Cell and Tissue Research

, Volume 373, Issue 1, pp 267–286 | Cite as

Peripheral and central autonomic nervous system: does the sympathetic or parasympathetic nervous system bear the brunt of the pathology during the course of sporadic PD?

  • Satoshi OrimoEmail author
  • Estifanos Ghebremedhin
  • Ellen Gelpi


It is a well-established fact that the sympathetic, parasympathetic and enteric nervous systems are affected at early stages in Parkinson’s disease (PD). However, it is not yet clarified whether the earliest pathological events preferentially occur in any of these three divisions of the autonomic nervous system (ANS). Significant involvement of the peripheral autonomic nervous system of the heart and gastrointestinal tract has been documented in PD. Accumulating evidence suggests that the PD pathology spreads centripetally from the peripheral to central nervous system through autonomic nerve fibers, implicating the ANS as a major culprit in PD pathogenesis and a potential target for therapy. This study begins with a brief overview of the structures of the central and peripheral autonomic nervous system and then outlines the major clinicopathological manifestations of cardiovascular and gastrointestinal disturbances in PD.


Parkinson’s disease α-Synuclein Lewy body Autonomic nervous system Cardiovascular autonomic test Gastrointestinal system Parasympathetic Sympathetic Enteric nervous system Orthostatic hypotension Heart rate variability meta-Iodobenzylguanidine cardiac scintigraphy Tyrosine hydroxylase 



Part of these studies has been possible thanks to the SINBAR Innsbruck-Barcelona collaboration, the IDIBAPS Barcelona Brain Bank, the Fondo De Investigación Sanitaria (FIS)-Instituto de Salud Carlos III and the Spanish Ministry of Economy and Competitiveness PI13/01455.


  1. Adler CH, Connor DJ, Hentz JG, Sabbagh MN, Caviness JN, Shill HA, Noble B, Beach TG (2010) Incidental Lewy body disease: clinical comparison to a control cohort. Mov Disord 25:642–646PubMedPubMedCentralCrossRefGoogle Scholar
  2. Adler CH, Dugger BN, Hinni ML, Lott DG, Driver-Dunckley E, Hidalgo J, Henry-Watson J, Serrano G, Sue LI, Nagel T, Duffy A, Shill HA, Akiyama H, Walker DG, Beach TG (2014) Submandibular gland needle biopsy for the diagnosis of Parkinson disease. Neurology 82:858–864PubMedPubMedCentralCrossRefGoogle Scholar
  3. Adler CH, Dugger BN, Hentz JG, Hinni ML, Lott DG, Driver-Dunckley E, Mehta S, Serrano G, Sue LI, Duffy A, Intorcia A, Filon J, Pullen J, Walker DG, Beach TG (2016) Peripheral synucleinopathy in early Parkinson’s disease: submandibular gland needle biopsy findings. Mov Disord 31:250–256PubMedPubMedCentralCrossRefGoogle Scholar
  4. Alafuzoff I, Parkkinen L, Al-Sarraj S, Arzberger T, Bell J, Bodi I, Bogdanovic N, Budka H, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Kamphorst W, King A, Korkolopoulou P, Kovács GG, Larionov S, Meyronet D, Monoranu C, Morris J, Parchi P, Patsouris E, Roggendorf W, Seilhean D, Streichenberger N, Thal DR, Kretzschmar H, BrainNet Europe Consortium (2008) Assessment of α-synuclein pathology: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 67:125–143PubMedCrossRefGoogle Scholar
  5. Aldecoa I, Navarro-Otano J, Stefanova N, Sprenger FS, Seppi K, Poewe W, Cuatrecasas M, Valldeoriola F, Gelpi E, Tolosa E (2015) Alpha-synuclein immunoreactivity patterns in the enteric nervous system. Neurosci Lett 602:145–149PubMedCrossRefGoogle Scholar
  6. Amino T, Orimo S, Ihoh Y, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 15:29–34PubMedCrossRefGoogle Scholar
  7. Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M, Diep L, Keim PS, Shen X, Chataway T, Schlossmacher MG, Seubert P, Schenk D, Sinha S, Gai WP, Chilcote TJ (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752PubMedCrossRefGoogle Scholar
  8. Annerino DM, Arshad S, Taylor GM, Adler CH, Beach TG, Greene JG (2012) Parkinson’s disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol 124:665–680PubMedPubMedCentralCrossRefGoogle Scholar
  9. Arai K, Kato N, Kawashima K, Hattori T (2000) Pure autonomic failure in association with human a-synucleinopathy. Neurosci Lett 296:171–173PubMedCrossRefGoogle Scholar
