Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Olfactory dysfunction in Parkinson disease

Abstract

Olfactory dysfunction is among the earliest nonmotor features of Parkinson disease (PD). Such dysfunction is present in approximately 90% of early-stage PD cases and can precede the onset of motor symptoms by years. The mechanisms responsible for olfactory dysfunction are currently unknown. As equivalent deficits are observed in Alzheimer disease, Down syndrome, and the Parkinson–dementia complex of Guam, a common pathological substrate may be involved. Given that olfactory loss occurs to a lesser extent or is absent in disorders such as multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy, olfactory testing can be useful in differential diagnosis. The olfactory dysfunction in PD and a number of related diseases with smell loss correlates with decreased numbers of neurons in structures such as the locus coeruleus, the raphe nuclei, and the nucleus basalis of Meynart. These neuroanatomical findings, together with evidence for involvement of the autonomic nervous system in numerous PD-related symptoms, suggest that deficits in cholinergic, noradrenergic and serotonergic function may contribute to the olfactory loss. This Review discusses the current understanding of olfactory dysfunction in PD, including factors that may be related to its cause.

Key Points

  • Olfactory dysfunction is an early and sensitive marker of the preclinical phase of Parkinson disease (PD)

  • Analogous olfactory dysfunction occurs in other—but not all—neurodegenerative diseases, suggesting the involvement of a common neuropathological substrate

  • PD is a multisystem disorder in which brain neuropathology seems to begin in the olfactory bulb and the dorsal motor nucleus complex of the glossopharyngeal and vagus nerves

  • Damage to largely nondopaminergic neurotransmitter systems may contribute to, or possibly even cause, the olfactory loss observed in PD and some other neurodegenerative diseases

  • Many environmental risk factors for PD, including older age, head trauma, and exposure to metal ions, viruses and pesticides, are also risk factors for smell loss that is independent of PD

  • Air pollution-related toxins, including nanoparticles, can enter the brain via the olfactory epithelium and induce inflammatory responses and PD-like neuropathology in the olfactory bulb and other forebrain structures

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Braak staging system of Parkinson disease, showing the initiation sites in the olfactory bulb and the medulla oblongata, through to the later infiltration of Lewy pathology into cortical regions.
Figure 2: The major afferent projections and structures of the olfactory system.
Figure 3: Schematic diagram showing major layers of the olfactory bulb and interactions between different types of bulbar cells.

Similar content being viewed by others

References

  1. Deems, D. A. et al. Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch. Otolaryngol. Head Neck Surg. 117, 519–528 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Wilson, R. S., Yu, L. & Bennett, D. A. Odor identification and mortality in old age. Chem. Senses 36, 63–67 (2011).

    Article  PubMed  Google Scholar 

  3. Doty, R. L. Olfaction in Parkinson's disease and related disorders.. Neurobiol. Dis. 46, 527–552 (2012).

    Article  PubMed  Google Scholar 

  4. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  5. Doty, R. L. Olfaction in Parkinson's disease and related disorders. Neurobiol. Dis. 46, 527–552 (2012). http://dx.doi.org/10.1016/j.nbd.2011.10.026.

    Article  PubMed  Google Scholar 

  6. Mesholam, R. I., Moberg, P. J., Mahr, R. N. & Doty, R. L. Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer's and Parkinson's diseases. Arch. Neurol. 55, 84–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Doty, R. L., McKeown, D. A., Lee, W. W. & Shaman, P. A study of the test–retest reliability of ten olfactory tests. Chem. Senses 20, 645–656 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Hedner, M., Larsson, M., Arnold, N., Zucco, G. M. & Hummel, T. Cognitive factors in odor detection, odor discrimination, and odor identification tasks. J. Clin. Exp. Neuropsychol. 32, 1062–1067 (2010).

