): 1987–1991.
- Tumilasci OR, Cersósimo MG, Belforte JE, et al. Quantitative study of salivary secretion in Parkinson's disease. Mov Disord. 2006; 21(5): 660–667.
- Masters JM, Bestwick J, Warner TT, et al. Systematic review and meta-analysis of salivary protein concentration in Parkinson's disease. Mov Disord. 2015; 30(14): 1971–1972.
- Masters JM, Noyce AJ, Warner TT, et al. Elevated salivary protein in Parkinson's disease and salivary DJ-1 as a potential marker of disease severity. Parkinsonism Relat Disord. 2015; 21(10): 1251–1255.
- Gelpi E, Navarro-Otano J, Tolosa E, et al. Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord. 2014; 29(8): 1010–1018.
- Del Tredici K, Hawkes CH, Ghebremedhin E, et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson's disease. Acta Neuropathol. 2010; 119(6): 703–713.
- Cersósimo MG, Perandones C, Micheli FE, et al. Alpha-synuclein immunoreactivity in minor salivary gland biopsies of Parkinson's disease patients. Mov Disord. 2011; 26(1): 188–190.
- Adler CH, Dugger BN, Hentz JG, et al. Peripheral Synucleinopathy in Early Parkinson's Disease: Submandibular Gland Needle Biopsy Findings. Mov Disord. 2016; 31(2): 250–256.
- Beach TG, Adler CH, Dugger BN, et al. Arizona Parkinson’s Disease Consortium. Submandibular gland biopsy for the diagnosis of Parkinson disease. J Neuropathol Exp Neurol. 2013; 72(2): 130–136.
- Adler CH, Dugger BN, Hinni ML, et al. Submandibular gland needle biopsy for the diagnosis of Parkinson disease. Neurology. 2014; 82(10): 858–864.
- Moher D, Liberati A, Tetzlaff J, et al. PRISMA Group, PRISMA Group, PRISMA Group, PRISMA Group, PRISMA Group, PRISMA Group, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med. 2009; 3(3): e123–e130.
- Devic I, Hwang H, Edgar JS, et al. Salivary α-synuclein and DJ-1: potential biomarkers for Parkinson's disease. Brain. 2011; 134(Pt 7): e178.
- Stewart T, Sui YT, Gonzalez-Cuyar LF, et al. Cheek cell-derived α-synuclein and DJ-1 do not differentiate Parkinson's disease from control. Neurobiol Aging. 2014; 35(2): 418–420.
- Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature. 1997; 388(6645): 839–840.
- Spillantini MG, Crowther RA, Jakes R, et al. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proc Natl Acad Sci U S A. 1998; 95(11): 6469–6473.
- Baba M, Nakajo S, Tu PH, et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol. 1998; 152(4): 879–884.
- Vivacqua G, Latorre A, Suppa A, et al. Abnormal Salivary Total and Oligomeric Alpha-Synuclein in Parkinson's Disease. PLoS One. 2016; 11(3): e0151156.
- Vivacqua G, Suppa A, Mancinelli R, et al. Salivary alpha-synuclein in the diagnosis of Parkinson's disease and Progressive Supranuclear Palsy. Parkinsonism Relat Disord. 2019; 63: 143–148.
- Al-Nimer MSM, Mshatat SF, Abdulla HI. Saliva α-Synuclein and A High Extinction Coefficient Protein: A Novel Approach in Assessment Biomarkers of Parkinson's Disease. N Am J Med Sci. 2014; 6(12): 633–637.
- Goldman JG, Andrews H, Amara A, et al. Fox Investigation of New Biomarker Discovery. Cerebrospinal fluid, plasma, and saliva in the BioFIND study: Relationships among biomarkers and Parkinson's disease Features. Mov Disord. 2018; 33(2): 282–288.
- Kang W, Chen W, Yang Q, et al. Salivary total α-synuclein, oligomeric α-synuclein and SNCA variants in Parkinson's disease patients. Sci Rep. 2016; 6: 28143.
- Cao Z, Wu Y, Liu G, et al. α-Synuclein in salivary extracellular vesicles as a potential biomarker of Parkinson's disease. Neurosci Lett. 2019; 696: 114–120.
