Volume 15, Issue 1, Pages 41-46 (January 2009)

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Smoking and tea consumption delay onset of Parkinson's disease

Received 19 July 2007; received in revised form 5 January 2008; accepted 18 February 2008.

Abstract

Cigarette smoking, coffee and tea drinking may protect against Parkinson's disease (PD). These factors were assessed, retrospectively, to measure their effect on the age of PD onset. The study population consisted of 278 consecutive PD patients. Smoking ≥10 pack-years delayed age of PD onset by 3.2 years (p<0.05). Consumption of tea more than 3 cups per day delayed age of motor symptoms onset by 7.7 years (p<0.01). Coffee consumption exceeding 3 cups per day advanced the age of PD onset by 4.8 years (p=0.03). Thus, tea consumption and smoking can delay the age of PD onset, while coffee drinking may have the opposite effect.

Keywords: Parkinson's disease, Coffee, Tea, Smoking, Age of onset, Pack-years, Cup-years, Neuroprotection

Article Outline

• Abstract

• 1. Introduction

• 2. Methods

• 3. Results

• 4. Discussion

• 4.1. Strength of the association

• 4.2. Consistency

• 4.3. Specificity of the association

• 4.4. Temporality

• 4.5. Biological gradient

• 4.6. Biological plausibility and experimental evidence

• Acknowledgment

• References

• Copyright

1. Introduction

An association between smoking and lower prevalence of PD was first noted by Dorn [1], [2] in 1958 and confirmed by Kahn [3] and by Hammond [4]. Subsequent studies [5], [6], [7], [8], [9], [10], [11], [12] supported the conclusion that smoking was associated with decreased prevalence of PD, although several investigators [13], [14], [15], [16], [17], [18] still claimed that the association was spurious and a few groups failed to demonstrate a significant association [19], [20], [21], [22], [23]. Overall, however, most recent studies [24], [25], [26], [27], [28], [29], [30], [31], [32] tend to support that smoking is inversely related to PD.

An association between coffee consumption and PD was also studied. Nefzger et al. [5] observed a higher control percentage of PD patients who avoided drinking coffee. Additional case–control studies mostly confirmed the initial observation [32], [33], [34], [35], [36], [37] with few exceptions [14], [38], [39]. Two recent prospective studies have also found an inverse relationship between coffee consumption and the incidence of PD [40], [41].

Tea consumption was suggested as a third possible protective factor against PD [32], [35], [39], [42] although one study [41] found such an effect only for men but not for women, and another [37] reported tea to be a risk factor.

In a recent study conducted on the same study population as the present report [43] we found that smoking, coffee or tea consumption did not slow down the rate of disease progression in patients with established PD. The overall objective of the present study was to examine whether these variables influence the natural history of PD, with an emphasis on age of motor symptoms onset. Obviously, any factor which delays the age of onset of a disease may reduce the measured prevalence of that disease also because some people may die from other causes before they develop clinical symptoms. Some previous studies mentioned the effect of cigarette smoking and coffee drinking on age of symptoms onset in PD while there are no studies that looked at the effect of tea drinking on this parameter. Among the studies examining the effect of smoking on age of motor symptoms onset, some [6], [7], [12], [14], [16], unexpectedly, found an earlier age of onset (implying a toxic, rather than protective effect of smoking) while others found no effect [19], [25], [28], [36]. Most of these studies compared PD smokers to patients who never smoked. One study compared current smokers with past smokers [28] revealing an earlier age of onset for current smokers. Two studies compared heavy smokers to lighter smokers reporting no difference in one [25] and a delayed age of motor symptoms onset among heavy smokers in the other [28]. The only study that examined the effect of coffee consumption on age of motor symptoms onset [36] found that drinking coffee was associated with delayed age of motor symptoms onset in comparison to patients who never drank coffee.

2. Methods

PD patients were recruited from the Movement Disorders Unit (MDU) in Tel Aviv Sourasky Medical Center. Consecutive patients with a clinical diagnosis of PD were identified through our computerized database. PD was diagnosed according to the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria [44], namely the presence of parkinsonism with all three of the following: (1) no other known cause for the development of parkinsonism (e.g. stroke, head injury, history of encephalitis, absence of neuroleptic treatment six months prior to disease onset, hydrocephalus, brain tumor; (2) no record of unresponsiveness to levodopa at a dose of at least 1g/day combined with carbidopa; and (3) no prominent or early signs (prior to or within a year after motor symptoms onset) of more extensive nervous system involvement (e.g. dementia, apraxia or dysautonomia).

