Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter November 24, 2018

Alpha-synuclein in salivary gland as biomarker for Parkinson’s disease

Flaminia Campo, Raffaella Carletti, Massimo Fusconi, Clelia Pellicano, Francesco E. Pontieri, Cira R. Di Gioia and Marco de Vincentiis

Abstract

Estimates of the accuracy of clinical diagnosis of Parkinson’s disease (PD) range between 46% and 90%, the accuracy of diagnosis dependent on prolonged clinical observation and clinical response to levodopa. For this reason, we need reliable diagnostic biomarkers. The cardinal hallmark of PD is alpha-synuclein aggregation in the brain. Demonstrating pathological alpha-synuclein in live patients would be useful for identifying and monitoring PD patients. By autopsy studies and in vivo studies, the presence of alpha-synuclein has been demonstrated even outside the central nervous system and the gastro-enteric tract appears to be the most promising candidate tissue for biopsy-taking and the esophagus and salivary glands appear to be the area with the highest concentration of alpha-synuclein. The purpose of our study is to conduct a review to determine the utility of salivary gland biopsy for the histological diagnosis of PD. A computerized medline study was carried out through the use of pubmed: using the MeSH terms: ‘salivary gland biopsy for PD’, ‘PD and dysphagia’, ‘alpha-synuclein and salivary gland’. We found 9 articles about minor salivary glands and submandibular gland biopsy for diagnosis of PD. According to the results of this review, the submandibular gland biopsy is the test with the increased sensitivity and specificity compared to the biopsy of the minor salivary glands (sensitivity: 0.85 and 0.37 respectability and specificity: 0.96 and 0.94 respectively). New studies are necessary on a wider population to confirm these results.

  1. Funding: This study was not funded.

  2. Conflict of interest statement: The authors have no conflict of interest. There are not financial or personal relationships with other people or organizations that could inappropriately influence the authors’ actions.

  3. Ethical approval: This article does not contain any studies with animals performed by any of the authors.

References

Adler, C.H., Dugger, B.N., Hinni, M.L., Lott, D.G., Driver-Dunckley, E., Hidalgo, J., Henry-Watson, J., Serrano, G., Sue, L.I., Nagel, T., et al. (2014). Submandibular gland needle biopsy for the diagnosis of Parkinson disease. Neurology 82, 858–864.10.1212/WNL.0000000000000204Search in Google Scholar

Adler, C.H., Dugger, B.N., Hentz, J.G., Hinni, M.L., Lott, D.G., Driver-Dunckley, E., Mehta, S., Serrano, G., Sue, L.I., Duffy, A., et al. (2016). Peripheral synucleinopathy in early Parkinson’s disease: submandibular gland needle biopsy findings. Mov. Disord. 31, 250–256.10.1002/mds.26476Search in Google Scholar PubMed

Beach, T.G., Adler, C.H., Dugger, B.N., Serrano, G., Hidalgo, J., Henry-Watson, J., Shill, H.A., Sue, L.I., Sabbagh, M.N., Akiyama, H., et al. (2013). Submandibular gland biopsy for the diagnosis of Parkinson disease. J. Neuropathol. Exp. Neurol. 72, 130–136.10.1097/NEN.0b013e3182805c72Search in Google Scholar

Bennett, M.C. (2005). The role of α-synuclein in neurodegenerative diseases. Pharmacol. Ther. 5, 311–331.10.1016/j.pharmthera.2004.10.010Search in Google Scholar

Campbell, B.C., McLean, C.A., Culvenor, J.G., Gai, W.P., Blumbergs, P.C., Jäkälä, P., Beyreuther, K., Masters, C.L., and Li, Q.X. (2001). The solubility of α-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J. Neurochem. 76, 87–96.10.1046/j.1471-4159.2001.00021.xSearch in Google Scholar PubMed

Carletti, R., Campo, F., Fusconi, M., Pellicano, C., De Vincentiis, M., Pontieri, F.E., and Di Gioia, C.R. (2018). Phosphorylated α-synuclein immunoreactivity in nerve fibers from minor salivary glands in Parkinson’s disease. Parkinsonism Relat. Disord. 38, 99–101.10.1016/j.parkreldis.2017.02.031Search in Google Scholar

