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Acta Neuropathologica

, 122:61 | Cite as

Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders

  • Iñaki-Carril Mundiñano
  • Maria-Cristina Caballero
  • Cristina Ordóñez
  • Maria Hernandez
  • Carla DiCaudo
  • Irene Marcilla
  • Maria-Elena Erro
  • Maria-Teresa Tuñon
  • Maria-Rosario LuquinEmail author
Original Paper

Abstract

Olfactory dysfunction is a frequent and early feature of patients with neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) and is very uncommon in patients with frontotemporal dementia (FTD). Mechanisms underlying this clinical manifestation are poorly understood but the premature deposition of protein aggregates in the olfactory bulb (OB) of these patients might impair its synaptic organization, thus accounting for the smell deficits. Tau, β-amyloid and alpha-synuclein deposits were studied in 41 human OBs with histological diagnosis of AD (n = 24), PD (n = 6), FTD (n = 11) and compared with the OB of 15 control subjects. Tau pathology was present in the OB of all patients, irrespective of the histological diagnosis, while β-amyloid and alpha-synuclein protein deposit were frequently observed in AD and PD, respectively. Using stereological techniques we found an increased number of dopaminergic periglomerular neurons in the OB of AD, PD and FTD patients when compared with age-matched controls. Moreover, volumetric measurements of OBs showed a significant decrease only in AD patients, while the OB volume was similar to control in PD or FTD cases. The increased dopaminergic tone created in the OBs of these patients could reflect a compensatory mechanism created by the early degeneration of other neurotransmitter systems and might contribute to the olfactory dysfunction exhibited by patients with neurodegenerative disorders.

Keywords

Olfactory bulb Parkinson’s disease Alzheimer’s disease Frontotemporal dementia Dopaminergic cells Alpha-synuclein Tau β-Amyloid 

Notes

Acknowledgments

This study was supported by the Government of Navarra (Ref Go Na46/07) and by the UTE-project/Foundation for Applied Medical Research (FIMA).