  10. Bacon SJ, Smith AD (1993) A monosynaptic pathway from an identified vasomotor centre in the medial prefrontal cortex to an autonomic area in the thoracic spinal cord. Neuroscience 54:719–728PubMedCrossRefGoogle Scholar
  11. Barrenschee M, Zorenkov D, Böttner M, Lange C, Cossais F, Bernadette Scharf A, Deuschl G, Schneider SA, Ellrichmann M, Fritscher-Ravens A, Wedel T (2017) Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathol Commun 5:1PubMedPubMedCentralCrossRefGoogle Scholar
  12. Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White CL III, Akiyama H, Caviness JN, Shill HA, Sabbagh MN, Walker DG (2010) Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 119:689–702PubMedPubMedCentralCrossRefGoogle Scholar
  13. Beach TG, Adler CH, Dugger BN, Serrano G, Hidalgo J, Henry-Watson J, Shill HA, Sue LI, Sabbagh MN, Akiyama H, Arizona Parkinson’s Disease Consortium (2013) Submandibular gland biopsy for the diagnosis of Parkinson disease. J Neuropathol Exp Neurol 72:130–136PubMedPubMedCentralCrossRefGoogle Scholar
  14. Beach TG, Corbillé A-G, Letournel F, Kordower JH, Kremer T, Munoz DG, Intorcia A, Hentz J, Adler CH, Sue LI, Walker J, Serrano G, Derkinderen P (2016) Multicenter assessment of immunohistochemical methods for pathological alpha-synuclein in sigmoid colon of autopsied Parkinson’s disease and control subjects. J Parkinsons Dis 6:761–770PubMedPubMedCentralCrossRefGoogle Scholar
  15. Benarroch EE, Schmeichel AM, Sandroni P, Low PA, Parisi JE (2006) Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body diseases. Neurology 66:378–383PubMedCrossRefGoogle Scholar
  16. Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) Alpha-synuclein pathology of the spinal cord and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 32:284–295PubMedCrossRefGoogle Scholar
  17. Borghammer P (2018) How does Parkinson’s disease begin? Perspectives on neuroanatomical pathways, prions, and histology. Mov Disord 33:48–57PubMedCrossRefGoogle Scholar
  18. Böttner M, Zorenkov D, Hellwig I, Barrenschee M, Harde J, Fricke T, Deuschl G, Egberts J-H, Becker T, Fritscher-Ravens A, Arlt A, Wedel T (2012) Expression pattern and localization of alpha-synuclein in the human enteric nervous system. Neurobiol Dis 48:474–480PubMedCrossRefGoogle Scholar
  19. Braak H, Del Tredici K (2009) Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv Anat Embryol Cell Biol 201:1–119.Google Scholar
  20. Braak H, Rueb U, Gai WP, Del Tredici K (2003a) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536PubMedCrossRefGoogle Scholar
  21. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E (2003b) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  22. Braak H, Ghebremedhin E, Udo Rueb U, Bratzke HJ, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134PubMedCrossRefGoogle Scholar
  23. Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396:67–72PubMedCrossRefGoogle Scholar
  24. Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre-and postganglionic neurons. Acta Neuropathol 113:421–429PubMedCrossRefGoogle Scholar
  25. Buob A, Winter H, Kindermann M, Becker G, Möller JC, Oertel WH, Böhm M (2010) Parasympathetic but not sympathetic cardiac dysfunction at early stages of PD. Clin Res Cardiol 99:701–706PubMedCrossRefGoogle Scholar
  26. Bussolati G, Leonardo E (2008) Technical pitfalls potentially affecting diagnoses in immunohistochemistry. J Clin Pathol 61:1184–1192PubMedCrossRefGoogle Scholar
  27. Cersosimo MG, Benarroch EE (2012a) Pathological correlates of gastrointestinal dysfunction in Parkinson’s disease. Neurobiol Dis 46:559–564PubMedCrossRefGoogle Scholar
  28. Cersosimo MG, Benarroch EE (2012b) Autonomic involvement in Parkinson’s disease: pathology, pathophysiology, clinical features and possible peripheral biomarkers. J Neurol Sci 313:57–63PubMedCrossRefGoogle Scholar
  29. Cersosimo MG, Raina GB, Calandra CR, Pellene A, Gutiérrez C, Micheli FE, Benarroch EE (2011) Dry mouth: an overlooked autonomic symptom of Parkinson’s disease. J Parkinsons Dis 1:169–173PubMedGoogle Scholar
