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How does smoking affect olfaction in Parkinson's disease?
Journal of the Neurological Sciences 340 (2014) 215–217
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
How does smoking affect olfaction in Parkinson's disease? Marcello Moccia a, Marina Picillo a, Roberto Erro b, Carmine Vitale c,d, Marianna Amboni d, Raffaele Palladino e,f, Dante Luigi Cioffi g, Paolo Barone g, Maria Teresa Pellecchia g,⁎ a
Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom University of Naples Parthenope, Naples, Italy d IDC Hermitage-Capodimonte, Naples, Italy e Department of Primary Care and Public Health, Imperial College, London, United Kingdom f Department of Public Health, Federico II University, Naples, Italy g Center for Neurodegenerative Diseases (CEMAND), University of Salerno, Italy b c
a r t i c l e
i n f o
Article history: Received 20 November 2013 Received in revised form 21 January 2014 Accepted 18 February 2014 Available online 24 February 2014 Keywords: Parkinson's disease Smell Olfaction Smoking Nicotine Neuroprotection
a b s t r a c t Smoke-induced upper airway damage and Parkinson's disease (PD) can be considered independent risk factors for smell impairment. Interestingly, cigarette smoking has been strongly associated with reduced risk of PD and, therefore, has been suggested to have neuroprotective effects. Our pilot study aimed to evaluate the relationship between smoking and olfaction in PD patients and matched controls. Sixty-eight PD patients and 61 healthy controls were categorized in relation to PD diagnosis and current smoking status, and evaluated by means of the Italian version of the University of Pennsylvania 40-item Smell Identification Test (UPSIT-40). ANOVA analysis with post-hoc Bonferroni correction showed that non-smoker controls presented a higher UPSIT-40 total score than smoker controls (p b 0.001), non-smoker PD patients (p b 0.001) and smoker PD patients (p b 0.001). In this view, smoking seems to affect olfaction in controls but not in PD patients, and no significant differences were found when comparing smoker controls, smoker PD patients and non-smoker PD patients. Several epidemiological studies showed a negative effect of smoking on olfaction in the general population. Otherwise the sense of smell is similar in smoker and non-smoker PD patients. These results suggest that PD and smoking are not independent risk factors for impairment of sense of smell, but they might variably interact. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Hyposmia is a common finding in Parkinson's disease (PD) because of early alpha-synuclein accumulation in olfactory bulb and nucleus [1]. On the other hand, it is known from population studies that olfaction might be impaired by smoking [2]. Accordingly, smoke-induced upper airway damage and PD neurodegeneration could be considered independent risk factors for smell impairment. Interestingly, cigarette smoking has been strongly associated with reduced risk of PD and, therefore, has been suggested to have neuroprotective effects [3,4]. In particular, nicotine has been shown to protect nigrostriatal cells against ongoing degeneration in animal models of PD acting at nicotinic receptors or via receptor-independent mechanisms (i.e. mitochondrial pathways) [4,5]. Thus, although cigarette smoking might impair olfaction in
⁎ Corresponding author at: Center for Neurodegenerative Diseases (CEMAND), University of Salerno, 84131, Italy. Tel./fax: +39 089672328. E-mail address: [email protected] (M.T. Pellecchia).
http://dx.doi.org/10.1016/j.jns.2014.02.018 0022-510X/© 2014 Elsevier B.V. All rights reserved.