    Article  PubMed  Google Scholar 

  9. Doty, R. L., Smith, R., McKeown, D. A. & Raj, J. Tests of human olfactory function: principal components analysis suggests that most measure a common source of variance. Percept. Psychophys. 56, 701–707 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Doty, R. L., Stern, M. B., Pfeiffer, C., Gollomp, S. M. & Hurtig, H. I. Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 55, 138–142 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bohnen, N. I., Studenski, S. A., Constantine, G. M. & Moore, R. Y. Diagnostic performance of clinical motor and non-motor tests of Parkinson disease: a matched case–control study. Eur. J. Neurol. 15, 685–691 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Deeb, J. et al. A basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and DaTSCAN in the diagnosis of Parkinson's disease. Q. J. Med. 103, 941–952 (2010).

    Article  CAS  Google Scholar 

  13. McKeown, D. A. et al. Olfactory function in young adolescents with Down's syndrome. J. Neurol. Neurosurg. Psychiatry 61, 412–414 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Doty, R. L. et al. Odor identification deficit of the parkinsonism-dementia complex of Guam: equivalence to that of Alzheimer's and idiopathic Parkinson's disease. Neurology 41, 77–80 (1991).

    Article  CAS  PubMed  Google Scholar 

  15. Hawkes, C. H. & Doty, R. L. The Neurology of Olfaction (Cambridge University Press, Cambridge, 2009).

    Book  Google Scholar 

  16. Doty, R. L. et al. Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson's disease. Neurology 43, 962–965 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Wenning, G. K. et al. Olfactory function in atypical parkinsonian syndromes. Acta Neurol. Scand. 91, 247–250 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Doty, R. L., Singh, A., Tetrud, J. & Langston, J. W. Lack of major olfactory dysfunction in MPTP-induced parkinsonism. Ann. Neurol. 32, 97–100 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Goldstein, D. S. et al. Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat. Disord. 14, 600–607 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Busenbark, K. L., Huber, S. I., Greer, G., Pahwa, R. & Koller, W. C. Olfactory function in essential tremor. Neurology 42, 1631–1632 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Shah, M., Muhammed, N., Findley, L. J. & Hawkes, C. H. Olfactory tests in the diagnosis of essential tremor. Parkinsonism Relat. Disord. 14, 563–568 (2008).

    Article  PubMed  Google Scholar 

  22. Suchowersky, O. et al. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 66, 968–975 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Barz, S. et al. Chemosensory event-related potentials in response to trigeminal and olfactory stimulation in idiopathic Parkinson's disease. Neurology 49, 1424–1431 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Doty, R. L., Riklan, M., Deems, D. A., Reynolds, C. & Stellar, S. The olfactory and cognitive deficits of Parkinson's disease: evidence for independence. Ann. Neurol. 25, 166–171 (1989).

    Article  CAS  PubMed  Google Scholar 

  25. Hawkes, C. H., Shephard, B. C. & Daniel, S. E. Olfactory dysfunction in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 62, 436–446 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Herting, B., Schulze, S., Reichmann, H., Haehner, A. & Hummel, T. A longitudinal study of olfactory function in patients with idiopathic Parkinson's disease. J. Neurol. 255, 367–370 (2008).

    Article  PubMed  Google Scholar 

  27. Tissingh, G. et al. Loss of olfaction in de novo and treated Parkinson's disease: possible implications for early diagnosis. Mov. Disord. 16, 41–46 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Bohnen, N. I. et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease. Brain 133, 1747–1754 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Postuma, R. & Gagnon, J. F. Cognition and olfaction in Parkinson's disease. Brain 133, e160 (2010).

    Article  PubMed  Google Scholar 

  30. Parrao, T., Chana, P., Venegas, P., Behrens, M. I. & Aylwin, M. L. Olfactory deficits and cognitive dysfunction in Parkinson's disease. Neurodegener. Dis. http://dx.doi.org/10.1159/000335915.

  31. Boesveldt, S. et al. A comparative study of odor identification and odor discrimination deficits in Parkinson's disease. Mov. Disord. 23, 1984–1990 (2008).

