Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-669899f699-8p65j Total loading time: 0 Render date: 2025-05-01T01:01:09.346Z Has data issue: false hasContentIssue false

Chapter 10 - Olfactory Dysfunction in Parkinson’s Disease and Related Disorders

Published online by Cambridge University Press:  05 March 2022

By
Richard L. Doty  and
Christopher H. Hawkes
Edited by
Néstor Gálvez-Jiménez ,
Amos D. Korczyn  and
Ramón Lugo-Sanchez
Néstor Gálvez-Jiménez
Affiliation:
Florida International University
Amos D. Korczyn
Affiliation:
Tel-Aviv University
Ramón Lugo-Sanchez
Affiliation:
Cleveland Clinic
Get access

Summary

Smell dysfunction is among the earliest and most salient non-motor signs of Parkinson’s disease (PD), occurring in an estimated 90% of so-called sporadic cases years before the onset of the classic motor symptoms. Until olfaction is tested formally, the vast majority of PD patients are unaware of their loss, which is usually less than total. The smell problem is rarely identified by neurologists, reflecting, in part, their failure to enquire about smell function let alone testing the olfactory nerve formally. The Quality Standards Committee of the American Academy of Neurology has designated olfactory dysfunction as one of the key diagnostic criteria for PD [1] and the Movement Disorder Society has recommended olfactory testing in the diagnosis of PD [2] and in the identification of prodromal PD [3].

Type
Chapter
Information
Non-motor Parkinson's Disease , pp. 99 - 114
Publisher: Cambridge University Press
Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Suchowersky, O, Reich, S, Perlmutter, J, et al. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66: 968–975.Google Scholar
Postuma, RB, Berg, D, Stern, M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015; 30: 1591–1601.Google Scholar
Berg, D, Postuma, RB, Adler, CH, et al. MDS research criteria for prodromal Parkinson’s disease. Mov Disord 2015; 30: 1600–1611.Google Scholar
Chaudhuri, KR, Martinez-Martin, P, Schapira, AHV, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: The NMSQuest study. Mov Disord 2006; 21: 916–923.Google Scholar
Pence, TS, Reiter, ER, DiNardo, LJ, Costanzo, RM. Risk factors for hazardous events in olfactory-impaired patients. JAMA Otolaryngol Head Neck Surg 2014; 140: 951–955.Google Scholar
Chalke, HD, Dewhurst, JR, Ward, CW. Loss of smell in old people. Pub Health 1958; 72: 223–230.CrossRefGoogle ScholarPubMed
Doty, RL, Shaman, P, Applebaum, SL, et al. Smell identification ability: changes with age. Science 1984; 226: 1441–1443.Google Scholar
Hawkes, CH, Doty, RL. Smell and Taste Disorders. Cambridge University Press; 2018.Google Scholar
Doty, RL, Bromley, SM, Stern, MB. Olfactory testing as an aid in the diagnosis of Parkinson’s disease: development of optimal discrimination criteria. Neurodegeneration 1995; 4: 93–97.Google Scholar
Bohnen, NI, Muller, ML, Kotagal, V, et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain 2010; 133: 1747–1754.Google Scholar
Parrao, T, Chana, P, Venegas, P, et al. Olfactory deficits and cognitive dysfunction in Parkinson’s disease. Neurodegener Dis 2012; 10: 179–182.CrossRefGoogle ScholarPubMed
Doty, RL, Riklan, M, Deems, DA, Reynolds, C, Stellar, S. The olfactory and cognitive deficits of Parkinson’s disease: evidence for independence. Ann Neurol 1989; 25: 166–171.Google Scholar
Hawkes, CH, Shephard, BC. Selective anosmia in Parkinson’s disease? Lancet 1993; 341: 435–436.Google Scholar
Joseph, T, Auger, SD, Peress, L, et al. Screening performance of abbreviated versions of the UPSIT smell test. J Neurol 2019; 266: 1897–1906.Google Scholar
Ponsen, MM, Stoffers, D, Booij, J, et al. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 2004; 56: 173–181.CrossRefGoogle ScholarPubMed