the general population, its possible neuroprotective efficacy might reduce PD neurodegeneration and hypothetically prevent hyposmia. The latter hypothesis was recently studied in a parkin mutant Drosophila, where nicotine exposure was shown to rescue olfactory deficits [6]. Our pilot study aimed to evaluate the relationship between smoking and olfaction in PD patients and matched controls. 2. Patients and methods Data were derived from the University of Pennsylvania 40-item Smell Identification Test (UPSIT-40) Italian validation study [7]. We included 68 PD patients consecutively recruited at the Movement Disorder Unit of Federico II University in Naples, and 61 controls recruited among staff and visitors of the same hospital [7]. Among those subjects, we identified 4 groups considering disease (PD +/−) and current smoking status (S+/−): smoker PD patients (PD +S+), non-smoker PD patients (PD + S −), smoker controls (PD − S +) and non-smoker controls (PD−S−). In particular, current smoking habits were evaluated by the self-reported questionnaire of UPSIT-40; former and passive
216
M. Moccia et al. / Journal of the Neurological Sciences 340 (2014) 215–217
smokers were not included in the present study. Considering the possibility that smokers would be less prevalent in both PD patients and controls due to epidemiological reasons [3,4], groups were tested for normal distribution in order to verify the reliability of statistical tests. In particular, normality was tested by graphical methods, including box-and-whisker plot and histogram graphs. A regression model considering the interaction term between smoking and PD (smoking ∗ disease) was performed as a preliminary test to judge the interaction between these two factors. Once the interaction term was tested, the main outcome of the study was defined as the association between PD diagnosis and current smoking status, with four different sub-categories: PD − S −, PD − S +, PD + S −, and PD+S+. Analysis of variance (ANOVA) was performed to study the association between the UPSIT-40 total score and the main variable of interest. Then, ANOVA analysis with post-hoc Bonferroni correction was performed to investigate the differences within the main variable of interest. Moreover, a linear regression model was performed in order to adjust results for age, gender and disease duration. Statistical results were considered significant if p b 0.05. Statistical analysis was performed using Stata 12.0. Fig. 1. UPSIT-40 total score in smoker PD patients (PD+S+), non-smoker PD patients (PD+S−), smoker controls (PD−S+) and non-smoker controls (PD−S−); significant p value from analysis of variance (ANOVA) with post-hoc Bonferroni correction.
3. Results Normal distribution was positively tested in categorized groups (Table 1). The regression model considering the interaction term between smoking and PD showed that “smoking” and “disease” both represented factors of worst olfaction (p b 0.001; coefficients, respectively, −11.1 ± 1.8 and −9.6 ± 1.0), while the interaction “smoking ∗ disease” resulted to be positively related to UPSIT-40 total score (p = 0.001; coefficient 8.4 ± 2.6). ANOVA analysis showed that the UPSIT-40 total score was significantly associated with the outcome variable (p b 0.001). Furthermore, ANOVA analysis with post-hoc Bonferroni correction showed that PD−S − status predicted a higher UPSIT-40 total score than PD− S+ (p b 0.001), PD+S− (p b 0.001) and PD+S+ (p b 0.001) (Fig. 1). The latter analysis did not find any significant relation among PD−S+, PD+S− and PD+S+. Linear regression analysis demonstrated that UPSIT-40 total was related to groups (p b 0.001), age (p = 0.045) and gender (p = 0.008; adj. R-squared = 0.467), but not to disease duration (p = 0.32) [7]. 4. Discussion Several epidemiological studies showed a quantitative and qualitative negative effect of smoking on olfaction in the general population [2,8,9]. Otherwise, several studies assessing smell in PD patients failed to show this effect, but missed to discuss this result or attributed it to the reduced sample size [7,10–13]. For instance, in the cross-sectional study we previously performed, smoking status was shown to be an independent predictor of the UPSIT-40 total score for the whole population [7]. However, group analysis indicates that the observed difference in sense of smell was mainly based on the comparison
Table 1 Demographic and clinical features of smoker PD patients (PD+S+), non-smoker PD patients (PD+S−), smoker controls (PD−S+) and non-smoker controls (PD−S−).
Number of subjects Age (mean ± SD) Men/woman (%) Disease duration (years ± SD) UPSIT-40 total score Mean ± SD Min./max. IQR
PD+S+
PD+S−
PD−S+
PD−S−
10 60.3 ± 6.7 70/30 4.4 ± 3.4
58 62.2 ± 9.2 57/43 4.8 ± 3.7
10 62.8 ± 6.8 60/40
51 59.0 ± 8.8 59/41
17.2 ± 5.7 9/21 6
16.8 ± 4.9 6/31 7
21.1 ± 6.8 11/26 4
27.7 ± 4.9 14/36 6
SD: standard deviation; NS: not significant; IQR: interquartile range.