PD motor symptoms onset was defined as the year in which any motor disturbances that later could be attributed to PD were first noticed by the patient, a family relative, or a caregiver as recorded in the medical file. Of 300 consecutive patients, 283 (94%) agreed to participate. Information was collected according to a preformed structured questionnaire with a closed questions format. All subjects were interviewed by one investigator (BK) in a direct manner; 182 patients (64%) during regular visits to the clinic and 96 patients (36%) over the phone. Information was obtained from a first degree relative for subjects with dementia (n=22). Five patients were excluded from the study because close family members could not be contacted, thus leaving a total of 278 patients who had validated answers. To minimize bias, the participants were blinded to the hypothesis being investigated.

Information about tobacco consumption was limited to cigarette smoking. The patients were asked about the number of cigarettes he/she was smoking per day and number of years smoked until PD motor symptoms onset as well as the age of onset and termination of smoking. The number of pack-years (PY) was computed by multiplying the average number of packs per day (cigarettes per day divided by 20) by the number of years smoked.

Analysis of variance (ANOVA) was used to examine the effect of the time that has passed since smoking cessation on age of motor symptoms onset. That is, patients who noticed first motor symptoms of PD before the age of 50 years consisted of one group, patients who developed symptoms between the ages of 51 and 60 constituted a second group and patients who developed PD at 61–70 and above 70 years comprised the third and fourth groups, respectively. For each group the period of time, in years, that has passed since the patient had quitted smoking up to the age of motor symptoms onset was calculated.

For coffee and tea consumption, the number of cups per day (caffeine free or herbal tea drinks were excluded), the duration of drinking prior to PD symptom onset and the age of initiation or termination were noted. Additional information included year of birth and the severity of the disease during the last MDU visit, according to the Hoehn and Yahr (H & Y) scale [45].

To assess the relationship between smoking and coffee or tea drinking to the age of PD onset, linear regression was used [46]. The dependent variable was age of PD motor symptoms onset and the independent variables were smoking, categorized according to PY, coffee or tea consumption, categorized according to number of cups per day, and gender.

The independent variables, that is, smoking, coffee and tea drinking, were categorized in such a way that the number of cases in each category will be similar. Drinking was categorized into three groups: none, <2, 2–3, and >3 cups per day. Cigarette exposure was divided to: none, 1–9 PY, and ≥10 PY.

ANOVA was assessed prior to each analysis of linear regression so as to enable a comparison between the observed and the predicted results. All statistical calculations were performed with the SPSS software. The study was approved by the Tel-Aviv Sourasky Medical Center Ethics Committee.

3. Results

Data of 174 (62.6%) men and 104 (37.4%) women were analyzed. The mean age of the study population was 68.4±10.7 years and age at motor symptoms onset was 58.1±11.3 years to give a mean disease duration of 10.3±5.8 years.

Men and women had similar current age and age at symptoms onset. About 40% of the patients (111/278) had a history of smoking, 90 men and 21 women. The mean age at smoking initiation was 20.3±5.2 years. Among these “ever-smokers” 94% had quit smoking prior to the date of PD onset and only 17 patients (6%) were still smoking at the time of PD motor symptoms onset. Among “ever-smokers”, 49 patients (45%) smoked up to 10 PY. Patients who smoked 10 PY or more (n=62) had their PD motor symptoms onset delayed by 3,2 years compared to never-smokers (p=0.04) (Table 1).

Table 1.

The effect of cigarette smoking on age of motor symptoms onset


Variable	No. of cases	Age of symptoms onset, mean±SD	Ba	95% CI b	Predicted mean age at onset (constant+B)	p-Value
Gender
Female	104	56.9±11.2			56.6
Male	174	58.8±11.4	1.3	−1.3 to 3.9	57.9	0.32

Smoking (pack-years)
0	167	57.2±11.3			56.6
1–9	49	57.1±12.2	−0.7	−3.9 to 2.6	55.9	0.7
≥10	62	61.2±10.4	3.2	0.1–6.3	59.8	0.04

Linear regressions analysis model: pack-years, number of tea cups, number of coffee cups, and gender were included in the model.

Regression coefficient.

CI, confidence interval.

Analysis of tea or coffee consumption revealed that the vast majority of tea or coffee drinkers continued to consume tea or coffee (174/179, 97% tea drinkers, and 151/180, 84% coffee drinkers) during and after PD motor symptoms onset. Thus, we have decided to use values of cups per day and not cup-years in order to avoid a situation in which patients who developed PD at a later age will accumulate tea or coffee cups per year which might deviate the results.

About 64% of the patients (n=179) were, or had been, tea drinkers, 111 men and 68 women. A significant delayed age of motor symptoms onset by 7.7 years was seen among those who drank in excess of 3 cups of tea per day (Table 2).

