Contribution of Olfactory Tests to Diagnosis of Neurodegenerative Diseases

Czech version

Authors: Lenka Martinec Nováková ^1–3 ; H. Štěpánková ³; J. Vodička ⁴; J. Havlíček ^2,3
Authors‘ workplace: Katedra obecné antropologie, FHS UK v Praze ¹; Katedra zoologie, PřF UK v Praze ²; Národní ústav duševního zdraví, Klecany ³; Klinika otorinolaryngologie a chirurgie hlavy a krku FZS Univerzity Pardubice a Pardubická krajská nemocnice, a. s. ⁴
Published in: Cesk Slov Neurol N 2015; 78/111(5): 517-525
Category: Review Article

Overview

In many neurodegenerative diseases, changes in olfactory perception have been identified that can be tested with psychophysical tests. Olfactory testing is of particular significance in Alzheimer’s and Parkinson’s disease, where olfactory decline precedes other clinical symptoms. Olfactory decline may indicate a neurological disorder, aid in differential diagnosis, or help to estimate disease prognosis. This review presents olfactory dysfunction profiles in selected neurodegenerative diseases with an emphasis on Alzheimer’s and Parkinson’s disease, assessment of quanti- and qualitative olfactory dysfunction, focusing on widely used psychophysical tests suitable for routine olfactory testing in everyday clinical practice, and contribution of olfactory testing to the diagnosis of the selected neurodegenerative diseases. In Alzheimer’s disease, identification is more severely affected than detection thresholds, whereas in Parkinson’s disease, decline is more homogeneous across various olfactory measures and increase in detection thresholds is more prominent.

Key words:
olfaction – neurodegenerative diseases – hyposmia – anosmia – Alzheimer’s disease – Parkinson’s disease – mild cognitive impairment

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Sources

1. Ansari KA, Johnson A. Olfactory function in patients with Parkinson’s disease. J Chronic Dis 1975; 28(9): 493– 497.

2. Waldton S. Clinical observations of impaired cranial nerve function in senile dementia. Acta Psychiatr Scand 1974; 50(5): 539– 547.

3. Doty RL. Olfaction in Parkinson‘s disease and related disorders. Neurobiol Dis 2012; 46(3): 527– 552. doi: 10.1016/ j.nbd.2011.10.026.

4. Sun GH, Raji CA, MacEachern MP, Burke JF. Olfactory identification testing as a predictor of the development of Alzheimer‘s dementia: a systematic review. Laryngoscope 2012; 122(7): 1455– 1462. doi: 10.1002/ lary.23365.

5. Hawkes CH, Doty RL. Neurodegenerative diseases that affect olfaction. In: Hawkes CH, Doty RL (eds). The Neurology of Olfaction. New York: Cambridge University Press 2009: 153– 214.

6. Mondon K, Naudin M, Beaufils E, Atanasova B. Perception of taste and smell in normal and pathological aging: an update. Geriatr Psychol Neuropsychiatr Vieil 2014; 12(3): 313– 320. doi: 10.1684/ pnv.2014.0484.

7. Doty RL, Kamath V. The influences of age on olfaction: a review. Front Psychol 2014; 5: 20. doi: 10.3389/ fpsyg.2014.00020.

8. Schofield PW, Finnie S, Yong YM. The role of olfactory challenge tests in incipient dementia and clinical trial design. Curr Neurol Neurosci Rep 2014; 14(9): 479. doi: 10.1007/ s11910‑ 014‑ 0479‑ z.

9. Doty RL. Odor perception in neurodegenerative diseases. In: Doty RL (ed.). Handbook of Olfaction and Gustation. 2nd ed. New York, NY: Marcel Dekker 2003: 479–502.

10. 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(1): 84– 90.

11. Nordin S, Monsch AU, Murphy C. Unawareness of smell loss in normal aging and Alzheimer’s disease: discrepancy between self‑ reported and diagnosed smell sensitivity. J Gerontol B Psychol Sci Soc Sci 1995; 50(4): P187– P192.