Cersósimo, M.G., Perandones, C., Micheli, F.E., Raina, G.B., Beron, A.M., Nasswetter, G., Radrizzani, M., and Benarroch E.E. (2011). Alpha-synuclein immunoreactivity in minor salivary gland biopsies of Parkinson’s disease patients. Mov. Disord. 26, 188–190.10.1002/mds.23344Search in Google Scholar PubMed

de Lau, L.M. and Breteler, M.M. (2006). Epidemiology of Parkinson’s disease. Lancet Neurol. 5, 525–535.10.1016/S1474-4422(06)70471-9Search in Google Scholar PubMed

Del Tredici, K., Hawkes, C.H., Ghebremedhin, E., and Braak, H. (2010). Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta. Neuropathol. 119, 703–713.10.1007/s00401-010-0665-2Search in Google Scholar PubMed

Dickson, D.W., Braak, H., Duda, J.E., Duyckaerts, C., Gasser, T., Halliday, G.M., Hardy, J., Leverenz, J.B., Del Tredici, K., Wszolek, Z.K., et al. (2009). Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol. 8, 1150–1157.10.1016/S1474-4422(09)70238-8Search in Google Scholar PubMed

Folgoas, E., Lebouvier, T., Leclair-Visonneau, L., Cersosimo, M.G., Barthelaix, A., Derkinderen, P., and Letournel, F. (2013). Diagnostic value of minor salivary glands biopsy for the detection of Lewy pathology. Neurosci. Lett. 551, 62–64.10.1016/j.neulet.2013.07.016Search in Google Scholar PubMed

Gao, L., Chen, H., Li, X., Li, F., Ou-Yang, Q., and Feng, T. (2015). The diagnostic value of minor salivary gland biopsy in clinically diagnosed patients with Parkinson’s disease: comparison with DAT Pet scans. Neurol. Sci. 36, 1575–1580.10.1007/s10072-015-2190-5Search in Google Scholar PubMed

Hughes, A.J., Daniel, S.E., Kilford, L., and Lees, A.J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181–184.10.1136/jnnp.55.3.181Search in Google Scholar PubMed

Hughes, A.J., Daniel, S.E., and Lees, A.J. (2001). Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 57, 1497–1499.10.1212/WNL.57.8.1497Search in Google Scholar PubMed

Inagi, K., Schultz, E., and Ford, C.N. (1998). An anatomic study of the rat larynx: establishing the rat model for neuromuscular function. Otolaryngol. Head Neck Surg. 118, 74–81.10.1016/S0194-5998(98)70378-XSearch in Google Scholar PubMed

Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., de Silva, H.A., Kittel, A., and Saitoh T. (1995). The precursor protein of non-A β component of Alzheimer’s disease amyloid is a presynapticprotein of the central nervous system. Neuron 14, 467–475.10.1016/0896-6273(95)90302-XSearch in Google Scholar PubMed

Jean, A. (1984). Control of the central swallowing program by inputs from the peripheral receptors. J. Autonomic Nervous Syst. 10, 225–233.10.1016/0165-1838(84)90017-1Search in Google Scholar

Kalf, J.G., Munneke, M., van den Engel-Hoek, L., de Swart, B.J., Borm, G.F., Bloem, B.R., and Zwarts, M.J. (2011). Pathophysiology of diurnal drooling in Parkinson’s disease. Mov. Disord. 26, 1670–1676.10.1002/mds.23720Search in Google Scholar PubMed

Li, J.Y., Englund, E., Holton, J.L., Soulet, D., Hagell, P., Lees, A.J., Lashley, T., Quinn, N.P., Rehncrona, S., Björklund, A., et al. (2008). Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503.10.1038/nm1746Search in Google Scholar PubMed

Marshall, J.F. (1979). Somatosensory inattention after dopamine-depleting intracerebral 6-OHDA injections: spontaneous recovery and pharmacological control. Brain Res. 177, 311–324.10.1016/0006-8993(79)90782-0Search in Google Scholar PubMed

Mochizuki, H., Choong, C.J., and Masliah, E. (2018). A refined concept: α-synuclein dysregulation disease. Neurochem. Int. 119, 84–96.10.1016/j.neuint.2017.12.011Search in Google Scholar PubMed

