Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies

The relationship between smoking and neurological diseases has always been controversial. Even the expected association between smoking and increased risk for cerebrovascular disease has been debated for years. It was at the end of the 1980s that smoking became definitively accepted as a risk factor for ischemic stroke. More recently, two other neurological diseases have been studied in relation to smoking: Parkinson's disease (PD) and Alzheimer's disease (AD). Many epidemiological studies have found a highly significant negative association between cigarette smoking and these two neurodegenerative disorders. The risk of AD or PD in nonsmokers has generally been about twice that of smokers. That is, patients with AD or PD are approximately 50% less likely to have smoked cigarettes during their lifetime than are age- and gender-matched controls. Alternatively, cigarette smokers are 50% less likely to have PD or AD than are age- and gender-matched nonsmokers. This statistically significant negative association has been interpreted as suggesting that cigarette smoking exerts an undefined, biologic, neuroprotective influence against the development of PD and AD. A review of all studies that either support or refute this hypothesis is presented separately for PD and AD.     

Cigarette smoking and Parkinson's disease: a case-control study in a population characterized by a high prevalence of pesticide exposure.

Epidemiological studies have been consistent in showing that cigarette smoking is inversely associated with Parkinson's disease (PD), whereas pesticide use is positively associated with PD. However, the relationship between PD and cigarette smoking remains poorly understood. Our objective was to study the relationship between cigarette smoking and PD in a population characterized by a high prevalence of pesticide exposure. This case-control study was carried out among subjects enrolled in the Mutualite Sociale Agricole, the French health insurance organization for workers connected to the agricultural world. We included 247 cases and 676 controls matched on age, sex, and region of residency. Information on smoking was obtained through in-person interviews. Pesticide exposure was assessed using a case-by-case expert evaluation procedure. We found an inverse relationship between ever cigarette smoking and PD (odds ratio [OR] = 0.6; 95% confidence interval [CI] = 0.4-0.9). The strength of this association increased with the number of pack-years. This relationship was present even when smoking was considered as long as 40 years before PD onset. An inverse association was also present among subjects professionally exposed to pesticides (OR = 0.5; 95% CI = 0.3-0.8) and was independent of the duration of exposure among men. We confirm the inverse association between cigarette smoking and PD in a population characterized by a high prevalence of professional pesticide exposure. The relationship between PD and cigarette smoking was not significantly modified or confounded by exposure to pesticides.     

Voluptuary habits and clinical subtypes of Parkinson's disease: The FRAGAMP case–control study

We evaluated the possible association between smoking, coffee drinking, and alcohol consumption and Parkinson's disease (PD). The FRAGAMP study is a large Italian multicenter case–control study carried out to evaluate the possible role of environmental and genetic factors in PD. Adjusted ORs were estimated using unconditional logistic regression. Smoking, coffee, and alcohol consumption were also considered as surrogate markers of lifestyle and analysis was carried out considering the presence of at least one, two, or three factors. This latter analysis was separately performed considering Tremor‐Dominant (TD) and Akinetic‐Rigid (AR) patients. Four hundred ninety‐two PD patients (292 men and 200 women) and 459 controls (160 men and 299 women) were enrolled in the study. Multivariate analysis showed a significant negative association between PD and cigarette smoking (OR 0.51; 95%CI 0.36–0.72), coffee drinking (OR 0.61; 95%CI 0.43–0.87) and wine consumption (OR 0.62; 95%CI 0.44–0.86); a significant trend dose‐effect (P < 0.05) has been found for all the factors studied. We have also found a trend dose‐effect for the presence of at least one, two or three factors with a greater risk reduction (83%) for the presence of three factors. However, a different strength of association between TD and AR was found with a greater risk reduction for the AR patients. We found a significant inverse association between PD smoking, coffee, and alcohol consumption. When analysis was carried out considering the association of these factors as possible surrogate markers of a peculiar lifestyle the association was stronger for the AR phenotype. © 2010 Movement Disorder Society.     