    Article  PubMed  Google Scholar 

  32. Goetz, C. G. et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov. Disord. 23, 2129–2170 (2008).

    Article  PubMed  Google Scholar 

  33. Stephenson, R. et al. Impaired olfaction and subsequent risk of long-term complications of Parkinson's disease. Mov. Disord. 23, 866 (2008).

    Article  Google Scholar 

  34. Siderowf, A. et al. [99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 64, 1716–1720 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Berendse, H. W., Roos, D. S., Raijmakers, P. & Doty, R. L. Motor and non-motor correlates of olfactory dysfunction in Parkinson's disease. J. Neurol. Sci. 310, 21–24 (2011).

    Article  PubMed  Google Scholar 

  36. Bohnen, N. I., Gedela, S., Herath, P., Constantine, G. M. & Moore, R. Y. Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity. Neurosci. Lett. 447, 12–16 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Goldstein, D. S., Sewell, L. & Holmes, C. Association of anosmia with autonomic failure in Parkinson disease. Neurology 74, 245–251 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lee, P. H., Yeo, S. H., Kim, H. J. & Youm, H. Y. Correlation between cardiac 123I-MIBG and odor identification in patients with Parkinson's disease and multiple system atrophy. Mov. Disord. 21, 1975–1977 (2006).

    Article  PubMed  Google Scholar 

  39. Ross, G. W. et al. Association of olfactory dysfunction with risk for future Parkinson's disease. Ann. Neurol. 63, 167–173 (2008).

    Article  PubMed  Google Scholar 

  40. Doty, R. L., Marcus, A. & Lee, W. W. Development of the 12-item cross-cultural smell identification test (CC-SIT). Laryngoscope 106, 353–356 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Marras, C. et al. Smell identification ability in twin pairs discordant for Parkinson's disease. Mov. Disord. 20, 687–693 (2005).

    Article  PubMed  Google Scholar 

  42. Morrish, P. K., Rakshi, J. S., Bailey, D. L., Sawle, G. V. & Brooks, D. J. Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET. J. Neurol. Neurosurg. Psychiatry 64, 314–319 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hilker, R. et al. Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity. Arch. Neurol. 62, 378–382 (2005).

    Article  PubMed  Google Scholar 

  44. Montgomery, E. B. Jr, Baker, K. B., Lyons, K. & Koller, W. C. Abnormal performance on the PD test battery by asymptomatic first-degree relatives. Neurology 52, 757–762 (1999).

    Article  PubMed  Google Scholar 

  45. Berendse, H. W. et al. Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell. Ann. Neurol. 50, 34–41 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Ponsen, M. M. et al. Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Ann. Neurol. 56, 173–181 (2004).

    Article  PubMed  Google Scholar 

  47. Siderowf, A. et al. Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome study. Mov. Disord. 27, 406–412 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Tanner, C. M. et al. Parkinson disease in twins: an etiologic study. J. Am. Med. Assoc. 281, 341–346 (1999).

    Article  CAS  Google Scholar 

  49. Elbaz, A. et al. Validity of family history data on PD: evidence for a family information bias. Neurology 61, 11–17 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Correia, G. L. et al. Worldwide frequency of G2019S LRRK2 mutation in Parkinson's disease: a systematic review. Parkinsonism Relat. Disord. 16, 237–242 (2010).

    Article  Google Scholar 

  51. Silveira-Moriyama, L. et al. Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data. Neurology 71, 1021–1026 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Saunders-Pullman, R. et al. Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology 77, 319–324 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Johansen, K. K., White, L. R., Farrer, M. J. & Aasly, J. O. Subclinical signs in LRRK2 mutation carriers. Parkinsonism Relat. Disord. 17, 528–532 (2011).

