Acta Neuropathologica

, Volume 119, Issue 6, pp 723–735 | Cite as

α-Synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein- and substance P-positive cells

  • Isabel Ubeda-Bañon
  • Daniel Saiz-Sanchez
  • Carlos de la Rosa-Prieto
  • Lucia Argandoña-Palacios
  • Susana Garcia-Muñozguren
  • Alino Martinez-Marcos
Original Paper

Abstract

Hyposmia is an early symptom of idiopathic Parkinson’s disease but the pathological bases of such dysfunction are largely unknown. The distribution of α-synuclein, which forms Lewy bodies and Lewy neurites, and the types of neurons (based on their neurotransmitters) affected by α-synucleinopathy were investigated in the olfactory system in Parkinson’s disease. Immunohistochemical distribution of α-synuclein and its co-localization with tyrosine hydroxylase, somatostatin, calbindin, calretinin, parvalbumin and substance P in the olfactory bulb, anterior olfactory nucleus, olfactory tubercle and piriform, periamygdaloid and rostral entorhinal cortices of idiopathic Parkinson’s disease cases (n = 11) and age-matched controls (n = 11) were investigated. Lewy bodies and Lewy neurites were present in the olfactory bulb, particularly in mitral cells and in the inner plexiform layer. α-synuclein was particularly abundant in the different divisions of the anterior olfactory nucleus (bulbar, intrapeduncular, retrobulbar and cortical). In contrast, Lewy bodies and Lewy neurites were less abundant in the olfactory tubercle and olfactory cortices. In the olfactory bulb, anterior olfactory nucleus and olfactory cortices, cells affected by α-synucleinopathy rarely co-localized tyrosine hydroxylase or somatostatin, but they frequently co-localized calbindin, calretinin, parvalbumin and substance P. The present data provide evidence that α-synucleinopathy affects neurons along the olfactory pathway. Dopamine- and somatostatin-positive cells are rarely affected; whereas the cell types most vulnerable to neurodegeneration include glutamate- (mitral cells), calcium-binding protein- and substance P-positive cells. These results provide data on the distribution and cell types involved by α-synucleinopathy in the human olfactory system during Parkinson disease that may be useful for future clinical investigation.

Keywords

α-Synuclein Lewy body Immunohistochemistry Olfactory Parkinson Hyposmia 

Abbreviations

ACC

Nucleus accumbens

AON

Anterior olfactory nucleus

AONb

Bulbar anterior olfactory nucleus

AONcal

Cortical anterior lateral anterior olfactory nucleus

AONcam

Cortical anterior medial anterior olfactory nucleus

AONpal

Cortical posterior lateral anterior olfactory nucleus

AONcpm

Cortical posterior medial anterior olfactory nucleus

AONi

Intrapeduncular anterior olfactory nucleus

AONr

Retrobulbar anterior olfactory nucleus

BL

Basolateral amygdala

BM

Basomedial amygdala

CB

Calbindin

Ce

Central amydala

CR

Calretinin

EC

Entorhinal cortex

EPL

External plexiform layer

GL

Glomerular layer

GCL

Granule cell layer

IPD

Idiopathic Parkinson’s disease

Me

Medial amgydala

MOB

Main olfactory bulb

molf

Medial olfactory radiation

NT

Neurotrace

olfr

Olfactory radiation

ONL

Outer nerve layer

OP

Olfactory peduncle

ot

Olfactory tract

PAC

Periamygdaloid cortex

PD

Parkinson’s disease

Pir

Piriform cortex

PMOL

Posteromedial orbital lobule

PV

Parvalbumin

S

Subiculum

SA

Stratum album

SG

Straight gyrus

SMT

Somatostatin

SP

Substance P

SYN

α-Synuclein

TH

Tyrosine hydroxylase

Supplementary material

401_2010_687_MOESM1_ESM.doc (36 kb)
Supplementary material 1 (DOC 36 kb)

