Abstract
A retrospective autopsy-based study of the human submandibular gland, one of the three major salivary glands, together with anatomically related peripheral structures (cervical superior ganglion, cervical sympathetic trunk, vagal nerve at the level of the carotid bifurcation), was conducted on a cohort consisting of 33 individuals, including 9 patients with neuropathologically confirmed Parkinson’s disease (PD), three individuals with incidental Lewy body disease (iLBD), 2 individuals with neuropathologically confirmed multiple system atrophy (MSA), and 19 controls, using α-synuclein immunohistochemistry in 100 μm polyethylene glycol-embedded tissue sections. Lewy pathology (LP) was present in the submandibular glands and cervical superior ganglia in PD (9/9 cases) and iLBD (2/3 cases) but not in MSA or controls. The cervical sympathetic trunk (7/9 PD cases, 2/3 iLBD cases) and peripheral vagal nerves (9/9 PD cases, 2/3 iLBD cases) also displayed LP. The results are discussed within the context of hyposmia as well as autonomic dysfunction in PD (sialorrhea, sialopenia, dysphagia). Potential disease-related changes in salivary volume, contents, and viscosity might make it possible, in combination with other tests, to employ human saliva as a biomarker.
Similar content being viewed by others
References
Bagheri H, Damase-Michel C, Lapeyre-Mestre M et al (1999) A study of salivary secretion in Parkinson’s disease. Clin Neuropharmacol 22:213–215
Baltadzhieva R, Gurevich T, Korczyn AD (2005) Autonomic impairment in amyotrophic lateral sclerosis. Curr Opin Neurol 18:487–493
Bassotti G, Germani U, Pagliaricci S et al (1998) Esophageal manometric abnormalities in Parkinson’s disease. Dysphagia 13:28–41
Bateson MC, Gibberd FB, Wilson RSE (1973) Salivary symptoms in Parkinson’s disease. Arch Neurol 29:274–275
Blessing WW (2004) Lower brain stem regulation of visceral, cardiovascular, and respiratory function. In: Paxinos G, Mai JK (eds) The human nervous system, 2nd edn. Elsevier, London, pp 464–478
Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neurobiol Appl Neurol 32:284–295
Boyce HW, Bakheet MR (2005) Sialorrhea: a review of a vexing, often unrecognized sign of oropharyngeal and esophageal disease. J Clin Gastroenterol 39:89–97
Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259
Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211
Braak H, de Vos RAI, Bohl J, Del Tredici K (2006) Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 39:67–72
Braak H, Sastre M, Bohl JRE, de Vos RAI, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113:421–429
Bradley RM, Fukami H, Suwabe T (2005) Neurobiology of the gustatory–salivary reflex. Chem Senses 30:i70–i71
Byrne KG, Pfeiffer RM, Quigley EMM (1994) Gastrointestinal dysfunction in Parkinson’s disease: a report of clinical experience at a single center. J Clin Gastroenterol 19:11–16
Cersósimo MG, Benarroch EE (2008) Neural control of the gastrointestinal tract: implications for Parkinson disease. Mov Disord 23:1065–1073
Chatoo AH, Lee VM, Linden RA (1953) Evidence for synergism between the masticatory and gustatory parotid salivary reflexes in humans. J Physiol 459:34
Chou KL, Evatt M, Hinson V, Kompoliti K (2007) Sialorrhea in Parkinson’s disease: a review. Mov Disord 22:2306–2313
Cook DI, van Lennep EW, Roberts ML, Young JA (1994) Secretion by the major salivary glands. In: Johnson LR (ed) Physiology of the gastrointestinal tract, 3rd edn. Raven, New York, pp 1061–1117
Crawford JM (1997) The oral cavity and gastrointestinal tract. In: Kumar V, Cotran RS, Robbins SL (eds) Basic pathology. W.B. Saunders, Philadelphia, pp 470–515
Del Tredici K, Rüb U, de Vos RAI, Bohl JRE, Braak H (2002) Where does Parkinson pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426
den Hartog Jager WA, Bethlem J (1960) The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23:283–290
Dickson DW, Fujishiro H, DelleDonne A et al (2008) Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 115:437–444
Dickson DW, Braak H, Duda JE et al (2009) Diagnostic criteria for the neuropathological assessment of Parkinson disease. Lancet Neurol 8:1150–1157
Doty RL, Deems D, Stellar S (1988) Olfactory dysfunction in Parkinson’s disease: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 38:1237–1244
Doty RL, Stern MB, Pfeiffer C, Gollomp SM, Hurtig HI (1992) Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 55:138–142
Edwards LL, Pfeiffer RF, Quigley EMM, Hofman R, Balluff M (1991) Gastrointestinal symptoms in Parkinson’s disease. Mov Disord 6:151–156