Poor metabolization of n-hexane in Parkinson's disease

Although genomic screening studies have identified several genes associated with Parkinson's disease (PD), there is evidence that environmental factors are also involved in the pathogenesis of the disease and that hydrocarbon-solvents may be one of them. The genetic component is less evident in late-onset PD. To assess whether age and PD may affect the catabolism of the hydrocarbon n-hexane, a two-part study was performed. In the first part the urinary levels of its main metabolites, 2,5-hexanedione and 2,5-dimethylpyrroles, were measured in 108 patients and 108 healthy controls, matched by age and sex. Metabolite urinary excretion was significantly reduced in PD patients as compared with controls and was inversely related to age in both groups. In the second part the same comparison was made between 24 non-smoking and 10 smoking patients, matched to controls, after smoking of a hydrocarbon-rich cigarette. In these subjects also n-hexane and 2,5-hexanedione blood levels were measured. There was no appreciable difference in n-hexane blood levels between patients and controls in non-smokers, whereas there was a significant increase in patients over controls in smokers (p < 0.01). 2,5-hexanedione blood levels were significantly lower in patients than in healthy controls, both in non-smokers and in smokers, but the reduction was more pronounced in smokers (−46.3 % versus −10.7 %). The same was true for 2,5-hexanedione and 2,5-dimethylpyrrole urinary levels. This study suggests that aging and PD may be associated with a reduction in the capacity to eliminate the hydrocarbon n-hexane. This metabolic alteration may play a role in the pathogenesis of PD. Received: 18 March 2002, Received in revised form: 9 October 2002, Accepted: 29 November 2002 Funding: Fondazione Grigioni per il Morbo di Parkinson Associazione Italiana Parkinsoniani. Correspondence to Gianni Pezzoli     

Alpha-synuclein mRNA expression in sporadic Parkinson's disease.

The expression of alpha-synuclein gene can be influenced by the genomic load and/or epigenetic factors. By using quantitative real-time polymerase chain reaction techniques, we demonstrated that the alpha-synuclein gene mRNA expression in sporadic PD did not differ from healthy controls (median [range] 0.110 ]0.012-0.628] vs. 0.120 [0.028-0.447]; P = 0.15). There was no difference in the alpha-synuclein gene dosage between PD patients with high and low mRNA expression. Multivariate analysis did not reveal age, gender, or cigarette smoking as confounding variables. Our study suggests that there was no significant alteration of alpha-synuclein mRNA expression in our sporadic PD patients compared to controls. However, the role of alpha-synuclein mRNA expression in select groups of sporadic PD patients and its interaction with environmental agents need to be further determined.     

Smoking and cognitive function in Parkinson's disease.

The risk of dementia among Parkinson's disease (PD) patients is greatly elevated compared to controls, yet little is known about determinants of cognitive function among PD patients. We assessed the relation between cigarette smoking prior to disease onset and later cognitive function among PD patients (n = 286) and age- and sex-matched controls (n = 1144) participating in the Nurses' Health Study and Health Professionals Follow-up Study. Both groups completed telephone-administered assessments of cognitive function. We used linear regression to calculate mean differences in cognitive test scores across smoking categories, adjusted for age, education, sex, age at onset of PD, and years since diagnosis. PD patients scored significantly worse on all tests than their matched controls. In analyses only among PD cases, but not among controls, current smokers at PD onset scored worse than never smokers on the Telephone Interview for Cognitive Status (difference = -0.82, 95% CI: -1.33, -0.30, P = 0.002) as well as on a global score combining results of all tests (difference = -0.36, 95% CI: -0.72, 0.01, P = 0.06). This difference was equivalent to the difference in global score observed among controls approximately 10 years apart in age. Analyses of pack-years of smoking prior to disease onset gave similar results. These findings, nested in prospective cohort studies, suggest that cigarette smoking prior to disease onset is associated with worse cognitive function in PD.     