References

  1. 1.
    Alafuzoff I, Arzberger T, Al-Sarraj S et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathol 18:484–496PubMedGoogle Scholar
  2. 2.
    Alafuzoff I, Parkkinen L, Al-Sarraj S et al (2008) Assessment of alpha-synuclein pathology: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 67:125–143PubMedCrossRefGoogle Scholar
  3. 3.
    Alafuzoff I, Thal DR, Arzberger T et al (2009) Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:309–320PubMedCrossRefGoogle Scholar
  4. 4.
    American-Psychiatric-Association (ed) (1987) Diagnostic and statistical manual of mental disorders. Third, revised edn. Washington, DCGoogle Scholar
  5. 5.
    Arnold SE, Lee EB, Moberg PJ et al (2010) Olfactory epithelium amyloid-beta and paired helical filament-tau pathology in Alzheimer disease. Ann Neurol 67:462–469PubMedCrossRefGoogle Scholar
  6. 6.
    Attems J, Jellinger KA (2006) Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 25:265–271PubMedGoogle Scholar
  7. 7.
    Beach TG, White CL, Hamilton RL et al (2008) Evaluation of alpha-synuclein immunohistochemical methods used by invited experts. Acta Neuropathol 116:277–288PubMedCrossRefGoogle Scholar
  8. 8.
    Beach TG, White CL 3rd, Hladik CL et al (2009) Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 117:169–174PubMedCrossRefGoogle Scholar
  9. 9.
    Belzunegui S, Sebastián WS, Garrido-Gil P et al (2007) The number of dopaminergic cells is increased in the olfactory bulb of monkeys chronically exposed to MPTP. Synapse 61:1006–1012PubMedCrossRefGoogle Scholar
  10. 10.
    Berkowicz DA, Trombley PQ (2000) Dopaminergic modulation at the olfactory nerve synapse. Brain Res 855:90–99PubMedCrossRefGoogle Scholar
  11. 11.
    Bhatnagar KP, Kennedy RC, Baron G, Greenberg RA (1987) Number of mitral cells and the bulb volume in the aging human olfactory bulb: a quantitative morphological study. Anat Rec 218:73–87PubMedCrossRefGoogle Scholar
  12. 12.
    Bohnen NI, Gedela S, Herath P, Constantine GM, Moore RY (2008) Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity. Neurosci Lett 447:12–16PubMedCrossRefGoogle Scholar
  13. 13.
    Bohnen NI, Muller ML, Kotagal V et al (2010) Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain 133:1747–1754PubMedCrossRefGoogle Scholar
  14. 14.
    Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259PubMedCrossRefGoogle Scholar
  15. 15.
    Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  16. 16.
    Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404PubMedCrossRefGoogle Scholar
  17. 17.
    Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22PubMedCrossRefGoogle Scholar
  18. 18.
    Cavalieri B (1966) Geometria degli indivisibile. Unione Tipografico-Editrice. TorinoGoogle Scholar
  19. 19.
    Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM (2010) Synergistic interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30:7281–7289PubMedCrossRefGoogle Scholar
  20. 20.
    Cras P, Smith MA, Richey PL, Siedlak SL, Mulvihill P, Perry G (1995) Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer disease. Acta Neuropathol 89:291–295PubMedCrossRefGoogle Scholar
  21. 21.
    Christen-Zaech S, Kraftsik R, Pillevuit O et al (2003) Early olfactory involvement in Alzheimer’s disease. Can J Neurol Sci 30:20–25PubMedGoogle Scholar
  22. 22.
    Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H (2008) Olfaction in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 29:693–706PubMedCrossRefGoogle Scholar
  23. 23.
    Doty RL, Reyes PF, Gregor T (1987) Presence of both odor identification and detection deficits in Alzheimer’s disease. Brain Res Bull 18:597–600PubMedCrossRefGoogle Scholar
  24. 24.
    Duda JE (2010) Olfactory system pathology as a model of Lewy neurodegenerative disease. J Neurol Sci 289:49–54PubMedCrossRefGoogle Scholar
  25. 25.
    Ennis M, Zimmer LA, Shipley MT (1996) Olfactory nerve stimulation activates rat mitral cells via NMDA and non-NMDA receptors in vitro. Neuroreport 7:989–992PubMedCrossRefGoogle Scholar
  26. 26.
    Esiri MM, Wilcock GK (1984) The olfactory bulbs in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 47:56–60PubMedCrossRefGoogle Scholar
  27. 27.
    Fusetti M, Fioretti AB, Silvagni F et al (2010) Smell and preclinical Alzheimer disease: study of 29 patients with amnesic mild cognitive impairment. J Otolaryngol Head Neck Surg 39:175–181PubMedGoogle Scholar
  28. 28.
    German DC, Manaye KF, White CL 3rd et al (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32:667–676PubMedCrossRefGoogle Scholar