Edwards LL, Quigley EM, Harned RK, Hofmann R, Pfeiffer RF (1994) Characterization of swallowing and defecation in Parkinson’s disease. Am J Gastroenterol 1:15–25
Emmelin N (1987) Nerve interactions in salivary glands. J Dent Res 66:509–517
Evatt ML, Chaudhuri KR, Chou KL et al (2009) Dysautonomia rating scales in Parkinson’s disease: sialorrhea, dysphagia, and constipation—critique and recommendations by Movement Disorders Task Force on Rating Scales for Parkinson’s disease. Mov Disord 24:635–646
Forno LS, Norville RL (1976) Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol 34:183–197
Frigerio R, Fujishiro H, Ahn TB et al (2009) Incidental Lewy body disease: do some cases represent a preclinical stage of dementia with Lewy bodies? Neurobiol Aging. doi:10.1016/j.neurobiolaging.2009.05.019
Fujishiro H, Frigerio R, Burnett M et al (2008) Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson’s disease. Mov Disord 23:1085–1092
Fumimura Y, Ikemura M, Saito Y et al (2007) Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lewy body disease. J Neuropathol Exp Neurol 66:354–362
Garrett JR (1967) The innervation of normal human submandibular and parotid salivary glands. Arch Oral Biol 12:1417
Garrett JR (1987) The proper role of nerves in salivatory secretion—a review. J Dent Res 66:387–397
Gerling G, Garrett JR, Paterson KL et al (2008) Innervation and secretory function of transplanted human submandibular salivary glands. Transplantation 85:135–140
Ghebremedhin E, Del Tredici K, Langston JW, Braak H (2009) Diminished tyrosine hydroxylase immunoreactivity in the cardiac conduction system and myocardium in Parkinson’s disease: an anatomical study. Acta Neuropathol 118:777–784
Giess R, Werner E, Beck M et al (2002) Impaired salivary gland function reveals autonomic dysfunction in amyotrophic lateral sclerosis. J Neurol 249:1246–1249
Gilman S, Wenning GK, Low PA et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676
Goetz CG, Power W, Rascol O et al (2004) Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19:1020–1028
Goldstein DS, Holmes CS, Dendi R, Bruce SR, Li ST (2002) Orthostatic hypotension from sympathetic denervation in Parkinson’s disease. Neurology 58:1247–1255
Hawkes CH, Shephard BC, Daniel SE (1997) Olfactory dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry 62:436–444
Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG (2008) The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 23:837–844
Hornby PJ, Abrahams TP (2000) Central control of lower esophageal sphincter relaxation. Am J Med 108(Suppl 4):90S–98S
Iwanaga K, Wakabayashi K, Yoshimoto M et al (1999) Lewy body type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 52:1269–1271
Kaplan MD, Baum BJ (1993) The function of saliva. Dysphagia 9:225–229
Klosen P, Maessen X, de Aguilar P (1993) PEG embedding for immunocytochemistry: application to the analysis of immunoreactivity loss during histological processing. J Histochem Cytochem 41:455–463
Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of α-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253
Kyriacou K, Garrett JR (1988) Morphological changes in the rabbit submandibular gland after parasympathetic or sympathetic denervation. Arch Oral Biol 33:281–290
Leopold NA, Kagel MC (1995) Prepharyngeal dysphagia in Parkinson’s disease. Dysphagia 11:14–22
Leopold NA, Kagel MC (1997) Pharyngo-esophageal dysphagia in Parkinson’s disease. Dysphagia 12:11–18
Loewy AD (1991) Forebrain nuclei involved in autonomic control. Prog Brain Res 87:253–268
Markesbery WR, Jicha GA, Liu H, Schmitt FA (2009) Lewy body pathology in normal elderly subjects. J Neuropathol Exp Neurol 68:816–822
Martinez-Madrigal F, Micheau C (1989) Histology of the major salivary glands. Am J Surg Pathol 13:879–899
Martinez-Marin P, Schapira AHV, Stocchi F et al (2007) Prevalence of nonmotor symptoms in Parkinson’s disease in an international setting: study using nonmotor symptoms questionnaire in 545 patients. Mov Disord 23:1623–1629
McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872
Miki Y, Mori F, Wakabayashi K, Kuroda N, Orimo S (2009) Incidental Lewy body disease restricted to the heart and stellate ganglion. Mov Disord 24:2299–2301
Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F et al (2007) Do α-synuclein aggregates in autonomic plexuses predate Lewy body disorders? A cohort study. Neurology 68:2012–2018
Nishie M, Mori F, Yoshimoto M, Takahashi H, Wakabayashi K (2004) A quantitative investigation of neuronal cytoplasmic and intranuclear inclusions in the pontine and inferior olivary nuclei in multiple system atrophy. Neuropathol Appl Neurobiol 30:546–554
Orimo S, Takahashi A, Uchihara T et al (2007) Degeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson’s disease. Brain Pathol 17:24–30
Orimo S, Uchihara T, Nakamura A et al (2008) Axonal α-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 131:642–650
Pfeiffer RF (1998) Gastrointestinal dysfunction in Parkinson’s disease. Clin Neurosci 5:136–146
Pfeiffer RF (2003) Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2:107–116
Probst A, Bloch A, Tolnay M (2008) New insights into the pathology of Parkinson’s disease: does the peripheral autonomic nervous system become central? Eur J Neurol 15(Suppl 1):1–4
Proctor GB, Carpenter GH (2007) Regulation of salivary gland function by autonomic nerves. Auton Neurosci Basic Clin 133:3–18
Proulx M, de Courval FP, Wiseman MA, Panisset M (2005) Salivary production in Parkinson’s disease. Mov Disord 20:204–207
Qualman SJ, Haupt HM, Yang P, Hamilton SR (1984) Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Similarity to Parkinson’s disease. Gastroenterology 87:848–856
Richards WG, Sugarbaker DJ (1995) Neuronal control of esophageal function. Chest Surg Clin North Am 5:157–171
Robbins JA, Logemann JA, Kirshner HS (1986) Swallowing and speech production in Parkinson’s disease. Ann Neurol 19:283–287
Ross GW, Petrovitch H, Abbott RD et al (2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21:2062–2067
Schwab RS, England AS (1958) Parkinson’s disease. J Chronic Dis 8:448–501
Shannon IL, Suddick RP, Chauncey HH (1969) Effect of atropine-induced flow rate depression on composition of unstimulated human parotid fluid. Arch Oral Biol 14:761–770
Siddiqui MF, Rast S, Lynn MJ, Auchus AP, Pfeiffer RF (2002) Autonomic dysfunction in Parkinson’s disease: a comprehensive symptom survey. Parkinsonism Rel Disord 8:277–284
Silvers AR, Som PM (1998) Salivary glands. Radiol Clin North Am 36:941–966
Sone M, Yoshida M, Hashizume Y, Hishikawa N, Sobue G (2005) α-Synuclein-immunoreactive structure formation is enhanced in sympathetic ganglia of patients with multiple system atrophy. Acta Neuropathol 110:19–26
Takeda S, Yamazaki K, Miyakawa T, Arai H (1993) Parkinson’s disease with involvement of the parasympathetic ganglia. Acta Neuropathol 86:397–398
Taki J, Nakajima K, Hwang EH et al (2000) Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27:566–573
Tissingh G, Berendse HW, Bergmanns P et al (2001) Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov Disord 16:41–46
Tumilasci OR, Cersósimo MG, Belforte JE, Micheli FE, Benarroch EE, Pazo JH (2006) Quantitative study of salivary secretion in Parkinson’s disease. Mov Disord 21:660–667
Verbaan D, Marinus J, Visser M, van Rooden SM, Stiggelbout AM, van Hilten JJ (2007) Patient-reported autonomic symptoms in Parkinson’s disease. Neurology 69:333–341
Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F (1988) Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol 76:217–221
Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F (1990) Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol 79:581–583
Wakabayashi K, Takahashi H, Obata K, Ikuta F (1992) Immunocytochemical localization of synaptic vesicle-specific protein in Lewy body-containing neurons in Parkinson’s disease. Neurosci Lett 138:237–240
Wakabayashi K, Takahashi H, Ohama E, Takeda S, Ikuta F (1993) Lewy bodies in the visceral autonomic nervous system in Parkinson’s disease. Adv Neurol 60:609–612
Acknowledgments
This study was made possible by funding from the German Research Council (Deutsche Forschungsgemeinschaft, DFG), the Hilde Ulrichs Foundation (Florstadt-Staden), and the Michael J. Fox Foundation for Parkinson’s Research. A summary of the findings reported in this paper was presented at the Alpha-synuclein Summit held in New York City on 14 January 2009 under the auspices of the Michael J. Fox Foundation. The authors also wish to thank Prof. Albert C. Ludolph (Director, Department of Neurology, University of Ulm) and Dr. med. dent. Clemens Stadler (Blaustein) for ongoing discussions. They acknowledge Ms. Siegrid Baumann, Ms. Gabrielle Ehmke, Ms. Verena Hofmann (immunohistochemistry, Center for Clinical Research, University of Ulm), Mr. Stephan Mayer (graphics, Department of Neurology, University of Ulm) for their technical expertise, and the Braak Collection (Goethe University Frankfurt).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Del Tredici, K., Hawkes, C.H., Ghebremedhin, E. et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol 119, 703–713 (2010). https://doi.org/10.1007/s00401-010-0665-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-010-0665-2