Table 2.

Effect of coffee and tea consumption on age of PD onset


Variable	No. of cases	Age of symptoms onset, mean±SD	Ba	95% CI b	Predicted mean age at onset (constant+B)	p-Value
Coffee (daily cups)
None	98	59.5±10.6			56.9
<2	80	58±12.0	−1.8	−5.1 to 1.5	55.1	0.29
2–3	65	57.6±12.0	−2.9	−6.4 to 0.7	54.0	0.12
>3	35	55±10.0	−4.8	−9.2 to −0.4	52.1	0.03

Tea (daily cups)
None	99	57.4±12.1			56.9
<2	100	56.7±10.9	−0.5	−3.6 to 2.6	56.4	0.73
2–3	53	58.9±11.2	1.6	−2.1 to 5.4	58.5	0.4
>3	26	64.5±8.2	7.7	2.9–12.6	64.6	< 0.01

Linear regressions analysis model: pack-years, number of tea cups, number of coffee cups, and gender were included in the model. Effect of gender was not significant.

Regression coefficient.

CI, confidence interval.

About 65% of the patients (n=180) were, or had been, coffee drinkers, 122 men and 58 women. An earlier age of PD motor symptoms onset by 4.8 years was evident for coffee drinkers at an amount exceeding 3 cups a day (p<0.01) (Table 2).

The analysis that examined the relationships between the time that has elapsed since smoking cessation and age of motor symptoms onset revealed that except for the group that developed PD symptoms before the age of 50, most smokers quit smoking in their mid-forties. Thus, implying that a later age of motor symptoms onset was not related to accruement of pack-years. In addition, it is evident that the group of PD patients that stopped smoking at a younger age, developed parkinsonian symptoms at an earlier age (Fig. 1).

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Fig. 1 The relationship between mean age of smoking cessation to age of motor symptoms onset.

Chi-square analysis for Fisher's exact test which compared patients who quit or continued smoking before or after the age of 58 has revealed that 32% (14/44) of patients who developed motor symptoms before the age of 58 were still smoking at disease onset and only 12% (8/66) of patients who developed motor symptoms at the age of 58 or above were still smoking at that time (p=0.015).

4. Discussion

Previous studies on the effects of smoking, coffee and tea consumption reported conflicting results. One of the reasons for the confusion can be patients selection and the type of control groups. For example, the diagnosis of parkinsonism is unclear at the initial stages of the disease, and at least 10% of the initially diagnosed PD are later diagnosed differently [47]. In the same line of thought, the control groups could have included people with preclinical stage of PD. In the present study these difficulties were reduced by not having a control group. In addition, the long duration of follow up after our patients in a specialized movement disorders unit minimized diagnostic errors. At the base of the present study is the assumption that a disease modifying factor can affect the prevalence of a disease but also its age of onset.

Since epidemiological study designs can rarely establish causality, the results of the present study will be discussed using Hill's criteria as a framework for concluding causation [48].

4.1. Strength of the association

The delayed age of PD motor symptoms onset among cigarette smokers (≥10 PY) and tea drinkers (>3 cups per day) was statistically significant. The risk effect of coffee consumption (>3 cups per day) was also found to be statistically significant.

4.2. Consistency

This study, unlike most other similar studies, has examined solely PD patients. As was mentioned earlier, most published studies [7], [12], [14], [16], [25], [28], [36] did not find a protective effect of smoking on age of motor symptoms onset. This lack of effect has been used as an argument against disease modifying effect of smoking [15]. In the present study heavy smokers developed PD at a significantly older age. It is possible, though, that older people with PD may simply have had more time to accumulate pack-years. However, our results show that the average age for smoking cessation, regardless of the age at which the patient has developed PD, was in the mid-forties (see Fig. 1). Thus, most patients smoked similar number of years. The large percentage of former smokers (94%) is in line with other studies [39], [49].

To the best of our knowledge, Benedetti et al. [36] was the only group who examined the effect of coffee on age of PD motor symptoms onset. They found that coffee delayed age of onset by 8 years (median age of onset of coffee drinkers was 72 vs. 64 for patients who never drank coffee).

Surprisingly, tea has not been investigated in relation to PD as extensively as coffee, and the present study is the first to report the effect of tea on age of PD motor symptoms onset.

4.3. Specificity of the association

Specificity refers to a situation in which a cause leads to only one outcome, and that outcome results from only one cause. This situation is rarely encountered, though its presence is a strong argument for causality. Since smokers or tea and coffee drinkers are not absolutely protected from PD and since caffeine and especially smoking lead to a variety of other effects, the association found in this study cannot be regarded as truly specific.