12. Hummel T, Welge‑ Lüessen A. Assessment of olfactory function. In: Hummel T, Welge‑ Lüessen A (eds). Taste and Smell. An Update. Advances in Oto‑ Rhino‑ Laryngology. Basel: Karger 2006: 84– 98.

13. Doty RL, Deems DA, Frye RE, Pelberg R, Shapiro A. Olfactory sensitivity, nasal resistance, and autonomic function in patients with multiple chemical sensitivities. Arch Otolaryngol Head Neck Surg 1988; 114(12): 1422– 1427.

14. Hawkes CH, Doty RL. General disorders of olfaction. In: Hawkes CH, Doty RL (eds). The Neurology of Olfaction. New York, NY: Cambridge University Press 2009: 111– 152.

15. Landis BN, Hummel T, Hugentobler M, Giger R, Lacroix JS. Ratings of overall olfactory function. Chem Senses 2003; 28(8): 691– 694.

16. Soter A, Kim J, Jackman A, Tourbier I, Kaul A, Doty RL. Accuracy of self‑ report in detecting taste dysfunction. Laryngoscope 2008; 118(4): 611– 617.

17. Marschner H, Gudziol H, Guntinas‑ Lichius O. Olfactory dysfunctions are substantially more frequent than they are complained. Laryngorhinootologie 2010; 89(11): 654– 659. doi: 10.1055/ s‑ 0030‑ 1262779.

18. Shu CH, Lee PL, Lan MY, Lee YL. Factors affecting the impact of olfactory loss on the quality of life and emotional coping ability. Rhinology 2011; 49(3): 337– 341. doi: 10.4193/ Rhino10.130.

19. Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM. Prevalence of olfactory impairment in older adults. JAMA 2002; 288(18): 2307– 2312.

20. Hoffman HJ, Ishii EK, Macturk RH. Age‑related changes in the prevalence of smell/ taste problems among the United States adult population – results of the 1994 disability supplement to the National Health Interview Survey (NHIS). Ann N Y Acad Sci 1998; 855: 716– 722.

21. Nordin S, Bramerson A, Bende M. Prevalence of self‑ reported poor odor detection sensitivity: the Skövde population‑based study. Acta Otolaryngol (Stockh) 2004; 124(10): 1171– 1173.

22. Frasnelli J, Landis BN, Heilmann S, Hauswald B, Huttenbrink KB, Lacroix JS et al. Clinical presentation of qualitative olfactory dysfunction. Eur Arch Otorhinolaryngol 2004; 261(7): 411– 415.

23. Simmen D, Briner HR. Olfaction in rhinology – methods of assessing the sense of smell. Rhinology 2006; 44(2): 98– 101.

24. Leopold D. Distortion of olfactory perception: Diagnosis and treatment. Chem Senses 2002; 27(7): 611– 615.

25. Landis BN, Frasnelli J, Hummel T. Euosmia: a rare form of parosmia. Acta Otolaryngol (Stockh) 2006; 126(1): 101– 103.

26. Bramerson A, Johansson L, Ek L, Nordin S, Bende M. Prevalence of olfactory dysfunction: the Skövde population‑based study. Laryngoscope 2004; 114(4): 733– 737.

27. Vennemann MM, Hummel T, Berger K. The association between smoking and smell and taste impairment in the general population. J Neurol 2008; 255(8): 1121– 1126. doi: 10.1007/ s00415‑ 008‑ 0807‑ 9.

28. Landis BN, Konnerth CG, Hummel T. A study on the frequency of olfactory dysfunction. Laryngoscope 2004; 114(10): 1764– 1769.

29. Nordin S, Bramerson A, Millqvist E, Bende M. Prevalence of parosmia: the Skövde population‑based studies. Rhinology 2007; 45(1): 50– 53.