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: 1237–1244.Google Scholar
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 Psychiat 1992; 55: 138–142.CrossRefGoogle ScholarPubMed
Braak, H, Del, TK, Rub, U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24: 197–211.Google Scholar
Doty, RL. Olfactory dysfunction in neurodegenerative diseases: is there a common pathological substrate? Lancet Neurol 2017; 16: 478–488.Google Scholar
Crino, PB, Martin, JA, Hill, WD, et al. Beta-Amyloid peptide and amyloid precursor proteins in olfactory mucosa of patients with Alzheimer’s disease, Parkinson’s disease, and Down syndrome. Ann Otol Rhinol Laryngol 1995; 104: 655–661.CrossRefGoogle ScholarPubMed
Duda, JE, Shah, U, Arnold, SE, Lee, VM, Trojanowski, JQ. The expression of alpha-, beta-, and gamma-synucleins in olfactory mucosa from patients with and without neurodegenerative diseases. Exp Neurol 1999; 160: 515–522.CrossRefGoogle ScholarPubMed
Witt, M, Bormann, K, Gudziol, V, et al. Biopsies of olfactory epithelium in patients with Parkinson’s disease. Mov Disord 2009; 24: 906–914.CrossRefGoogle ScholarPubMed
Funabe, S, Takao, M, Saito, Y, et al. Neuropathologic analysis of Lewy-related alpha-synucleinopathy in olfactory mucosa. Neuropathology 2013; 33: 47–58.Google Scholar
Saito, Y, Shioya, A, Sano, T, et al. Lewy body pathology involves the olfactory cells in Parkinson’s disease and related disorders. Mov Disord 2016; 31: 135–138.CrossRefGoogle ScholarPubMed
Daniel, SE, Hawkes, CH. Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology [letter]. Lancet 1992; 340: 186.CrossRefGoogle ScholarPubMed
Pearce, RK, Hawkes, CH, Daniel, SE. The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 1995; 10: 283–287.CrossRefGoogle ScholarPubMed
Beach, TG, White, CL, III, Hladik, CL, et al. Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 2009; 117: 169–174.Google Scholar
Jellinger, KA. Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 2009; 117: 215–216.Google Scholar
Zapiec, B, Dieriks, BV, Tan, S, et al. A ventral glomerular deficit in Parkinson’s disease revealed by whole olfactory bulb reconstruction. Brain 2017; 140: 2722–2736.Google Scholar
Braak, H, Ghebremedhin, E, Rub, U, Bratzke, H, Del, TK. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318: 121–134.CrossRefGoogle ScholarPubMed
Ubeda-Banon, I, Saiz-Sanchez, D, Rosa-Prieto, C, et al. Alpha-Synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein- and substance P-positive cells. Acta Neuropathol 2010; 119: 723–735.Google Scholar
Ubeda-Banon, I, Saiz-Sanchez, D, Rosa-Prieto, C, Martinez-Marcos, A. Alpha-Synuclein in the olfactory system of a mouse model of Parkinson’s disease: correlation with olfactory projections. Brain Struct Funct 2012; 217: 447–458.Google Scholar
Chesselet, MF, Richter, F, Zhu, C, et al. A progressive mouse model of Parkinson’s disease: the Thy1-aSyn (“Line 61”) mice. Neurotherapeutics 2012; 9: 297–314.CrossRefGoogle ScholarPubMed
Egea, J, Buendia, I, Parada, E, et al. Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol 2015; 97: 463–472.Google Scholar
Boeckxstaens, G. The clinical importance of the anti-inflammatory vagovagal reflex. Handb Clin Neurol 2013; 117: 119–134.CrossRefGoogle ScholarPubMed
McKinney, M, Jacksonville, MC. Brain cholinergic vulnerability: relevance to behavior and disease. Biochem Pharmacol 2005; 70: 1115–1124.Google Scholar
Takada-Takatori, Y, Kume, T, Sugimoto, M, et al. Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 2006; 51: 474–486.Google Scholar
Shinotoh, H, Namba, H, Yamaguchi, M, et al. Positron emission tomographic measurement of acetylcholinesterase activity reveals differential loss of ascending cholinergic systems in Parkinson’s disease and progressive supranuclear palsy. Ann Neurol 1999; 46: 62–69.3.0.CO;2-P>CrossRefGoogle ScholarPubMed