  29. 29.
    Ghatpande AS, Gelperin A (2009) Presynaptic muscarinic receptors enhance glutamate release at the mitral/tufted to granule cell dendrodendritic synapse in the rat main olfactory bulb. J Neurophysiol 101:2052–2061PubMedCrossRefGoogle Scholar
  30. 30.
    Gomez-Isla T, Hollister R, West H et al (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41:17–24PubMedCrossRefGoogle Scholar
  31. 31.
    Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28:327–335PubMedCrossRefGoogle Scholar
  32. 32.
    Gundersen HJ, Bendtsen TF, Korbo L et al (1988) Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379–394PubMedCrossRefGoogle Scholar
  33. 33.
    Haehner A, Boesveldt S, Berendse HW et al (2009) Prevalence of smell loss in Parkinson’s disease—a multicenter study. Parkinsonism Relat Disord 15:490–494PubMedCrossRefGoogle Scholar
  34. 34.
    Hawkes C (2003) Olfaction in neurodegenerative disorder. Mov Disord 18:364–372PubMedCrossRefGoogle Scholar
  35. 35.
    Hawkes CH, Shephard BC, Daniel SE (1997) Olfactory dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry 62:436–446PubMedCrossRefGoogle Scholar
  36. 36.
    Hirano S, Shinotoh H, Shimada H et al (2010) Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia. Brain 133:2058–2068PubMedCrossRefGoogle Scholar
  37. 37.
    Hoogland PV, Huisman E (1999) Tyrosine hydroxylase immunoreactive structures in the aged human olfactory bulb and olfactory peduncle. J Chem Neuroanat 17:153PubMedCrossRefGoogle Scholar
  38. 38.
    Hoogland PV, van den Berg R, Huisman E (2003) Misrouted olfactory fibres and ectopic olfactory glomeruli in normal humans and in Parkinson and Alzheimer patients. Neuropathol Appl Neurobiol 29:303–311PubMedCrossRefGoogle Scholar
  39. 39.
    Hsia AY, Vincent JD, Lledo PM (1999) Dopamine depresses synaptic inputs into the olfactory bulb. J Neurophysiol 82:1082–1085PubMedGoogle Scholar
  40. 40.
    Huey ED, Putnam KT, Grafman J (2006) A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. Neurology 66:17–22PubMedCrossRefGoogle Scholar
  41. 41.
    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 55:181–184PubMedCrossRefGoogle Scholar
  42. 42.
    Huisman E, Uylings HBM, Hoogland PV (2004) A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson’s disease. Mov Disord 19:687–692PubMedCrossRefGoogle Scholar
  43. 43.
    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 23:1407–1413PubMedCrossRefGoogle Scholar
  44. 44.
    Hummel T, Witt M, Reichmann H, Welge-Luessen A, Haehner A (2010) Immunohistochemical, volumetric, and functional neuroimaging studies in patients with idiopathic Parkinson’s disease. J Neurol Sci 289:119–122PubMedCrossRefGoogle Scholar
  45. 45.
    Ibarretxe-Bilbao N, Junque C, Marti MJ et al (2010) Olfactory impairment in Parkinson’s disease and white matter abnormalities in central olfactory areas: a voxel-based diffusion tensor imaging study. Mov Disord 25:1888–1894PubMedCrossRefGoogle Scholar
  46. 46.
    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)PubMedCrossRefGoogle Scholar
  47. 47.
    Kása P, Rakonczay Z, Gulya K (1997) The cholinergic system in Alzheimer’s disease. Prog Neurobiol 52:511–535PubMedCrossRefGoogle Scholar
  48. 48.
    Kovács CL (1999) B-Amyloid deposition and neurofibrillary tangle formation in the olfactory bulb in ageing and Alzheimer’s disease. Neuropathol Appl Neurobiol 25:481–491PubMedCrossRefGoogle Scholar
  49. 49.
    Kovacs I, Torok I, Zombori J, Kasa P (1998) Cholinergic structures and neuropathologic alterations in the olfactory bulb of Alzheimer’s disease brain samples. Brain Res 789:167–170PubMedCrossRefGoogle Scholar
  50. 50.
    Kovács T (2004) Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders. Ageing Res Rev 3:215PubMedCrossRefGoogle Scholar
  51. 51.
    Kril JJ, Patel S, Harding AJ, Halliday GM (2002) Neuron loss from the hippocampus of Alzheimer’s disease exceeds extracellular neurofibrillary tangle formation. Acta Neuropathol 103:370–376PubMedCrossRefGoogle Scholar
  52. 52.
    Lehericy S, Hirsch EC, Cervera-Pierot P et al (1993) Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease. J Comp Neurol 330:15–31PubMedCrossRefGoogle Scholar
  53. 53.
    Luzzi S, Snowden JS, Neary D, Coccia M, Provinciali L, Lambon Ralph MA (2007) Distinct patterns of olfactory impairment in Alzheimer’s disease, semantic dementia, frontotemporal dementia, and corticobasal degeneration. Neuropsychologia 45:1823–1831PubMedCrossRefGoogle Scholar
  54. 54.
    BJ Maher, Westbrook GL (2008) Co-transmission of dopamine and GABA in periglomerular cells. J Neurophysiol 99:1559–1564CrossRefGoogle Scholar
  55. 55.
    McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872PubMedCrossRefGoogle Scholar
  56. 56.
    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944PubMedGoogle Scholar
  57. 57.
    McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ (2001) Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick’s Disease. Arch Neurol 58:1803–1809PubMedCrossRefGoogle Scholar
  58. 58.
    Mesholam RI, Moberg PJ, Mahr RN, Doty RL (1998) Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol 55:84–90PubMedCrossRefGoogle Scholar
  59. 59.
    Mossner R, Schmitt A, Syagailo Y, Gerlach M, Riederer P, Lesch KP (2000) The serotonin transporter in Alzheimer’s and Parkinson’s disease. J Neural Transm Suppl (60):345–350Google Scholar
  60. 60.
    Mueller A, Abolmaali ND, Hakimi AR et al (2005) Olfactory bulb volumes in patients with idiopathic Parkinson’s disease a pilot study. J Neural Transm 112:1363PubMedCrossRefGoogle Scholar
  61. 61.
    Nai Q, Dong HW, Hayar A, Linster C, Ennis M (2009) Noradrenergic regulation of GABAergic inhibition of main olfactory bulb mitral cells varies as a function of concentration and receptor subtype. J Neurophysiol 101:2472–2484PubMedCrossRefGoogle Scholar
  62. 62.
    Nai Q, Dong HW, Linster C, Ennis M (2010) Activation of alpha1 and alpha2 noradrenergic receptors exert opposing effects on excitability of main olfactory bulb granule cells. Neuroscience 169:882–892PubMedCrossRefGoogle Scholar
  63. 63.
    Ohm TG, Braak H (1987) Olfactory bulb changes in Alzheimer’s disease. Acta Neuropathol 73:365–369PubMedCrossRefGoogle Scholar
  64. 64.
    Pardini M, Huey ED, Cavanagh AL, Grafman J (2009) Olfactory function in corticobasal syndrome and frontotemporal dementia. Arch Neurol 66:92–96PubMedCrossRefGoogle Scholar
  65. 65.
    Parkkinen L, Silveira-Moriyama L, Holton JL, Lees AJ, Revesz T (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)PubMedCrossRefGoogle Scholar
  66. 66.
    Pearce RKB, Hawkes CH, Daniel SE (1995) The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 10:283–287PubMedCrossRefGoogle Scholar
  67. 67.
    Petzold GC, Hagiwara A, Murthy VN (2009) Serotonergic modulation of odor input to the mammalian olfactory bulb. Nat Neurosci 12:784–791PubMedCrossRefGoogle Scholar
  68. 68.
    Porritt MJ, Batchelor PE, Hughes AJ, Kalnins R, Donnan GA, Howells DW (2000) New dopaminergic neurons in Parkinson’s disease striatum. Lancet 356:44–45PubMedCrossRefGoogle Scholar
  69. 69.
    Pressler RT, Inoue T, Strowbridge BW (2007) Muscarinic receptor activation modulates granule cell excitability and potentiates inhibition onto mitral cells in the rat olfactory bulb. J Neurosci 27:10969–10981PubMedCrossRefGoogle Scholar
  70. 70.
    Price JL, Davis PB, Morris JC, White DL (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 12:295–312PubMedCrossRefGoogle Scholar
  71. 71.
    Ridha B, Anderson V, Barnes J et al (2008) Volumetric MRI and cognitive measures in Alzheimer disease. J Neurol 255:567PubMedCrossRefGoogle Scholar
  72. 72.
    Rombaux P, Potier H, Markessis E, Duprez T, Hummel T (2010) Olfactory bulb volume and depth of olfactory sulcus in patients with idiopathic olfactory loss. Eur Arch Otorhinolaryngol 267(10):1551–1556PubMedCrossRefGoogle Scholar
  73. 73.
    Rommelfanger KS, Weinshenker D (2007) Norepinephrine: the redheaded stepchild of Parkinson’s disease. Biochem Pharmacol 74:177–190PubMedCrossRefGoogle Scholar
  74. 74.
    Ross GW, Petrovitch H, Abbott RD et al (2008) Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann Neurol 63:167–173PubMedCrossRefGoogle Scholar
  75. 75.
    Ruberg M, Rieger F, Villageois A, Bonnet AM, Agid Y (1986) Acetylcholinesterase and butyrylcholinesterase in frontal cortex and cerebrospinal fluid of demented and non-demented patients with Parkinson’s disease. Brain Res 362:83–91PubMedCrossRefGoogle Scholar
  76. 76.
    San Sebastian W, Guillen J, Manrique M et al (2007) Modification of the number and phenotype of striatal dopaminergic cells by carotid body graft. Brain 130:1306–1316PubMedCrossRefGoogle Scholar
  77. 77.
    Scott DA, Tabarean I, Tang Y, Cartier A, Masliah E, Roy S (2010) A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci 30:8083–8095PubMedCrossRefGoogle Scholar
  78. 78.
    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 67:1072–1083PubMedCrossRefGoogle Scholar