  30. Cersosimo MG, Raina GB, Pecci C, Pellene A, Calandra CR, Gutiérrez C, Micheli FE, Benarroch EE (2013) Gastrointestinal manifestations in Parkinson’s disease: prevalence and occurrence before motor symptoms. J Neurol 260:1332–1338PubMedCrossRefGoogle Scholar
  31. Chaudhuri KR, Healy DG, Schapira AH (2006) Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 5:235–245PubMedCrossRefGoogle Scholar
  32. Corbillé AG, Coron E, Neunlist M, Derkinderen P, Lebouvier T (2014) Appraisal of the dopaminergic and noradrenergic innervation of the submucosal plexus in PD. J Parkinsons Dis 4:571–576PubMedGoogle Scholar
  33. Courbon F, Brefel-Courbon C, Thalamas C, Alibelli MJ, Berry I, Montastruc JL, Rascol O, Senard JM (2003) Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson’s disease. Mov Disord 18:890–897PubMedCrossRefGoogle Scholar
  34. Croisier E, MRes DE, Deprez M, Goldring K, Dexter DT, Pearce RK, Graeber MB, Roncaroli F (2006) Comparative study of commercially available anti-alpha-synuclein antibodies. Neuropathol Appl Neurobiol 32:351–356PubMedCrossRefGoogle Scholar
  35. Del Tredici K, Braak H (2012) Spinal cord lesions in sporadic Parkinson’s disease. Acta Neuropathol 124:643–664PubMedCrossRefGoogle Scholar
  36. Del Tredici K, Duda JE (2011) Peripheral Lewy body pathology in Parkinson’s disease and incidental Lewy body disease: four cases. J Neurol Sci 310:100–106PubMedCrossRefGoogle Scholar
  37. Del Tredici K, Rueb U, de Vos RAI, Bohl JRE, Braak H (2002) Where does Parkinson pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426PubMedCrossRefGoogle Scholar
  38. Del Tredici K, Hawkes CH, Ghebremedhin E, Braak H (2010) Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta Neuropathol 119:703–713PubMedCrossRefGoogle Scholar
  39. 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 23:283–290CrossRefGoogle Scholar
  40. Deuchars SA (2007) Multi-tasking in the spinal cord—do “sympathetic” interneurons work harder than we give them credit for? J Physiol 580:723–729PubMedPubMedCentralCrossRefGoogle Scholar
  41. Eadie MJ (1963) The pathology of certain medullary nuclei in parkinsonism. Brain 86:781–792PubMedCrossRefGoogle Scholar
  42. Ebbesson SOE (1965) Quantitative studies of superior cervical sympathetic ganglia in a variety of primates including man. 1. The ratio of preganglionic fibers to ganglionic neurons. J Morph 124:117–132CrossRefGoogle Scholar
  43. Fedorova TD, Seidelin LB, Knudsen K, Schacht AC, Geday J, Pavese N, Brooks DJ, Borghammer P (2017) Decreased intestinal acetylcholinesterase in early Parkinson disease: an 11C-donepezil PET study. Neurology 88:775–781PubMedCrossRefGoogle Scholar
  44. Folgoas E, Lebouvier T, Leclair-Visonneau L, Cersosimo MG, Barthelaix A, Derkinderen P, Letournel F (2013) Diagnostic value of minor salivary glands for the detection of Lewy pathology. Neurosci Lett 551:62–64PubMedCrossRefGoogle Scholar
  45. Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272PubMedCrossRefGoogle Scholar
  46. Gai WP, Blessing WW (1996) Human brainstem preganglionic parasympathetic neurons localized by markers for nitric oxide synthesis. Brain 119:1145–1152PubMedCrossRefGoogle Scholar
  47. Gai WP, Geffen LB, Denoroy L, Blessing WW (1992) Age-related loss of dorsal vagal neurons in Parkinson’s disease. Neurology 42:2106–2111PubMedCrossRefGoogle Scholar
  48. Gai WP, Blessing WW, Blumbergs PC (1995) Ubiquitin-positive degenerating neurites in the brainstem in Parkinson’s disease. Brain 118:1447–1459PubMedCrossRefGoogle Scholar
  49. Gao L, Chen H, Li X, Li F, Ou-Yang Q, 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 36:1575–1580PubMedCrossRefGoogle Scholar
  50. Gelpi E, Navarro-Otano J, Tolosa E, Gaig C, Compta Y, Rey MJ, Marti MJ, Hernandez I, Valldeoriola F, Rene R, Ribalta T (2014) Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders. Mov Disord 29:1010–1018PubMedCrossRefGoogle Scholar
  51. 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 118:777–784PubMedCrossRefGoogle Scholar
  52. Giancola F, Torresan F, Repossi R, Bianco F, Latorre R, Ioannou A, Guarino M, Volta U, Clavenzani P, Mazzoni M, Chiocchetti R, Bazzoli F, Travagli RA, Sternini C, De Giorgio R (2017) Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson’s disease and chronic constipation. Neurogastroenterol Motil 29(5).