References

  1. 1.
    Attems J, Jellinger KA (2006) Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 25:265–271PubMedGoogle Scholar
  2. 2.
    Beach TG, Adler CH, Lue L et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634CrossRefPubMedGoogle Scholar
  3. 3.
    Beach TG, White CL III, Hladik CL et al (2009) Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117:169–174CrossRefPubMedGoogle Scholar
  4. 4.
    Becker G, Muller A, Braune S et al (2002) Early diagnosis of Parkinson’s disease. J Neurol 249:40–48CrossRefGoogle Scholar
  5. 5.
    Bedard A, Parent A (2004) Evidence of newly generated neurons in the human olfactory bulb. Dev Brain Res 151:159–168CrossRefGoogle Scholar
  6. 6.
    Berendse HW, Ponsen MM (2006) Detection of preclinical Parkinson’s disease along the olfactory trac(t). J Neural Transm 70:321–325CrossRefGoogle Scholar
  7. 7.
    Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefPubMedGoogle Scholar
  8. 8.
    Braak H, Rub U, Gai WP et al (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536CrossRefPubMedGoogle Scholar
  9. 9.
    Braak H, de Vos RA, Bohl J et al (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 396:67–72CrossRefPubMedGoogle Scholar
  10. 10.
    Braak H, Del Tredici K (2008) Cortico-basal ganglia-cortical circuitry in Parkinson’s disease reconsidered. Exp Neurol 212:226–229CrossRefPubMedGoogle Scholar
  11. 11.
    Brundin P, Li JY, Holton JL et al (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9:741–745CrossRefPubMedGoogle Scholar
  12. 12.
    Chaudhuri KR, Naidu Y (2008) Early Parkinson’s disease and non-motor issues. J Neurol 255:33–38CrossRefPubMedGoogle Scholar
  13. 13.
    Daniel SE, Hawkes CH (1992) Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology. Lancet 340:186CrossRefPubMedGoogle Scholar
  14. 14.
    Del Tredici K, Rüb U, De Vos RA et al (2002) Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426PubMedGoogle Scholar
  15. 15.
    Doty RL (2008) The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 63:7–15CrossRefPubMedGoogle Scholar
  16. 16.
    Duda JE, Shah U, Arnold SE et al (1999) The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp Neurol 160:515–522CrossRefPubMedGoogle Scholar
  17. 17.
    Fahn S (2008) The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord 23(Suppl 3):S497–S508CrossRefPubMedGoogle Scholar
  18. 18.
    Greffard S, Verny M, Bonnet AM et al (2010) A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol Aging 31:99–103CrossRefPubMedGoogle Scholar
  19. 19.
    Haehner A, Hummel T, Hummel C et al (2007) Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord 22:839–842CrossRefPubMedGoogle Scholar
  20. 20.
    Haehner A, Boesveldt S, Berendse HW et al (2009) Prevalence of smell loss in Parkinson’s disease—a multicenter study. Parkinsonism Relat Disord 15:490–494CrossRefPubMedGoogle Scholar
  21. 21.
    Harding AJ, Stimson E, Henderson JM et al (2002) Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain 125:2431–2445CrossRefPubMedGoogle Scholar
  22. 22.
    Hawkes CH, Shephard BC, Daniel SE (1999) Is Parkinson’s disease a primary olfactory disorder? Qjm 92:473–480CrossRefPubMedGoogle Scholar
  23. 23.
    Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614CrossRefPubMedGoogle Scholar
  24. 24.
    Hawkes CH (2008) The prodromal phase of sporadic Parkinson’s disease: does it exist and if so how long is it? Mov Disord 23:1799–1807CrossRefPubMedGoogle Scholar
  25. 25.
