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
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Olfactory dysfunction is an early and sensitive marker of the preclinical phase of Parkinson disease (PD)
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Analogous olfactory dysfunction occurs in other—but not all—neurodegenerative diseases, suggesting the involvement of a common neuropathological substrate
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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
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Damage to largely nondopaminergic neurotransmitter systems may contribute to, or possibly even cause, the olfactory loss observed in PD and some other neurodegenerative diseases
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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
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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
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References
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).
Wilson, R. S., Yu, L. & Bennett, D. A. Odor identification and mortality in old age. Chem. Senses 36, 63–67 (2011).
Doty, R. L. Olfaction in Parkinson's disease and related disorders.. Neurobiol. Dis. 46, 527–552 (2012).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).
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.
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).
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).
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).
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).
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).
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).
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).
McKeown, D. A. et al. Olfactory function in young adolescents with Down's syndrome. J. Neurol. Neurosurg. Psychiatry 61, 412–414 (1996).
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).
Hawkes, C. H. & Doty, R. L. The Neurology of Olfaction (Cambridge University Press, Cambridge, 2009).
Doty, R. L. et al. Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson's disease. Neurology 43, 962–965 (1993).
Wenning, G. K. et al. Olfactory function in atypical parkinsonian syndromes. Acta Neurol. Scand. 91, 247–250 (1995).
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).
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).
Busenbark, K. L., Huber, S. I., Greer, G., Pahwa, R. & Koller, W. C. Olfactory function in essential tremor. Neurology 42, 1631–1632 (1992).
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).
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).
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).
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).
Hawkes, C. H., Shephard, B. C. & Daniel, S. E. Olfactory dysfunction in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 62, 436–446 (1997).
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).
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).
Bohnen, N. I. et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease. Brain 133, 1747–1754 (2010).
Postuma, R. & Gagnon, J. F. Cognition and olfaction in Parkinson's disease. Brain 133, e160 (2010).
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.
Boesveldt, S. et al. A comparative study of odor identification and odor discrimination deficits in Parkinson's disease. Mov. Disord. 23, 1984–1990 (2008).
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).
Stephenson, R. et al. Impaired olfaction and subsequent risk of long-term complications of Parkinson's disease. Mov. Disord. 23, 866 (2008).
Siderowf, A. et al. [99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 64, 1716–1720 (2005).
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).
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).
Goldstein, D. S., Sewell, L. & Holmes, C. Association of anosmia with autonomic failure in Parkinson disease. Neurology 74, 245–251 (2010).
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).
Ross, G. W. et al. Association of olfactory dysfunction with risk for future Parkinson's disease. Ann. Neurol. 63, 167–173 (2008).
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).
Marras, C. et al. Smell identification ability in twin pairs discordant for Parkinson's disease. Mov. Disord. 20, 687–693 (2005).
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).
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).
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).
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).
Ponsen, M. M. et al. Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Ann. Neurol. 56, 173–181 (2004).
Siderowf, A. et al. Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome study. Mov. Disord. 27, 406–412 (2012).
Tanner, C. M. et al. Parkinson disease in twins: an etiologic study. J. Am. Med. Assoc. 281, 341–346 (1999).
Elbaz, A. et al. Validity of family history data on PD: evidence for a family information bias. Neurology 61, 11–17 (2003).
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).
Silveira-Moriyama, L. et al. Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data. Neurology 71, 1021–1026 (2008).
Saunders-Pullman, R. et al. Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology 77, 319–324 (2011).
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).
Tanner, C. et al. Follow-up of elderly male twin pairs discordant for Parkinson's disease (PD). Neurology 68, A86 (2007).
Moberg, P. J. & Doty, R. L. Olfactory function in Huntington's disease patients and at-risk offspring. Int. J. Neurosci. 89, 133–139 (1997).
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).
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).
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).
Pearce, R. K., Hawkes, C. H. & Daniel, S. E. The anterior olfactory nucleus in Parkinson's disease. Mov. Disord. 10, 283–287 (1995).
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).
Beach, T. G. et al. Olfactory bulb α-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol. 117, 169–174 (2009).
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).
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).
Silveira-Moriyama, L. et al. Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci. Lett. 453, 77–80 (2009).
Doty, R. L. The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann. Neurol. 63, 7–15 (2008).
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).
Lei, P. et al. Tau protein: relevance to Parkinson's disease. Int. J. Biochem. Cell Biol. 42, 1775–1778 (2010).
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).
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).
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).
Smith, R. L., Baker, H. & Greer, C. A. Immunohistochemical analyses of the human olfactory bulb. J. Comp. Neurol. 333, 519–530 (1993).
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).
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).
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).
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).
Yahr, M. D. Parkinson's disease—overview of its current status. Mt Sinai J. Med. 44, 183–191 (1977).
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).
Ruberg, M. et al. Dopaminergic and cholinergic lesions in progressive supranuclear palsy. Ann. Neurol. 18, 523–529 (1985).
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).
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).
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.
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).
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).
Bohnen, N. I. et al. Selective hyposmia and nigrostriatal dopaminergic denervation in Parkinson's disease. J. Neurol. 254, 84–90 (2007).
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).
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).
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).
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).
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).
Feinstein, D. L. et al. Noradrenergic regulation of inflammatory gene expression in brain. Neurochem. Int. 41, 357–365 (2002).
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).