  53. Gjerløff T, Fedorova T, Knudsen K, Munk OL, Nahimi A, Jacobsen S, Danielsen EH, Terkelsen AJ, Hansen J, Pavese N, Brooks DJ, Borghammer P (2015) Imaging acetylcholinesterase density in peripheral organs in Parkinson’s disease with 11C-donepezil PET. Brain 138:653–663PubMedCrossRefGoogle Scholar
  54. Goedert M, Spillantini MG, Del Tredici K, Braak H (2013) 100 years of Lewy pathology. Nat Rev Neurol 9:13–24PubMedCrossRefGoogle Scholar
  55. Goedert M, Masuda-Suzukake M, Falcon B (2017) Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration. Brain 140:266–278PubMedCrossRefGoogle Scholar
  56. Gold A, Turkalp ZT, Munoz DG (2013) Enteric alpha-synuclein expression is increased in Parkinson’s disease but not Alzheimer’s disease. Mov Disord 28:237–240PubMedCrossRefGoogle Scholar
  57. Goldstein DS, Holmes C, Cannon RO III, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696–702PubMedCrossRefGoogle Scholar
  58. Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133:338–347PubMedCrossRefGoogle Scholar
  59. Gray MT, Munoz DG, Gray DA, Schlossmacher MG, Woulfe JM (2014) Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects. Mov Disord 29:991–998PubMedCrossRefGoogle Scholar
  60. Grube D (1980) Immunoreactivities of gastrin (G-) cells. II. Non-specific binding of immunoglobulins to G-cells by ionic interactions. Histochemistry 66:149–167PubMedCrossRefGoogle Scholar
  61. Grundy G (2006) Signalling the state of the digestive tract. Auton Neurosci 125:76–80PubMedCrossRefGoogle Scholar
  62. Halliday GM, Blumbergs PC, Cotton RG, Blessing WW, Geffen LB (1990) Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res 510:104–107PubMedCrossRefGoogle Scholar
  63. Hardoff R, Sula M, Tamir A, Soil A, Front A, Badarna S, Honigman S, Giladi N (2001) Gastric emptying time and gastric motility in patients with Parkinson’s disease. Mov Disord 16:1041–1047PubMedCrossRefGoogle Scholar
  64. Hilton D, Stephens M, Kirk L, Edwards P, Potter R, Zajicek J, Broughton E, Hagan H, Carroll C (2014) Accumulation of α-synuclein in the bowel of patients in the preclinical phase of Parkinson’s disease. Acta Neuropathol 127:235–241PubMedCrossRefGoogle Scholar
  65. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, Wang ZY, Roybon L, Melki R, Li JY (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128:805–820PubMedCrossRefGoogle Scholar
  66. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184PubMedPubMedCentralCrossRefGoogle Scholar
  67. Hunter S (1985) The rostral mesencephalon in Parkinson’s disease and Alzheimer’s disease. Acta Neuropathol 68:53–58PubMedCrossRefGoogle Scholar
  68. Iranzo A, Tolosa E, Gelpi E (2013) Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behavior disorder: an observational cohort study. Lancet Neurol 12:443–453PubMedCrossRefGoogle Scholar
  69. Iranzo A, Gelpi E, Tolosa E, Molinuevo JL, Serradell M, Gaig C, Santamaria J (2014) Neuropathology of prodromal Lewy body disease. Mov Disord 29:410–415PubMedCrossRefGoogle Scholar
  70. Iwanaga K, Wakabayashi K, Yoshimoto M, Tomita I, Satoh H, Takashima H, Satoh A, Seto M, Tsujihata M, Takahashi H (1999) Lewy body-type degeneration in cardiac plexus in Parkinson's and incidental Lewy body diseases. Neurology 52:1269–1271PubMedCrossRefGoogle Scholar
  71. Jain S, Goldstein DS (2012) Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis. Neurobiol Dis 46:572–580PubMedCrossRefGoogle Scholar
  72. Janes RD, Brandys JC, Hopkins DA, Johnstone DE, Murphy DA, Armour JA (1986) Anatomy of human extrinsic cardiac nerves and ganglia. Am J Cardiol 57:299–309PubMedCrossRefGoogle Scholar
  73. Jellinger K (2003) a-Synuclein pathology in Parkinson’s and Alzheimer’s disease brain: incidence and topographic distribution—a pilot study. Acta Neuropathol 106:191–202PubMedCrossRefGoogle Scholar
  74. Jellinger KA (2008) A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol 116:1–16PubMedCrossRefGoogle Scholar
  75. Junqueira and Carneiro (1971) Histologie 3rd Ed. Verdauungsorgane, chapter 20. Springer Verlag, Berlin, pp 465–514Google Scholar