The harmful effects of smoking have raised the argument of selective mortality. This argument proposes that since smokers are at increased risk of acquiring serious smoking related diseases, they may not survive long enough to develop PD [5]. The fact that the majority of the smokers in this study were light to moderate smokers (75% smoked up to 20 PY) might stand against the theory of selective mortality. However, it is also possible that some PD patients who were heavy smokers did not survive to enter the present study.

A theory related to selective mortality is the interaction effect on mortality between smoking and PD, that is, smoking confers especially greater mortality in the presence of PD [14]. This theory does not contradict the result of delayed age of onset for smokers found in this study.

4.4. Temporality

The fourth characteristic is the temporal relationship of the association. What came first, the exposure or the disease? In chronic diseases with long latencies, it is not always easy to prove that a possible ‘cause’ actually preceded the disease, potentially leading to a ‘cause and effect’ bias.

Another possible explanation for reduced smoking among PD patients is that of specific personality characteristics of PD patients. That is, subjects with PD exhibit personality differences potentially correlated with an affinity to avoid habituating lifestyle behaviors like smoking [50]. Since we examined the effect of smoking on age of PD motor symptoms onset and not the prevalence of PD among smokers/nonsmokers or the prevalence of smoking, the possibility of personality characteristics would be less relevant here.

4.5. Biological gradient

The fifth criterion states that if the association is one which can reveal a biological gradient or dose–response curve then that would add a great deal to the evidence for causality.

It is evident from our results that cigarette smoking and tea drinking behave as protective factors. Increased consumption yields later age at motor symptoms onset. On the other hand, increased coffee consumption enhanced age of motor symptoms onset. The latter was somewhat an unexpected finding especially in light of the protective effect obtained through tea drinking, since both coffee and tea are sources of caffeine. This might suggest that other components in tea have a protective effect.

4.6. Biological plausibility and experimental evidence

The last point brings up the 2 final criteria of biological plausibility and experimental evidence. Plausible explanations exist for a direct effect of smoking on PD risk, either through relief of PD symptoms or by neuroprotection. Cigarette smoke is known to contain thousands of chemical substances [51], the most studied of which is nicotine. The pharmacologic effects of nicotine in the nigral dopaminergic neurons include stimulation of dopamine release [52], prevention of glutamate-induced neurotoxicity [53], reduced damage caused by MPTP [54], inhibition of free-radical damage [55], and inhibition of monoamine oxidase B [56].

In tea, free-radical scavenging phenolic compounds with potential neuroprotective effect may exist particularly epigallocatechin-3-gallate, which, to the best of our knowledge, is not found in coffee [57], [58], [59], [60].

Caffeine is known to enhance dopamine neurotransmission via antagonism of adenosine receptors, particularly the A2A subtype [61]. The latter is co-localized with dopamine D2 receptors. Stimulation of this adenosine receptor decreases dopamine neurotransmission and reduces the effectiveness of D2 agonists [61]. Although caffeine may be more abundant in coffee than in tea, no protective association for coffee consumption was found, which was somewhat an unanticipated finding, and suggests an effect of other chemicals found in tea and not in coffee, such as the catechins [62].

Our results, then, provide evidence for a ‘causal’ relationship between smoking and tea consumption according to a number of Hill's criteria (strength of the association, dose–response relationship, and biological plausibility), at least to some extent.

The main limitation of this study is reliance on self-report. As a result, misclassification bias should be considered when interpreting the results. The information on age at onset was retrieved from the medical records but are of course not totally accurate, since these are not discrete events and are based on subjective evaluation and recollection. Among the exposures of interest here, data for cigarette smoking were probably most complete since it is easier to remember a past exposure to a variable that is highly associated with a large number of diseases. Pipe and cigar smoke were not recorded in the study since these forms of nicotine consumption are much less common than cigarette smoking. We did not ask about specific types of tea (black, green). A distinction was made, however, between tea with caffeine and “tea” composed of herbs and the latter was disregarded. A joint epidemiological and experimental evidence that distinguishes effects among the specific tea types and component chemicals will be necessary before firmer conclusions can be drawn.

Acknowledgments

We thank Mrs. E. Shabtai and Mr. D. Commaneshter for their statistical support and the National Parkinson Foundation (Miami, USA) for their financial support.

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a Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel

b Department of Neurology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

c Department of Neurology, Sourasky Medical Center, Tel Aviv, Israel

Corresponding author. Department of Physiology and Pharmacology, Sieratzki Chair of Neurology, Tel Aviv University, Ramat Aviv 69978, Israel. Tel.: +972 3 6974229; fax: +972 3 6409113.

PII: S1353-8020(08)00093-X

doi:10.1016/j.parkreldis.2008.02.011

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