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).
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).
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).
Petzold, G. C., Hagiwara, A. & Murthy, V. N. Serotonergic modulation of odor input to the mammalian olfactory bulb. Nat. Neurosci. 12, 784–791 (2009).
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).
Huot, P., Fox, S. H. & Brotchie, J. M. The serotonergic system in Parkinson's disease. Prog. Neurobiol. 95, 163–212 (2011).
Braak, E. et al. α-Synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei. Acta Neuropathol. 101, 195–201 (2001).
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).
Kovacs, G. G. et al. Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders. Neuroreport 14, 73–76 (2003).
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).
Tsukatani, T. et al. Bulbar morphology and expression of bulbar dopamine and parvalbumin in experimentally-induced anosmic rats. Acta Otolaryngol. 115, 539–542 (1995).
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).
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).
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).
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).
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).
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).
Doty, R. L. et al. Smell identification ability: changes with age. Science 226, 1441–1443 (1984).
Doty, R. L. et al. Olfactory dysfunction in patients with head trauma. Arch. Neurol. 54, 1131–1140 (1997).
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).
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).
Gobba, F. Olfactory toxicity: long-term effects of occupational exposures. Int. Arch. Occup. Environ. Health 79, 322–331 (2006).
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).
Doty, R. L. in Textbook of Clinical Neurology (eds Goltz, C. G. & Pappert, E. J.) 90–101 (W. B. Saunders, Philadelphia, 1998).
Leopold, D. A. et al. Anterior distribution of human olfactory epithelium. Laryngoscope 110, 417–421 (2000).
Baker, H. & Genter, M. B. in Handbook of Olfaction and Gustation (ed. Doty, R. L.) 549–573 (Marcel Dekker, New York, 2003).
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).
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).
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).
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).
Antunes, M. B., Bowler, R. & Doty, R. L. San-Francisco/Oakland Bay Bridge welder study: olfactory function. Neurology 69, 1278–1284 (2007).
Thompson, K. et al. Olfactory uptake of manganese requires DMT1 and is enhanced by anemia. FASEB J. 21, 223–230 (2007).
Tallkvist, J. & Tjalve, H. Effect of dietary iron-deficiency on the disposition of nickel in rats. Toxicol. Lett. 92, 131–138 (1997).
Perl, D. P. & Olanow, C. W. The neuropathology of manganese-induced parkinsonism. J. Neuropathol. Exp. Neurol. 66, 675–682 (2007).
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).
Doty, R. L. in Frontiers in Parkinson's Disease Research (eds Prediger, R. D. & Raisman-Vozari, R.) in press (Nova Science Publishers, New York).
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).
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).
Casals, J., Elizan, T. S. & Yahr, M. D. Postencephalitic parkinsonism—a review. J. Neural Transm. 105, 645–676 (1998).
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).
Doty, R. L. Office procedures for quantitative assessment of olfactory function. Am. J. Rhinol. 21, 460–473 (2007).
Eibenstein, A. et al. Modern psychophysical tests to assess olfactory function. Neurol. Sci. 26, 147–155 (2005).
Kobal, G. & Hummel, T. Olfactory (chemosensory) event-related potentials. Toxicol. Ind. Health 10, 587–596 (1994).
Doty, R. L. in Handbook of Olfaction and Gustation (ed. Doty, R. L.) 479–502 (Marcel Dekker, New York, 2003).
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).
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).
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).
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).
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).
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).
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).
Quinn, N. P., Rossor, M. N. & Marsden, C. D. Olfactory threshold in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 50, 88–89 (1987).
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).
Bostantjopoulou, S. et al. Clinical features of parkinsonian patients with the α-synuclein (G209A) mutation. Mov. Disord. 16, 1007–1013 (2001).
Kruger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18, 106–108 (1998).
Alcalay, R. N. et al. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology 76, 319–326 (2011).
Khan, N. L. et al. Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 62, 1224–1226 (2004).
Eggers, C. et al. Progression of subtle motor signs in PINK1 mutation carriers with mild dopaminergic deficit. Neurology 74, 1798–1805 (2010).
Ferraris, A. et al. Olfactory dysfunction in Parkinsonism caused by PINK1 mutations. Mov. Disord. 24, 2350–2357 (2009).
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).
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).
Markopoulou, K. et al. Olfactory dysfunction in familial parkinsonism. Neurology 49, 1262–1267 (1997).
Marras, C. et al. Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology 77, 325–333 (2011).
Silveira-Moriyama, L. et al. Olfactory heterogeneity in LRRK2 related Parkinsonism. Mov. Disord. 25, 2879–2883 (2010).
Goker-Alpan, O. et al. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch. Neurol. 65, 1353–1357 (2008).
Saunders-Pullman, R. et al. Gaucher disease ascertained through a Parkinson's center: imaging and clinical characterization. Mov. Disord. 25, 1364–1372 (2010).
Cleland, T. A. & Linster, C. in Handbook of Olfaction and Gustation (ed. Doty, R. L.) 165–180 (Marcel Dekker, New York, 2003).
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.
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R. L. Doty is President and a major shareholder of Sensonics, a manufacturer and distributor of smell and taste tests.
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Doty, R. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol 8, 329–339 (2012). https://doi.org/10.1038/nrneurol.2012.80
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DOI: https://doi.org/10.1038/nrneurol.2012.80
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