  76. Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) The dorsal motor nucleus of the vagus is not an obligatory trigger site of Parkinson’s disease: a critical analysis of alpha-synuclein staging. Neuropathol Appl Neurobiol 34:284–295PubMedCrossRefGoogle Scholar
  77. Kaufmann H, Goldstein DS (2013) Autonomic dysfunction in Parkinson’s disease. In: Buijs RM, Swaab DF (eds) Handbook of clinical neurology, 3rd edn. Elsevier, Amsterdam, pp 259–278Google Scholar
  78. Klos KJ, Ahlskog JE, Josephs KA, Apaydin H, Parisi JE, Boeve BF, DeLucia MW, Dickson DW (2006) Alpha-synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 66:1100–1102PubMedCrossRefGoogle Scholar
  79. Kozicz T, Bittencourt JC, May PJ, Reiner A, Gamlin PDR, Palkovits M, Horn AKE, Toledo CAB, Ryabinin AE (2011) The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J Comp Neurol 519:1413–1434PubMedPubMedCentralCrossRefGoogle Scholar
  80. Krassioukov AV, Bygrave MA, Puckett WR, Bunge RP, Rogers KA (1998) Human sympathetic preganglionic neurons and motoneurons retrogradely labelled with DiI. J Auton Nerv Syst 70:123–128PubMedCrossRefGoogle Scholar
  81. Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of alpha-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253PubMedCrossRefGoogle Scholar
  82. Langley JN (1898) On the union of cranial autonomic (visceral) fibers with nerve cells of the superior cervical ganglion. J Physiol 23:240–270PubMedPubMedCentralCrossRefGoogle Scholar
  83. Langley JN (1921) The autonomic nervous system. Part I. W. Heffer & Sons, CambridgeGoogle Scholar
  84. Langston JW (2006) The Parkinson’s complex: parkinsonism is just the tip of the iceberg. Ann Neurol 59:591–596PubMedCrossRefGoogle Scholar
  85. Langston JW, Forno LS (1978) The hypothalamus in Parkinson’s disease. Ann Neurol 3:129–133PubMedCrossRefGoogle Scholar
  86. Lebouvier T, Chaumette T, Damier P, Coron E, Touchefeu Y, Vrignaud S, Naveilhan P, Galmiche JP, Bruley d, Varannes S, Derkinderen P, Neunlist M (2008) Pathological lesions in colonic biopsies during Parkinson’s disease. Gut 57:1741–1743PubMedCrossRefGoogle Scholar
  87. Lebouvier T, Coron E, Chaumette T, Paillusson S, Bruley des Varannes S, Neunlist M, Derkinderen P (2010a) Routine colonic biopsies as a new tool to study the enteric nervous system in living patients. Neurogastroenterol Motil 22:e11–e14PubMedGoogle Scholar
  88. Lebouvier T, Neunlist M, Bruley des Varannes S, Coron E, Drouard A, N’Guyen JM, Chaumette T, Tasselli M, Paillusson S, Flamand M, Galmiche JP, Damier P, Derkinderen P (2010b) Colonic biopsies to assess the neuropathology of Parkinson’s disease and its relationship with symptoms. PLoS One 5:e12728PubMedPubMedCentralCrossRefGoogle Scholar
  89. Lee PH, Kim JS, Shin DH, Yoon SN, Huh K (2006) Cardiac 123I-MIBG scintigraphy in patients with drug induced parkinsonism. J Neurol Neurosurg Psychiatry 77:372–374PubMedCrossRefGoogle Scholar
  90. Lionnet A, Leclair-Visonneau L, Neunlist M, Murayama S, Takao M, Adler CH, Derkinderen P, Beach TG (2018) Does Parkinson’s disease start in the gut? Acta Neuropathol 135:1–12PubMedCrossRefGoogle Scholar
  91. Loewy AD, Spyer KM (1990) Central regulation of autonomic functions. New York, OxfordGoogle Scholar
  92. Loewy AD, Saper CB, Yamodis ND (1978) Re-evaluation of the efferent projections of the Edinger-Westphal nucleus in the cat. Brain Res 141:153–159PubMedCrossRefGoogle Scholar
  93. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC (2006) Functional bowel disorders. Gastroenterology 130:1480–1491PubMedCrossRefGoogle Scholar
  94. Miki Y, Mori F, Wakabayashi K, Kuroda N, Orimo S (2009) Incidental Lewy body disease restricted to the heart and stellate ganglia. Mov Disord 24:2299–2301PubMedCrossRefGoogle Scholar
  95. Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, Ortega-Moreno A, Rebollo AC, Gomez-Rio M, Concha A, Munoz DG (2007) Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders?: a cohort study. Neurology 68:2012–2018PubMedCrossRefGoogle Scholar