- Zhang Li, Shimoji M, Thomas B, et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet. 2005; 14(14): 2063–2073.
- Kang WY, Yang Q, Jiang XF, et al. Salivary DJ-1 could be an indicator of Parkinson's disease progression. Front Aging Neurosci. 2014; 6: 102.
- Masters J, Noyce A, Lynham S, et al. comprehensive characterisation of the salivary proteome of patients with Parkinson's disease. 20th International Congress of Parkinson's Disease and Movement Disorders. ; 2016.
- Skogar O, Fall PA, Hallgren G, et al. Diurnal salivary cortisol concentrations in Parkinson's disease: increased total secretion and morning cortisol concentrations. Int J Gen Med. 2011; 4: 561–569.
- Costa CM, Oliveira GL, Fonseca AC, et al. Levels of cortisol and neurotrophic factor brain-derived in Parkinson's disease. Neurosci Lett. 2019; 708: 134359.
- Djamshidian A, O'Sullivan SS, Papadopoulos A, et al. Salivary cortisol levels in Parkinson's disease and its correlation to risk behaviour. J Neurol Neurosurg Psychiatry. 2011; 82(10): 1107–1111.
- Bolitho SJ, Naismith SL, Rajaratnam SMW, et al. Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease. Sleep Med. 2014; 15(3): 342–347.
- Schröder JB, Marian T, Claus I, et al. Substance P Saliva Reduction Predicts Pharyngeal Dysphagia in Parkinson's Disease. Front Neurol. 2019; 10: 386.
- Fedorova T, Knudsen CS, Mouridsen K, et al. Salivary acetylcholinesterase activity is increased in Parkinson's disease: a potential marker of parasympathetic dysfunction. Parkinsons Dis. 2015; 2015: 156479.
- Huskić J, Paperniku A, Husić A, et al. Significantly reduced salivary nitric oxide synthesis in patients with Parkinson's disease. Bosn J Basic Med Sci. 2005; 5(3): 86–89.
- Song W, Kothari V, Velly AM, et al. Evaluation of salivary heme oxygenase-1 as a potential biomarker of early Parkinson's disease. Mov Disord. 2018; 33(4): 583–591.
- Bermejo-Pareja F, Antequera D, Vargas T, et al. Saliva levels of Abeta1-42 as potential biomarker of Alzheimer's disease: a pilot study. BMC Neurol. 2010; 10: 108.
- Chuang YH, Paul KC, Bronstein JM, et al. Parkinson's disease is associated with DNA methylation levels in human blood and saliva. Genome Med. 2017; 9(1): 76.
- Kalia LV, Kalia SK, McLean PJ, et al. α-Synuclein oligomers and clinical implications for Parkinson disease. Ann Neurol. 2013; 73(2): 155–169.
- Roberts RF, Wade-Martins R, Alegre-Abarrategui J. Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson's disease brain. Brain. 2015; 138(Pt 6): 1642–1657.
- Zhou Bo, Wen M, Yu WF, et al. The Diagnostic and Differential Diagnosis Utility of Cerebrospinal Fluid α -Synuclein Levels in Parkinson's Disease: A Meta-Analysis. Parkinsons Dis. 2015; 2015: 567386.
- Hamm-Alvarez SF, Okamoto CT, Janga SR, et al. Oligomeric α-synuclein is increased in basal tears of Parkinson's patients. Biomark Med. 2019; 13(11): 941–952.
- Fall PA, Saleh A, Fredrickson M, et al. Survival time, mortality, and cause of death in elderly patients with Parkinson's disease: a 9-year follow-up. Mov Disord. 2003; 18(11): 1312–1316.
- Gomar-Vercher S, Simón-Soro A, Montiel-Company JM, et al. Stimulated and unstimulated saliva samples have significantly different bacterial profiles. PLoS One. 2018; 13(6): e0198021.
- Hong Z, Shi M, Chung KA, et al. DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease. Brain. 2010; 133(Pt 3): 713–726.
- Barbe AG, Heinzler A, Derman S, et al. Hyposalivation and xerostomia among Parkinson's disease patients and its impact on quality of life. Oral Dis. 2017; 23(4): 464–470.