    Article  PubMed  Google Scholar 

  54. Tanner, C. et al. Follow-up of elderly male twin pairs discordant for Parkinson's disease (PD). Neurology 68, A86 (2007).

    Article  Google Scholar 

  55. Moberg, P. J. & Doty, R. L. Olfactory function in Huntington's disease patients and at-risk offspring. Int. J. Neurosci. 89, 133–139 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Ruiz-Martinez, J. et al. Olfactory deficits and cardiac 123I-MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations. Mov. Disord. 26, 2026–2031 (2011).

    Article  PubMed  Google Scholar 

  57. Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. & Del, T. K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 318, 121–134 (2004).

    Article  PubMed  Google Scholar 

  58. Braak, H., Rub, U., Gai, W. P. & Del, T. K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm. 110, 517–536 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Pearce, R. K., Hawkes, C. H. & Daniel, S. E. The anterior olfactory nucleus in Parkinson's disease. Mov. Disord. 10, 283–287 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Duda, J. E., Shah, U., Arnold, S. E., Lee, V. M. & Trojanowski, J. Q. The expression of α-, β-, and γ-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp. Neurol. 160, 515–522 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. Beach, T. G. et al. Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol. 117, 169–174 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Sengoku, R. et al. Incidence and extent of Lewy body-related α-synucleinopathy in aging human olfactory bulb. J. Neuropathol. Exp. Neurol. 67, 1072–1083 (2008).

    Article  PubMed  Google Scholar 

  63. Harding, A. J., Stimson, E., Henderson, J. M. & Halliday, G. M. Clinical correlates of selective pathology in the amygdala of patients with Parkinson's disease. Brain 125, 2431–2445 (2002).

    Article  PubMed  Google Scholar 

  64. Silveira-Moriyama, L. et al. Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci. Lett. 453, 77–80 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Doty, R. L. The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann. Neurol. 63, 7–15 (2008).

    Article  PubMed  Google Scholar 

  66. Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lei, P. et al. Tau protein: relevance to Parkinson's disease. Int. J. Biochem. Cell Biol. 42, 1775–1778 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Ishizawa, T., Mattila, P., Davies, P., Wang, D. & Dickson, D. W. Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J. Neuropathol. Exp. Neurol. 62, 389–397 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Tsuboi, Y., Wszolek, Z. K., Graff-Radford, N. R., Cookson, N. & Dickson, D. W. Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein ɛ4. Neuropathol. Appl. Neurobiol. 29, 503–510 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Mundinano, I. C. et al. Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders. Acta Neuropathol. 122, 61–74 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Smith, R. L., Baker, H. & Greer, C. A. Immunohistochemical analyses of the human olfactory bulb. J. Comp. Neurol. 333, 519–530 (1993).

    Article  CAS  PubMed  Google Scholar 

  72. Macknin, J. B., Higuchi, M., Lee, V. M., Trojanowski, J. Q. & Doty, R. L. Olfactory dysfunction occurs in transgenic mice overexpressing human tau protein. Brain Res. 1000, 174–178 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Arendt, T., Bigl, V., Arendt, A. & Tennstedt, A. Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's disease. Acta Neuropathol. 61, 101–108 (1983).

    Article  CAS  PubMed  Google Scholar 

  74. Rogers, J. D., Brogan, D. & Mirra, S. S. The nucleus basalis of Meynert in neurological disease: a quantitative morphological study. Ann. Neurol. 17, 163–170 (1985).

    Article  CAS  PubMed  Google Scholar 

  75. Moscavitch, S. D., Szyper-Kravitz, M. & Shoenfeld, Y. Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders: the olfactory and immune system interrelationship. Clin. Immunol. 130, 235–243 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Yahr, M. D. Parkinson's disease—overview of its current status. Mt Sinai J. Med. 44, 183–191 (1977).