between PD and non-smoker controls, since olfaction in smoker controls is not different from PD patients. Moreover, the sense of smell is similar in smoker and non-smoker PD patients. Thus, a smokingrelated olfactory impairment was observed in controls but not in PD patients. These results suggest that PD and smoking are not independent risk factors for impairment of sense of smell, but they might variably interact. In particular, nicotine has been recently suggested to have a neuroprotective activity on olfaction in a model of parkin mutant Drosophila [6]. Although our small cross-sectional study is not adequate to justify a similar conclusion, we cannot exclude that nicotine may exert some neuroprotective effect on olfaction also in PD patients. The present observation has several limitations not allowing to clearly defining a causal association or interaction, such as the low statistical power, the lack of follow-up data and the low sample size of the smoker groups. In particular smokers were a low percentage in both PD and control groups. However, a low rate of smokers among PD patients was expected according to epidemiological studies [3,4], and controls presented the same rate of smokers [7]. Nevertheless, our results are in line with previous studies [7,10–13] and can justify further studies in larger populations to evaluate the relationship between smoking and PD, in order to increase our knowledge on possible neuroprotective strategies in PD.
Sources of funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Conflict of interest statement None of the authors have any conflicts of interest to state.
Ethical standards This study has been approved by the appropriate ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Patients gave informed consent to publication of the findings.
M. Moccia et al. / Journal of the Neurological Sciences 340 (2014) 215–217
References [1] Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson's disease. Parkinsonism Relat Disord 2010;16(2):79–84. [2] Katotomichelakis M, Balatsouras D, Tripsianis G, Davris S, Maroudias N, Danielides V, et al. The effect of smoking on the olfactory function. Rhinology 2007;45(4):273–80. [3] Nicoletti A, Pugliese P, Nicoletti G, Arabia G, Annesi G, Mari MD, et al. Voluptuary habits and clinical subtypes of Parkinson's disease: the FRAGAMP case–control study. Mov Disord 2010;25(14):2387–94. [4] Quik M, Perez XA, Bordia T. Nicotine as a potential neuroprotective agent for Parkinson's disease. Mov Disord 2012;27(8):947–57. [5] Xie YX, Bezard E, Zhao BL. Investigating the receptor-independent neuroprotective mechanisms of nicotine in mitochondria. J Biol Chem 2005;280(37):32405–12. [6] Chambers RP, Call GB, Meyer D, Smith J, Techau JA, Pearman K, et al. Nicotine increases lifespan and rescues olfactory and motor deficits in a Drosophila model of Parkinson's disease. Behav Brain Res 2013;253:95–102. [7] Picillo M, Pellecchia MT, Erro R, Amboni M, Vitale C, Iavarone A, et al. The use of University of Pennsylvania Smell Identification Test in the diagnosis of Parkinson's disease in Italy. Neurol Sci 2013;35(3):379–83.
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[8] Frye RE, Schwartz BS, Doty RL. Dose-related effects of cigarette smoking on olfactory function. JAMA 1990;263:1233–6. [9] Picillo M, Iavarone A, Pellecchia MT, Amboni M, Erro R, Moccia M, et al. Validation of an Italian version of the 40-item University of Pennsylvania Smell Identification Test that is physician administered: our experience on one-hundred and thirty eight healthy subjects. Clin Otolaryngol Dec 26 2013 [in press]. [10] Double KL, Rowe DB, Hayes M, Chan DK, Blackie J, Corbett A, et al. Identifying the pattern of olfactory deficits in Parkinson disease using the brief smell identification test. Arch Neurol 2003;60(4):545–9. [11] Silveira-Moriyama L, Carvalho Mde J, Katzenschlager R, Petrie A, Ranvaud R, Barbosa ER, et al. The use of smell identification tests in the diagnosis of Parkinson's disease in Brazil. Mov Disord 2008;23(16):2328–34. [12] Rodríguez-Violante M, Lees AJ, Cervantes-Arriaga A, Corona T, Silveira-Moriyama L. Use of smell test identification in Parkinson's disease in Mexico: a matched case– control study. Mov Disord 2011;26(1):173–6. [13] Silveira-Moriyama L, Petrie A, Williams DR, Evans A, Katzenschlager R, Barbosa ER, et al. The use of a color coded probability scale to interpret smell tests in suspected parkinsonism. Mov Disord 2009;24(8):1144–53.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