  96. Molander C, Xu Q, Grant G (1984) The cytoarchitectonic organisation of the spinal cord in the rat. I. The lower thoracic and lumbosacral cord. J Comp Neurol 230:133–141PubMedCrossRefGoogle Scholar
  97. Nakamura K, Mori F, Tanji K, Miki Y, Toyoshima Y, Kakita A, Takahashi H, Yamada M, Wakabayashi K (2016) α-Synuclein pathology in cranial and spinal nerves in Lewy body disease. Neuropathology 36:262–269PubMedCrossRefGoogle Scholar
  98. Notari S, Moleres FJ, Hunter SB, Belay ED, Schonberger LB, Cali I, Parchi P, Shieh WJ, Brown P, Zaki S, Zou W-Q, Gambetti P (2010) Multiorgan detection and characterization of protease-resistant prion protein in a case of variant CJD examined in the United States. PLoS One 5:e8765PubMedPubMedCentralCrossRefGoogle Scholar
  99. Oinas M, Paetau A, Myllykangas L, Notkola IL, Kalimo H, Polvikoski T (2010) a-Synuclein pathology in the spinal cord autonomic nuclei associates with a-synuclein pathology in the brain: a population-based Vantaa 85+ study. Acta Neuropathol 119:715–722PubMedCrossRefGoogle Scholar
  100. Oka H, Toyoda C, Yogo M, Mochio S (2011) Cardiovascular dysautonomia in de novo Parkinson’s disease without orthostatic hypotension. Eur J Neurol 18:286–292PubMedCrossRefGoogle Scholar
  101. Okada Y, Ito Y, Aida J, Yasuhara M, Ohkawa S, Hirokawa K (2004) Lewy bodies in the sinoatrial nodal ganglion: clinicopathological studies. Pathol Int 54:682–687PubMedCrossRefGoogle Scholar
  102. Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H (1999) 123I-Metaiodobenzylguanidine myocardial scintigraphy in Parkinson’s disease. J Neurol Neurosurg Psychiatry 67:189–194PubMedPubMedCentralCrossRefGoogle Scholar
  103. Orimo S, Oka T, Miura H, Tsuchiya K, Mori F, Wakabayashi K, Nagao T, Yokochi M (2002) Sympathetic cardiac denervation in Parkinson’s disease and pure autonomic failure but not in multiple system atrophy. J Neurol Neurosurg Psychiatry 73:776–777PubMedPubMedCentralCrossRefGoogle Scholar
  104. Orimo S, Amino T, Ito Y, Takahashi A, Kojo T, Uchihara T, Tsuchiya K, Mori F, Wakabayashi K, Takahashi H (2005) Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol 109:583–588PubMedCrossRefGoogle Scholar
  105. Orimo S, Takahashi A, Uchihara T, Mori F, Kakita A, Wakabayashi K, Takahashi H (2007) Degeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson’s disease. Brain Pathol 17:24–30PubMedCrossRefGoogle Scholar
  106. Orimo S, Uchihara T, Nakamura A, Mori F, Kakita A, Wakabayashi K, Takahashi H (2008) Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 131:642–650PubMedCrossRefGoogle Scholar
  107. Orimo S, Suzuki M, Inaba A, Mizusawa H (2012) 123I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other neurodegenerative parkinsonism: a systematic review and meta-analysis. Parkinsonism Relat Disord 18:49–500CrossRefGoogle Scholar
  108. Orimo S, Yogo M, Nakamura T, Suzuki M, Watanabe H (2016) Brain imaging in Aging Special Issue of Ageing Research Reviews. 123I-Meta-iodobenzylguanidine (MIBG) cardiac scintigraphy in α-synucleinopathies. Aging Res Rev 30:122–133CrossRefGoogle Scholar
  109. Oyanagi K, Wakabayashi K, Ohama E, Takeda S, Horikawa Y, Morita T, Ikuta F (1990) Lewy bodies in the lower sacral parasympathetic neurons of a patient with Parkinson’s disease. Acta Neuropathol 80:558–559PubMedCrossRefGoogle Scholar
  110. Petras JM, Cummings JF (1972) Autonomic neurons in the spinal cord of the rhesus monkey: a correlation of the findings of cytoarchitectonics and sympathectomy with fiber degeneration following dorsal rhizotomy. J Comp Neurol 146:189–218PubMedCrossRefGoogle Scholar
  111. Pfeiffer RF (2011) Gastrointestinal dysfunction in Parkinson’s disease. Parkinsonism Relat Disord 17:10–15PubMedCrossRefGoogle Scholar
  112. Phillips RJ, Walter GC, Wilder SL, Baronowsky EA, Powley TL (2008) Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson’s disease? Neuroscience 153:733–750PubMedPubMedCentralCrossRefGoogle Scholar