Dose-dependent protective effect of coffee, tea, and smoking in Parkinson's disease: a study in ethnic Chinese

INTRODUCTION: Few studies have examined the relationship of coffee and tea in Parkinson's disease (PD). The potential protective effect of coffee intake and risk of PD has not been studied in a Chinese population. There is a high prevalence of caffeine takers among Chinese in our population. OBJECTIVE: We undertook a case control study to examine the relationship between coffee and tea drinking, cigarette smoking, and other enviromental factors and risk of PD among ethnic Chinese in our population. METHODS AND RESULTS: 300 PD and 500 population controls were initially screened. Two hundred case control pairs matched for age, gender, and race were finally included in the analysis. Univariate analysis revealed significant association of PD with coffee drinking (p<0.0005), tea drinking (p=0.019), alcohol drinking (p=0.001), cigarette smoking (p<0.0005), and exposure to heavy metals (p=0.006). Conditional logistic regression analysis demonstrated that amount of coffee drunk (OR 0.787, 95%CI 0.664-0.932, p=0.006), amount of tea drunk (OR 0.724, 95%CI 0.559-0.937, p=0.014), number of cigarettes smoked (OR 0.384, 95%CI 0.204-0.722, p=0.003), history of heavy metal and toxin exposure (OR 11.837, 95%CI 1.075-130.366, p=0.044), and heart disease (OR 5.518, 95%CI 1.377-22.116, p=0.016) to be significant factors associated with PD. One unit of coffee and tea (3 cups/day for 10 years) would lead to a 22% and 28% risk reduction of PD. One unit of cigarette smoke (3 packs/day for 10 years) reduced the risk of PD by 62%. CONCLUSIONS: We demonstrated a dose-dependent protective effect of PD in coffee and tea drinkers and smokers in an ethnic Chinese population. A history of exposure to heavy metals increased the risk of PD, supporting the multifactorial etiologies of the disease.     

Cigarette smoking in Parkinson's disease: Influence on disease progression

Previous studies have shown an inverse association between smoking and the prevalence of Parkinson's disease (PD), suggesting that smoking may induce a biological protection against nigral neuronal damage. In 1993, we examined the frequency of cigarette smokers among 239 patients with PD and two control groups. In addition, the progression of parkinsonism and other clinical features were followed prospectively in smoking and nonsmoking PD patients over an 8‐year period. Mortality in the two PD groups was also examined. We found a 50% higher prevalence of smokers in the control groups than in patients with PD. In contrast, during the follow‐up period, there were no significant differences in progression of parkinsonism, cognitive impairment, and mood in smoking and nonsmoking patients with PD. Mortality was also similar in the two groups. The lack of influence on disease progression may indicate that cigarette smoking does not have a major neuroprotective effect in patients with already diagnosed PD. © 2004 Movement Disorder Society     

A case-control study on cigarette,alcohol, and coffee consumption preceding Parkinson's disease

OBJECTIVE: To investigate the association between cigarette smoking, alcohol drinking, coffee consumption and Parkinson's disease (PD). METHODS: We selected subjects affected by idiopathic PD, with a Mini-Mental State Examination of > or =24, and controls matched 1 to 1 with cases by age (+/- 2 years) and sex. Controls were randomly selected from the resident list of the same municipality of residence of the cases. We assessed cigarette smoking, alcohol drinking, and coffee consumption preceding the onset of PD or the corresponding time for controls using a structured questionnaire, which also evaluated the duration and dose of exposure. Using conditional logistic regression analysis, we calculated adjusted OR and 95% CI. RESULTS: We interviewed 150 PD patients and 150 matched controls. Cigarette smoking (ever vs. never smokers OR = 0.66, 95% CI = 0.41-1.05, p = 0.08) did not show a statistically significant association with PD. We observed an inverse association between alcohol drinking (ever vs. never OR = 0.61, 95% CI = 0.39-0.97, p = 0.037) and coffee consumption (ever vs. never OR = 0.16, 95% CI 0.05-0.46, p = 0.0001) and PD. These associations remained significant after adjustment for other covariates: OR for ever vs. never alcohol consumption was 0.62 (95% CI = 0.43-0.89, p = 0.009) and that for coffee drinking 0.19 (95% CI = 0.07-0.52, p = 0.001). Heavy coffee consumption confirmed the inverse association between coffee and PD (more than 81 cup/year vs. none: OR = 0.20, 95% CI = 0.08-0.47, p < or = 0.0001). CONCLUSIONS: Consistent with previous studies, our results suggest an inverse association between coffee drinking, alcohol consumption and PD. The multiple inverse association observed may indicate a complex interaction between genetic and environmental factors.     