How does smoking affect olfaction in Parkinson's disease? Marcello Moccia a, Marina Picillo a, Roberto Erro b, Carmine Vitale c,d, Marianna Amboni d, Raffaele Palladino e,f, Dante Luigi Cioffi g, Paolo Barone g, Maria Teresa Pellecchia g,⁎ a
Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom University of Naples Parthenope, Naples, Italy d IDC Hermitage-Capodimonte, Naples, Italy e Department of Primary Care and Public Health, Imperial College, London, United Kingdom f Department of Public Health, Federico II University, Naples, Italy g Center for Neurodegenerative Diseases (CEMAND), University of Salerno, Italy b c
a r t i c l e
i n f o
Article history: Received 20 November 2013 Received in revised form 21 January 2014 Accepted 18 February 2014 Available online 24 February 2014 Keywords: Parkinson's disease Smell Olfaction Smoking Nicotine Neuroprotection
a b s t r a c t Smoke-induced upper airway damage and Parkinson's disease (PD) can be considered independent risk factors for smell impairment. Interestingly, cigarette smoking has been strongly associated with reduced risk of PD and, therefore, has been suggested to have neuroprotective effects. Our pilot study aimed to evaluate the relationship between smoking and olfaction in PD patients and matched controls. Sixty-eight PD patients and 61 healthy controls were categorized in relation to PD diagnosis and current smoking status, and evaluated by means of the Italian version of the University of Pennsylvania 40-item Smell Identification Test (UPSIT-40). ANOVA analysis with post-hoc Bonferroni correction showed that non-smoker controls presented a higher UPSIT-40 total score than smoker controls (p b 0.001), non-smoker PD patients (p b 0.001) and smoker PD patients (p b 0.001). In this view, smoking seems to affect olfaction in controls but not in PD patients, and no significant differences were found when comparing smoker controls, smoker PD patients and non-smoker PD patients. Several epidemiological studies showed a negative effect of smoking on olfaction in the general population. Otherwise the sense of smell is similar in smoker and non-smoker PD patients. These results suggest that PD and smoking are not independent risk factors for impairment of sense of smell, but they might variably interact. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Hyposmia is a common finding in Parkinson's disease (PD) because of early alpha-synuclein accumulation in olfactory bulb and nucleus [1]. On the other hand, it is known from population studies that olfaction might be impaired by smoking [2]. Accordingly, smoke-induced upper airway damage and PD neurodegeneration could be considered independent risk factors for smell impairment. Interestingly, cigarette smoking has been strongly associated with reduced risk of PD and, therefore, has been suggested to have neuroprotective effects [3,4]. In particular, nicotine has been shown to protect nigrostriatal cells against ongoing degeneration in animal models of PD acting at nicotinic receptors or via receptor-independent mechanisms (i.e. mitochondrial pathways) [4,5]. Thus, although cigarette smoking might impair olfaction in
⁎ Corresponding author at: Center for Neurodegenerative Diseases (CEMAND), University of Salerno, 84131, Italy. Tel./fax: +39 089672328. E-mail address: [email protected] (M.T. Pellecchia).
http://dx.doi.org/10.1016/j.jns.2014.02.018 0022-510X/© 2014 Elsevier B.V. All rights reserved.