  113. Postuma RB, Gagnon JF, Bertrand JA, Génier Marchand D, Montplaisir JY (2015) Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials. Neurology 84:1104–1113PubMedPubMedCentralCrossRefGoogle Scholar
  114. Pouclet H, Lebouvier T, Coron E, des Varannes SB, Rouaud T, Roy M, Neunlist M, Derkinderen P (2011) A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson’ disease. Neurobiol Dis 45:305–309PubMedCrossRefGoogle Scholar
  115. Pouclet H, Lebouvier T, Coron E, Des Varannes SB, Neunlist M, Derkinderen P (2012) A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson’s disease. Neurogastroenterol Motil 24:e202–e205PubMedCrossRefGoogle Scholar
  116. Probst A, Bloch A, Tolnay M (2008) New insights into the pathology of Parkinson’s disease: does the peripheral autonomic system become central? Eur J Neurol 15(Suppl 1):1–4PubMedCrossRefGoogle Scholar
  117. 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 87:848–856PubMedGoogle Scholar
  118. Rajput AH, Rozdilsky B (1976) Dysautonomia in Parkinsonism: a clinicopathological study. J Neurol Neurosurg Psychiatry 39(1092–1):100Google Scholar
  119. Recasens A, Dehay B (2014) Alpha-synuclein spreading in Parkinson’s disease. Front Neuroanat 8:1–9CrossRefGoogle Scholar
  120. Rexed B (1952) The cytoarchitectonic organization of the spinal cord in the cat. J Comp Neurol 96:415–466CrossRefGoogle Scholar
  121. Ryabinin AE, Tsivkovskaia NO, Ryabinin SA (2005) Urocortin 1-containing neurons in the human Edinger-Westphal nucleus. Neuroscience 134:1317–1323PubMedCrossRefGoogle Scholar
  122. Sánchez-Ferro Á, Rábano A, Catalán MJ, Rodríguez-Valcárcel FC, Fernández Díez S, Herreros-Rodríguez J, García-Cobos E, Álvarez-Santullano MM, López-Manzanares L, Mosqueira AJ, Vela Desojo L, López-Lozano JJ, López-Valdés E, Sánchez-Sánchez R, Molina-Arjona JA (2015) In vivo gastric detection of α-synuclein inclusions in Parkinson’s disease. Mov Disord 30:517–524PubMedCrossRefGoogle Scholar
  123. Sandroni P (2012) Clinical evaluation of autonomic disorders. In: Robertson D, Bioggioni I, Burnstock G, Low PA, Paton JFR (eds) Primer on the autonomic nervous system, 3rd edn. Academic Press, London, pp 377–382CrossRefGoogle Scholar
  124. Seidel K, Mahlke J, Siswanto S, Krüger R, Heinsen H, Auburger G, Bouzrou M, Grinberg LT, Wicht H, Korf HW, den Dunnen W, Rüb U (2015) The brainstem pathologies of Parkinson’s disease and dementia with Lewy bodies. Brain Pathol 25:121–135PubMedCrossRefGoogle Scholar
  125. Shannon KM, Keshavarzian A, Mutlu E, Dodiya HB, Daian D, Jaglin JA, Kordower JH (2012a) Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov Disord 27:709–715PubMedCrossRefGoogle Scholar
  126. Shannon KM, Keshavarzian A, Dodiya HB, Jakate S, Kordower JH (2012b) Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s disease? Evidence from 3 cases. Mov Disord 27:716–719PubMedCrossRefGoogle Scholar
  127. Singaram C, Ashraf W, Gaumnitz EA, Torbey C, Sengupta A, Pfeiffer R, Quigley EM (1995) Dopaminergic defect of enteric nervous system in Parkinson’s disease patients with chronic constipation. Lancet 346(8979):861–864PubMedCrossRefGoogle Scholar
  128. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388(6645):839–840PubMedCrossRefGoogle Scholar
  129. Sprenger FS, Stefanova N, Gelpi E, Seppi K, Navarro-Otano J, Offner F, Vilas D, Valldeoriola F, Pont-Sunyer C, Aldecoa I, Gaig C, Gines A, Cuatrecasas M, Högl B, Frauscher B, Iranzo A, Wenning GK, Vogel W, Tolosa E, Poewe W (2015) Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder. Neurology 85:1761–1768PubMedPubMedCentralCrossRefGoogle Scholar
  130. Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P (2016) Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol 79:940–949PubMedCrossRefGoogle Scholar
  131. Su A, Gandhy R, Barlow C, Triadafilopoulos G (2017) Clinical and manometric characteristics of patients with Parkinson’s disease and esophageal symptoms. Dis Esophagus 30:1–6CrossRefPubMedGoogle Scholar
