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Olfactory Dysfunction in Neurodegenerative Diseases

  • Rhinosinusitis (J Mullol, Section Editor)
  • Published:
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Abstract

Purpose of Review

The sense of smell is today one of the focuses of interest in aging and neurodegenerative disease research. In several neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, the olfactory dysfunction is one of the initial symptoms appearing years before motor symptoms and cognitive decline, being considered a clinical marker of these diseases’ early stages and a marker of disease progression and cognitive decline. Overall and under the umbrella of precision medicine, attention to olfactory function may help to improve chances of success for neuroprotective and disease-modifying therapeutic strategies.

Recent Findings

The use of olfaction, as clinical marker for neurodegenerative diseases is helpful in the characterization of prodromal stages of these diseases, early diagnostic strategies, differential diagnosis, and potentially prediction of treatment success. Understanding the mechanisms underlying olfactory dysfunction is central to determine its association with neurodegenerative disorders. Several anatomical systems and environmental factors may underlie or contribute to olfactory loss associated with neurological diseases, although the direct biological link to each disorder remains unclear and, thus, requires further investigation.

Summary

In this review, we describe the neurobiology of olfaction, and the most common olfactory function measurements in neurodegenerative diseases. We also highlight the evidence for the presence of olfactory dysfunction in several neurodegenerative diseases, its value as a clinical marker for early stages of the diseases when combined with other clinical, biological, and neuroimage markers, and its role as a useful symptom for the differential diagnosis and follow-up of disease. The neuropathological correlations and the changes in neurotransmitter systems related with olfactory dysfunction in the neurodegenerative diseases are also described.

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References

Papers of particular interest, published recently, have been highlighted as:•• Of major Importance

  1. Hummel T, Landis BN, Hüttenbrik KB. Smell and taste disorders. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2011;10:Doc04.

    PubMed  Google Scholar 

  2. Doty RL, Kamath V. The influences of age on olfaction: a review. Front Psychol. 2014;5:1–20.

    Article  Google Scholar 

  3. Ottaviano G, Zuccarello D, Frasson G, Scarpa B, Nardello E, Foresta C, et al. Olfactory sensitivity and sexual desire in young adult and elderly men: an introductory investigation. Am J Rhinol Allergy. 2013;27:157–61.

    Article  PubMed  Google Scholar 

  4. Ottaviano G, Frasson G, Nardello E, Martini A. Olfaction deterioration in cognitive disorders in the elderly. Aging Clin Exp Res. 2016;28:37–45.

    Article  PubMed  Google Scholar 

  5. Sorokowska A, Sorokowski P, Havlicek J. Body odor based personality judgements: the effects of fraganced cosmetics. Front Psychol. 2016;7:530.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mullol J, Alobid I, Mariño-Sánchez F, Quintó L, de Haro J, Bernal-Sprekelsen M, et al. Furthering the understanding of olfaction, prevalence of loss of smell and risk factors: a population-based survey (OLFACAT study). BMJ Open. 2012;2:e001256.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Rey NL, Wesson DW, Brundin P. The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol Dis. 2018;109:226–48.

    Article  PubMed  CAS  Google Scholar 

  8. Boesveldt S, Postma EM, Boak D, et al. Anosmia—a clinical review. Chem Senses. 2017;42:513–23.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Doty RL. Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrates? Lancet Neurol. 2017;16:478–88.

    Article  PubMed  Google Scholar 

  10. Mariño-Sánchez FS, Alobid I, Centellas S, Alberca C, Guilemany JM, Canals JM, et al. Smell training increases cognitive smell skills of wine tasters compared to the general healthy population. The WINECAT Study. Rhinology. 2010;48:273–6.

    Article  PubMed  Google Scholar 

  11. Banks SJ, Sreenivasan KR, Weintraub DM, et al. Structural and functional MRI differences in master sommeliers: a pilot study on expertise in the brain. Front Hum Neurosci. 2016;10:414.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Delon-Martin C, Palilly J, Fonlupt P, Veyrac A, Royet JP. Perfurmers’ expertise induces structural reorganization in olfactory brain regions. Neuroimage. 2013;68:55–62.

    Article  PubMed  Google Scholar 

  13. Frasnelli J, Hummel T. Olfactory dysfunction and daily life. Eur Arch Otorhinolaryngol. 2005;262:231–5.

    Article  PubMed  Google Scholar 

  14. Attems J, Wlaker L, Jellinger KA. Olfaction and aging: a mini-review. Gerontology. 2015;61:485–90.

    Article  PubMed  CAS  Google Scholar 

  15. Vassilaki M, Christianson TJ, Mielke MM, et al. Neuroimaging biomarkers and impaired olfaction in cognitively normal individuals. Ann Neurol. 2017;81:871–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Temmel AF, Quint C, Schickinger-Fischer B, Klimek L, Stoller E, Hummel T. Characteristics of olfactory disorders in relation to major causes of olfactory loss. Arch Otolaryngol Head Neck Surg. 2002;128:635–41.

    Article  PubMed  Google Scholar 

  17. Hoffman HJ, Rawal S, Li CM, Duffy VB. New chemosensory component in the US National Health and Nutrition Examination Survey (NHANES): first-year results for measured olfactory dysfunction. Rev Endrocr Metab Disord. 2016;17:221–40.

    Article  CAS  Google Scholar 

  18. Hummel T, Nordin S. Olfatory disorders and their consequences for quality of life. Acta Otolaryngol. 2005;125:116–21.

    Article  PubMed  Google Scholar 

  19. Pence TS, Reiter ER, DiNardo LJ, Costanzo RM. Risk factors for hazardous events in olfactory-impaired patients. JAMA Otolaryngol Head Neck Surg. 2014;140:951–5.

    Article  PubMed  Google Scholar 

  20. Jaume F, Quintó L, Alobid J, Mullol J. Overuse of diagnostic tools and medications in acute rhinosinusitis in Spain: a population-based study (the PROSINUS study). BMJ Open. 2018;8:e018788.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Langdon C, Guillemany JM, Valls M, Alobid I, Bartra J, Dávila I, et al. Allergic rhinitis causes loss of smell in children. Pediatr Allergy Immunol. 2016;27:867–70.

    Article  PubMed  Google Scholar 

  22. Langdon C, Lehrer E, Berenguer J, Laxe S, Alobid I, Quintó L, et al. Olfactory training in posttraumatic smell impairment: mild improvement in threshold performances-results from a randomized controlled study. J Neurotrauma. 2018;

  23. Bahuleyan B, Singh S. Olfactory memory impairment in neurodegenerative diseases. J Clin Diagnostic Res. 2012;6:1437–41.

    Google Scholar 

  24. Doty RL. Olfaction in Parkinson’s diseases and related disorders. Neurobiol Dis. 2012;46:527–52.

    Article  PubMed  Google Scholar 

  25. Hummel T, Whitcroft KL, Andrews P, et al. Position paper on olfactory dysfunction. Rhinol Suppl. 2017;54:1–30.

    PubMed  CAS  Google Scholar 

  26. Morley JF, Duda JE. Olfaction as a biomarker in Parkinson’s disease. Biomark Med. 2010;4:661–70.

    Article  PubMed  CAS  Google Scholar 

  27. Bowman GL. Biomarkers for early detection of Parkinson’s disease: a scent of consistency with olfactory dysfunction. Neurology. 2017;89:1432–4.

    Article  PubMed  Google Scholar 

  28. Fullard ME, Morley JF, Duda JE. Olfactory dysfunction as an early biomarker in Parkinson’s disease. Neurosci Bull. 2017;33:515–25.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Krismer F, Pinter B, Mueller C, et al. Sniffing the diagnosis: olfactory testing in neurodegenerative parkinsonism. Parkinsonism Relat Disord. 2017;35:36–41.

    Article  PubMed  CAS  Google Scholar 

  30. Morley JF, Cohen A, Silveira-Moriyama L, et al. Optimizing olfactory testing for the diagnosis of Parkinson’s disease: item analysis of the university of Pennsylvania smell identification test. NPJ Parkinsonism Dis. 2018;4:2.

    Article  Google Scholar 

  31. Tabert MH, Liu X, 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;58:155–60.

    Article  PubMed  Google Scholar 

  32. Growdon ME, Schultz AP, Dagley AS, Amarigilio RE, Hedden T, Rentz DM, et al. Odor identification and Alzheimer disease biomarkers in clinically normal elderly. Neurology. 2015;84:2153–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Lafaille-Magnan ME, Poirier J, Etienne P, Tremblay-Mercier J, Frenette J, Rosa-Neto P, et al. PREVENT-AD Research Group. Odor identification as a biomarker of preclinical AD in older adults at risk. Neurology. 2017;89:327–35.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Woodward MR, Amrutkar CV, Ahah HC, Benedict RH, Rajakrishnan S, Doody RS, et al. Validation of olfactory deficit as a biomarker of Alzheimer disease. Neurol Clin Pract. 2017;7:5–14.

    Article  PubMed  PubMed Central  Google Scholar 

  35. McShane RH, Nagy Z, Esiri MM, King E, Joachim C, Sulivan N, et al. Anosmia in dementia is associated with Lewy bodies rather than Alzheimer’s pathology. J Neurol Neurosurg Psychiatry. 2001;70:739–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. McKeith I, Taylor JP, Thomas A, Donaghy P, Kane J. Revisiting DLB diagnosis: a consideration of prodromal DLB and of the diagnostic overlap with Alzheimer disease. J Geriatr Psychiatry Neurol. 2016;29:249–53.

    Article  PubMed  Google Scholar 

  37. Mahlknecht P, Iranzo A, Högi B, et al. Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD. Neurology. 2015;84:654–8.

    Article  PubMed  Google Scholar 

  38. Wilson DA, Sullivan RM. Cortical processing of odor subjects. Neuron. 2011;72:506–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Misiak M, Hipolito MM, Ressom HW, Obisesan TO, Manaye KF, Nwlia EA. Apo E4 alleles and impaired olfaction as predictors of Alzheimer’s disease. Clin Exp Psychol. 2017;3:169.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kay RB, Meyer EA, Illig KR, Brunjes PC. Spatial distribution of neural activity in the anterior olfactory nucleus evoked by odor and electrical stimulation. J Comp Neurol. 2011;519:277–89.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Gottfried JA. Central mechanisms of odour object perception. Nat Rev Neurosci. 2010;11:628–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Doty RL, Philip S, Reddy K, Kerr KL. Influences of antihypertensive and antihyperlipidemic drugs on the senses of taste and smell: a review. J Hypertens. 2003;21:1805–13.

    Article  PubMed  CAS  Google Scholar 

  43. Buck L, Axel R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell. 1991;65:175–87.

    Article  PubMed  CAS  Google Scholar 

  44. Masurkar AV, Devanand DP. Olfactory dysfunction in the elderly: basic circuitry and alterations with normal aging and Alzheimer’s disease. Curr Geriatr Rep. 2014;3:91–100.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Verhagen JV, Wesson DW, Netoff TI, White JA, Wachowiak M. Sniffing controls and adaptive filter of sensory input to the olfactory bulb. Nat Neurosci. 2007;10:631–9.

    Article  PubMed  CAS  Google Scholar 

  46. Carey RM, Wachowiak M. Effect of sniffing on the temporal structure of mitral/tufted cell output from the olfactory bulb. J Neurosci. 2011;31:10615–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Chess A, Simon I, Cedar H, Axel R. Allelic inactivation regulates olfactory receptor gene expression. Cell. 1994;78:823–34.

    Article  PubMed  CAS  Google Scholar 

  48. Shykind BM, Rohani SC, O’Donnell S, Nemes A, Mendelsohn M, Sun Y, et al. Gene switching and the stability of odorant receptor gene choice. Cell. 2004;117:801–15.

    Article  PubMed  CAS  Google Scholar 

  49. Mombaerts P, Wang F, Dulac C, Chao SK, Nemes A, Mendelsohn M, et al. Visualizing an olfactory sensory map. Cell. 1996;87:675–86.

    Article  PubMed  CAS  Google Scholar 

  50. Liu A, Savya S, Urban NN. Early odorant exposure increases the number of mitral cells associated with a single glomerulus. J Neurosci. 2016;36:11646–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bushdid C, Magnasco MO, Vosshall LB, Keller A. Humans can discriminate more than 1 trillion olfactory stimuli. Science. 2014;343:1370–272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Dunkel A, Steinhaus M, Kotthoff M, Nowak B, Krautwurst D, Schieberle P, et al. Nature’s chemical signatures in human olfaction: a foodborne perspective for future biotechnology. Angew Chem Int Ed Engl. 2014;53:7124–43.

    Article  PubMed  CAS  Google Scholar 

  53. Keller A, Vosshall LB. Olfactory perception of chemically diverse molecules. BMC Neurosci. 2016;17:55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Nagayama S, Takakhashi YK, Yoshihara Y, Mori K. Mitral and tufted cells differ in the decoding manner of odor maps in the rat olfactory bulb. J Neurophysiol. 2004;91:2532–40.

    Article  PubMed  Google Scholar 

  55. Linster C, Fontanini A. Functional neuromodulation of chemosensation in vertebrates. Curr Opin Neurobiol. 2014;29:82–7.

    Article  PubMed  CAS  Google Scholar 

  56. Bendahmane M, Cameron M, Ennis M, Fletcher ML. Increased olfactory bulb acetycholine bi-directionally modulates glomerular odor sensitivity. Scientifc Reports. 2016;6:25808.

    Article  CAS  Google Scholar 

  57. Huang Z, Thiebaud N, Fadool DA. Differential serotonergic modulation across the main and accessory olfactory bulbs. J Physiol. 2017;595:3515–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Höglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, et al. Dopamine depletion impairs precursor cell proliferation in Parkinson’s disease. Nature Neurosci. 2004;7:726–35.

    Article  PubMed  CAS  Google Scholar 

  59. Grier BD, Belluscio L, Cheetham CE. Olfactory sensory activity modulates microglial-neuronal interactions during dopaminergic cell loss in the olfactory bulb. Front Cell Neurosci. 2016;10:178.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Höglinger GU, Alvarez-Fischer D, Arias-Carrión I, Djufri M, Windolph A, Keber U, et al. A new dopaminergic nigro-olfactory projection. Acta Neuropathol. 2015;130:333–48.

    Article  PubMed  CAS  Google Scholar 

  61. Alvarez-Buylla A, Kohwi M, Nguyen TM, Merkle FT. The heterogeneity of adult neural stem cells and the emerging complexity of their niche. Cold Spring Harb Symp Quant Biol. 2008;73:357–65.

    Article  PubMed  CAS  Google Scholar 

  62. Lledo PM, Valley M. Adult olfactory bulb neurogenesis. Cold Spring Harb Perspect Biol. 2016;8:a018945.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Hardy D, Saghatelyan A. Different forms of structural plasticity in the adult olfactory bulb. Neurogenesis. 2017;4:e1301850.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Ubeda-Bañón I, Saiz-Sanchez D, de la Rosa-Prieto C, Martinez-Marcos A. α-Synuclein in the olfactory system in Parkinsons’ disease: role of neural connections on spreading pathology. Brain Struct Funct. 2014;19:1513–26.

    Google Scholar 

  65. Doty RL. Olfactory dysfunction and its measurement in the clinic. World J Otorhinolaryngol Head Neck Surg. 2015;1:28–33.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology. 1988;38:1237–44.

    Article  PubMed  CAS  Google Scholar 

  67. Silveira-Moriyama L, Sirisena D, Gamage P, Gamage R, de Silva R, Lees AJ. Adapting the sniffin’ sticks to diagnose Parkinson’s disease in Sri Lanka. Mov Disord. 2009;24:1229–33.

    Article  PubMed  Google Scholar 

  68. Kobal G, Hummel T, Sekinger B, Baez S, Roscher S, Wolf S. “Sniffin’sticks”: screening of olfactory performance. Rhinology. 1996;34:222–6.

    PubMed  CAS  Google Scholar 

  69. 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;22:39–52.

    Article  PubMed  CAS  Google Scholar 

  70. Haehner A, Tosch C, Wolz M, Klingelhoefer L, fauser M, Storch A, et al. Olfactory training in patients with Parkinson’s disease. PLoS One. 2013;8:e61680.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Doty RL, Marcus A, Lee WW. Development of the 12-item cross-cultural smell identification test (CC-SIT). Laryngoscope. 1996;106:353–6.

    Article  PubMed  CAS  Google Scholar 

  72. Rodriguez-Violante M, Glonzalez-Latapi P, Camacho-Ordoñez A, Martínez-Ramírez D, Morales-Briceño H, Cervantes-Arriaga A. Low specificity and sensitivity of smell identification testing for the diagnosis of Parkinson’s disease. Arq Neuropsiquiatry. 2014;72:33–7.

    Article  Google Scholar 

  73. Cardesin A, Alobid I, Benítez P, Sierra E, de Haro J, Bernal-Sprekelsen M, et al. Barcelona Smell Test-24 (BAST-24): validation and smell characteristics in the healthy Spanish population. Rhinology. 2006;44:83–9.

    PubMed  Google Scholar 

  74. Iijima M, Kobayakawa T, Saito S, Osawa M, Tsutsumo Y, Hashimoto S, et al. Smell identification in Japanese Parkinson’s disease patients: using the odor stick identification test for Japanese subjects. Intern Med. 2008;47:1887–92.

    Article  PubMed  Google Scholar 

  75. Maremmani C, Rossi G, Tambasco N, et al. The validity and reliability of the Italian olfactory identification test (IOIT) in healthy subjects and in Parkinson’s disease patients. Parkinsonism Relat Disord. 2012;18:788–93.

    Article  PubMed  Google Scholar 

  76. Mariño-Sánchez F, Valls-Mateus M, Haag O, Alobid I, Busquet J, Mullol J. Smell loss is associated with severe and uncontrolled disease in children and adolescents with persisting allergic rhinitis. J Allergy Clin Immunol Pract. 2018.

  77. Vilas D, Quintana M, Pont-Sunyer C, et al. Olfactory characterization of idiopathic Parkinson’s disease and LRRK2 associated parkinsonism: a practical approach (submitted).

  78. Liu G, Zong G, Doty RL, Sun Q. Prevalence and risk factors of taste and smell impairment in a nationwide representative sample of the US population: a cross-sectional study. BMJ Open. 2016;6:e013246.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Gros A, Manera V, de March CA, et al. Olfactory disturbances in ageing with and without dementia: towards new diagnostic tools. J Laryngol Otol. 2017;131:572–9.

    Article  PubMed  CAS  Google Scholar 

  80. 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;11:465–9.

    Article  PubMed  CAS  Google Scholar 

  81. Devanand DP. Olfactory identification deficits, cognitive decline, and dementia in older adults. Am J Geriatr Psychiatry. 2016;24:1151–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Doty RL, Sharman P, Applebaum SL, Giberson R, Siksorski L, Rosenberg L. Smell identification ability: changes with age. Science. 1984;226:1441–3.

    Article  PubMed  CAS  Google Scholar 

  83. Choudhury ES, Moberg P, Doty RL. Influences of age and sex on a microencapsulated odor memory test. Chem Senses. 2003;28:799–805.

    Article  PubMed  Google Scholar 

  84. Oliveira-Pinto AV, Santos RM, Coutinho RA, et al. Sexual dimorphism in the human olfactory bulb: females have more neurons and glial cells than males. PLoS Ones. 2014;9:e111733.

    Article  CAS  Google Scholar 

  85. Xydakis MS, Belluscio L. Detection of neurodegenerative disease using olfaction. Lancet Neurol. 2017;16:415–6.

    Article  PubMed  Google Scholar 

  86. Hummel T, Heilmann S, Murphy C. Age-related changes in chemosensory functions. In: Rouby C, et al., editors. Olfaction, taste and cognition. New York: Cambridge University Press; 2002. p. 451–6.

    Google Scholar 

  87. Murphy C, Nordin S, Acosta L. Odor learning, recall, and recognition memory in young and elderly adults. Neuropsychology. 1997;11:126–37.

    Article  PubMed  CAS  Google Scholar 

  88. Suzuki Y, Critchley HD, Suckling J, et al. Functional magnetic resonance imaging of odor identification: the effect of aging. J Gerontol A Biol Sci Med Sci. 2001;56:M756–60.

    Article  PubMed  CAS  Google Scholar 

  89. Cerf-Ducastel B, Murphy C. fMRI brain activation in response to odors is reduced in primary olfactory areas of elderly subjects. Brain Res. 2003;986:39–53.

    Article  PubMed  CAS  Google Scholar 

  90. Ferdon S, Murphy C. The cerebellum and olfaction in the aging brain: a functional magnetic resonance imaging study. Neuroimage. 2003;20:12–21.

    Article  PubMed  Google Scholar 

  91. Rawson NE. Olfactory loss in aging. Sci Aging Knowl Environ. 2006;5:pe6.

    Google Scholar 

  92. Doty RL. The olfactory system and its disorders. Semin Neurol. 2009;29:74–81.

    Article  PubMed  Google Scholar 

  93. Mobley AS, Rodriguez-Gil DJ, Imamura F, Greer CA. Aging in the olfactory system. Trends Neurosci. 2014;37:77–84.

    Article  PubMed  CAS  Google Scholar 

  94. Paik SI, Lehman MN, Seiden AM, Duncan HJ, Smith DV. Human olfactory biopsy. The influence of age and receptor distribution. Arch Otolaryngol Head Neck Surg. 1992;118:731–8.

    Article  PubMed  CAS  Google Scholar 

  95. Rosli Y, Brecjenridge LJ, Smith RA. An ultrastrucutral study of age-related changes in mouse olfactory epithelium. J Electron Microsc. 1999;48:77–84.

    Article  CAS  Google Scholar 

  96. Ueha R, Schichino S, Ueha S, Kondo K, Kikuta S, Nishijima H, et al. Reduction of proliferating olfactory cells and low expression of extracellular matrix genes are hallmarks of the aged olfactory mucosa. Front Aging Neurosci. 2018;10:86.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Buschhüter D, Smitka M, Puschmann S, Gerber JC, Abolmaali ND, Hummel T. Correlation between olfactory bulb volume and olfactory function. Neuroimage. 2008;42:498–502.

    Article  PubMed  Google Scholar 

  98. Rombaux P, Duprez T, Hummel T. Olfactory bulb volume in the clinical assessment of olfactory dysfunction. Rhinology. 2009;47:3–9.

    PubMed  CAS  Google Scholar 

  99. Rombaux P, Huart C, Deggouj N, Duprez T, Hummel T. Prognostic value of olfactory bulb volume measurement for recovery in postinfectious and posttraumatic olfactory loss. Otolaryngol Head Neck Surg. 2012;147:1136–41.

    Article  PubMed  Google Scholar 

  100. Paschen L, Schmidt N, Wolff S, Cnyrim C, van Eimeren T, Zeuner KE, et al. The olfactory bulb volume in patients with idiopathic Parkinson’s disease. Eur J Neurol. 2015;22:1068–73.

    Article  PubMed  CAS  Google Scholar 

  101. Mazal PP, Haehner A, Hummel T. Relation of the volume of the olfactory bulb to psychophysical measures of olfactory function. Eur Arch Otorhinolaryngol. 2016;273:1–7.

    Article  PubMed  Google Scholar 

  102. •• Marin C, Laxe S, Langdon C, Berenguer J, Lehrer E, Mariño-Sánchez F, et al. Olfactory function in an excitotoxic model for secondary neuronal degeneration: role of dopaminergic interneurons. Neuroscience. 2017;364:28–44. Preclinical evidence of the lack of correlation between olfactory dysfunction and recovery and the olfactory bulbs volume.

    Article  PubMed  CAS  Google Scholar 

  103. Segura B, Baggio HC, Sola E, Palacios EM, Vendrell P, Bargalló N, et al. Neuroanatomical correlates of olfactory loss in normal aged subjects. Behav Brain Res. 2013;246:148–53.

    Article  PubMed  Google Scholar 

  104. Adjei S, Houck AL, Ma K, Wesson DW. Age-dependent alterations in the number, volume, and localization of islands of Calleja within the olfactory tubercle. Neurobiol Aging. 2013;34:2676–82.

    Article  PubMed  Google Scholar 

  105. Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Benner DA. Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry. 2007;64:802–8.

    Article  PubMed  Google Scholar 

  106. Gopinath B, Sue CM, Kifley A, Mitchell P. The association between olfactory impairment and total mortality in older adults. J Gerontol A Biol Sci Med Sci. 2012;67:204–9.

    Article  PubMed  Google Scholar 

  107. Devanand DP, Lee S, Manly J, Andrews H, Schupf N, Masurkar A, et al. Olfactory identification deficits and increased mortality in the community. Ann Neurol. 2015;78:401–11.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Almkvist O, Berglund B, Nordin S. Odor detectability in successfully aged elderly and young adults. Reports from the Dept of Psychology, Stockholm University. 1992;744:1–12.

  109. Mackay-Sim A, Johnston AN, Owen C, Burne TH. Olfactory ability in the healthy population: reassessing presbyosmia. Chem Senses. 2006;31:763–71.

    Article  PubMed  Google Scholar 

  110. Schubert CR, Carmichael LL, Murphy C, Klein BE, Kelin R, Cruickshanks KJ. Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults. J Am Geriatr Soc. 2008;56:1517–21.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Kreisi WC, Jin P, Lee S, et al. Odor identification ability predicts PET amyloid status and memory decline in older adults. J Alzheimers Dis. 2018;62:1759–66.

    Article  CAS  Google Scholar 

  112. Kovacs T. Mechanisms of olfactory dysfunction in aging and neurodegenerative disorders. Ageing Res Rev. 2004;3:215–32.

    Article  PubMed  Google Scholar 

  113. Gerkin RC, Adler CH, Hentz JG, et al. Improved diagnosis of Parkinson’s disease from a detailed olfactory phenotype. Ann Clin Transl Neurol. 2017;4:714–21.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Godoy MD, Voegels RL, de Pinna F, Imamura R, Farfel JM. Olfaction in neurologic and neurodegenerative diseases: a literature review. Int Arch Otorhinolaryngol. 2015;19:176–9.

    PubMed  Google Scholar 

  115. Hawkes C. Olfaction in neurodegenerative disorder. Adv Otorhinolaryngol. 2006;63:133–51.

    PubMed  Google Scholar 

  116. Attems J, Walker K, Jellinger KA. Olfactory bulb involvement in neurodegenerative diseases. Acta Neuropathol. 2014;127:459–75.

    Article  PubMed  CAS  Google Scholar 

  117. Driver-Dunckley E, Adler CH, Hentz JG, Dugger BN, Shill HA, Caviness JN, et al. Olfactory dysfunction in incidental Lewy body disease and Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:1260–2.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Velayudhan L. Smell identfication function and Alzheimer’s disease: a selective review. Curr Opin Psychiatry. 2015;28:173–9.

    PubMed  Google Scholar 

  119. Huang SF, Chen K, Wu JJ, et al. Odor identification test in idiopathic REM-behavior disorder and Parkinson’s disease in China. PLoS One. 2016;11:e0160199.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Adler CH. Premotor symptoms and early diagnosis of Parkinson’s disease. Int J Neurosci. 2011;121(Suppl 2):3–8.

    Article  PubMed  Google Scholar 

  121. Hüttenbrink KB, Hummel T, Berg D, Gasser T, Hähner A. Olfactory dysfunction: common in later life and early warning of neurodegenerative disease. Dtsch Arztebl Int. 2013;110:1–7.

    PubMed  PubMed Central  Google Scholar 

  122. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.

    Article  PubMed  CAS  Google Scholar 

  123. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.

    Article  PubMed  Google Scholar 

  124. Doty RL. The olfactory vector hypothesis of neurodegenerative disease: is it viable? Ann Neurol. 2008;63:7–15.

    Article  PubMed  Google Scholar 

  125. Hobson DE. Asymmetry in parkinsonism, spreading pathogens and the nose. Parkinsonism Relat Disord. 2012;18:1–9.

    Article  PubMed  Google Scholar 

  126. Adler CH, Connor DJ, Hentz JG, Sabbagh MN, Caviness JN, Shill HA, et al. Incidental Lewy body disease: clinical comparison to a control cohort. Mov Disord. 2010;25:642–6.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Beach TG, Adler C, Lue L, et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 2009;117:613–34.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Jellinger KA. Lewy body-related alpha-synucleopathy in the aged human brain. J Neural Transm. 2004;111:1219–35.

    Article  PubMed  CAS  Google Scholar 

  129. Saito Y, Ruberu NN, Sawabe M, Arai T, Kazam H, Hosoi T, et al. Lewy body-related alpha-synucleinopathy in aging. J Neuropathol Exp Neurol. 2004;63:742–9.

    Article  PubMed  Google Scholar 

  130. Ross GW, Abbott RD, Petrovitch H, et al. Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord. 2006;12:2062–7.

    Article  Google Scholar 

  131. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep behavior disorder as an early marker for a neurodegenerative disorder: a description study. Lancet. 2006;5:572–7.

    Article  PubMed  Google Scholar 

  132. Iranzo A, Tolosa E, Gelpi E, et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye movement sleep behavior disorder: and observational cohort study. Lancet Neurol. 2013;12:443–53.

    Article  PubMed  Google Scholar 

  133. Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY. Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder. Ann Neurol. 2011;69:811–8.

    Article  PubMed  Google Scholar 

  134. Park JW, Kwon DY, Choi JH, Park MH, Yoon HK. Olfactory dysfunctions in drug-naïve Parkinson’s disease with mild cognitive impairment. Parkinsonism Relat Disord. 2018;46:69–73.

    Article  PubMed  Google Scholar 

  135. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson’s disease. Nat Rev Neurosci. 2017;18:435–50.

    Article  PubMed  CAS  Google Scholar 

  136. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.

    Article  PubMed  CAS  Google Scholar 

  137. Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15(Suppl 1):14–20.

    Article  PubMed  Google Scholar 

  138. Schapira AH, Tolosa E. Molecular and clinical prodrome of Parkinson’s disease: implications for treatment. Nat Rev Neurol. 2010;6:309–17.

    Article  PubMed  CAS  Google Scholar 

  139. Haehner A, Boesveldt S, Berendse HW, et al. Prevalence of smell loss in Parkinson’s disease—a multicenter study. Park Relat Disord. 2009;15:490–4.

    Article  CAS  Google Scholar 

  140. Silveira-Moriyama L, Guedes LC, Kngsbury A, Ayling H, Shaw K, et al. Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data. Neurology. 2008;71:1021–6.

    Article  PubMed  CAS  Google Scholar 

  141. Saunders-Pullman R, Stanley K, Wang C, et al. Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology. 2011;77:319–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Vilas D, Ispierto L, Alvarez R, et al. Clinical and imaging markers in premotor LRRK2 G2019S mutation carriers. Parkinsonism Relat Disord. 2015;21:1170–6.

    Article  PubMed  Google Scholar 

  143. Ponsen MM, Stiffers D, Booij J, Van Eck-Smit BLF, Wolters EC, Berendse HW. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol. 2004;56:173–81.

    Article  PubMed  Google Scholar 

  144. Hawkes CH, Shephard BC, Daniel SE. Olfactory dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1997;62:436–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Haugen J, Müller ML, Kotagal V, Albin RL, Koeppe RA, Scott PJ, et al. Prevalence of impaired odor identification in Parkinson disease with imaging evidence of nigrostriatal denervation. J Neural Transm. 2016;123:421–4.

    Article  PubMed  CAS  Google Scholar 

  146. Morley JF, Duda JE. Use of hyposmia and other non-motor symptoms to distinguish between drug-induced parkinsonism and Parkinson’s disease. J Parkinson Dis. 2014;4:169–73.

    Google Scholar 

  147. Mesholam RI, Moberg PJ, Mahr RN, Doty RL. Olfaction in neurodegenerative disease: a meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s disease. Arch Neurol. 1998;55:84–90.

    Article  PubMed  CAS  Google Scholar 

  148. 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.

    Article  PubMed  Google Scholar 

  149. Hawkes CH, Shephard BC. Selective anosmia in Parkinson’s disease? Lancet. 1993;341:435–6.

    Article  PubMed  CAS  Google Scholar 

  150. Haehner A, Maboshe W, Baptista RB, Storch A, Reichmann H, Hummel T. Selective hyposmia in Parkinson’s disease? J Neurol. 2013;260:3158–60.

    Article  Google Scholar 

  151. Chen H, Huang X, Guo X, et al. Smoking duration, intensity, and risk of Parkinson’s disease. Neurology. 2010;74:878–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Thacker EL, O’Reilly EJ, Weisskopf MG, et al. Temporal relationship between cigarette smoking and risk of Parkinson’s disease. Neurology. 2007;68:764–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Sharer JD, Leon-Sarmietno FE, Morley JF, Weintraub D, Doty RL. Olfactory dysfunction in Parkinson’s disease: positive effect of cigarette smoking. Mov Disord. 2015;30:859–62.

    Article  PubMed  Google Scholar 

  154. Lucassen EB, Sterling NW, Lee EY, Cehn H, Lewis MM, Kong L, et al. History of smoking and olfaction in Parkinson’s disease. Mov Disord. 2014;29:1069–74.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Witt M, Bormann K, Gudziol V, et al. Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord. 2009;24:906–14.

    Article  PubMed  Google Scholar 

  156. Hummel T, Witt M, Reichmnn H, Welge-Luessen A, Haehner A. Immunohistochemical, volumetric, and functional neuroimaging studies in patients with idiopathic Parkinson’s disease. J Neurol Sci. 2010;289:119–22.

    Article  PubMed  CAS  Google Scholar 

  157. Schneider SA, Boettner M, Alexoudi A, Zorenkov D, Deuschl G, Wedel T. Can we use peripheral tissue biopsies to diagnose Parkinson’s disease? A review of the literature. Eur J Neurol. 2016;23:247–61.

    Article  PubMed  CAS  Google Scholar 

  158. Brodoehl S, Klingner C, Volk GF, Bitter T, Witte OW, Redecker C. Decreased olfactory bulb volume in idiopathic Parkinson’s disease detected by 3.0-Tesla magnetic resonance imaging. Mov Disord. 2012;27:1019–25.

    Article  PubMed  Google Scholar 

  159. Chen S, Tan HY, Wu ZH, Sun CP, He JX, Li XC, et al. Imaging of olfactory bulb and gray matter volumes in brain areas associated with olfactory function in patients with Parkinson’s disease and multiple system atrophy. Eur J Radiol. 2014;83:564–70.

    Article  PubMed  Google Scholar 

  160. Li J, Gu CZ, Su JB, Zhu LH, Zhou Y, Huang HY, et al. Changes in olfactory bulb volume in Parkinson’s disease: a systematic review and meta-analysis. PLoS One. 2016;11:e0149286.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Tanik N, Serin HI, Celikbilek A, Inan LE, Gundogdu F. Associations of olfactory bulb and depth of olfactory sulcus with basal ganglia and hippocampus in patients with Parkinson’s disease. Neurosci Lett. 2016;620:111–4.

    Article  PubMed  CAS  Google Scholar 

  162. Sengoku R, Matsushima S, Bono K, et al. Olfactory function combined with morphology distinguishes Parkinson’s disease. Parkinsonism Relat Disord. 2015;21:771–7.

    Article  PubMed  Google Scholar 

  163. Mueller A, Abolmaali ND, Hakimi AR, Gloeckler T, Herting B, Reichmann H, et al. Olfactory bulb volumes in patients with idiopathic Parkinson’s disease a pilot study. J Neural Transm. 2005;112:1363–70.

    Article  PubMed  CAS  Google Scholar 

  164. Hakyemez HA, Veyseller B, Ozer F, Pzben S, Bayraktar GI, Gurbuz D, et al. Relationship of olfactory function with olfactory bulbs volume, disease duration and Unified Parkinson’s disease rating scale scores in patients with early stage of idiopathic Parkinson’s disease. J Clin Neurosci. 2013;20:1469–70.

    Article  PubMed  Google Scholar 

  165. Altinayar S, Oner S, Can S, Kizilay A, Kamisili S, Sarac K. Olfactory dysfunction and its relation olfactory bulb volume in Parkinson’s disease. Eur Rev Med Pharmacol Sci. 2014;18:3659–64.

    PubMed  CAS  Google Scholar 

  166. Scherfler C, Schocke MF, Seppi K, Esterhammer R, Brenneis C, Jaschke W, et al. Voxel-wise analysis of diffusion weighted imaging reveals disruption of the olfactory tract in Parkinson’s disease. Brain. 2006;129:538–42.

    Article  PubMed  Google Scholar 

  167. Ibarretxe-Bilbao N, Junque C, Marti MJ, Valldeoriola F, Vendrell P, Bargallo N, et al. Olfactory impairment in Parkinson’s disease and white matter abnormalities in central olfactory areas: a voxel-based diffusion tensor imaging study. Mov Disord. 2010;25:1888–94.

    Article  PubMed  Google Scholar 

  168. Iannilli E, Stephan L, Hummel T, Reichmann H, Haehner A. Olfactory impairment in Parkinson’s disease is a consequence of central nervous system decline. J Neurol. 2017;264:1236–46.

    Article  PubMed  Google Scholar 

  169. Westermann B, Wattendorf E, Schwedtfeger U, et al. Functional imaging of the cerebral olfactory system in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2008;79:19–24.

    Article  PubMed  CAS  Google Scholar 

  170. Su M, Wang S, Fang W, Zhu Y, Li R, Sheng K, et al. Alterations in the limbic/paralimbic cirtices of Parkinson’s disease patients with hyposmia under resting-state functional MRI by regional homogeneity and functional connectivity analysis. Parkinsonism Relat Disord. 2015;21:698–703.

    Article  PubMed  Google Scholar 

  171. Tolosa E, Gaig C, Santamaria J, Compta Y. Diagnosis and the premotor phase of Parkinson disease. Neurology. 2009;72(Suppl):S12–20.

    Article  PubMed  Google Scholar 

  172. Reichmann H. Premotor diagnosis of Parkinson’s disease. Neurosci Bull. 2017;33:526–34.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Ross GW, Petrovich H, Abbot RD, et al. Association of olfactory dysfunction with risk for future Parkinsons’ disease. Ann Neurol. 2008;63:167–73.

    Article  PubMed  Google Scholar 

  174. Berendse HW, Booij J, Francot CM, Bergmans PL, Hijman R, Stoof JC, et al. Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease patients’ relatives with a decreased sense of smell. Ann Neurol. 2001;50:34–41.

    Article  PubMed  CAS  Google Scholar 

  175. Pont-Sunyer C, Hotter A, Haig C, et al. The onset of nomotor symptoms in Parkinson’s disease (the ONSET PD study). Mov Disord. 2015;30:229–37.

    Article  PubMed  Google Scholar 

  176. 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;22:839–42.

    Article  PubMed  Google Scholar 

  177. Dickson DW, Fujishiro H, DellDonne A, et al. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol. 2008;115:437–44.

    Article  PubMed  Google Scholar 

  178. Haehner A, Schöpf V, Loureiro A, Linn J, Reichmann H, Hummel T, et al. Susbtantia nigra fractional anisotropy changes confirm the PD at-risk status of paitients with idiopathic smell loss. Parkinsonism Relat Disord. 2018;50:113–6.

    Article  PubMed  Google Scholar 

  179. Berendse HW, Ponsen MM. Diagnosing premotor Parkinson’s disease using a two-step approach combining olfactory testing and DAT SPECT imaging. Parkinsonism Relat Disord. 2009;15(Suppl 3):S26–30.

    Article  PubMed  Google Scholar 

  180. Ponsen MM, Stoffers D, Wolters EC, Booij J, Berendse HW. Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2010;81:396–9.

    Article  PubMed  Google Scholar 

  181. Sierra M, Sánchez-Juan P, Martínez-Rodríguez MI, et al. Olfaction and imaging biomarkers in premotor LRRK2 G2019S-associated Parkinson disease. Neurology. 2013;80:621–6.

    Article  PubMed  CAS  Google Scholar 

  182. Jennings D, Siderowf A, Stern M, Seibyil J, Eberly S, Oakes D, et al. Conversion to Parkinson Disease in the PARS hyposmic and dopamine transporter-deficit prodromal cohort. JAMA Neurol. 2017;74:933–40.

    Article  PubMed  PubMed Central  Google Scholar 

  183. 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;55:138–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. 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;255:367–70.

    Article  PubMed  Google Scholar 

  185. Cavaco S, Gonçalves A, Mendes A, et al. Abnormal olfaction in Parkinson’s disease is related to faster disease progression. Behav Neurol. 2015: 976589.

  186. 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;16:41–6.

    Article  PubMed  CAS  Google Scholar 

  187. 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;23:1984–90.

    Article  PubMed  Google Scholar 

  188. Siderowf A, Newberg A, Chou KL, et al. [99mTc]TRODAT-1-SPECT imaging correlates with odor identification in early Parkinson disease. Neurology. 2005;64:1716–20.

    Article  PubMed  CAS  Google Scholar 

  189. Lee EY, Eslinger PJ, Du G, Kong L, Lewis MM, Huang X. Olfactory-related cortical atrophy is associated with olfactory dysfunction in Parkinson’s disease. Mov Disord. 2014;29:1205–8.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Fullard ME, Tran B, Xie SX, et al. Olfactory impairment predicts cognitive decline in early Parkinson’s disease. Parkinsonism Relat Disord. 2016;25:45–51.

    Article  PubMed  PubMed Central  Google Scholar 

  191. Kang SH, Lee HM, Seo WK, Kim JH, Koh SB. The combined effect of REM sleep behavior disorder and hyposmia on cognition and motor phenotype in Parkinson’s disease. J Neurol Sci. 2016;368:374–8.

    Article  PubMed  Google Scholar 

  192. Domellöf ME, Lundin KF, Edström M, Forsgren L. Olfactory dysfunction and dementia in newly diagnosed patients with Parkinson’s disease. Parkinsonism Relat Disord. 2017;38:41–7.

    Article  PubMed  Google Scholar 

  193. Stephenson R, Houghton D, Sundarararjan S, Doty RL, Stern M, Xie SX, et al. Odor identification deficits are associated with increased risk of neuropsychiatric complications in patients with Parkinson’s disease. Mov Disord. 2010;25:2099–104.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Baba T, Kikuchi A, Hirayama K, et al. Severe olfactory dysfunction is a prodromal symptom or dementia associated with Parkinson’s disease: a 3 years longitudinal study. Brain. 2012;135:161–9.

    Article  PubMed  Google Scholar 

  195. Alves J, Petrsyan A, Magalhaes R. Olfactory dysfunction in dementia. World J Clin Cases. 2014;2:661–7.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Bibi M, Mollenhauer B, Esselmann H, et al. CSF amyloid-beta-peptides in Alzheimer’s disease dementia, dementia with Lewy bodies and Parkinson’s disease dementia. Brain. 2006;129:1177–87.

    Article  Google Scholar 

  197. Compta Y, Santamaría J, Ratti L, Tolosa E, Iranzo A, Muñoz E, et al. Cerebrospinal hypocretin, daytime sleepiness and sleep architecture in Parkinson’s dementia. Brain. 2009;132:3308–17.

    Article  PubMed  Google Scholar 

  198. Siderowf A, Xie SX, Hurtig H, et al. CSF amyloid (beta) 1-42 predicts cognitive decline in Parkinson’s disease. Neurology. 2010;75:1055–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Parnetti L, Farotti L, Eusebi P, et al. Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson’s disease. Front Aging Neurosci. 2014;6:53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Goldstein DS, Holmes C, Bentho O, et al. Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple atrophy. Parkinsonism Relat Disord. 2008;14:600–7.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Silveira-Moriyama L, Hughes G, Church A, et al. Hyposmia in progressive supranuclear palsy. Mov Disord. 2010;25:570–7.

    Article  PubMed  Google Scholar 

  202. Suzuki M, Hashimoto M, Yoshioka M, Murakami M, Kawasaki K, Urashima M. The odor stick identification test for Japanese differentiates Parkinson’s disease form multiple system atrophy and progressive supranuclear palsy. BMC Neurol. 2011;11:157.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Glass PG, Lees AJ, Mathias C, et al. Olfaction in pathologically proven patients with multiple system atrophy. Mov Disord. 2012;27:327–8.

    Article  PubMed  Google Scholar 

  204. Wenning GK, Shephard B, hawkes C, Petruckevitch A, Lees A, Quinn N. Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand. 1995;81:247–50.

    Article  Google Scholar 

  205. Müller A, Müngersdorf M, Reichmann H, Strehle G, Hummel T. Olfactory function in parkinsonian syndromes. J Clin Neurosci. 2002;9:521–4.

    Article  PubMed  Google Scholar 

  206. Brigo F, Erro R, Marangi A, Bhatia K, Tinazzi M. Differentiating drug-induced parkinsonism from Parkinson’s disease: an update on non-motor symptoms and investigations. Parkinsonism Relat Disord. 2014;20:808–14.

    Article  PubMed  Google Scholar 

  207. Katzenschlager R, Lees AJ. Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr opin Neurol. 2004;17:417–23.

    Article  PubMed  Google Scholar 

  208. Kertelge L, Brüggemann N, Schmidt A, et al. Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson’s disease. Mov Disord. 2010;25:2665–9.

    Article  PubMed  Google Scholar 

  209. Paisán-Ruiz C, Lewis PA, Singleton AB. LRRK2: cause, risk, and mechanism. J Parkinson Dis. 2013;3:85–103.

    Google Scholar 

  210. Silveira-Moriyama L, Munhoz RP, de J Carvalho M, et al. Olfactory heterogeneity in LRRK2 related parkinsonism. Mov Disord. 2010;25:2879–83.

    Article  PubMed  Google Scholar 

  211. Bardien S, Lesage S, Brice A, Carr J. Genetic characteristic of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson’s disease. Parkinsonism Relat Disord. 2011;17:501–8.

    Article  PubMed  Google Scholar 

  212. Gaig C, Vilas D, Infante J, Sierra M, et al. Non-motor symptoms in LRRK2 G2019S associated Parkinson’s disease. PLoS One. 2014;9:e108982.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Johansen KK, Waro BJ, Aasly JO. Olfactory dysfunction in sporadic Parkinson’s disease and LRRK2 carriers. Acta Neurol Scand. 2014;129:300–6.

    Article  PubMed  CAS  Google Scholar 

  214. Saunders-Pullman R, Mirelman A, Wang C, et al. Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker? Ann Clin Transl Neurol. 2014;1:670–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Pont-Sunyer C, Tolosa E, Caspell-Garcia C, et al. The prodromal phase of leucine-rich repeat kinase 2-associated Parkinson’s disease: clinical and imaging studies. Mov Disord. 2017;32:726–38.

    Article  PubMed  CAS  Google Scholar 

  216. Mirelman A, Heman T, Yasinovsky K, et al. Fall risk and gait in Parkinson’s disease: the role of the LRRK2 G2019S mutation. Mov Disord. 2013;28:1683–90.

    Article  PubMed  CAS  Google Scholar 

  217. Poulopulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson’s disease. Mov Disord. 2012;27:831–42.

    Article  CAS  Google Scholar 

  218. Kalia LV, Lang AE, Hazrati LN, et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson’s disease. JAMA Neurol. 2015;72:100–5.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Sierra M, Martínez-Rodríguez I, Sánchez-Juan P, et al. Prospective clinical and DaT-SPECT imaging in premotor LRRK2 G2019S-associated Parkinson disease. Neurology. 2017;89:439–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Bostantjopoulou S, Katsarou Z, Papadimitriou A, Veletza V, Hatzigeorgiou G, Lees A. Clinical features of parkinsonian patients with the alpha-synuclein (G209A) mutation. Mov Disord. 2001;16:1007–13.

    Article  PubMed  CAS  Google Scholar 

  221. Tijero B, Gomez-Esteban JC, Llorens V, et al. Cardiac sympathetic denervation precedes nigrostriatal loss in the E46K mutation of the alpha-synuclein gene (SNCA). Clin Auton Res. 2010;20:267–9.

    Article  PubMed  CAS  Google Scholar 

  222. Papadimitriou D, Antonelou R, Miligkos M, et al. Motor and non-motor features of carriers of the p.A53T alpha-synuclein mutation: A longitudinal study. Mov Disord. 2016;31:1226–30.

    Article  PubMed  CAS  Google Scholar 

  223. Alcalay RN, Siderowf A, Ottman R, et al. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology. 2011;76:319–26.

    Article  PubMed  CAS  Google Scholar 

  224. Malek N, Swallow DM, Grosset KA, et al. Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson’s disease patients. Acta Neurol Scand. 2016;134:271–6.

    Article  PubMed  CAS  Google Scholar 

  225. Ferraris A, Ialongo T, Passali GC, et al. Olfactory dysfunction in Parkinsonism caused by PINK1 mutations. Mov Disord. 2009;24:2350–7.

    PubMed  Google Scholar 

  226. Saunders-Pullman R, Hagenah J, Dhawan V, et al. Gaucher disease ascertained through a Parkinson’s center: imaging and clinical characterization. Mov Disord. 2010;25:1364–72.

    Article  PubMed  PubMed Central  Google Scholar 

  227. McNeill A, Duran R, Proukakis C, et al. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Mov Disord. 2012;27:526–32.

    Article  PubMed  PubMed Central  Google Scholar 

  228. Beavan M, McNeill A, Proukakis CH, et al. Evolution of prodromal clinical markers of Parkinson disease in a glucocerebrosidase mutation positive cohort. JAMA Neurol. 2015;72:201–8.

    Article  PubMed  PubMed Central  Google Scholar 

  229. Del Tredici K, Rüb U, De Vos RA, Bohl JR, Braak H. Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol. 2002;61:413–26.

    Article  PubMed  Google Scholar 

  230. Silveira-Moriyama L, Holton JL, Kngsbury A, Ayling H, Petrie A, Sterlacci W, et al. Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci Lett. 2009;453:77–80.

    Article  PubMed  CAS  Google Scholar 

  231. •• Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ, et al. Widespread transneuronal propagation of α-synucleopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med. 2016;213:1759–78. Preclinical evidence that α-synuclein fibrils injected at the olfactory bulb level induces olfactory deficits and spread to multiple brain regions, being the first evidence of a transneuronal, progressive propagation of Parkinson’s diasease (PD)-like α-synuclein pathology.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Mason DM, Nouraei N, Pant DB, Miner KM, Hutchinson DF, Luk KC, et al. Transmission of α-synucleinopathy from olfactory structures deep into the temporal lobe. Mol Neurodegener. 2016;11:49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Duda JE, Shah E, Arnold SE, Lee VM, Tojanowski JQ. The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative disease. Exp Neurol. 1999;160:515–22.

    Article  PubMed  CAS  Google Scholar 

  234. Ferrer I, López-González I, Carmona M, Dalfó E, Pujol A, Martínez A. Neurochemistry and the non-motor aspects of PD. Neurobiol Dis. 2012;46:508–26.

    Article  PubMed  CAS  Google Scholar 

  235. Huisman E, Uylings HB, Hoogland PV. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinsons’s disease. Mov Disord. 2004;19:687–92.

    Article  PubMed  Google Scholar 

  236. Huisman E, Uylings HB, Hoogland PV. Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson’s disease patients. Mov Disord. 2008;23:1407–13.

    Article  PubMed  Google Scholar 

  237. Mundiñano LC, Caballero MC, Ordóñez C, et al. Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders. Acta Neuropathol. 2011;122:61–74.

    Article  PubMed  CAS  Google Scholar 

  238. Hubbard PS, Esiri MM, Reading M, MCShane R, Nagy Z. Alpha-synuclein pathology in the olfactory pathways of dementia patients. J Anat. 2007;211:117–24.

    Article  PubMed  PubMed Central  Google Scholar 

  239. Ubeda-Bañón I, Flores-Cuadrado A, Saiz-Sanchez D, Martinez-Marcos A. Differential effects of Parkinson’s disease on interneuron subtypes within the human anterior olfactory nucleus. Front Neuroanat. 2017;11:113.

    Article  PubMed  PubMed Central  Google Scholar 

  240. Harding AJ, Stimson E, Henderson JM, Halliday GM. Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain. 2002;125:2431–45.

    Article  PubMed  Google Scholar 

  241. Wattendorf E, Welge-Lüssen A, Fiedler K, Bilecen D, Wolfensberger M, Fuhr P, et al. Olfactory impairment predicts brain atrophy in Parkinson’s disease. J Neurosci. 2009;29:15410–3.

    Article  PubMed  CAS  Google Scholar 

  242. Tsuboi Y, Wszolek ZK, Graff-Radford NR, Cookson N, Dickson DW. Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4. Neuropathol Appl Neurobiol. 2003;29:503–10.

    Article  PubMed  CAS  Google Scholar 

  243. Müller ML, Bohnen NI. Cholinergic dysfunctionin Parkinson’s disease. Curr Neurol Neurosci Rep. 2013;13:377.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Levey AI, Hersch SM, Rye DB, Sunahara RK, Niznik HB, Kitt CA, et al. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc Natl Acada Sci USA. 1993;90:8861–5.

    Article  CAS  Google Scholar 

  245. Gutierrez-Mecinas M, Crespo C, Blasco-Ibáñez JM, et al. Distribution of D2 dopamine receptor in the olfactory glomeruli of the rat olfactory bulb. Eur J Neurosci. 2005;22:1357–67.

    Article  PubMed  Google Scholar 

  246. Doty RL, Risser JM. Influence of the D-2 dopamine receptor agonist quinpirole on the odor detection performance of rats before and after spiperone administration. Psychopharmacology. 1989;98:310–5.

    Article  PubMed  CAS  Google Scholar 

  247. Escanilla O, Yuhas C, Marzan D, Linster C. Dopaminergic modulation of olfactory bulb processing affects odor discrimination learning in rats. Behav Neurosci. 2009;123:828–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Wei CJ, Linster C, Cleland TA. Dopamine D2 receptor activation modulates perceived odor intensity. Behav Neurosci. 2006;120:393–400.

    Article  PubMed  CAS  Google Scholar 

  249. Bastien-Dionne PO, David LS, Parent A, Saghatelyan A. Role of sensory activity on chemospecific populations of interneurons in the adult olfactory bulb. J Comp Neurol. 2010;518:1847–61.

    Article  PubMed  CAS  Google Scholar 

  250. Sawada M, Kaneko N, Inada H, Wake H, Kato Y, Yanagawa Y, et al. Sensory input regulates spatial and subtype-specific patterns of neuronal turnover in the adult olfactory bulb. J Neurosci. 2011;31:11587–96.

    Article  PubMed  CAS  Google Scholar 

  251. Motles E, Tetas M, Gomez A. Behavioral effects evoked by SKF38393 and LY171555 in adult cats. Physiol Behav. 1995;57:983–8.

    Article  PubMed  CAS  Google Scholar 

  252. Deeb J, Shah M, Muhammed N, Gunasekera R, Gannon K, Findley LJ, 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. QJM. 2010;103:941–52.

    Article  PubMed  CAS  Google Scholar 

  253. 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;254:84–90.

    Article  PubMed  CAS  Google Scholar 

  254. Winner B, Desplats P, Hagl C, et al. Dopamine receptor activation promotes adult neurogenesis in an acute Parkinson model. Exp Neurol. 2009;219:543–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  255. Zaborsky L, Carlsen J, Brashear HR, Heimer L. Cholinergic afferents to the olfactory bulb in the rat with special emphasis on the projection neurons in the nucleus of the horizontal limb of the diagonal band. J Comp Neurol. 1986;243:488–509.

    Article  Google Scholar 

  256. D’Souza RD, Vijayaraghavan S. Nicotinic receptor-mediated filtering of mitral cell responses to olfactory nerve inputs involves the a3b4 subtype. J Neurosci. 2012;32:3261–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  257. D’Souza RD, Parsa PC, Vijayaraghavan S. Nicotinic receptors modulate olfactory bulb external tufted cells via an excitation-dependent inhibitory mechanism. J Neurophsyiol. 2013;110:1544–53.

    Article  CAS  Google Scholar 

  258. Li G, Linster C, Cleland TA. Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells. J Neurophsyiol. 2015;114:3177–200.

    Article  CAS  Google Scholar 

  259. Doty RL, Bagla R, Kim N. Physostigmine enhances performance on an odor mixture discrimination test. Physiol Behav. 1999;65:801–4.

    Article  PubMed  CAS  Google Scholar 

  260. Chaudhury D, Escanilla O, Linster C. Bulbar acetylcholine enhances neural perceptual odor discrimination. J Neurosci. 2009;29:52–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  261. Mandairon N, Peace ST, Boudadi K, Boxhorn CE, Narla VA, Suffis SD, et al. Compensatory responses to age-related decline in odor quality acuity: cholinergic neuromodulation and olfactory enrichment. Neurobiol Aging. 2011;32:2254–65.

    Article  PubMed  CAS  Google Scholar 

  262. Devore S, Manella LC, Linster C. Blocking muscarinic receptors in the olfactory bulb impairs performance on an olfactory short-term memory task. Front Behav Neurosci. 2012;6:59.

    PubMed  PubMed Central  CAS  Google Scholar 

  263. Oh E, Park J, Youn J, Kim JS, Park S, Jang W. Olfactory dysfunction in early Parkinson’s disease is associated with short latency afferent inhibition reflecting central cholinergic dysfunction. Clin Neurophysiol. 2017;128:1061–8.

    Article  PubMed  Google Scholar 

  264. Versace V, Langthaler PB, Sebastianelli L, Höller Y, Brigo D, Orioli A, et al. Impaired cholinergic transmission in patients with Parkinson’s disease and olfactory dysfunction. J Neurol Sci. 2017;377:55–61.

    Article  PubMed  CAS  Google Scholar 

  265. Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, et al. Differential muscarinic modulation in the olfactory bulb. J Neurosci. 2015;35:10773–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  266. McLean JH, Shipley MT. Serotonergic afferents to the rat olfactory bulb: I. Origins and laminar specificity of serotonergic inputs in the adult rat. J Neurosci. 1987;7:3016–28.

    Article  PubMed  CAS  Google Scholar 

  267. Brill J, Shao Z, Puche AC, Wachowiak M, Shipley MT. Serotonin increases synaptic activity in olfactory bulb glomeruli. J Neurophysiol. 2016;115:1208–19.

    Article  PubMed  PubMed Central  Google Scholar 

  268. Qamhawi Z, Towey D, Shah B, et al. Clinical correlates of raphe serotonergic dysfunction in early Parkinson’s disease. Brain. 2015;138:2964–73.

    Article  PubMed  Google Scholar 

  269. Vermeiren Y, Janssens J, Van Dam D, De Deyn PP. Serotonergic dysfunction in amyotrophic lateral sclerosis and Parkinson’s disease: similar mechanisms, dissimilar outcomes. Front Neurosci. 2018;12:185.

    Article  PubMed  PubMed Central  Google Scholar 

  270. Kovacs CG, Klöppel S, Fischer I, Domer S, Lindeck-Pozza E, Birner P, et al. Nucleus-specific alteration of raphe neurons in human neurodegenerative disorders. Neuroreport. 2003;14:73–6.

    Article  PubMed  CAS  Google Scholar 

  271. McKeith IG, Dickson DW, Lwe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65:1863–72.

    Article  PubMed  CAS  Google Scholar 

  272. Gilbert PE, Barr PJ, Murphy C. Differences in olfactory and visual memory in patients with pathologically confirmed Alzheimer’s disease and the Lewy body variant of Alzheimer’s disease. J Int Neurospychol Soc. 2004;10:835–42.

    Google Scholar 

  273. Funabe S, Takao M, Saito Y, et al. Neuropathologic analysis of Lewy-related α-synucleinopathy in olfactory mucosa. Neuropathology. 2013;33:47–58.

    Article  PubMed  CAS  Google Scholar 

  274. Hepp DH, Vergoossen DL, Huisman E, et al. Distribution and load of amyloid-b pathology in Parkinson disease and dementia with Lewy bodies. J Neuropathol Exp Neurol. 2016;75:936–45.

    Article  PubMed  CAS  Google Scholar 

  275. McKhann GM, Knopman DS, Cheretkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9.

    Article  PubMed  PubMed Central  Google Scholar 

  276. Zou YM, Lu D, Liu LP, Zhang HH, Zhou YY. Olfactory dysfunction in Alzheimer’s disease. Neuropsychiatry Dis Treat. 2016;12:869–75.

    Article  Google Scholar 

  277. Sun GH, Raji CA, Maceachern P, Burke JF. Olfactory identification testing as a predictor of the development of Alzheimer’s dementia: a systematic review. Laryngoscope. 2012;122:1455–62.

    Article  PubMed  Google Scholar 

  278. Bahar-Fuchs A, Chételat G, Villemagner VL, Moss S, Pike K, Masters CL, et al. Olfactory deficits and amyloid-β burden in Alzheimer’s disease, mild cognitive impairment, and healthy aging: a PIB PET study. J Alzheimers Dis. 2010;22:1081–7.

    Article  PubMed  Google Scholar 

  279. Kim JY, Rasheed A, Yoo SJ, Kim SY, Cho B, Son G, et al. Distinct amyloid precursor protein processing machineries of the olfactory system. Biochem Biophys Res Commun. 2018;495:533–8.

    Article  PubMed  CAS  Google Scholar 

  280. Serby M, Larson P, Kalkstein D. The nature and course of olfactory deficits in Alzheimer’s disease. Am J Psychiatry. 1991;148:357–60.

    Article  PubMed  CAS  Google Scholar 

  281. Velayudhan L, Pritchard M, Powell JF, Proitsi P, Lovestone S. Smell identification function as a severity and progression marker in Alzheimer’s disease. Int Psychogeriatr. 2013;25:1157–66.

    Article  PubMed  Google Scholar 

  282. Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H. Olfaction in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2008;29:693–706.

    Article  PubMed  Google Scholar 

  283. Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA. Olfactory impairment in presymptomatic Alzheimer’s disease. Ann NY Acad Sci. 2009;1170:730–5.

    Article  PubMed  Google Scholar 

  284. Devanand DP, Michaels-Marston KS, Liu X, 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;157:1399–405.

    Article  PubMed  CAS  Google Scholar 

  285. Bahar-Fuchs A, Moss S, Rowe C, Savage G. Awareness of olfactory deficits in healthy aging, amnestic mild cognitive impairment and Alzheimer’s disease. Int Psychogeriatr. 2011;23:1097–106.

    Article  PubMed  Google Scholar 

  286. Devanand DP, Lee S, Manly J, et al. Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community. Neurology. 2015;84:182–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  287. Doty RL, Reyes PF, Gregor T. Presence of both odor identification and detection deficits in Alzheimer’s disease. Brain Res Bull. 1987;18:597–600.

    Article  PubMed  CAS  Google Scholar 

  288. 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;28:391–9.

    Article  PubMed  Google Scholar 

  289. Devanand DP, Liu X, Tabert MH, et al. Combining early markers strongly conversion from mild cognitive impairment to Alzheimer’s disease. Biol Psychiatr. 2008;64:871–9.

    Article  Google Scholar 

  290. Murphy C, Jernigan TL, Fennema-Notestine C. Left hippocampal volume loss in Alzheimer’s disease is reflected in performance on odor identification: a structural MRI study. J Int Neuropsychol Soc. 2003;9:459–71.

    Article  PubMed  Google Scholar 

  291. Wang J, Eslinger PJ, Doty RL, et al. Olfactory deficit detected by fMRI in early Alzheimer’s disease. Brain Res. 2010;1357:184–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  292. Kovacs T, Cairns NJ, Lantos PL. Beta-amyloid deposition and neurofibrillary tangle formation in the olfactory bulb in ageing and Alzheimer’s disease. Neuropathol Appl Neurobiol. 1999;25:481–91.

    Article  PubMed  CAS  Google Scholar 

  293. 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;30:505–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  294. Xu W, Fitzgerald S, Nixon RA, Levy E, Wilson DA. Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AβPP metabolites in the Tg2576 mouse model of Alzheimer’s disease. Exp Neurol. 2015;264:82–91.

    Article  PubMed  CAS  Google Scholar 

  295. Hu B, Geng C, Hou XY. Oligomeric amyloid-b peptide disrupts olfactory information output by impairment of local inhibitory circuits in rat olfactory bulb. Neurobiol Aging. 2017;51:113–21.

    Article  PubMed  CAS  Google Scholar 

  296. •• Risacher SL, Tallman EF, West JD, et al. Olfactory identification in subjective cognitive decline and mild cognitive impairment: association with tau but not amyloid positron emission tomography. Alzheimers Dement. 2017;9:57–66. Using amyloid positron emission tomography, magnetic resonance and UPSIT test, the present report demonstrates that olfactory deficit may be a good marker for tau and neurodegeneration in preclinical or prodromal Alzheimer’s disease.

    Google Scholar 

  297. Attems J, Jellinger KA. Olfactory tau pathology in Alzheimer disease and mild cognitive impairment. Clin Neuropathol. 2006;25:265–71.

    PubMed  CAS  Google Scholar 

  298. Goedert M. The ordered assembly of tau is the gain-of-toxic function that causes human tauopathies. Alzheimers Dement. 2016;12:1040–50.

    Article  PubMed  Google Scholar 

  299. Oleson S, Murphy C. Olfactory dysfunction in ApoE E4/4 homozygotes with Alzheimer’s disease. J Alzheimers Dis. 2015;46:791–803.

    Article  PubMed  CAS  Google Scholar 

  300. Juottonen K, Lehtovirta M, Helisalmi S, Riekkinen PJ Sr, Soininen H. Major decrease in the volume of the entorhinal cortex in patients with Alzheimer’s disease carrying the apolipoprotein E epsilon 4 allele. J Neurol Neurosurg Psychiatry. 1998;65:322–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  301. Olofsson JK, Rönnlund 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-epsilon4. Behav Genet. 2009;39:496–503.

    Article  PubMed  Google Scholar 

  302. Devanand DP, Tabert MH, Cuasay K, et al. Olfactory identification deficits and MCI in a multi-ethnic elderly community sample. Neurobiol Aging. 2010;31:1593–600.

    Article  PubMed  CAS  Google Scholar 

  303. Lehéricy S, Hirsch EC, Cervera-Piérot P, et al. Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease. J Comp Neurol. 1993;330:15–31.

    Article  PubMed  Google Scholar 

  304. Tiraboschi P, Hansen LA, Alford M, Merdes A, Masliah E, Thal LJ, et al. Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry. 2002;59:946951.

    Article  Google Scholar 

  305. Ahlskog JE, Waring SC, Petersen RC, et al. Olfactory dysfunction in Guamanian ALS, parkinsonism, and dementia. Neurology. 1998;51:1672–7.

    Article  PubMed  CAS  Google Scholar 

  306. Günther R, Schrempf W, Häher A, Hummel T, Wolz M, Storch A, et al. Impairment in respiratory function contributes to olfactory impairment in amyotrophic lateral sclerosis. Front Neurosci. 2018;9:79.

    Article  Google Scholar 

  307. Hawkes CH, Shepard BC, Geddes JF, Body GD, Martin JE. Olfactory disorder in motor neuron disease. Exp Neurol. 1998;150:248–53.

    Article  PubMed  CAS  Google Scholar 

  308. Pilotto A, Rossi F, Rinaldi F, et al. Exploring olfactory function and its relation with behavioural and cognitive impairment in amyotrophic lateral sclerosis patients: a cross-sectional study. Neurodegener Dis. 2016;16:411–6.

    Article  PubMed  Google Scholar 

  309. Eisen A, Braak H, Tredici KD, Lemon R, Ludolph AC, Kiernan MC. Cortical influences drive amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2017;88:917–24.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. INGENIO, IRCE, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CELLEX, Department 2B, Villarroel 170, 08036, Barcelona, Catalonia, Spain

    Concepció Marin, Cristóbal Langdon, Isam Alobid, Mauricio López-Chacón & Joaquim Mullol

  2. Neurodegenerative Diseases Unit, Neurology Service, University Hospital Germans Trias i Pujol, Badalona, Catalonia, Spain

    Dolores Vilas

  3. Rhinology Unit and Smell Clinic, ENT Department, Hospital Clínic, Barcelona, Catalonia, Spain

    Cristóbal Langdon, Isam Alobid, Mauricio López-Chacón & Joaquim Mullol

  4. Centre for Biomedical Investigation in Respiratory Diseases (CIBERES), Barcelona, Spain

    Isam Alobid & Joaquim Mullol

  5. Smell and Taste Clinic, Department of Otorhinolaryngology, Technische Universität Dresden, Dresden, Germany

    Antje Haehner & Thomas Hummel

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  1. Concepció Marin
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Marin, C., Vilas, D., Langdon, C. et al. Olfactory Dysfunction in Neurodegenerative Diseases. Curr Allergy Asthma Rep 18, 42 (2018). https://doi.org/10.1007/s11882-018-0796-4

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