the general population, its possible neuroprotective efficacy might reduce PD neurodegeneration and hypothetically prevent hyposmia. The latter hypothesis was recently studied in a parkin mutant Drosophila, where nicotine exposure was shown to rescue olfactory deficits [6]. Our pilot study aimed to evaluate the relationship between smoking and olfaction in PD patients and matched controls. 2. Patients and methods Data were derived from the University of Pennsylvania 40-item Smell Identification Test (UPSIT-40) Italian validation study [7]. We included 68 PD patients consecutively recruited at the Movement Disorder Unit of Federico II University in Naples, and 61 controls recruited among staff and visitors of the same hospital [7]. Among those subjects, we identified 4 groups considering disease (PD +/−) and current smoking status (S+/−): smoker PD patients (PD +S+), non-smoker PD patients (PD + S −), smoker controls (PD − S +) and non-smoker controls (PD−S−). In particular, current smoking habits were evaluated by the self-reported questionnaire of UPSIT-40; former and passive
216
M. Moccia et al. / Journal of the Neurological Sciences 340 (2014) 215–217
smokers were not included in the present study. Considering the possibility that smokers would be less prevalent in both PD patients and controls due to epidemiological reasons [3,4], groups were tested for normal distribution in order to verify the reliability of statistical tests. In particular, normality was tested by graphical methods, including box-and-whisker plot and histogram graphs. A regression model considering the interaction term between smoking and PD (smoking ∗ disease) was performed as a preliminary test to judge the interaction between these two factors. Once the interaction term was tested, the main outcome of the study was defined as the association between PD diagnosis and current smoking status, with four different sub-categories: PD − S −, PD − S +, PD + S −, and PD+S+. Analysis of variance (ANOVA) was performed to study the association between the UPSIT-40 total score and the main variable of interest. Then, ANOVA analysis with post-hoc Bonferroni correction was performed to investigate the differences within the main variable of interest. Moreover, a linear regression model was performed in order to adjust results for age, gender and disease duration. Statistical results were considered significant if p b 0.05. Statistical analysis was performed using Stata 12.0. Fig. 1. UPSIT-40 total score in smoker PD patients (PD+S+), non-smoker PD patients (PD+S−), smoker controls (PD−S+) and non-smoker controls (PD−S−); significant p value from analysis of variance (ANOVA) with post-hoc Bonferroni correction.
3. Results Normal distribution was positively tested in categorized groups (Table 1). The regression model considering the interaction term between smoking and PD showed that “smoking” and “disease” both represented factors of worst olfaction (p b 0.001; coefficients, respectively, −11.1 ± 1.8 and −9.6 ± 1.0), while the interaction “smoking ∗ disease” resulted to be positively related to UPSIT-40 total score (p = 0.001; coefficient 8.4 ± 2.6). ANOVA analysis showed that the UPSIT-40 total score was significantly associated with the outcome variable (p b 0.001). Furthermore, ANOVA analysis with post-hoc Bonferroni correction showed that PD−S − status predicted a higher UPSIT-40 total score than PD− S+ (p b 0.001), PD+S− (p b 0.001) and PD+S+ (p b 0.001) (Fig. 1). The latter analysis did not find any significant relation among PD−S+, PD+S− and PD+S+. Linear regression analysis demonstrated that UPSIT-40 total was related to groups (p b 0.001), age (p = 0.045) and gender (p = 0.008; adj. R-squared = 0.467), but not to disease duration (p = 0.32) [7]. 4. Discussion Several epidemiological studies showed a quantitative and qualitative negative effect of smoking on olfaction in the general population [2,8,9]. Otherwise, several studies assessing smell in PD patients failed to show this effect, but missed to discuss this result or attributed it to the reduced sample size [7,10–13]. For instance, in the cross-sectional study we previously performed, smoking status was shown to be an independent predictor of the UPSIT-40 total score for the whole population [7]. However, group analysis indicates that the observed difference in sense of smell was mainly based on the comparison
Table 1 Demographic and clinical features of smoker PD patients (PD+S+), non-smoker PD patients (PD+S−), smoker controls (PD−S+) and non-smoker controls (PD−S−).
Number of subjects Age (mean ± SD) Men/woman (%) Disease duration (years ± SD) UPSIT-40 total score Mean ± SD Min./max. IQR
PD+S+
PD+S−
PD−S+
PD−S−
10 60.3 ± 6.7 70/30 4.4 ± 3.4
58 62.2 ± 9.2 57/43 4.8 ± 3.7
10 62.8 ± 6.8 60/40
51 59.0 ± 8.8 59/41
17.2 ± 5.7 9/21 6
16.8 ± 4.9 6/31 7
21.1 ± 6.8 11/26 4
27.7 ± 4.9 14/36 6
SD: standard deviation; NS: not significant; IQR: interquartile range.