  132. Sumikura H, Takao M, Hatsuta H, Ito S, Uchino A, Nogami A, Saito Y, Mochizuki H, Murayama S (2015) Distribution of α-synuclein in the spinal cord and dorsal root ganglia in an autopsy cohort of elderly persons. Acta Neuropathol Commun 3:57PubMedPubMedCentralCrossRefGoogle Scholar
  133. Takahashi M, Ikemura M, Oka T, Uchihara T, Wakabayashi K, Kakita A, Takahashi H, Yoshida M, Toru S, Kobayashi T, Orimo S (2015) Quantitative correlation between cardiac MIBG uptake and remaining axons in the cardiac sympathetic nerve in Lewy body disease. J Neurol Neurosurg Psychiatry 86:939–944PubMedCrossRefGoogle Scholar
  134. Takeda S, Yamazaki K, Miyakawa T, Arai H (1993) Parkinson’s disease with involvement of the parasympathetic ganglia. Acta Neuropathol 86:397–398PubMedCrossRefGoogle Scholar
  135. Taki J, Nakajima K, Hwang E-H, Matsunari I, Komai K, Yoshita M, Sakajiri K, Tonami N (2000) Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27:566–573PubMedCrossRefGoogle Scholar
  136. Tamura T, Yoshida M, Hashizume Y, Sobue G (2012) Lewy body-related a-synucleinopathy in the spinal cord of cases with incidental Lewy body disease. Neuropathology 32:13–22PubMedCrossRefGoogle Scholar
  137. Tolosa E, Wenning G, Poewe W (2006) The diagnosis of Parkinson’s disease. Lancet Neurol 5:75–86PubMedCrossRefGoogle Scholar
  138. Treglia G, Cason E, Stefanelli A, Cocciolillo F, Di Giuda D, Fagioli G, Giordano A (2012) MIBG scintigraphy in differential diagnosis of Parkinsonism: a meta-analysis. Clin Auton Res 22:43–55PubMedCrossRefGoogle Scholar
  139. Uchiyama M, Isse K, Tanaka K, Yokota N, Hamamoto M, Aida S, Ito Y, Yoshimura M, Okawa M (1995) Incidental Lewy body disease in a patient with REM sleep behaviour disorder. Neurology 45:709–712PubMedCrossRefGoogle Scholar
  140. Ulusoy A, Phillips RJ, Helwig M, Klinkenberg M, Powley TL, Di Monte DA (2017) Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections. Acta Neuropathol 133:381–383PubMedCrossRefGoogle Scholar
  141. VanderHorst VG, Samardzic T, Saper CB, Anderson MP, Nag S, Schneider JA, Bennett DA, Buchman AS (2015) Alpha-synuclein pathology accumulates in sacral spinal visceral sensory pathways. Ann Neurol 78:142–149PubMedPubMedCentralCrossRefGoogle Scholar
  142. Vilas D, Iranzo A, Tolosa E, Aldecoa I, Berenguer J, Vilaseca I, Martí C, Serradell M, Lomeña F, Alós L, Gaig C, Santamaria J, Gelpi E (2016) Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. Lancet Neurol 15:708–718PubMedCrossRefGoogle Scholar
  143. Visanji NP, Marras C, Kern DS, Al Dakheel A, Gao A, Liu LW, Lang AE, Hazrati LN (2015) Colonic mucosal α-synuclein lacks specificity as a biomarker for Parkinson disease. Neurology 84:609–616PubMedPubMedCentralCrossRefGoogle Scholar
  144. Wakabayashi K, Takahashi H (1997a) The intermediolateral nucleus and Clarke’s column in Parkinson’s disease. Acta Neuropathol 94:287–289PubMedCrossRefGoogle Scholar
  145. Wakabayashi K, Takahashi H (1997b) Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 38(Suppl 2):2–7PubMedCrossRefGoogle Scholar
  146. 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 76:217–221PubMedCrossRefGoogle Scholar
  147. Wakabayashi K, Takahashi H, Ohama E, Ikuta F (1990) Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol 79:581–583PubMedCrossRefGoogle Scholar
  148. Watanabe H, Ieda T, Katayama T, Takeda A, Aiba I, Doyu M, Hirayama M, Sobue G (2001) Cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake in dementia with Lewy bodies: comparison with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 70:781–783PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Satoshi Orimo
    • 1
    Email author
  • Estifanos Ghebremedhin
    • 2
  • Ellen Gelpi
    • 3
    • 4
  1. 1.Department of NeurologyKanto Central HospitalTokyoJapan
  2. 2.Institute of Clinical NeuroanatomyJ. W. Goethe-UniversityFrankfurt/MainGermany
  3. 3.Neurological Tissue Bank of the Biobank-Hospital Clinic-IDIBAPSBarcelonaSpain
  4. 4.Institute of NeurologyMedical University of ViennaViennaAustria

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