Differential effect of environmental risk factors on postural instability gait difficulties and tremor dominant Parkinson's disease

Both environmental and genetic factors contribute to the development of Parkinson's disease (PD). We have examined environmental risk factors in a Norwegian population of incident PD patients and controls, the Norwegian ParkWest study. All five neurological wards in the study area of Western Norway participated in the study. A 4‐step diagnostic procedure was used to establish a representative cohort of patients with incident PD at a high level of diagnostic accuracy. 212 incident PD patients and 175 age‐ and gender‐matched controls were included. PD patients and controls were asked for information on occupation, education, exposure to pesticides, tobacco, alcohol, and caffeine. Agricultural work was associated with a higher risk of PD (OR 1.75 (1.03–3.0) P = 0.009). There were no differences as to other occupations. Smoking (OR 0.63 (0.42–0.95) P = 0.016) and alcohol use (OR 0.55 P = 0.008) were associated with a lower risk for PD. Interestingly, this inverse association was only seen in postural instability gait difficulties (PIGD) PD (P = 0.046 for smoking, P = 0.07 for alcohol consumption), and not in tremor dominant (TD) PD which was similar to controls. Consumption of coffee was lower in PD patients (3.3 ± 1.8 cups per day vs. 3.8 ± 2.0 in controls P = 0.02). In the regression model including intake of alcohol, coffee, and smoke, only coffee (P = 0.007) and alcohol intake (P = 0.021) remained significant whereas smoking was no longer significant. Thus, it seems as though only coffee intake reduces the risk of PD in general while associations to alcohol and smoking differ between PIGD and TD‐PD patients. © 2010 Movement Disorder Society     

Combined effects of smoking,coffee, and NSAIDs on Parkinson's disease risk

Inverse associations of Parkinson's disease (PD) with cigarette smoking, coffee drinking, and nonsteroidal anti‐inflammatory drug (NSAID) use have been reported individually, but their joint effects have not been examined. To quantify associations with PD for the individual, two‐way and three‐way combinations of these factors, a case–control association study with 1,186 PD patients and 928 controls was conducted. The study setting was the NeuroGenetics Research Consortium. Subjects completed a structured questionnaire regarding smoking, coffee, and NSAID consumption. Odds ratios were calculated using unconditional logistic regression. Smoking, coffee, and over the counter NSAID use as individual factors exhibited significantly reduced risks of 20% to 30%. The two‐way and three‐way combinations were associated with risk reduction of 37% to 49%, and 62%, respectively. Smoking and coffee exhibited significant inverse risk trends with increasing cumulative exposures, suggesting dose–response relations. With respect to the combination of all three exposures, persons who were at the highest exposure strata for smoking and coffee and used NSAIDs had an estimated 87% reduction in risk (OR = 0.13, 95% CI = 0.06–0.29). Whether this finding reflects true biologic protection needs to be investigated. © 2007 Movement Disorder Society     

Parkinson's disease, smoking and family history

There is growing evidence that both genetic and environmental factors play a role in the etiology of Parkinson's disease (PD). The hypothesis of an interaction between genetic and environmental risk factors has been little explored, and never using a population-based case-control study design. Our objective was to investigate the possible interaction between smoking and family history in the etiology of PD, as a part of a collaborative population-based case-control study. We included 149 nondemented PD patients ascertained in three European prevalence surveys using a two-phase design. Each patient was matched by age (±2 years), gender, and center to three controls drawn from the same populations (n=375). Presence of PD among first-degree relatives and smoking history were assessed through an interview for 127 cased and 306 controls. In the overall sample we found suggestive evidence that family history and eversmoking interact in determining the risk of PD (P=0.09), with individuals exposed to both risk factors having the highest risk (OR=10.0; 95% CI=2.0–49.6). Analyses were repeated after stratification into two age-groups (cutoff: 75 years). In older patients, the joint exposure to both risk factors was associated with a significant increase in the risk of PD (OR=17.6; 95% CI=1.9–160.5). Among younger subjects, the OR for joint exposure was not significant. In conclusion, our findings suggest that smoking and family history interact synergistically on a multiplicative scale in determining the risk of PD in individuals older than 75 years. Received: 28 January 2000 / Received in revised form: 1 May 2000 / Accepted: 28 May 2000     