    CAS  PubMed  Google Scholar 

  77. Tong, Z. Y., Kingsbury, A. E. & Foster, O. J. Up-regulation of tyrosine hydroxylase mRNA in a sub-population of A10 dopamine neurons in Parkinson's disease. Brain Res. Mol. Brain Res. 79, 45–54 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Ruberg, M. et al. Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann. Neurol. 18, 523–529 (1985).

    Article  CAS  PubMed  Google Scholar 

  79. Huisman, E., Uylings, H. B. & Hoogland, P. V. Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson's disease patients. Mov. Disord. 23, 1407–1413 (2008).

    Article  PubMed  Google Scholar 

  80. Huisman, E., Uylings, H. B. & Hoogland, P. V. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov. Disord. 19, 687–692 (2004).

    Article  PubMed  Google Scholar 

  81. Lelan, F. et al. Effects of human alpha-synuclein A53T–A30P mutations on SVZ and local olfactory bulb cell proliferation in a transgenic rat model of Parkinson disease. Parkinsons Dis. http://dx.doi.org/10.4061/2011/987084.

  82. Belzunegui, S., Sebastian, W. S. & Garrido-Gil, P. The number of dopaminergic cells is increased in the olfactory bulb of monkeys chronically exposed to MPTP. Synapse 61, 1006–1012 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Yamada, M., Onodera, M., Mizuno, Y. & Mochizuki, H. Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated adult mice. Neuroscience 124, 173–181 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Bohnen, N. I. et al. Selective hyposmia and nigrostriatal dopaminergic denervation in Parkinson's disease. J. Neurol. 254, 84–90 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Wong, K. K., Muller, M. L., Kuwabara, H., Studenski, S. A. & Bohnen, N. I. Olfactory loss and nigrostriatal dopaminergic denervation in the elderly. Neurosci. Lett. 284, 163–167 (2010).

    Article  CAS  Google Scholar 

  86. Zarow, C., Lyness, S. A., Mortimer, J. A. & Chui, H. C. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch. Neurol. 60, 337–341 (2003).

    Article  PubMed  Google Scholar 

  87. Del Tredici, K., Rub, U., De Vos, R. A., Bohl, J. R. & Braak, H. Where does Parkinson disease pathology begin in the brain? J. Neuropathol. Exp. Neurol. 61, 413–426 (2002).

    Article  PubMed  Google Scholar 

  88. Doty, R. L., Ferguson-Segall, M., Lucki, I. & Kreider, M. Effects of intrabulbar injections of 6-hydroxydopamine on ethyl acetate odor detection in castrate and non-castrate male rats. Brain Res. 444, 95–103 (1988).

    Article  CAS  PubMed  Google Scholar 

  89. Garland, E. M., Raj, S. R., Peltier, A. C., Robertson, D. & Biaggioni, I. A cross-sectional study contrasting olfactory function in autonomic disorders. Neurology 76, 456–460 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Feinstein, D. L. et al. Noradrenergic regulation of inflammatory gene expression in brain. Neurochem. Int. 41, 357–365 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Kalinin, S. et al. Degeneration of noradrenergic fibres from the locus coeruleus causes tight-junction disorganisation in the rat brain. Eur. J. Neurosci. 24, 3393–3400 (2006).

    Article  PubMed  Google Scholar 

  92. Fornai, F., Alessandri, M. G., Torracca, M. T., Bassi, L. & Corsini, G. U. Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletions. J. Pharmacol. Exp. Ther. 283, 100–107 (1997).

    CAS  PubMed  Google Scholar 

  93. Mavridis, M., Degryse, A. D., Lategan, A. J., Marien, M. R. & Colpaert, F. C. in Noradrenergic Mechanisms in Parkinson's Disease (eds Briley, M. & Marien, M.) 25–57 (CRC Press, Boca Raton, 1994).