Shimada, H, Hirano, S, Shinotoh, H, et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 2009; 73: 273–278.CrossRefGoogle ScholarPubMed
Huisman, E, Uylings, HBM, Hoogland, PV. A 100% increase of 687 dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson’s disease. Mov Disord 2004; 19: 687–692.Google Scholar
Huisman, E, Uylings, HBM, Hoogland, PV. Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson’s disease patients. Mov Disord 2008; 23: 1407–1413.Google Scholar
Belzunegui, S, Sebastian, WS, Garrido-Gil, P, et al. The number of dopaminergic cells is increased in the olfactory bulb of monkeys chronically exposed to MPTP. Synapse 2007; 61: 1006–1012.Google Scholar
Lelan, F, Boyer, C, Thinard, R, et al. Effects of human alpha-synuclein A53T-A30P mutations on SVZ and local olfactory bulb cell proliferation in a transgenic rat model of Parkinson disease. Parkinsons Dis 2011; 2011: 987084.Google Scholar
Ubeda-Banon, I, Saiz-Sanchez, D, Rosa-Prieto, C, et al. Staging of alpha-synuclein in the olfactory bulb in a model of Parkinson’s disease: cell types involved. Mov Disord 2010; 25: 1701–1707.CrossRefGoogle Scholar
Yamada, M, Onodera, M, Mizuno, Y, Mochizuki, H. Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated adult mice. Neuroscience 2004; 124(1): 173–181.Google Scholar
Garland, EM, Raj, SR, Peltier, AC, Robertson, D, Biaggioni, I. A cross-sectional study contrasting olfactory function in autonomic disorders. Neurology 2011; 76: 456–460.Google Scholar
Jepma, M, Deinum, J, Asplund, CL, et al. Neurocognitive function in dopamine-beta-hydroxylase deficiency. Neuropsychopharmacology 2011; 36: 1608–1619.Google Scholar
Doucette, W, Milder, J, Restrepo, D. Adrenergic modulation of olfactory bulb circuitry affects odor discrimination. Learn Mem 2007; 14: 539–547.Google Scholar
Doty, RL, Ferguson-Segall, M, Lucki, I, Kreider, M. Effects of intrabulbar injections of 6-hydroxydopamine on ethyl acetate odor detection in castrate and non-castrate male rats. Brain Res 1988; 444: 95–103.Google Scholar
Hensiek, AE, Bhatia, K, Hawkes, CH. Olfactory function in drug-induced parkinsonism. J Neurol 2000; 247(Suppl 3): 82.Google Scholar
Kruger, S, Haehner, A, Thiem, C, Hummel, T. Neuroleptic-induced parkinsonism is associated with olfactory dysfunction. J Neurol 2008; 255: 1574–1579.Google Scholar
Bovi, T, Antonini, A, Ottaviani, S, et al. The status of olfactory function and the striatal dopaminergic system in drug-induced parkinsonism. J Neurol 2010; 257: 1882–1889.Google Scholar
Lee, PH, Yeo, SH, Yong, SW, Kim, YJ. Odour identification test and its relation to cardiac I-123-metaiodobenzylguanidine in patients with drug induced parkinsonism. J Neurol Neurosurg Psychiatry 2007; 78: 1250–1252.Google Scholar
Morley, JF, Cheng, G, Dubroff, JG, et al. Olfactory impairment predicts underlying dopaminergic deficit in presumed drug-induced parkinsonism. Mov Disord Clin Pract 2017; 4: 603–606.Google Scholar
Doty, RL, Singh, A, Tetrud, J, Langston, JW. Lack of major olfactory dysfunction in MPTP-induced parkinsonism. Ann Neurol 1992; 32: 97–100.Google Scholar
Miwa, T, Watanabe, A, Mitsumoto, Y, et al. Olfactory impairment and Parkinson’s disease-like symptoms observed in the common marmoset following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Acta Oto-Laryngologica 2004; 124: 80–84.CrossRefGoogle Scholar
Kurtenbach, S, Wewering, S, Hatt, H, Neuhaus, EM, Lubbert, H. Olfaction in three genetic and two MPTP-induced Parkinson’s disease mouse models. PLoS One 2013; 8: e77509.Google Scholar
Prediger, RD, Aguiar, AS, Jr., Rojas-Mayorquin, AE, et al. Single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57BL/6 mice models early preclinical phase of Parkinson’s disease. Neurotox Res 2010; 17: 114–129.Google Scholar
Prediger, RDS, Batista, LC, Medeiros, R, et al. The risk is in the air: intranasal administration of MPTP to rats reproducing clinical features of Parkinson’s disease. Exp Neurol 2006; 202: 391–403.Google Scholar
Louis, ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol 2009; 66: 1202–1208.Google Scholar
Laroia, H, Louis, ED. Association between essential tremor and other neurodegenerative diseases: what is the epidemiological evidence? Neuroepidemiology 2011; 37: 1–10.CrossRefGoogle ScholarPubMed
Busenbark, KL, Huber, SI, Greer, G, Pahwa, R, Koller, WC. Olfactory function in essential tremor. Neurology 1992; 42: 1631–1632.Google Scholar
Shah, M, Muhammed, N, Findley, LJ, Hawkes, CH. Olfactory tests in the diagnosis of essential tremor. Parkinsonism Relat Disord 2008; 14: 563–568.CrossRefGoogle ScholarPubMed
Djaldetti, R, Nageris, BI, Lorberboym, M, et al. [I-123]-FP-CIT SPECT and olfaction test in patients with combined postural and rest tremor. J Neural Transm 2008; 115: 469–472.Google Scholar
Louis, ED, Rios, E, Pellegrino, KM, et al. Higher blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations correlate with lower olfactory scores in essential tremor. Neurotoxicology 2008; 29: 460–465.Google Scholar
Louis, ED, Vonsattel, JPG, Honig, LS, et al. Neuropathologic findings in essential tremor. Neurology 2006; 66: 1756–1759.Google Scholar
Louis, ED, Vonsattel, JP, Honig, LS, et al. Essential tremor associated with pathologic changes in the cerebellum. Arch Neurol 2006; 63: 1189–1193.Google Scholar
Lesage, S, Ibanez, P, Lohmann, E, et al. G2019S LRRK2 mutation in French and North African families with Parkinson’s disease. Ann Neurol 2005; 58: 784–787.Google Scholar
Silveira-Moriyama, L, Holton, JL, Kingsbury, A, et al. Regional differences in the severity of Lewy body pathology across the olfactory cortex. Neurosci Lett 2009; 453: 77–80.Google Scholar
Silveira-Moriyama, L, Guedes, LC, Kingsbury, A, et al. Hyposmia in G2019S LRRK2-related parkinsonism: clinical and pathologic data. Neurology 2008; 71: 1021–1026.Google Scholar
Ferreira, JJ, Guedes, LC, Rosa, MM, et al. High prevalence of LRRK2 mutations in familial and sporadic Parkinson’s disease in Portugal. Mov Disord 2007; 22: 1194–1201.Google Scholar
Silveira-Moriyama, L, Munhoz, RP, de JC, , Raskin, S et al. Olfactory heterogeneity in LRRK2 related Parkinsonism. Mov Disord 2010; 25: 2879–2883.CrossRefGoogle ScholarPubMed
Kertelge, L, Bruggemann, N, Schmidt, A, et al.Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson’s disease. Mov Disord 2010; 25: 2665–2669.Google Scholar
Lohmann, E, Leclere, L, De, AF, et al. A clinical, neuropsychological and olfactory evaluation of a large family with LRRK2 mutations. Parkinsonism Relat Disord 2009; 15: 273–276.Google Scholar
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: 670–678.Google Scholar
Sierra, M, Sanchez-Juan, P, Martinez-Rodriguez, MI, et al. Olfaction and imaging biomarkers in premotor LRRK2 G2019S-associated Parkinson disease. Neurology 2013; 80: 621–626.Google Scholar
Johansen, KK, White, LR, Farrer, MJ, Aasly, JO. Subclinical signs in LRRK2 mutation carriers. Parkinsonism Relat Disord 2011; 17: 528–532.Google Scholar
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: 1364–1372.Google Scholar
Goker-Alpan, O, Lopez, G, Vithayathil, J, et al. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol 2008; 65: 1353–1357.Google Scholar
Brockmann, K, Srulijes, K, Hauser, AK, et al. GBA-associated PD presents with nonmotor characteristics. Neurology 2011; 77: 276–280.Google Scholar
McNeill, A, Duran, R, Proukakis, C, et al. Hyposmia and cognitive impairment in Gaucher disease patients and carriers. Mov Disord 2012; 27: 526–532.Google Scholar
Beavan, M, McNeill, A, Proukakis, C, et al. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol 2015; 72: 201–208.Google Scholar