30. Henkin RI. Hyperosmia and depression following exposure to toxic vapors. JAMA 1990; 264(21): 2803.

31. Grant AC. Interictal perceptual function in epilepsy. Epilepsy Behav 2005; 6(4): 511– 519.

32. Blau JN, Solomon F. Smell and other sensory disturbances in migraine. J Neurol 1985; 232(5): 275– 276.

33. Hirsch AR. Olfaction in migraineurs. Headache 1992; 32(5): 233– 236.

34. Vodička J. Rozdělení poruch čichu. In: Chrobok V (ed.). Poruchy čichu a chuti. Havlíčkův Brod: Tobiáš 2012: 56– 60.

35. Vodička J, Pellant A. Metody vyšetření čichu v klinické praxi. Otorinolaryng a Foniat 2004; 53: 7– 10.

36. Doty RL, Laing DG. Psychophysical measurement of human olfactory function, including odorant mixture assessment. In: Doty RL (ed.). Handbook of Olfaction and Gustation. 2nd ed. New York, NY: Marcel Dekker 2003: 203– 228.

37. Flanagan DP, Harrison PL. Contemporary Intellectual Assessment: Theories, Tests, and Issues. 3rd ed. New York, NY: Guilford Press 2012.

38. Hawkes CH, Doty RL. Clinical evaluation. In: Hawkes CH,Doty RL (eds). The Neurology of Olfaction. New York, NY: Cambridge University Press 2009: 59– 109.

39. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. ‚Sniffin‘ Sticks‘: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses 1997; 22(1): 3– 52.

40. Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984; 94(2): 176– 178.

41. Vodicka J, Pellant A, Chrobok V. Screening of olfactory function using odourized markers. Rhinology 2007; 45(2): 164– 168.

42. Vodička J, Pecková LK, A, Ehler E, Chrobok V. Vyšetření čichu u neurologických onemocnění pomocí Testu parfémovaných fixů. Cesk Slov Neurol N 2010; 73/ 106(1): 45– 50.

43. Magerová H, Vyhnálek M, Laczó J, Bojar M, Hort J. Přínos vyšetření čichu v časné diagnostice demencí. Cesk Slov Neurol N 2008; 71/ 104(3): 298– 302.

44. Doty RL. The Smell Identification Test administration manual. Haddon Heights, NJ: Sensonics 1995.

45. Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984; 32(3): 489– 502.

46. Doty RL, Marcus A, Lee WW. Development of the 12- item Cross‑ Cultural Smell Identification Test (CC‑ SIT). Laryngoscope 1996; 106(3): 353– 356.

47. Vodička J, Menšíková A, Balatková Z, Shejbalová H, Racková R, Matoušek P et al. Fyziologické hodnoty čichových testů v české populaci. Otorinolaryng Foniat 2011; 60(3): 119– 124.

48. Brothánková P, Vodička J. Normální hodnoty Nového testu libosti pachů u zdravé populace. Cesk Slov Neurol N 2015; 78/ 111(1): 78– 82.

49. Mortimer JA, Borenstein AR, Gosche KM, Snowdon DA. Very early detection of Alzheimer neuropathology and the role of brain reserve in modifying its clinical expression. J Geriatr Psychiatry Neurol 2005; 18(4): 218– 223.

50. Humpel C. Identifying and validating biomarkers for Alzheimer‘s disease. Trends Biotechnol 2011; 29(1): 26– 32. doi: 10.1016/ j.tibtech.2010.09.007.

51. Craig‑ Schapiro R, Fagan AM, Holtzman DM. Biomarkers of Alzheimer‘s disease. Neurobiol Dis 2009; 35(2): 128– 140. doi: 10.1016/ j.nbd.2008.10.003.

52. Jack CR jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS,Weiner MW et al. Hypothetical model of dynamic biomarkers of the Alzheimer‘s pathological cascade. Lancet Neurol 2010; 9(1): 119– 128. doi: 10.1016/ S1474‑ 4422(09)70299‑ 6.

53. Murphy C. Loss of olfactory function in dementing disease. Physiol Behav 1999; 66(2): 177– 182.

54. Doty RL, Hawkes CH, Good KV, Duda JE. Odor perception and neuropathology in neurodegenerative diseases and schizophrenia. In: Doty RL (ed.). Handbook of Olfaction and Gustation. 3rd ed. Hoboken, NJ: John Wiley & Sons 2015: 403–451.

55. Serby M, Larson P, Kalkstein D. The nature and course of olfactory deficits in Alzheimer‘s disease. Am J Psychiatry 1991; 148(3): 357– 360.

56. Devanand DP, Michaels‑ Marston KS, Liu XH, Pelton GH,Padilla M, Marder K et al. Olfactory deficits in patients with mild cognitive impairment predict Alzheimer‘s disease at follow‑up. Am J Psychiatry 2000; 157(9): 1399– 1405.

57. Morgan CD, Nordin S, Murphy C. Odor identification as an early marker for Alzheimer‘s disease: impact of lexical functioning and detection sensitivity. J Clin Exp Neuropsychol 1995; 17(5): 793– 803.

58. Bacon AW, Bondi MW, Salmon DP, Murphy C. Very early changes in olfactory functioning due to Alzheimer‘s disease and the role of Apolipoprotein E in olfaction. In: Murphy C (ed.). Olfaction and Taste Xii: an International Symposium. New York Academy of Sciences. New York: New York Academy of Sciences 1998: 723– 731.

59. 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 epsilon 4 status. Neurology 1999; 53(7): 1480– 1487.

60. Nordin S, Bramerson A, Liden E, Bende M. The Scandinavian Odor‑ Identification Test: development, reliability, validity and normative data. Acta Otolaryngol (Stockh) 1998; 118(2): 226– 234.

61. Folstein MF, Folstein SE, McHugh PR. „Mini‑mental state“. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3): 189– 198.

62. Olofsson JK, Ronnlund M, Nordin S, Nyberg L, Nilsson LG,Larsson M. Odor identification deficit as a predictor of five‑year global cognitive change: interactive effects with age and ApoE‑ epsilon 4. Behav Genet 2009; 39(5): 496– 503. doi: 10.1007/ s10519‑ 009‑ 9289‑ 5.

63. Murphy C, Gilmore Mm, Seery CS, Salmon DP, Lasker BR.Olfactory thresholds are associated with degree of dementia in Alzheimer‘s disease. Neurobiol Aging 1990; 11(4): 465– 469.

64. Nordin S, Almkvist O, Berglund B, Wahlund LO. Olfactory dysfunction for pyridine and dementia progression in Alzheimer disease. Arch Neurol 1997; 54(8): 993– 998.

65. Schubert CR, Carmichael Ll, Murphy C, Klein BEK, Klein R, Cruickshanks KJ. Olfaction and the 5‑year incidence of cognitive impairment in an epidemiological study of older adults. J Am Geriatr Soc 2008; 56(8): 1517– 1521.

66. Murphy C, Anderson JA, Markison S. Psychophysical assessment of chemosensory disorders in clinical populations. In: Kurihara K, Suzuki N, Ogawa H (eds). Olfaction and taste XI. Tokyo: Springer Japan 1994: 609– 613.

67. Schiffman Ss, Graham BG, Sattely‑ Miller EA, Zervakis J,Welsh‑ Bohmer K. Taste, smell and neuropsychological performance of individuals at familial risk for Alzheimer‘s disease. Neurobiol Aging 2002; 23(3): 397– 404.

68. Djordjevic J, Jones‑ Gotman M, De Sousa K, Chertkow H. Olfaction in patients with mild cognitive impairment and Alzheimer‘s disease. Neurobiol Aging 2008; 29(5): 693– 706.

69. Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA. Olfactory impairment in presymptomatic Alzheimer‘s disease. Ann N Y Acad Sci 2009; 1170: 730– 735. doi: 10.1111/ j.1749‑ 6632.2009.04013.x.

70. Marigliano V, Gualdi G, Servello A, Marigliano B, Volpe LD, Fioretti A et al. Olfactory deficit and hippocampal volume loss for early diagnosis of Alzheimer disease: a pilot study. Alzheimer Dis Assoc Disord 2014; 28(2): 194– 197. doi: 10.1097/ WAD.0b013e31827bdb9f.

71. Tabert MH, Liu XH, Doty RL, Serby M, Zamora D, Pelton GH et al. A 10- item smell identification scale related to risk for Alzheimer‘s disease. Ann Neurol 2005; 58(1): 155– 160.

72. Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B et al. Delusions and hallucinations are associated with worse outcome in Alzheimer disease. Arch Neurol 2005; 62(10): 1601– 1608.

73. Cummings JL, Victoroff JI. Noncognitive neuropsychiatric syndromes in Alzheimer‘s disease. Cogn Behav Neurol 1990; 3(2): 140– 158.

74. Foerster 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(2): 581– 591. doi: 10.3233/ JAD‑ 2010‑ 091549.

75. Lopez OL, Becker JT, Brenner RP, Rosen J, Bajulaiye OI, Reynolds CF. Alzheimer‘s disease with delusions and hallucinations: neuropsychological and electroencephalographic correlates. Neurology 1991; 41(6): 906– 912.

76. Royet JP, Croisile B, Williamson‑ Vasta R, Hibert O, Serclerat D, Guerin J. Rating of different olfactory judgements in Alzheimer‘s disease. Chem Senses 2001; 26(4): 409– 417.

77. Markovic K, Reulbach U, Vassiliadu A, Lunkenheimer J,Lunkenheimer B, Spannenberger R et al. Good news for elderly persons: olfactory pleasure increases at later stages of the life span. J Gerontol A Biol Sci Med Sci 2007; 62(11): 1287– 1293.

78. Halliday GM, Barker RA, Rowe DB. Non‑ dopamine Lesions in Parkinson‘s Disease. 1st ed. Oxford: Oxford University Press 2011.

79. Braak H. Staging of brain pathology related to sporadic Parkinson‘s disease. Neurobiol Aging 2003; 24(2): 197– 211.

80. 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(1): 121– 134.

81. Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 1988; 38(8): 1237– 1244.

82. Alves G, Forsaa EB, Pedersen KF, Gjerstad MD, Larsen JP.Epidemiology of Parkinson‘s disease. J Neurol 2008; 255 (Suppl 5): 18– 32. doi: 10.1007/ s00415‑ 008‑ 5004‑ 3.

83. Rodriguez‑ Violante M, Gonzalez‑ Latapi P, Camacho‑ Ordonez A, Martinez‑ Ramirez D, Morales‑ Briceno H,Cervantes‑ Arriaga A. Low specificity and sensitivity of smell identification testing for the diagnosis of Parkinson‘s disease. Arq Neuropsiquiatr 2014; 72(1): 33– 37. doi: 10.1590/ 0004‑ 282X20130190.

84. Double KL, Rowe DB, Hayes M, Chan DKY, Blackie J, Corbett A et al. Identifying the pattern of olfactory deficits in Parkinson disease using the Brief Smell Identification Test. Arch Neurol 2003; 60(4): 545– 549.

85. Haehner A, Hummel T, Hummel C, Sommer U, Junghanns S, Reichmann H. Olfactory loss may be a first sign of idiopathic Parkinson‘s disease. Mov Disord 2007; 22(6): 839– 842.

86. Ponsen MM, Stoffers D, Booij J, van Eck‑ Smit BLF, Wolters EC, Berendse HW. Idiopathic hyposmia as a preclinical sign of Parkinson‘s disease. Ann Neurol 2004; 56(2): 173– 181.

87. Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J,Masaki K et al. Association of olfactory dysfunction with risk for future Parkinson‘s disease. Ann Neurol 2008; 63(2): 167– 173.

88. Markopoulou K, Larsen KW, Wszolek EK, Denson MA, Lang AE, Peiffer RF et al. Olfactory dysfunction in familial parkinsonism. Neurology 1997; 49(5): 1262– 1267.

89. Montgomery EB, Baker KB, Lyons K, Koller WC. Abnormal performance on the PD test battery by asymptomatic first‑ degree relatives. Neurology 1999; 52(4): 757– 762.

90. Radil T, Roth J, Růžička E, Tichý J, Wysocki CJ. Porucha čichu: příznak Parkinsonovy nemoci. Cesk Slov Neurol N 1995; 58/ 91(6): 286– 289.

91. Doty RL, Stern MB, Pfeiffer C, Gollomp SM, Hurtig HI. Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson‘s disease. J Neurol Neurosurg Psychiatry 1992; 55(2): 138– 142.

92. Boesveldt S, Verbaan D, Knol DL, van Hilten JJ, Berendse HW. Assessment of odor identification and discrimination in Dutch Parkinson‘s disease patients. Mov Disord 2007; 22: S161.

93. Bohnen NI, Gedela S, Kuwabara H, Constantine GM, Mathis CA, Studenski SA et al. Selective hyposmia and nigrostriatal dopaminergic denervation in Parkinson‘s disease. J Neurol 2007; 254(1): 84– 90.

94. Daum RF, Sekinger B, Kobal G, Lang CJG. Olfactory testing with „Sniffin‘ Sticks“ in idiopathic parkinsonism. Nervenarzt 2000; 71(8): 643– 650.

95. Hawkes CH, Shephard BC, Daniel SE. Olfactory dysfunction in Parkinson‘s disease. J Neurol Neurosurg Psychiatry 1997; 62(5): 436– 446.

96. Silveira‑ Moriyama L, Williams D, Katzenschlager R, Lees AJ. Pizza, mint, and licorice: smell testing in Parkinson‘s disease in a UK population. Mov Disord 2005; 20: S139.

97. Wehling E, Nordin S, Espeseth T, Reinvang I, Lundervold AJ. Unawareness of olfactory dysfunction and its association with cognitive functioning in middle aged and old adults. Arch Clin Neuropsychol 2011; 26(3): 260– 269. doi: 10.1093/ arclin/ acr019.

98. Sobel N, Thomason ME, Stappen I, Tanner CM, Tetrud JW, Bower JM et al. An impairment in sniffing contributes to the olfactory impairment in Parkinson‘s disease. Proc Natl Acad Sci U S A 2001; 98(7): 4154– 4159.

99. Quinn NP, Rossor MN, Marsden CD. Olfactory threshold in Parkinson‘s disease. J Neurol Neurosurg Psychiatry 1987; 50(1): 88– 89.

100. Roth J, Radil T, Ruzicka E, Jech R, Tichy J. Apomorphine does not influence olfactory thresholds in Parkinson‘s disease. Funct Neurol 1998; 13(2): 99– 103.

101. 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(5): 1424– 1431.

102. 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 2008; 255(3): 367– 370.

103. Siderowf A, Newberg A, Chou KL, Lloyd M, Colcher A,Hurtig HI et al. Tc‑ 99m TRODAT‑ 1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology 2005; 64(10): 1716– 1720.

104. Tissingh G, Berendse HW, Bergmans P, DeWaard R,Drukarch B, Stoof JC et al. Loss of olfaction in de novo and treated Parkinson‘s disease: Possible implications for early diagnosis. Mov Disord 2001; 16(1): 41– 46.

105. Wenning GK, Shephard B, Hawkes C, Petruckevitch A,Lees A, Quinn N. Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand 1995; 91(4): 247– 250.

106. Doty RL, Golbe LI, McKeown DA, Stern MB, Lehrach CM, Crawford D. Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson‘s disease. Neurology 1993; 43: 962– 965.

107. Silveira‑ Moriyama L, Hughes G, Church A, Ayling H,Williams DR, Petrie A et al. Hyposmia in progressive supranuclear palsy. Mov Disord 2010; 25(5): 570– 577.

108. Doty RL, Singh A, Tetrud J, Langston JW. Lack of major olfactory dysfunction in MPTP‑induced parkinsonism. Ann Neurol 1992; 32(1): 97– 100.

109. Busenbark KL, Huber SI, Greer G, Pahwa R, Koller WC. Olfactory function in essential tremor. Neurology 1992; 42(8): 1631– 1632.

110. Djaldetti R, Nageris BI, Lorberboym M, Treves TA, Melamed E, Yaniv E. I‑ 123- FP‑ CIT SPECT and olfaction test in patients with combined postural and rest tremor. J Neural Transm 2008; 115(3): 469– 472. doi: 10.1007/ s00702‑ 007‑ 0851‑ 0.

111. Shah M, Muhammed N, Findley LJ, Hawkes CH. Olfactory tests in the diagnosis of essential tremor. Parkinsonism Relat Disord 2008; 14(7): 563– 568. doi: 10.1016/ j.parkreldis.2007.12.006.

112. Louis ED, Bromley SM, Jurewicz EC, Watner D. Olfactory dysfunction in essential tremor: a deficit unrelated to disease duration or severity. Neurology 2002; 59(10): 1631– 1633.

113. Abele M, Riet A, Hummel T, Klockgether T, Wullner U.Olfactory dysfunction in cerebellar ataxia and multiple system atrophy. J Neurol 2003; 250(12): 1453– 1455.

114. Garland EM, Raj SR, Peltier AC, Robertson D, Biaggioni I. A cross‑ sectional study contrasting olfactory function in autonomic disorders. Neurology 2011; 76(5): 456– 460. doi: 10.1212/ WNL.0b013e31820a0caf.

115. Goldstein DS, Holmes C, Bentho O, Sato T, Moak J, Sharabi Y et al. Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 2008; 14(8): 600– 607. doi: 10.1016/ j.parkreldis.2008.01.010.

116. Muller A, Mungersdorf M, Reichmann H, Strehle G,Hummel T. Olfactory function in Parkinsonian syndromes. J Clin Neurosci 2002; 9(5): 521– 524.

117. Muller A, Reichmann H, Livermore A, Hummel T. Olfactory function in idiopathic Parkinson‘s disease (IPD): results from cross‑ sectional studies in IPD patients and long‑term follow‑up of de novo IPD patients. J Neural Transm 2002; 109(5– 6): 805– 811.

118. McKinnon JH, Demaerschalk BM, Caviness JN, Wellik KE, Adler CH, Wingerchuk DM. Sniffing out Parkinson disease: can olfactory testing differentiate parkinsonian disorders? Neurologist 2007; 13(6): 382– 385.

119. Ahlskog JE, Waring SC, Petersen RC, Esteban‑ Santillan C, Craig UK, O‘Brien PC et al. Olfactory dysfunction in Guamanian ALS, parkinsonism and dementia. Neurology 1998; 51(6): 1672– 1677.

120. Doty RL, Perl DP, Steele JC, Chen KM, Pierce JD, Reyes P et al. Odor identification deficit of the parkinsonism‑ dementia complex of Guam: equivalence to that of Alzheimer‘s and idiopathic Parkinson‘s disease. Neurology 1991; 41(5): 77– 81.

121. 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(1): 60– 74. doi: 10.1016/ j.bbr.2012.02.047.

122. Landis BN, Burkhard PR. Phantosmias and Parkinson disease. Arch Neurol 2008; 65(9): 1237– 1239. doi: 10.1001/ archneur.65.9.1237.

123. Landis BN, Reden J, Haehner A. Idiopathic phantosmia: outcome and clinical significance. ORL J Otorhinolaryngol Relat Spec 2010; 72(5): 252– 255. doi: 10.1159/ 000317024.

124. Bannier S, Berdague JL, Rieu I, de Chazeron I, Marques A, Derost P et al. Prevalence and phenomenology of olfactory hallucinations in Parkinson‘s disease. J Neurol Neurosurg Psychiatry 2012; 83(10): 1019– 1021. doi: 10.1136/ jnnp‑ 2012‑ 302414.

125. Hudry J, Thobois S, Broussolle E, Adeleine P, Royet JP.Evidence for deficiencies in perceptual and semantic olfactory processes in Parkinson‘s disease. Chem Senses 2003; 28(6): 537– 543.

126. Hummel T, Fliessbach K, Abele M, Okulla T, Reden J,Reichmann H et al. Olfactory fMRI in patients with Parkinson‘s disease. Front Integr Neurosci 2010; 4: 125. doi: 10.3389/ fnint.2010.00125.

127. Keller A, Vosshall LB. Human olfactory psychophysics. Curr Biol 2004; 14(20): R875– R878.

128. Hedner M, Larsson M, Arnold N, Zucco GM, Hummel T. Cognitive factors in odor detection, odor discrimination, and odor identification tasks. J Clin Exp Neuropsychol 2010; 32(10): 1062– 1067. doi: 10.1080/ 13803391003683070.

129. Green J, McDonald WM, Vitek JL, Evatt M, Freeman A, Haber M et al. Cognitive impairments in advanced PD without dementia. Neurology 2002; 59(9): 1320– 1324.

130. Swanberg Mm, Tractenberg RE, Mohs R, Thal LJ, Cummings JL. Executive dysfunction in Alzheimer disease. Arch Neurol 2004; 61(4): 556– 560.

131. Giffard B, Desgranges B, Nore‑Mary F, Lalevee C, de la Sayette V, Pasquier F et al. The nature of semantic memory deficits in Alzheimer‘s disease – new insights from hyperpriming effects. Brain 2001; 124(8): 1522– 1532.

132. Portin R, Laatu S, Revonsuo A, Rinne UK. Impairment of semantic knowledge in Parkinson disease. Arch Neurol 2000; 57(9): 1338– 1343.

133. de Araujo IE, Rolls ET, Velazco MI, Margot C, Cayeux I.Cognitive modulation of olfactory processing. Neuron 2005; 46(4): 671– 679.

134. Herz RS. The effect of verbal context on olfactory perception. J Exp Psychol Gen 2003; 132(4): 595– 606.

135. Rouby C, Pouliot S, Bensafi M. Odor hedonics and their modulators. Food Qual Prefer 2009; 20(8): 545– 549.

136. Schaal B. Prenatal and postnatal human olfactory development: influences on cognition and behavior. In: Doty RL (ed.). Handbook of Olfaction and Cognition. 3rd ed. Hoboken, NJ: John Wiley & Sons 2015: 305– 335.

137. Cometto‑ Muñiz JE, Simons C. Trigeminal Chemesthesis. In: Doty RL (ed.). Handbook of Olfaction and Gustation. 3rd ed. Hoboken, NJ: John Wiley & Sons 2015: 1091–1112.

138. Frank RA, Dulay MF, Gesteland RC. Assessment of the Sniff Magnitude Test as a clinical test of olfactory function. Physiol Behav 2003; 78(2): 195– 204.

139. Tourbier IA, Doty RL. Sniff magnitude test: relationship to odor identification, detection, and memory tests in a clinic population. Chem Senses 2007; 32(6): 515– 523.

140. McLaughlin NCR, Westervelt HJ. Odor identification deficits in frontotemporal dementia: a preliminary study. Arch Clin Neuropsychol 2008; 23(1): 119– 123.

141. Attems J, Jellinger KA. Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol 2006; 25(6): 265– 271.

142. Wesson DW, Wilson DA, Nixon RA. Should olfactory dysfunction be used as a biomarker of Alzheimer‘s disease? Expert Rev Neurother 2010; 10(5): 633– 635. doi: 10.1586/ern.10.33.