    Google Scholar 

  94. Fornai, F., Alessandri, M. G., Fascetti, F., Vaglini, F. & Corsini, G. U. Clonidine suppresses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced reductions of striatal dopamine and tyrosine hydroxylase activity in mice. J. Neurochem. 65, 704–709 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Petzold, G. C., Hagiwara, A. & Murthy, V. N. Serotonergic modulation of odor input to the mammalian olfactory bulb. Nat. Neurosci. 12, 784–791 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Scatton, B., Javoy-Agid, F., Rouquier, L., Dubois, B. & Agid, Y. Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson's disease. Brain Res. 275, 321–328 (1983).

    Article  CAS  PubMed  Google Scholar 

  97. Huot, P., Fox, S. H. & Brotchie, J. M. The serotonergic system in Parkinson's disease. Prog. Neurobiol. 95, 163–212 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Braak, E. et al. α-Synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei. Acta Neuropathol. 101, 195–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Di Matteo, V., Di Giovanni, G., Pierucci, M. & Esposito, E. Serotonin control of central dopaminergic function: focus on in vivo microdialysis studies. Prog. Brain Res. 172, 7–44 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Kovacs, G. G. et al. Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders. Neuroreport 14, 73–76 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Moriizumi, T., Tsukatani, T., Sakashita, H. & Miwa, T. Olfactory disturbance induced by deafferentation of serotonergic fibers in the olfactory bulb. Neuroscience 61, 733–738 (1994).

    Article  CAS  PubMed  Google Scholar 

  102. Tsukatani, T. et al. Bulbar morphology and expression of bulbar dopamine and parvalbumin in experimentally-induced anosmic rats. Acta Otolaryngol. 115, 539–542 (1995).

    Article  CAS  PubMed  Google Scholar 

  103. Carnevale, D., De Simone, R. & Minghetti, L. Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems. CNS Neurol. Disord. Drug Targets 6, 388–397 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Kim, Y. S. & Joh, T. H. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp. Mol. Med. 38, 333–347 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Wu, D. C. et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J. Neurosci. 22, 1763–1771 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Levesque, S. et al. Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. Environ. Health Perspect. 119, 1149–1155 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lalancette-Hebert, M., Phaneuf, D., Soucy, G., Weng, Y. C. & Kriz, J. Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation. Brain 132, 940–954 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Doty, R. L., Petersen, I., Mensah, N. & Christensen, K. Genetic and environmental influences on odor identification ability in the very old. Psychol. Aging 26, 864–871 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Doty, R. L. et al. Smell identification ability: changes with age. Science 226, 1441–1443 (1984).

    Article  CAS  PubMed  Google Scholar 

  110. Doty, R. L. et al. Olfactory dysfunction in patients with head trauma. Arch. Neurol. 54, 1131–1140 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. Calderon-Garciduenas, L. et al. Urban air pollution: influences on olfactory function and pathology in exposed children and young adults. Exp. Toxicol. Pathol. 62, 91–102 (2010).

    Article  PubMed  Google Scholar 

  112. Wang, J. H., Kwon, H. J. & Jang, Y. J. Detection of parainfluenza virus 3 in turbinate epithelial cells of postviral olfactory dysfunction patients. Laryngoscope 117, 1445–1449 (2007).

    Article  PubMed  Google Scholar 

  113. Gobba, F. Olfactory toxicity: long-term effects of occupational exposures. Int. Arch. Occup. Environ. Health 79, 322–331 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Genter, M. B., Owens, D. M., Carlone, H. B. & Crofton, K. M. Characterization of olfactory deficits in the rat following administration of 2,6-dichlorobenzonitrile (dichlobenil), 3,3'-iminodipropionitrile, or methimazole. Fundam. Appl. Toxicol. 29, 71–77 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Doty, R. L. in Textbook of Clinical Neurology (eds Goltz, C. G. & Pappert, E. J.) 90–101 (W. B. Saunders, Philadelphia, 1998).

    Google Scholar 

  116. Leopold, D. A. et al. Anterior distribution of human olfactory epithelium. Laryngoscope 110, 417–421 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Baker, H. & Genter, M. B. in Handbook of Olfaction and Gustation (ed. Doty, R. L.) 549–573 (Marcel Dekker, New York, 2003).