Iranzo, A. The REM sleep circuit and how its impairment leads to REM sleep behavior disorder. Cell Tissue Res 2018; 373: 245–266.Google Scholar
Schrempf, W, Katona, I, Dogan, I, et al. Reduced intraepidermal nerve fiber density in patients with REM sleep behavior disorder. Parkinsonism Relat Disord 2016; 29: 10–16.Google Scholar
Kyte, SL, Toma, W, Bagdas, D, et al. Nicotine prevents and reverses paclitaxel-induced mechanical allodynia in a mouse model of CIPN. J Pharmacol Exp Ther 2018; 364: 110–119.CrossRefGoogle Scholar
Sajjadian, A, Doty, RL, Gutnick, DN, et al. Olfactory dysfunction in amyotrophic lateral sclerosis. Neurodegeneration 1994; 3: 153–157.Google Scholar
Kotagal, V, Albin, RL, Muller, ML, et al. Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. Ann Neurol 2012; 71: 560–568.Google Scholar
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: 811–818.Google Scholar
Aguirre-Mardones, C, Iranzo, A, Vilas, D, et al. Prevalence and timeline of nonmotor symptoms in idiopathic rapid eye movement sleep behavior disorder. J Neurol 2015; 262: 1568–1578.Google Scholar
Killgore, WD, McBride, SA. Odor identification accuracy declines following 24 h of sleep deprivation. J Sleep Res 2006; 15: 111–116.Google Scholar
Kaufmann, H, Biaggioni, I. Autonomic failure in neurodegenerative disorders. Semin Neurol 2003; 23: 351–363.Google Scholar
Kovacs, T, Papp, MI, Cairns, NJ, Khan, MN, Lantos, PL. Olfactory bulb in multiple system atrophy. Mov Disord 2003; 18: 938–942.Google Scholar
Papp, MI, Kahn, JE, Lantos, PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 1989; 94: 79–100.Google Scholar
Wenning, GK, Shephard, B, Hawkes, C, et al. Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand 1995; 91: 247–250.Google Scholar
Muller, A, Mungersdorf, M, Reichmann, H, Strehle, G, Hummel, T. Olfactory function in Parkinsonian syndromes. J Clin Neurosci 2002; 9: 521–524.CrossRefGoogle ScholarPubMed
Abele, M, Riet, A, Hummel, T, Klockgether, T, Wullner, U. Olfactory dysfunction in cerebellar ataxia and multiple system atrophy. J Neurol 2003; 250: 1453–1455.Google Scholar
Goldstein, DS, Holmes, C, Bentho, O, et al. Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 2008; 14: 600–607.Google Scholar
Lee, PH, Yeo, SH, Kim, HJ, Youm, HY. Correlation between cardiac 123I-MIBG and odor identification in patients with Parkinson’s disease and multiple system atrophy. Mov Disord 2006; 21: 1975–1977.CrossRefGoogle ScholarPubMed
Doty, RL. Olfactory dysfunction in neurogenerative disorders. In Getchell, TV, Doty, RL, Bartoshuk, LM, Snow, JBJ (eds.). Smell and Taste in Health and Disease. Raven Press; 1991: 735–751.Google Scholar
Cox, TA, McDarby, JV, Lavine, L, Steele, JC, Calne, DB. A retinopathy on Guam with high prevalence in Lytico-Bodig. Ophthalmology 1989; 96: 1731–1735.Google Scholar
Kato, S, Hirano, A, Llena, JF, Ito, H, Yen, SH. Ultrastructural identification of neurofibrillary tangles in the spinal cords in Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam. Acta Neuropathol 1992; 83: 277–282.Google Scholar
Kokubo, Y, Ito, K, Fukunaga, T, Matsubara, H, Kuzuhara, S. Pigmentary retinopathy of ALS/PDC in Kii. Ophthalmology 2006; 113: 2111–2112.Google Scholar
Reed, D, Plato, C, Elizan, T, Kurland, LT. The amyotrophic lateral sclerosis/parkinsonism-dementia complex -- A ten-year follow-up on Guam. I. Epidemiological studies. Amer J Epidemiol 1966; 83: 54–73.Google Scholar
Reed, DM, Brody, JA. Amyotrophic lateral sclerosis and parkinsonism-dementia on Guam 1945–1972. I. Descriptive epidemiology. Amer J Epidemiol 1975; 101: 287–301.Google Scholar
Plato, CC, Garruto, RM, Galasko, D, et al. Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol 2003; 157: 149–157.Google Scholar