    Hawkes CH, Del Tredici K, Braak H (2009) Parkinson’s disease: the dual hit theory revisited. Ann N Y Acad Sci 1170:615–622CrossRefPubMedGoogle Scholar
  26. 26.
    Hawkes CH, Doty RL (2009) The Neurology of Olfaction. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  27. 27.
    Hoogland PV, Huisman E (1999) Tyrosine hydroxylase immunoreactive structures in the aged human olfactory bulb and olfactory peduncle. J Chem Neuroanat 17:153–161CrossRefPubMedGoogle Scholar
  28. 28.
    Hubbard PS, Esiri MM, Reading M et al (2007) Alpha-synuclein pathology in the olfactory pathways of dementia patients. J Anat 211:117–124CrossRefPubMedGoogle Scholar
  29. 29.
    Huisman E, Uylings HB, Hoogland PV (2008) Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson’s disease patients. Mov Disord 23:1407–1413CrossRefPubMedGoogle Scholar
  30. 30.
    Hummel T, Witt M, Reichmann H et al (2010) Immunohistochemical, volumetric, and functional neuroimaging studies in patients with idiopathic Parkinson’s disease. J Neurol Sci 289:119–122CrossRefPubMedGoogle Scholar
  31. 31.
    Ikemoto K, Nagatsu I, Kitahama K et al (1998) A dopamine-synthesizing cell group demonstrated in the human basal forebrain by dual labeling immunohistochemical technique of tyrosine hydroxylase and aromatic L-amino acid decarboxylase. Neurosci Lett 243:129–132CrossRefPubMedGoogle Scholar
  32. 32.
    Issidorides MR, Mytilineou C, Whetsell WO Jr et al (1978) Protein-rich cytoplasmic bodies of substantia nigra and locus ceruleus. A comparative study in Parkinsonian and normal brain. Arch Neurol 35:633–637PubMedGoogle Scholar
  33. 33.
    Jellinger KA, Attems J (2005) Alzheimer pathology in the olfactory bulb. Neuropathol Appl Neurobiol 31:203CrossRefPubMedGoogle Scholar
  34. 34.
    Jellinger KA (2009) Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117:215–216 (author reply 217–218)CrossRefPubMedGoogle Scholar
  35. 35.
    Kranick SM, Duda JE (2008) Olfactory dysfunction in Parkinson’s disease. Neurosignals 16:35–40CrossRefPubMedGoogle Scholar
  36. 36.
    Lees AJ (2007) Unresolved issues relating to the Shaking Palsy on the celebration of James Parkinson’s 250th birthday. Mov Disord 22:S327–S334CrossRefPubMedGoogle Scholar
  37. 37.
    Lerner A, Bagic A (2008) Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord 23:1076–1084CrossRefPubMedGoogle Scholar
  38. 38.
    Linazasoro G (2008) Olfaction testing in PD: risky conclusions. Mov Disord 23:1060CrossRefPubMedGoogle Scholar
  39. 39.
    Mai JK, Paxinos G, Voss T (2008) Atlas of the human brain. Elsevier, New YorkGoogle Scholar
  40. 40.
    Marek K, Jennings D (2009) Can we image premotor Parkinson disease? Neurology 72:S21–S26CrossRefPubMedGoogle Scholar
  41. 41.
    Michell AW, Lewis SJ, Foltynie T et al (2004) Biomarkers and Parkinson’s disease. Brain 127:1693–1705CrossRefPubMedGoogle Scholar
  42. 42.
    Mosharov EV, Larsen KE, Kanter E et al (2009) Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62:218–229CrossRefPubMedGoogle Scholar
  43. 43.
    Müller A, Mungersdorf M, Reichmann H et al (2002) Olfactory function in Parkinsonian syndromes. J Clin Neurosci 9:521–524CrossRefPubMedGoogle Scholar
  44. 44.
    Murase S, McKay RD (2006) A specific survival response in dopamine neurons at most risk in Parkinson’s disease. J Neurosci 26:9750–9760CrossRefPubMedGoogle Scholar
  45. 45.
    Ohm TG, Muller H, Ulfig N et al (1990) Glutamic-acid-decarboxylase-and parvalbumin-like-immunoreactive structures in the olfactory bulb of the human adult. J Comp Neurol 291:1–8CrossRefPubMedGoogle Scholar
