Top

Published in:

01-06-2010 | Original Paper

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

Authors: Isabel Ubeda-Bañon, Daniel Saiz-Sanchez, Carlos de la Rosa-Prieto, Lucia Argandoña-Palacios, Susana Garcia-Muñozguren, Alino Martinez-Marcos

Published in: Acta Neuropathologica | Issue 6/2010

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.

Available only for authorised users

Attems J, Jellinger KA (2006) Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 25:265–271PubMed

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 117:613–634CrossRefPubMed

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 117:169–174CrossRefPubMed

Becker G, Muller A, Braune S et al (2002) Early diagnosis of Parkinson’s disease. J Neurol 249:40–48CrossRef

Bedard A, Parent A (2004) Evidence of newly generated neurons in the human olfactory bulb. Dev Brain Res 151:159–168CrossRef

Berendse HW, Ponsen MM (2006) Detection of preclinical Parkinson’s disease along the olfactory trac(t). J Neural Transm 70:321–325CrossRef

Braak H, Del Tredici K, Rüb U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211CrossRefPubMed

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 110:517–536CrossRefPubMed

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 396:67–72CrossRefPubMed

10.

Braak H, Del Tredici K (2008) Cortico-basal ganglia-cortical circuitry in Parkinson’s disease reconsidered. Exp Neurol 212:226–229CrossRefPubMed

11.

Brundin P, Li JY, Holton JL et al (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9:741–745CrossRefPubMed

12.

Chaudhuri KR, Naidu Y (2008) Early Parkinson’s disease and non-motor issues. J Neurol 255:33–38CrossRefPubMed

13.

Daniel SE, Hawkes CH (1992) Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology. Lancet 340:186CrossRefPubMed

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 61:413–426PubMed

15.

Doty RL (2008) The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol 63:7–15CrossRefPubMed

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 160:515–522CrossRefPubMed

17.

Fahn S (2008) The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord 23(Suppl 3):S497–S508CrossRefPubMed

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 31:99–103CrossRefPubMed

19.

Haehner A, Hummel T, Hummel C et al (2007) Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord 22:839–842CrossRefPubMed

20.

Haehner A, Boesveldt S, Berendse HW et al (2009) Prevalence of smell loss in Parkinson’s disease—a multicenter study. Parkinsonism Relat Disord 15:490–494CrossRefPubMed

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 125:2431–2445CrossRefPubMed

22.

Hawkes CH, Shephard BC, Daniel SE (1999) Is Parkinson’s disease a primary olfactory disorder? Qjm 92:473–480CrossRefPubMed

23.

Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614CrossRefPubMed

24.

Hawkes CH (2008) The prodromal phase of sporadic Parkinson’s disease: does it exist and if so how long is it? Mov Disord 23:1799–1807CrossRefPubMed

25.

Hawkes CH, Del Tredici K, Braak H (2009) Parkinson’s disease: the dual hit theory revisited. Ann N Y Acad Sci 1170:615–622CrossRefPubMed

26.

Hawkes CH, Doty RL (2009) The Neurology of Olfaction. Cambridge University Press, CambridgeCrossRef

27.

Hoogland PV, Huisman E (1999) Tyrosine hydroxylase immunoreactive structures in the aged human olfactory bulb and olfactory peduncle. J Chem Neuroanat 17:153–161CrossRefPubMed

28.

Hubbard PS, Esiri MM, Reading M et al (2007) Alpha-synuclein pathology in the olfactory pathways of dementia patients. J Anat 211:117–124CrossRefPubMed

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 23:1407–1413CrossRefPubMed

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 289:119–122CrossRefPubMed

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 243:129–132CrossRefPubMed

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 35:633–637PubMed

33.

Jellinger KA, Attems J (2005) Alzheimer pathology in the olfactory bulb. Neuropathol Appl Neurobiol 31:203CrossRefPubMed

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)CrossRefPubMed

35.

Kranick SM, Duda JE (2008) Olfactory dysfunction in Parkinson’s disease. Neurosignals 16:35–40CrossRefPubMed

36.

Lees AJ (2007) Unresolved issues relating to the Shaking Palsy on the celebration of James Parkinson’s 250th birthday. Mov Disord 22:S327–S334CrossRefPubMed

37.

Lerner A, Bagic A (2008) Olfactory pathogenesis of idiopathic Parkinson disease revisited. Mov Disord 23:1076–1084CrossRefPubMed

38.

Linazasoro G (2008) Olfaction testing in PD: risky conclusions. Mov Disord 23:1060CrossRefPubMed

39.

Mai JK, Paxinos G, Voss T (2008) Atlas of the human brain. Elsevier, New York

40.

Marek K, Jennings D (2009) Can we image premotor Parkinson disease? Neurology 72:S21–S26CrossRefPubMed

41.

Michell AW, Lewis SJ, Foltynie T et al (2004) Biomarkers and Parkinson’s disease. Brain 127:1693–1705CrossRefPubMed

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 62:218–229CrossRefPubMed

43.

Müller A, Mungersdorf M, Reichmann H et al (2002) Olfactory function in Parkinsonian syndromes. J Clin Neurosci 9:521–524CrossRefPubMed

44.

Murase S, McKay RD (2006) A specific survival response in dopamine neurons at most risk in Parkinson’s disease. J Neurosci 26:9750–9760CrossRefPubMed

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 291:1–8CrossRefPubMed

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 42:823–840CrossRefPubMed

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)CrossRefPubMed

48.

Pearce RK, Hawkes CH, Daniel SE (1995) The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 10:283–287CrossRefPubMed

49.

Ponsen MM, Stoffers D, Booij J et al (2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56:173–181CrossRefPubMed

50.

Price JL (1990) Olfactory system. In: Paxinos G (ed) The human nervous system. Academic Press, San Diego, pp 979–998

51.

Ross GW, Abbott RD, Petrovitch H et al (2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21:2062–2067CrossRefPubMed

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.

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 67:1072–1083CrossRefPubMed

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 453:77–80CrossRefPubMed

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 548:140–148CrossRefPubMed

56.

Smith RL, Baker H, Greer CA (1993) Immunohistochemical analyses of the human olfactory bulb. J Comp Neurol 333:519–530CrossRefPubMed

57.

Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840CrossRefPubMed

58.

Stern MB (2004) The preclinical detection of Parkinson’s disease: ready for prime time? Ann Neurol 56:169–171CrossRefPubMed

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 128:126–137CrossRefPubMed

60.

Tolosa E, Compta Y, Gaig C (2007) The premotor phase of Parkinson’s disease. Parkinsonism Relat Disord 13(Suppl):S2–S7CrossRefPubMed

61.

Tolosa E, Gaig C, Santamaria J et al (2009) Diagnosis and the premotor phase of Parkinson disease. Neurology 72:S12–S20CrossRefPubMed

62.

Witt M, Bormann K, Gudziol V et al (2009) Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord 24:906–914CrossRefPubMed

Title: α-Synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein- and substance P-positive cells
Authors: Isabel Ubeda-Bañon
Daniel Saiz-Sanchez
Carlos de la Rosa-Prieto
Lucia Argandoña-Palacios
Susana Garcia-Muñozguren
Alino Martinez-Marcos
Publication date: 01-06-2010
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 6/2010
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-010-0687-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2010

Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease

α-Synuclein pathology in the spinal cord autonomic nuclei associates with α-synuclein pathology in the brain: a population-based Vantaa 85+ study

The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes

Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment

Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype

Von Economo neuron density in the anterior cingulate cortex is reduced in early onset schizophrenia