Maternal effect on Parkinson's disease

First-degree relatives of patients with Parkinson's disease (PD) are at higher risk for PD development than first-degree relatives of control subjects, but clinical twin studies have failed to demonstrate a genetic basis in PD. It is hypothesized that maternal exposure to certain environmental factors could lead to pathological changes in the ovum that predispose to the development of PD in the child. In this study of 299 patients and 295 controls, the age at onset of PD was found to correlate negatively with maternal age at birth of patient but not with paternal age. Mothers and fathers of patients with PD had an increased risk of PD as compared with parents of control subjects. These results suggest a maternal effect on PD that could be primarily environmental in nature.     

Risk factors of Parkinson's disease in Indian patients

Epidemiological data on risk factors of Parkinson's disease (PD) are not available from India. In a case control study, we investigated environmental and genetic risk factors in the etiology of idiopathic Parkinson's disease. Three hundred seventy-seven patients of Parkinson disease (301 men, 76 women, mean±SD age 56.78±11.08 years) and equal number of age matched (±3 years) neurological controls (271 men, 106 women, mean±SD age 56.62±11.17 years) were included in the study. Conditional logistic regression model was used to determine the risk factors of PD. We found that male gender, family history of Parkinson's disease, past history of depression of up to 10-year duration and well water drinking of more than 10-year duration were significantly associated with occurrence of Parkinson's disease, whereas tobacco smoking of up to 20-year duration and exposure to pets had protective effect. However, tobacco smoking of more than 20-year duration, well water drinking of up to 10-year duration, vegetarian dietary habit, occupation involving physical exertion, rural living, farming, exposure to insecticides, herbicides, rodenticides, alcohol intake and family history of neurodegenerative diseases had no significant correlation with occurrence of PD in the patient population studied. Results of our study support the hypothesis of multifactorial etiology of PD with environmental factors acting on a genetically susceptible host.     

CYP450, genetics and Parkinson's disease: gene x environment interactions hold the key

The ecogenetic theory contends that most cases of Parkinson's disease (PD) result from the actions of environmental factors in genetically susceptible individuals on a background of normal ageing. This notion is supported by epidemiologic data; family history of PD and exposures to environmental toxins such as pesticides increase risk, while cigarette smoking reduces risk. As a result, polymorphic genes that code for metabolic enzymes have been considered as candidates for conferring differential risk for PD. Given their prominence in xenobiotic metabolism, the cytochrome P450 (CYP) genes have come under great scrutiny. The activity of CYP2D6 is largely determined by genetic variability and common sequence variants exist in human populations that lead to poor metaboliser (PM) phenotypes. These have been extensively studied as genetic risk factors for PD with inconsistent results. However, these studies have disregarded interactive effects (e.g. gene x environment interactions) despite the assertions of the ecogenetic theory. Data from our group and others suggest that the CYP2D6 PM genotype interacts with certain environmental factors such as pesticide exposure and cigarette smoking to confer differential risk for PD. Previous failure to consider such interactions might, in part, explain the inconsistencies observed in the CYP2D6 genetic risk-factor literature. Our data illustrate, using CYP2D6 as an exemplar, that it is crucial to consider both genetic and environmental factors, and their interactions, in any examination of risk factors for PD.     