  46. 46.
    Ohm TG, Muller H, Braak E (1991) Calbindin-D-28k-like immunoreactive structures in the olfactory bulb and anterior olfactory nucleus of the human adult: distribution and cell typology—partial complementarity with parvalbumin. Neuroscience 42:823–840CrossRefPubMedGoogle Scholar
  47. 47.
    Parkkinen L, Silveira-Moriyama L, Holton JL et al (2009) Can olfactory bulb biopsy be justified for the diagnosis of Parkinson’s disease? Comments on “olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders”. Acta Neuropathol 117:213–214 (author reply 217–218)CrossRefPubMedGoogle Scholar
  48. 48.
    Pearce RK, Hawkes CH, Daniel SE (1995) The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 10:283–287CrossRefPubMedGoogle Scholar
  49. 49.
    Ponsen MM, Stoffers D, Booij J et al (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56:173–181CrossRefPubMedGoogle Scholar
  50. 50.
    Price JL (1990) Olfactory system. In: Paxinos G (ed) The human nervous system. Academic Press, San Diego, pp 979–998Google Scholar
  51. 51.
    Ross GW, Abbott RD, Petrovitch H et al (2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21:2062–2067CrossRefPubMedGoogle Scholar
  52. 52.
    Saiz-Sanchez D, Ubeda-Banon I, de la Rosa-Prieto C et al. (2010) Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol. doi:10.1016/j.expneurol.2009.06.010
  53. 53.
    Sengoku R, Saito Y, Ikemura M et al (2008) Incidence and extent of Lewy body-related alpha-synucleinopathy in aging human olfactory bulb. J Neuropathol Exp Neurol 67:1072–1083CrossRefPubMedGoogle Scholar
  54. 54.
    Silveira-Moriyama L, Holton JL, Kingsbury A et al (2009) Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci Lett 453:77–80CrossRefPubMedGoogle Scholar
  55. 55.
    Smith RL, Baker H, Kolstad K et al (1991) Localization of tyrosine hydroxylase and olfactory marker protein immunoreactivities in the human and macaque olfactory bulb. Brain Res 548:140–148CrossRefPubMedGoogle Scholar
  56. 56.
    Smith RL, Baker H, Greer CA (1993) Immunohistochemical analyses of the human olfactory bulb. J Comp Neurol 333:519–530CrossRefPubMedGoogle Scholar
  57. 57.
    Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840CrossRefPubMedGoogle Scholar
  58. 58.
    Stern MB (2004) The preclinical detection of Parkinson’s disease: ready for prime time? Ann Neurol 56:169–171CrossRefPubMedGoogle Scholar
  59. 59.
    Stiasny-Kolster K, Doerr Y, Moller JC et al (2005) Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 128:126–137CrossRefPubMedGoogle Scholar
  60. 60.
    Tolosa E, Compta Y, Gaig C (2007) The premotor phase of Parkinson’s disease. Parkinsonism Relat Disord 13(Suppl):S2–S7CrossRefPubMedGoogle Scholar
  61. 61.
    Tolosa E, Gaig C, Santamaria J et al (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology 72:S12–S20CrossRefPubMedGoogle Scholar
  62. 62.
    Witt M, Bormann K, Gudziol V et al (2009) Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord 24:906–914CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Isabel Ubeda-Bañon
    • 1
  • Daniel Saiz-Sanchez
    • 1
  • Carlos de la Rosa-Prieto
    • 1
  • Lucia Argandoña-Palacios
    • 2
  • Susana Garcia-Muñozguren
    • 2
  • Alino Martinez-Marcos
    • 1
  1. 1.Laboratorio de Neuroanatomía Humana, Facultad de Medicina/Centro Regional de Investigaciones BiomédicasUniversidad de Castilla-La ManchaAlbaceteSpain
  2. 2.Servicio de NeurologíaComplejo Hospitalario UniversitarioAlbaceteSpain

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