between PD and non-smoker controls, since olfaction in smoker controls is not different from PD patients. Moreover, the sense of smell is similar in smoker and non-smoker PD patients. Thus, a smokingrelated olfactory impairment was observed in controls but not in PD patients. These results suggest that PD and smoking are not independent risk factors for impairment of sense of smell, but they might variably interact. In particular, nicotine has been recently suggested to have a neuroprotective activity on olfaction in a model of parkin mutant Drosophila [6]. Although our small cross-sectional study is not adequate to justify a similar conclusion, we cannot exclude that nicotine may exert some neuroprotective effect on olfaction also in PD patients. The present observation has several limitations not allowing to clearly defining a causal association or interaction, such as the low statistical power, the lack of follow-up data and the low sample size of the smoker groups. In particular smokers were a low percentage in both PD and control groups. However, a low rate of smokers among PD patients was expected according to epidemiological studies [3,4], and controls presented the same rate of smokers [7]. Nevertheless, our results are in line with previous studies [7,10–13] and can justify further studies in larger populations to evaluate the relationship between smoking and PD, in order to increase our knowledge on possible neuroprotective strategies in PD.
Sources of funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Conflict of interest statement None of the authors have any conflicts of interest to state.
Ethical standards This study has been approved by the appropriate ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Patients gave informed consent to publication of the findings.
M. Moccia et al. / Journal of the Neurological Sciences 340 (2014) 215–217
References [1] Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson's disease. Parkinsonism Relat Disord 2010;16(2):79–84. [2] Katotomichelakis M, Balatsouras D, Tripsianis G, Davris S, Maroudias N, Danielides V, et al. The effect of smoking on the olfactory function. Rhinology 2007;45(4):273–80. [3] Nicoletti A, Pugliese P, Nicoletti G, Arabia G, Annesi G, Mari MD, et al. Voluptuary habits and clinical subtypes of Parkinson's disease: the FRAGAMP case–control study. Mov Disord 2010;25(14):2387–94. [4] Quik M, Perez XA, Bordia T. Nicotine as a potential neuroprotective agent for Parkinson's disease. Mov Disord 2012;27(8):947–57. [5] Xie YX, Bezard E, Zhao BL. Investigating the receptor-independent neuroprotective mechanisms of nicotine in mitochondria. J Biol Chem 2005;280(37):32405–12. [6] Chambers RP, Call GB, Meyer D, Smith J, Techau JA, Pearman K, et al. Nicotine increases lifespan and rescues olfactory and motor deficits in a Drosophila model of Parkinson's disease. Behav Brain Res 2013;253:95–102. [7] Picillo M, Pellecchia MT, Erro R, Amboni M, Vitale C, Iavarone A, et al. The use of University of Pennsylvania Smell Identification Test in the diagnosis of Parkinson's disease in Italy. Neurol Sci 2013;35(3):379–83.
217
[8] Frye RE, Schwartz BS, Doty RL. Dose-related effects of cigarette smoking on olfactory function. JAMA 1990;263:1233–6. [9] Picillo M, Iavarone A, Pellecchia MT, Amboni M, Erro R, Moccia M, et al. Validation of an Italian version of the 40-item University of Pennsylvania Smell Identification Test that is physician administered: our experience on one-hundred and thirty eight healthy subjects. Clin Otolaryngol Dec 26 2013 [in press]. [10] Double KL, Rowe DB, Hayes M, Chan DK, Blackie J, Corbett A, et al. Identifying the pattern of olfactory deficits in Parkinson disease using the brief smell identification test. Arch Neurol 2003;60(4):545–9. [11] Silveira-Moriyama L, Carvalho Mde J, Katzenschlager R, Petrie A, Ranvaud R, Barbosa ER, et al. The use of smell identification tests in the diagnosis of Parkinson's disease in Brazil. Mov Disord 2008;23(16):2328–34. [12] Rodríguez-Violante M, Lees AJ, Cervantes-Arriaga A, Corona T, Silveira-Moriyama L. Use of smell test identification in Parkinson's disease in Mexico: a matched case– control study. Mov Disord 2011;26(1):173–6. [13] Silveira-Moriyama L, Petrie A, Williams DR, Evans A, Katzenschlager R, Barbosa ER, et al. The use of a color coded probability scale to interpret smell tests in suspected parkinsonism. Mov Disord 2009;24(8):1144–53.