Oyanagi, K. The nature of the parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam and magnesium deficiency. Parkinsonism Relat Disord 2005; 11(Suppl 1): S17–S23.Google Scholar
Doty, RL, Perl, DP, Steele, JC, 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: 77–80.Google Scholar
Tzen, KY, Lu, CS, Yen, TC, Wey, SP, Ting, C. Differential diagnosis of Parkinson’s disease and vascular parkinsonism by Tc-99m-TRODAT-1. J Nuclear Med 2001; 42: 408–413.Google Scholar
Zijlmans, JCM, Thijssen, HOM, Vogels, OJM, et al. MRI in patients with suspected vascular parkinsonism. Neurology 1995; 45: 2183–2188.Google Scholar
Katzenschlager, R, Zijlmans, J, Evans, A, Watt, H, Lees, AJ. Olfactory function distinguishes vascular parkinsonism from Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004; 75: 1749–1752.Google Scholar
Navarro-Otano, J, Gaig, C, Muxi, A, et al. (123)I-MIBG cardiac uptake, smell identification and (123)I-FP-CIT SPECT in the differential diagnosis between vascular parkinsonism and Parkinson’s disease. Parkinsonism Relat Disord 2014; 20: 192–197.Google Scholar
Markopoulou, K, Larsen, KW, Wszolek, EK, et al. Olfactory dysfunction in familial parkinsonism. Neurology 1997; 49: 1262–1267.Google Scholar
Bostantjopoulou, S, Katsarou, Z, Papadimitriou, A, et al. Clinical features of parkinsonian patients with the alpha-synuclein (G209A) mutation. Mov Disord 2001; 16: 1007–1013.Google Scholar
Nishioka, K, Ross, OA, Ishii, K, et al. Expanding the clinical phenotype of SNCA duplication carriers. Mov Disord 2009; 24: 1811–1819.Google Scholar
Koros, C, Stamelou, M, Simitsi, A, et al. Selective cognitive impairment and hyposmia in p.A53T SNCA PD vs typical PD. Neurology 2018; 90: e864–e869.Google Scholar
Khan, NL, Katzenschlager, R, Watt, H, et al. Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 2004; 62: 1224–1226.Google Scholar
Alcalay, RN, Siderowf, A, Ottman, R, et al. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology 2011; 76: 319–326.Google Scholar
Ferraris, A, Ialongo, T, Passali, GC, et al. Olfactory dysfunction in Parkinsonism caused by PINK1 mutations. Mov Disord 2009; 24: 2350–2357.CrossRefGoogle ScholarPubMed
Eggers, C, Schmidt, A, Hagenah, J, et al. Progression of subtle motor signs in PINK1 mutation carriers with mild dopaminergic deficit. Neurology 2010; 74: 1798–1805.Google Scholar
Samaranch, L, Lorenzo-Betancor, O, Arbelo, JM, et al. PINK1-linked parkinsonism is associated with Lewy body pathology. Brain 2010; 133: 1128–1142.Google Scholar
Verbaan, D, Boesveldt, S, van Rooden, SM, et al. Is olfactory impairment in Parkinson disease related to phenotypic or genotypic characteristics? Neurology 2008; 71: 1877–1882.Google Scholar
Saunders-Pullman, R, Stanley, K, Wang, C, et al. Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology 2011; 77: 319–324.Google Scholar
Khan, NL, Jain, S, Lynch, JM, et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 2005; 128: 2786–2796.Google Scholar
Berg, D, Schweitzer, K, Leitner, P, et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson’s disease. Brain 2005; 128: 3000–3011.Google Scholar
Lin, CH, Tzen, KY, Yu, CY, et al. LRRK2 mutation in familial Parkinson’s disease in a Taiwanese population: clinical, PET, and functional studies. J Biomed Sci 2008; 15: 661–667.Google Scholar
Klein, C, Schneider, SA, Lang, AE. Hereditary parkinsonism: Parkinson disease look-alikes--an algorithm for clinicians to “PARK” genes and beyond. Mov Disord 2009; 24: 2042–2058.Google Scholar
Paisan-Ruiz, C, Li, A, Schneider, SA, et al. Widespread Lewy body and tau accumulation in childhood and adult-onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2012; 33: 814–823.Google Scholar
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.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×