  79. 79.
    Serby M, Larson P, Kalkstein D (1991) The nature and course of olfactory deficits in Alzheimer’s disease. Am J Psychiatry 148:357–360PubMedGoogle Scholar
  80. 80.
    Shimada H, Hirano S, Shinotoh H et al (2009) Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 73:273–278PubMedCrossRefGoogle Scholar
  81. 81.
    Smith RL, Baker H, Kolstad K, Spencer DD, Greer CA (1991) Localization of tyrosine hydroxylase and olfactory marker protein immunoreactivities in the human and macaque olfactory bulb. Brain Res 548:140–148PubMedCrossRefGoogle Scholar
  82. 82.
    Smutzer GS Arnold SE, Doty RL, Trojanowski JQ (2003) Olfactory system neuropathology in neurodegenerative diseases and schizophrenia. In: Doty RL (ed) Handbook of olfaction and gustation, 2nd edn. Marcel Dekker, New YorkGoogle Scholar
  83. 83.
    Stephenson R, Houghton D, Sundarararjan S et al (2010) Odor identification deficits are associated with increased risk of neuropsychiatric complications in patients with Parkinson’s disease. Mov Disord 25:2099–2104PubMedCrossRefGoogle Scholar
  84. 84.
    Talamo BR, Feng WH, Perez-Cruet M et al (1991) Pathologic changes in olfactory neurons in Alzheimer’s disease. Ann NY Acad Sci 640:1–7PubMedGoogle Scholar
  85. 85.
    Tande D, Hoglinger G, Debeir T, Freundlieb N, Hirsch EC, Francois C (2006) New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 129:1194–1200PubMedCrossRefGoogle Scholar
  86. 86.
    Thomann PA, Dos Santos V, Seidl U, Toro P, Essig M, Schröder J (2009) MRI-derived atrophy of the olfactory bulb and tract in mild cognitive impairment and Alzheimer’s disease. J Alzheimer’s Dis 17:213–221Google Scholar
  87. 87.
    Thomann PA, Dos Santos V, Toro P, Schönknecht P, Essig M, Schröder J (2009) Reduced olfactory bulb and tract volume in early Alzheimer’s disease—a MRI study. Neurobiol Aging 30:838–841PubMedCrossRefGoogle Scholar
  88. 88.
    Tsuboi Y, Wszolek ZK, Graff-Radford NR, Cookson N, Dickson DW (2003) Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4. Neuropathol Appl Neurobiol 29:503–510PubMedCrossRefGoogle Scholar
  89. 89.
    Ubeda-Banon I, Saiz-Sanchez D, de la Rosa-Prieto C, Argandona-Palacios L, Garcia-Munozguren S, Martinez-Marcos A (2010) Alpha-synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein- and substance P-positive cells. Acta Neuropathol 119:723–735PubMedCrossRefGoogle Scholar
  90. 90.
    Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577PubMedCrossRefGoogle Scholar
  91. 91.
    Vyhnalek M, Lodinska D, Varjassyova A, Horinek D, Laczo J, Hort J (2006) Olfactory function impairment in frontotemporal dementia is evident but less severe than in Alzheimer’s disease (Abstract). Eur J Neurol 13:71Google Scholar
  92. 92.
    Wattendorf E, Welge-Lussen A, Fiedler K et al (2009) Olfactory impairment predicts brain atrophy in Parkinson’s disease. J Neurosci 29:15410–15413PubMedCrossRefGoogle Scholar
  93. 93.
    Weinshenker D (2008) Functional consequences of locus coeruleus degeneration in Alzheimer’s disease. Curr Alzheimer Res 5:342–345PubMedCrossRefGoogle Scholar
  94. 94.
    Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA (2009) Olfactory impairment in presymptomatic Alzheimer’s disease. Ann NY Acad Sci 1170:730–735PubMedCrossRefGoogle Scholar
  95. 95.
    Witt M, Bormann K, Gudziol V et al (2009) Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord 24:906–914PubMedCrossRefGoogle Scholar
  96. 96.
    Yan Z, Feng J (2004) Alzheimer’s disease: interactions between cholinergic functions and beta-amyloid. Curr Alzheimer Res 1:241–248PubMedCrossRefGoogle Scholar
  97. 97.
    Yang Y, Schmitt HP (2001) Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic innervation. Immunocytochemical and quantitative study using a graph method. Acta Neuropathol 101:256–270PubMedGoogle Scholar
  98. 98.
    Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Iñaki-Carril Mundiñano
    • 1
  • Maria-Cristina Caballero
    • 2
  • Cristina Ordóñez
    • 1
  • Maria Hernandez
    • 1
  • Carla DiCaudo
    • 1
  • Irene Marcilla
    • 1
  • Maria-Elena Erro
    • 2
  • Maria-Teresa Tuñon
    • 2
  • Maria-Rosario Luquin
    • 1
    Email author
  1. 1.Laboratory of Regenerative Therapy, Neuroscience Division, CIMA and Department of NeurologyClínica Universidad de Navarra, PamplonaPamplonaSpain
  2. 2.Banco de Tejidos Neurológicos de Navarra, Centro de Investigación Biomédica, Hospital de NavarraPamplonaSpain

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