Mukherjee, A., Biswas, A., and Das, S.K. (2016). Gut dysfunction in Parkinson’s disease. World J. Gastroenterol. 22, 5742–5752.10.3748/wjg.v22.i25.5742Search in Google Scholar PubMed PubMed Central

Müller, T., Palluch, R., and Jackowski, J. (2011). Caries and periodontal disease in patients with Parkinson’s disease. Spec. Care Dentist. 31, 178–181.10.1111/j.1754-4505.2011.00205.xSearch in Google Scholar PubMed

Nicaretta, D.H., Rosso, A.L., Mattos, J.P., Maliska, C., and Costa, M.M. (2013). Dysphagia and sialorrhea: the relationship to Parkinson’s disease. Arq. Gastroenterol. 50, 42–49.10.1590/S0004-28032013000100009Search in Google Scholar PubMed

Proulx, M., de Courval, F.P., Wiseman, M.A., and Panisset, M. (2005). Salivary production in Parkinson’s disease. Mov. Disord. 20, 204–207.10.1002/mds.20189Search in Google Scholar PubMed

Rajput, A.H., Rozdilsky, B., and Rajput, A. (1991). Accuracy of clinical diagnosis in Parkinsonism – a prospective study. Can. J. Neurol. Sci. 18, 275–278.10.1017/S0317167100031814Search in Google Scholar PubMed

Schneider, S.A., Boettner, M., Alexoudi, A., Zorenkov, D., Deuschl, G., and Wedel, T. (2016). Can we use peripheral tissue biopsies to diagnose Parkinson’s disease? A review of the literature. Eur. J. Neurol. 23, 247–261.10.1111/ene.12753Search in Google Scholar PubMed

Spillantini, M.G. and Goedert, M. (2000). The α-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Ann. NY Acad. Sci. 920, 16–27.10.1111/j.1749-6632.2000.tb06900.xSearch in Google Scholar PubMed

Srivanitchapoom, P., Pandey, S., and Hallett, M. (2014). Drooling in Parkinson’s disease: a review. Parkinsonism Relat. Disord. 20, 1109–1118.10.1016/j.parkreldis.2014.08.013Search in Google Scholar PubMed PubMed Central

Uéda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D.A., Kondo, J., Ihara, Y., and Saitoh, T. (1993). Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimerdisease. Proc. Natl. Acad. Sci. USA 90, 11282–11286.10.1073/pnas.90.23.11282Search in Google Scholar PubMed PubMed Central

Vilas, D., Iranzo, A., Tolosa, E., Aldecoa, I., Berenguer, J., Vilaseca, I., Martí, C., Serradell, M., Lomeña, F., Alós, L., et al. (2016). Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye movement sleep behaviour disorder: a case-control study. Lancet Neurol. 15, 708–718.10.1016/S1474-4422(16)00080-6Search in Google Scholar PubMed

Visanji, N.P., Mollenhauer, B., Beach, T.G., Adler, C.H., Coffey, C.S., Kopil, C.M., Dave, K.D., Foroud, T., Chahine, L., and Jennings, D. (2017). Systemic synuclein sampling study (S4). The systemic synuclein sampling study: toward a biomarker for Parkinson’s disease. Biomark. Med. 11, 359–368.10.2217/bmm-2016-0366Search in Google Scholar PubMed

Weinreb, P.H., Zhen, W., Poon, A.W., Conway, K.A., and Lansbury, P.T. Jr. (1996). NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35, 13709–13715.10.1021/bi961799nSearch in Google Scholar PubMed

Wood, S.J., Wypych, J., Steavenson, S., Louis, J.C., Citron, M., and Biere, A.L. (1999). α-Synuclein fibrillogenesis is nucleation dependent. Implications for the pathogenesis of Parkinson’s disease. J. Biol. Chem. 274, 19509–19512.10.1074/jbc.274.28.19509Search in Google Scholar PubMed

Zlotnik, Y., Balash, Y., Korczyn, A.D., Giladi, N., and Gurevich, T. (2015). Disorders of the oral cavity in Parkinson’s disease and parkinsonian syndromes. Parkinsons Dis. 2015, 379482.10.1155/2015/379482Search in Google Scholar PubMed PubMed Central

Received: 2018-06-22
Accepted: 2018-08-10
Published Online: 2018-11-24
Published in Print: 2019-07-26

©2019 Walter de Gruyter GmbH, Berlin/Boston