    Google Scholar 

  118. Levesque, S., Surace, M. J., McDonald, J. & Block, M. L. Air pollution & the brain: subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease. J. Neuroinflammation 8, 105 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Calderon-Garciduenas, L. et al. Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. J. Alzheimers Dis. 28, 93–107 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Calderon-Garciduenas, L. et al. Air pollution is associated with brainstem auditory nuclei pathology and delayed brainstem auditory evoked potentials. Int. J. Dev. Neurosci. 29, 365–375 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Altman, K. W. et al. Odor identification ability and self-reported upper respiratory symptoms in workers at the post-9/11 World Trade Center site. Int. Arch. Occup. Environ. Health 84, 131–137 (2011).

    Article  PubMed  Google Scholar 

  122. Antunes, M. B., Bowler, R. & Doty, R. L. San-Francisco/Oakland Bay Bridge welder study: olfactory function. Neurology 69, 1278–1284 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Thompson, K. et al. Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. FASEB J. 21, 223–230 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Tallkvist, J. & Tjalve, H. Effect of dietary iron-deficiency on the disposition of nickel in rats. Toxicol. Lett. 92, 131–138 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Perl, D. P. & Olanow, C. W. The neuropathology of manganese-induced parkinsonism. J. Neuropathol. Exp. Neurol. 66, 675–682 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Lucchini, R. G., Martin, C. J. & Doney, B. C. From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure. Neuromolecular Med. 11, 311–321 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Doty, R. L. in Frontiers in Parkinson's Disease Research (eds Prediger, R. D. & Raisman-Vozari, R.) in press (Nova Science Publishers, New York).

  128. Prediger, R. D. et al. Intranasal administration of neurotoxicants in animals: support for the olfactory vector hypothesis of Parkinson's disease. Neurotox. Res. 21, 90–116 (2011).

    Article  PubMed  CAS  Google Scholar 

  129. Prediger, R. D. et al. Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson's disease. Neurotox. Res. 17, 114–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Casals, J., Elizan, T. S. & Yahr, M. D. Postencephalitic parkinsonism—a review. J. Neural Transm. 105, 645–676 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. McLean, J. H., Shipley, M. T., Bernstein, D. I. & Corbett, D. Selective lesions of neural pathways following viral inoculation of the olfactory bulb. Exp. Neurol. 122, 209–222 (1993).

    Article  CAS  PubMed  Google Scholar 

  132. Doty, R. L. Office procedures for quantitative assessment of olfactory function. Am. J. Rhinol. 21, 460–473 (2007).

    Article  PubMed  Google Scholar 

  133. Eibenstein, A. et al. Modern psychophysical tests to assess olfactory function. Neurol. Sci. 26, 147–155 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Kobal, G. & Hummel, T. Olfactory (chemosensory) event-related potentials. Toxicol. Ind. Health 10, 587–596 (1994).

    Article  CAS  PubMed  Google Scholar 

  135. Doty, R. L. in Handbook of Olfaction and Gustation (ed. Doty, R. L.) 479–502 (Marcel Dekker, New York, 2003).

    Book  Google Scholar 

  136. Doty, R. L., Shaman, P. & Dann, M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol. Behav. 32, 489–502 (1984).

    Article  CAS  PubMed  Google Scholar 

  137. Hummel, T., Kobal, G., Gudziol, H. & Mackay-Sim, A. Normative data for the “Sniffin' Sticks” including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than 3,000 subjects. Eur. Arch. Otorhinolaryngol. 264, 237–243 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Lehrner, J. P., Brucke, T., Dal-Bianco, P., Gatterer, G. & Kryspin-Exner, I. Olfactory functions in Parkinson's disease and Alzheimer's disease. Chem. Senses 22, 105–110 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Hummel, T., Sekinger, B., Wolf, S. R., Pauli, E. & Kobal, G. 'Sniffin' sticks': olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem. Senses 22, 39–52 (1997).

