Abstract
Olfactory dysfunction is an early and common symptom of many neurodegenerative diseases, particularly of Parkinson’s disease, Alzheimer’s disease, and mild cognitive impairment that heralds progression to dementia. Olfactory impairment is known to be related to several pathologic changes including the deposition of α-synuclein, hyperphosphorylated tau protein, neurofilament protein, Lewy bodies and neuritis inducing a complex cascade of molecular processes such as oxidative stress, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. The areas mainly showing these pathologic changes are the olfactory epithelium, olfactory bulb and tract, primary olfactory cortices, and their secondary target areas. Since early loss of olfactory function is common among several common neurodegenerative disorders, recent investigations have focused on its utility as a biomarker for early diagnosis and progression. Olfactory impairment appears to be an important sign for early detection, a useful biomarker for disease progression and a useful differentiator between neurological disorders.
REFERENCES
1. Barresi M, Ciurleo R, Giacoppo S, Foti Cuzzola V, Celi D, Bramanti P, et al. Evaluation of olfactory dysfunction in neurodegenerative diseases. J Neurol Sci. 2012; 323:16–24.
2. Trojanowski JQ, Newman PD, Hill WD, Lee VM. Human olfactory epithelium in normal aging, Alzheimer’s disease, and other neurodegenerative disorders. J Comp Neurol. 1991; 310:365–376.
4. Demarquay G, Ryvlin P, Royet JP. Olfaction and neurological diseases: a review of the literature. Rev Neurol (Paris). 2007; 163:155–167.
5. McLaughlin NC, Westervelt HJ. Odor identification deficits in frontotemporal dementia: a preliminary study. Arch Clin Neuropsychol. 2008; 23:119–123.
6. Pardini M, Huey ED, Cavanagh AL, Grafman J. Olfactory function in corticobasal syndrome and frontotemporal dementia. Arch Neurol. 2009; 66:92–96.
7. Nicola-Antoniu I. Olfactory dysfunctions in Alzheimer’s disease. In: Suzanne De La Monte, editor. The clinical spectrum of Alzheimer’s disease - The charge toward comprehensive diagnostic and therapeutic strategies. InTech; 2011. pp. 127-144.
8. Rahayel S, Frasnelli J, Joubert S. The effect of Alzheimer’s disease and Parkinson’s disease on olfaction: a meta-analysis. Behav Brain Res. 2012; 231:60–74.
9. Mesholam RI, Moberg PJ, Mahr RN, Doty RL. Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol. 1998; 55:84–90.
10. Attems J, Lintner F, Jellinger KA. Olfactory involvement in aging and Alzheimer’s disease: an autopsy study. J Alzheimers Dis. 2005; 7:149–157. discussion 73-80.
11. Conti MZ, Vicini-Chilovi B, Riva M, Zanetti M, Liberini P, Padovani A, et al. Odor identification deficit predicts clinical conversion from mild cognitive impairment to dementia due to Alzheimer’s disease. Arch Clin Neuropsychol. 2013; 28:391–399.
12. Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56:1133–1142.
13. Kovacs T. Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders. Ageing Res Rev. 2004; 3:215–232.
14. Devanand DP, Tabert MH, Cuasay K, Manly JJ, Schupf N, Brickman AM, et al. Olfactory identification deficits and MCI in a multi-ethnic elderly community sample. Neurobiol Aging. 2010; 31:1593–1600.
15. Wang J, Eslinger PJ, Doty RL, Zimmerman EK, Grunfeld R, Sun X, et al. Olfactory deficit detected by fMRI in early Alzheimer’s disease. Brain Res. 2010; 1357:184–194.
16. Forster S, Vaitl A, Teipel SJ, Yakushev I, Mustafa M, la Fougere C, et al. Functional representation of olfactory impairment in early Alzheimer’s disease. J Alzheimers Dis. 2010; 22:581–591.
17. Thomann PA, Dos Santos V, Seidl U, Toro P, Essig M, Schroder J. MRI-derived atrophy of the olfactory bulb and tract in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2009; 17:213–221.
18. Graves AB, Bowen JD, Rajaram L, McCormick WC, McCurry SM, Schellenberg GD, et al. Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E epsilon4 status. Neurology. 1999; 53:1480–1487.
19. Olofsson JK, Nordin S, Wiens S, Hedner M, Nilsson LG, Larsson M. Odor identification impairment in carriers of ApoE-varepsilon4 is independent of clinical dementia. Neurobiol Aging. 2010; 31:567–577.
20. Bahar-Fuchs A, Chetelat G, Villemagne VL, Moss S, Pike K, Masters CL, et al. Olfactory deficits and amyloid-beta burden in Alzheimer’s disease, mild cognitive impairment, and healthy aging: a PiB PET study. J Alzheimers Dis. 2010; 22:1081–1087.
21. Larsson M, Farde L, Hummel T, Witt M, Lindroth NE, Backman L. Age-related loss of olfactory sensitivity: association to dopamine transporter binding in putamen. Neuroscience. 2009; 161:422–426.
22. Wong KK, Muller ML, Kuwabara H, Studenski SA, Bohnen NI. Olfactory loss and nigrostriatal dopaminergic denervation in the elderly. Neurosci Lett. 2010; 484:163–167.
23. Wesson DW, Levy E, Nixon RA, Wilson DA. Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer’s disease mouse model. J Neurosci. 2010; 30:505–514.
24. Boesveldt S, Verbaan D, Knol DL, Visser M, van Rooden SM, van Hilten JJ, et al. A comparative study of odor identification and odor discrimination deficits in Parkinson’s disease. Mov Disord. 2008; 23:1984–1990.
25. Baba T, Kikuchi A, Hirayama K, Nishio Y, Hosokai Y, Kanno S, et al. Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson’s disease: a 3 year longitudinal study. Brain. 2012; 135:161–169.
26. Doty RL. Olfaction in Parkinson’s disease. Parkinsonism Relat Disord. 2007; 13 Suppl 3:S225–S228.
27. Morley JF, Duda JE. Olfaction as a biomarker in Parkinson’s disease. Biomark Med. 2010; 4:661–670.
28. 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. 2007; 264:237–243.
29. Alves G, Forsaa EB, Pedersen KF, Dreetz Gjerstad M, Larsen JP. Epidemiology of Parkinson’s disease. J Neurol. 2008; 255 Suppl 5:18–32.
30. Doty RL. Olfaction in Parkinson’s disease and related disorders. Neurobiol Dis. 2012; 46:527–552.
31. Meusel T, Westermann B, Fuhr P, Hummel T, Welge-Lussen A. The course of olfactory deficits in patients with Parkinson’s disease--a study based on psychophysical and electrophysiological measures. Neurosci Lett. 2010; 486:166–170.
32. Barz S, Hummel T, Pauli E, Majer M, Lang CJ, Kobal G. Chemosensory event-related potentials in response to trigeminal and olfactory stimulation in idiopathic Parkinson’s disease. Neurology. 1997; 49:1424–1431.
33. Berendse HW, Roos DS, Raijmakers P, Doty RL. Motor and non-motor correlates of olfactory dysfunction in Parkinson’s disease. J Neurol Sci. 2011; 310:21–24.
34. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004; 318:121–134.
35. Goldstein DS, Sewell L, Holmes C. Association of anosmia with autonomic failure in Parkinson disease. Neurology. 2010; 74:245–251.
36. Kang P, Kloke J, Jain S. Olfactory dysfunction and parasympathetic dysautonomia in Parkinson’s disease. Clin Auton Res. 2012; 22:161–166.
37. Bohnen NI, Gedela S, Kuwabara H, Constantine GM, Mathis CA, Studenski SA, et al. Studenski SA, et al. Selective hyposmia and nigrostriatal dopaminergic denervation in Parkinson’s disease. J Neurol. 2007; 254:84–90.
38. Oka H, Toyoda C, Yogo M, Mochio S. Olfactory dysfunction and cardiovascular dysautonomia in Parkinson’s disease. J Neurol. 2010; 257:969–976.
39. Bohnen NI, Muller ML, Kotagal V, Koeppe RA, Kilbourn MA, Albin RL, et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain. 2010; 133:1747–1754.
40. Takeda A. Severe olfactory dysfunction is a predictor of dementia with Parkinson’s disease. Rinsho Shinkeigaku. 2013; 53:91–97.
41. Bohnen NI, Muller ML. In vivo neurochemical imaging of olfactory dysfunction in Parkinson’s disease. J Neural Transm. 2013; 120:571–576.
42. Moessnang C, Frank G, Bogdahn U, Winkler J, Greenlee MW, Klucken J. Altered activation patterns within the olfactory network in Parkinson’s disease. Cereb Cortex. 2011; 21:1246–1253.
43. Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters E, Berendse HW. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol. 2004; 56:173–181.
44. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003; 24:197–211.
45. Katzenschlager R, Zijlmans J, Evans A, Watt H, Lees AJ. Olfactory function distinguishes vascular parkinsonism from Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2004; 75:1749–1752.
46. Wenning GK, Shephard B, Hawkes C, Petruckevitch A, Lees A, Quinn N. Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand. 1995; 91:247–250.
47. Busenbark KL, Huber SJ, Greer G, Pahwa R, Koller WC. Olfactory function in essential tremor. Neurology. 1992; 42:1631–1632.
48. Doty RL, Singh A, Tetrud J, Langston JW. Lack of major olfactory dysfunction in MPTP-induced parkinsonism. Ann Neurol. 1992; 32:97–100.
49. Mundinano IC, Hernandez M, Dicaudo C, Ordonez C, Marcilla I, Tunon MT, et al. Reduced cholinergic olfactory centrifugal inputs in patients with neurodegenerative disorders and MPTP-treated monkeys. Acta Neuropathol. 2013; 126:411–425.
50. Huttenbrink KB, Hummel T, Berg D, Gasser T, Hahner A. Olfactory dysfunction: common in later life and early warning of neurodegenerative disease. Dtsch Arztebl Int. 2013; 110:1–7.