The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients

While the cause of Parkinson's disease (PD) remains unknown, recent evidence suggests that certain external factors, ie, environmental agents, may act as neurotoxins, initiating the chain of oxidative reactions that ultimately destroy neurons in the substantia nigra. Young-onset PD might result from greater exposure to a putative neurotoxin. This hypothesis has rekindled interest in the epidemiology of PD. We therefore conducted a detailed analysis of various environmental exposures and early life experiences in 80 patients with old-onset PD (at an age older than 60 years), 69 young-onset patients (younger than 40 years), and 149 age- and sex-matched control subjects. Contrary to previous reports, we were unable to implicate well water or exposure to herbicides, pesticides, or industrial toxins as significant PD risk factors. A residential history of rural living was reported by more patient cases than control subjects and was marginally significant. On the other hand, at least one episode of head trauma "severe enough to cause vertigo, dizziness, blurred or double vision, seizures or convulsions, transient memory loss, personality changes, or paralysis" occurred significantly more often prior to disease onset in patients with both young-onset and old-onset PD than in control subjects (odds ratio = 2.7). When adjusted for head trauma and rural living, smoking was inversely associated with PD, as has been previously reported (odds ratio = 0.5). There were no significant differences in early life experiences or environmental exposures between young-onset and old-onset patients. We suggest that the risk of developing PD is influenced by a variety of factors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidemiologic studies of environmental exposures in Parkinson's disease

Parkinson's disease (PD) is the most common cause of the parkinsonian syndromes and the most frequent neurodegenerative disease after Alzheimer's disease. Because of the ageing of Western populations, an increasing number of persons will be affected with PD in the future and neither curative treatments nor preventive measures have been identified. PD is considered as a multifactorial disease, resulting from the effect of environmental factors and genetic susceptibility. Increasing age and male sex appear to be associated with an increased risk of PD. In addition, recent epidemiological studies have identified environmental exposures that influence the risk of PD. This review provides an overview of the epidemiologic evidence for environmental etiologies in PD; we will focus on two environmental exposures that have been quite consistently associated with PD -- cigarette smoking and pesticide exposure -- and will summarize briefly the findings for other exposures. Understanding the mechanisms underlying these epidemiological associations is an essential step for the understanding of the etiology of this neurodegenerative condition and, ideally, to develop neuroprotective drugs.     

The effect of cigarette smoking, tea, and coffee consumption on the progression of Parkinson's disease

Previous epidemiological studies found a negative association between cigarette smoking, tea or coffee drinking with the occurrence of Parkinson's disease (PD). However, it is unknown how these factors affect the rate of progression of the disease. A retrospective study was conducted among 278 consecutive PD patients. Data on smoking and coffee or tea consumption were obtained through direct or proxy interviews, and the time from onset of motor symptoms until reaching Hoehn & Yahr (H&Y) stage 3 was retrieved from the case records. Cox proportional hazards model and Kaplan-Meyer model were used to estimate whether the dependent variables (smoking, drinking coffee or tea) affect the rate of progression of the disease, which was measured by the time it took patients to reach H&Y stage 3. We found that disease progression was not affected by cigarette smoking, tea or coffee consumption. The present study suggests that these variables do not have a disease modifying effect in already diagnosed PD patients.     

Occupational and environmental risk factors for Parkinson's disease

The etiology of Parkinson's disease (PD) remains obscure. Current research suggests that a variety of occupational and environmental risk factors may be linked to PD. This paper provides an overview of major occupational and environmental factors that have been associated with the development of PD and tries to assess current thinking about these factors and their possible mechanisms of operation. While clear links to rural living, dietary factors, exposure to metals, head injury, and exposure to infectious diseases during childhood have not been established, there is general agreement that smoking and exposure to pesticides affect the probability of developing PD.     

A case-control study of twin pairs discordant for Parkinson's disease: a search for environmental risk factors

A previous study of twins with Parkinson's disease (PD) revealed low concordance, suggesting that genetic factors play a minor role in the etiology of PD. To identify possible environmental determinants of PD while maximally controlling for hereditary factors, 31 monozygotic twin pairs discordant for PD were interviewed by telephone. Information about possible risk factors was obtained from systematic and uniform interviews with cases and controls. The only statistically significant result was less cigarette smoking by PD patients (p less than 0.05). Thirteen dizygotic discordant twin pairs were evaluated with the same techniques, but there were no statistically significant differences between affected and unaffected twins.