    Article  CAS  PubMed  Google Scholar 

  140. Suzuki, M. et al. The odor stick identification test for Japanese differentiates Parkinson's disease from multiple system atrophy and progressive supra nuclear palsy. BMC Neurol. 11, 157 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Ogihara, H., Kobayashi, M., Nishida, K., Kitano, M. & Takeuchi, K. Applicability of the cross-culturally modified University of Pennsylvania Smell Identification Test in a Japanese population. Am. J. Rhinol. Allergy 25, 404–410 (2011).

    Article  PubMed  Google Scholar 

  142. Silveira-Moriyama, L. et al. The use of smell identification tests in the diagnosis of Parkinson's disease in Brazil. Mov. Disord. 23, 2328–2334 (2008).

    Article  PubMed  Google Scholar 

  143. Quinn, N. P., Rossor, M. N. & Marsden, C. D. Olfactory threshold in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 50, 88–89 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Choudhury, E. S., Moberg, P. & Doty, R. L. Influences of age and sex on a microencapsulated odor memory test. Chem. Senses 28, 799–805 (2003).

    Article  PubMed  Google Scholar 

  145. Bostantjopoulou, S. et al. Clinical features of parkinsonian patients with the α-synuclein (G209A) mutation. Mov. Disord. 16, 1007–1013 (2001).

    Article  CAS  PubMed  Google Scholar 

  146. Kruger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18, 106–108 (1998).

    Article  CAS  PubMed  Google Scholar 

  147. Alcalay, R. N. et al. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology 76, 319–326 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Khan, N. L. et al. Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 62, 1224–1226 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Eggers, C. et al. Progression of subtle motor signs in PINK1 mutation carriers with mild dopaminergic deficit. Neurology 74, 1798–1805 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Ferraris, A. et al. Olfactory dysfunction in Parkinsonism caused by PINK1 mutations. Mov. Disord. 24, 2350–2357 (2009).

    PubMed  Google Scholar 

  151. Ferreira, J. J. et al. High prevalence of LRRK2 mutations in familial and sporadic Parkinson's disease in Portugal. Mov. Disord. 22, 1194–1201 (2007).

    Article  PubMed  Google Scholar 

  152. Khan, N. L. et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128, 2786–2796 (2005).

    Article  PubMed  Google Scholar 

  153. Markopoulou, K. et al. Olfactory dysfunction in familial parkinsonism. Neurology 49, 1262–1267 (1997).

    Article  CAS  PubMed  Google Scholar 

  154. Marras, C. et al. Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology 77, 325–333 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Silveira-Moriyama, L. et al. Olfactory heterogeneity in LRRK2 related Parkinsonism. Mov. Disord. 25, 2879–2883 (2010).

    Article  PubMed  Google Scholar 

  156. Goker-Alpan, O. et al. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch. Neurol. 65, 1353–1357 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Saunders-Pullman, R. et al. Gaucher disease ascertained through a Parkinson's center: imaging and clinical characterization. Mov. Disord. 25, 1364–1372 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Cleland, T. A. & Linster, C. in Handbook of Olfaction and Gustation (ed. Doty, R. L.) 165–180 (Marcel Dekker, New York, 2003).

    Google Scholar 

Download references

Acknowledgements

I thank L. Calderón-Garcidueñas, K. Cathey, F. E. Leon-Sarmiento and A. Osman for their comments. This work was supported, in part, by grants NIEHS P30 ES013508 and USAMRAA W81XWH-09-1-0467.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

R. L. Doty is President and a major shareholder of Sensonics, a manufacturer and distributor of smell and taste tests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Doty, R. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol 8, 329–339 (2012). https://doi.org/10.1038/nrneurol.2012.80

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2012.80

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing