Smoking, alcohol, and coffee consumption preceding Parkinson’s disease
A case-control study
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Abstract
Objective: To study the association of PD with preceding smoking, alcohol, and coffee consumption using a case-control design.
Methods: The authors used the medical records linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, during the years 1976 to 1995. Each incident case was matched by age (±1 year) and sex to a general population control subject. The authors reviewed the complete medical records of cases and control subjects to abstract exposure information.
Results: For coffee consumption, the authors found an OR of 0.35 (95% CI = 0.16 to 0.78, p = 0.01), a dose–effect trend (p = 0.003), and a later age at PD onset in cases who drank coffee compared with those who never did (median 72 versus 64 years; p = 0.0002). The inverse association with coffee remained significant after adjustment for education, smoking, and alcohol drinking and was restricted to PD cases with onset at age <72 years and to men. The OR for cigarette smoking was 0.69 (95% CI = 0.45 to 1.08, p = 0.1). The authors found no association between PD and alcohol consumption. Extreme or unusual behaviors such as tobacco chewing or snuff use and a diagnosis of alcoholism were significantly more common in control subjects than cases.
Conclusions: These findings suggest an inverse association between coffee drinking and PD; however, this association does not imply that coffee has a direct protective effect against PD. Alternative explanations for the association should be considered.
The hypothesis that smoking is inversely associated with PD has been tested in numerous studies.1 In almost all reports, the OR (or the relative risk) was <1, and in the majority of studies, the reduction in risk was significant. This inverse association has been interpreted in several ways and remains controversial.1-3⇓⇓ An inverse association between coffee and PD was reported by several authors.4-7⇓⇓⇓ Other studies showed an inverse association between alcohol consumption and PD.7-9⇓⇓ This pattern of inverse associations with smoking, alcohol, and coffee consumption may suggest that these substances do not have a protective effect on the risk of PD but rather are markers of another underlying risk factor (secondary association).10
We hypothesize that individuals predisposed to develop PD have a premorbid personality manifesting early in life, which leads them to avoid the use of substances that cause dependence, are negatively sanctioned by society, or may jeopardize health, such as tobacco, alcohol, and coffee.1 In addition, we postulate that this personality leads them to refrain from extreme behaviors such as substance abuse (alcoholism, acute intoxication, etc). Several authors have described a characteristic personality of patients who later develop PD as moralistic, law-abiding, conscientious, orderly, and cautious.11-14⇓⇓⇓ These personality traits can be combined into the concept of “reduced novelty seeking.”13,15,16⇓⇓ Novelty-seeking behavior has been linked to substance use and addiction17 and in turn has been found to be less common in PD cases than in control subjects.13,16⇓
We tested this premorbid personality hypothesis through a population-based case-control study of smoking, alcohol, and coffee consumption in PD. Key features of this study based on a records linkage system (see below) were the inclusion of incident cases of PD and control subjects from a defined population and the access to historical documentation of smoking, alcohol, and coffee consumption.
Methods.
Cases.
We used the medical records linkage system of the Rochester Epidemiology Project to identify all subjects residing in Olmsted County, MN, who developed PD in the period 1976 to 1995.18 Medical care for the population of Olmsted County is provided primarily by the Mayo Clinic and its affiliated hospitals. Additional care providers include a smaller independent clinic and affiliated hospital (the Olmsted Medical Center), a state psychiatric hospital (closed in 1981), three independent practitioners, several nursing homes, and several out-of-county hospitals. All these providers participate in the Rochester Epidemiology Project, which provides the infrastructure for indexing and linking essentially all medical information of the county population.19,20⇓ The indexing of medical diagnoses and surgical interventions is based on the International Classification of Diseases, Adapted Code for Hospitals (H-ICDA).21 We ascertained potential cases of parkinsonism by searching the indexes for 53 H-ICDA diagnostic codes.21 Further details about the study population and the identification of incident cases were reported elsewhere.18 Note that we previously reported incidence data from this population for the 15 years from 1976 to 1990,18 whereas the present study extends for 5 more years through 1995 (a total of 20 years of incidence).
Our diagnostic criteria included two steps: the definition of parkinsonism as a syndrome and the definition of PD within the syndrome. Parkinsonism was defined as the presence of two of four cardinal signs: rest tremor, bradykinesia, rigidity, and impaired postural reflexes. PD was defined as the presence of parkinsonism with all three of the following: 1) no secondary cause (e.g., repeated stroke with step-wise progression, repeated head injury, history of encephalitis, neuroleptic treatment within 6 months before onset, hydrocephalus, brain tumor); 2) no documentation of unresponsiveness to levodopa at doses of at least 1 g/day in combination with carbidopa (applicable only to patients who were treated); 3) no prominent or early (within 1 year of onset) signs of more extensive nervous system involvement (e.g., dementia or dysautonomia) not explained otherwise.18 Onset of PD was defined as the year in which one of the four cardinal signs of PD was first noted by the patient, by family members, or by a care provider (as recorded in the medical record).
Control subjects.
Each case was individually matched by age (±1 year) and sex to a general population control subject residing in Olmsted County, MN, and free of PD, other parkinsonism, or tremor of any type in the index year (year of onset of PD in the matched case). The list of all county residents from which potential control subjects were drawn was provided by the records linkage system and was based on the enumeration of all individuals in contact with the system at least once in the 3 years following the index year.20 This enumeration of the total Olmsted County population at any given point in time has been shown to be complete by comparison with a random digit dialing telephone sample22 and by comparison with the census.23 Therefore, our control subjects were not selected through their diseases or health conditions, but rather on the basis of their residency status. Potential control subjects were selected randomly among all residents fulfilling the matching criteria. Records of potential control subjects were reviewed by a neurologist to exclude the presence of PD, other type of parkinsonism, or tremor of any type before or at the index year. Whenever a potential control was excluded because of parkinsonism or tremor or because county residency in the index year was not confirmed at record review, the next random choice was considered. The presence of dementia or other neurologic diseases was not an exclusion criterion. Because cases and matched control subjects were recruited over a 20-year period, it was possible that a person selected as a control subject at one point in time (index year) would later develop PD and be eligible for inclusion as a case in the study.24 Although we allowed for that possibility, it did not occur.
Reliability of case or control classification.
As part of an ongoing genetic and epidemiologic study, we are inviting all surviving PD cases and control subjects involved in the present study to come to the Department of Neurology at the Mayo Clinic for a standardized evaluation by one of three movement disorders specialists. Subjects willing to be examined but unable to travel are examined at their house (or institution). Presence or absence of PD or of parkinsonism is assessed without access to the medical record maintained in the records linkage system. As of March 1, 2000, we contacted 94 of the 196 cases; among those not contacted, 85 were deceased at the time of the study, and 17 are pending contact. Of these 94 cases, 53 underwent the examination. Fifty-two cases of PD were found to fulfill our diagnostic criteria for PD (98%); however, one case fulfilled the criteria for parkinsonism, but the diagnosis by type remained uncertain (2%). We also contacted 109 of the 196 control subjects; among those not contacted, 71 were deceased at the time of the study, and 16 are pending contact. Of these 109 control subjects, 56 underwent the examination. None of the control subjects examined were found affected by PD or parkinsonism, except for one who developed PD ∼7 years after the index year (and after 1995).
Exposure ascertainment.
The complete medical dossiers of cases and control subjects were reviewed by a neurologist to abstract information about smoking, alcohol, and coffee consumption preceding the onset of PD motor symptoms (or the index year for control subjects). Information about tobacco consumption included cigarette smoking, pipe smoking, cigar smoking, and tobacco chewing or snuff use. For cigarette smoking, we obtained information on number of cigarettes per day and number of years smoked. Whenever the number of cigarettes per day varied over time, we computed an average number of cigarettes per day (weighted by duration). If, for example, a man smoked 20 cigarettes/day between age 18 and 25, 30 cigarettes/day between age 26 and 40, and 10 cigarettes/day between age 41 and 72, the weighted average was ∼17 cigarettes/day for 55 years. Pack–years were directly abstracted from the record when available or computed by multiplying the average number of packs per day (cigarettes per day divided by 20) times the number of years smoked.
Information about alcohol consumption was collected with an attempt to define the amount of intake. However, because quantitative information was not homogeneously available in medical records, we used approximate doses such as “heavy,” “moderate,” and “light” or approximate frequencies of consumption such as “regular,” “occasional,” and “rare.” We also abstracted diagnoses of alcoholism.
For coffee consumption, we collected information about number of cups per day. Whenever the number of cups per day varied over time, we computed an average dose (weighted by duration) as described above for smoking.
Reliability of exposure information.
We assessed the reliability of information about cigarette smoking and other tobacco consumption obtained at medical record review (in the records linkage system) by interviewing a subsample of cases and control subjects. As part of an ongoing study, we conducted an independent telephone interview with a total of 199 individuals (88 direct interviews and 111 interviews with a proxy informant). Two proxy informants and one subject interviewed directly were unable to provide information about tobacco use; of the remaining 196 medical record–interview pairs, 91% (178/196) were in agreement about cigarette smoking ever versus never (91 negative and 87 positive agreements). However, the record documented cigarette smoking but the telephone interview missed it for 14 individuals (7%), and the interview yielded a positive response but the record did not contain the information for 4 subjects (2%). Agreement was also good for pipe smoking (89%), cigar smoking (90%), and tobacco chewing or snuff use (98%). Unfortunately, a similar reliability study was not possible for alcohol or coffee consumption because these two habits were not included in the telephone interview.
Data analysis.
Consistent with the matched design, matched pairs analyses were performed, and the OR was used to estimate the relative risk. For each study variable, we calculated an OR, a 95% CI, and a p value (two-tailed test, α = 0.05) using conditional logistic regression.24,25⇓ For primary analyses, we considered habits as ever versus never. For cigarette smoking, we also analyzed separately past and current smoking. Dose–effect contrasts were investigated for number of cigarettes per day, number of years smoked, number of pack–years (of cigarettes), and number of cups of coffee per day. Individuals missing information about a given exposure or dose were excluded from the corresponding analysis. Frequencies of missing information in cases and control subjects were compared using Fisher’s exact tests.
Conditional logistic regression models were used to investigate the independent effect of a risk or protective factor after adjustment for one or several other factors or to adjust for confounding variables (e.g., education). Whenever variables were dichotomized or polychotomized, the cutoffs were derived from the pooled distribution of cases and control subjects (e.g., using the median, tertiles, or quartiles). We also used a conditional logistic regression model to adjust for two additional putative risk factors for PD found in this same data base and reported elsewhere: anxiety disorders (ever versus never) and depressive disorders (ever versus never).26
Because we found consistently higher incidence rates of PD in men than women of all ages in this same Olmsted County population,18 we reanalyzed our data for men and women separately. In addition, because of the possible role of genetic factors in early-onset PD27 and the possible age-dependent effect of smoking on PD,3 we reanalyzed our data stratifying the cases by age at onset of PD in four quartiles. The effect of coffee on age at onset of PD among cases was explored using direct displays of data and box plots.28
Results.
We found 202 patients with onset of PD in the period 1976 to 1995, and these cases were matched by age and sex with 202 control subjects. However, six subjects (five cases and one control subject) did not authorize the use of their medical records for research and the corresponding pairs could not be studied. Therefore, we included 196 case-control pairs for a total of 392 subjects. Of the cases, 121 were men (62%) and 75 were women (38%); the median age at onset of PD was 71 years (range 41 to 97 years). Because of the matching, the distribution by age and sex was similar in control subjects. We investigated the duration of enrollment in the records linkage system for cases and control subjects; the median enrollment time was 51 years (range 8 to 87 years) for cases and 51 years (range 8 to 88 years) for control subjects (rank sum test, p = 0.5).
The numbers of cases and control subjects excluded from each of the analyses because of missing data are reported in tables 1, 2, and 3⇓⇓ (see footnotes). For smoking, information was missing for none of the cases and only 1% of control subjects; however, information on pack–years was missing for 15% of cases (14/94 smokers) and 21% of control subjects (23/107 smokers). For alcohol consumption, information was missing for 1% of cases and 4% of control subjects. For coffee consumption, information was missing for 9% of cases and 11% of control subjects; in addition, the dose was unknown for 15% of cases (22/147 coffee drinkers) and for 23% of control subjects (37/161 coffee drinkers). None of these percentages of missing information were significantly different in cases and control subjects.
Table 1 summarizes our case-control analyses for cigarette smoking and other tobacco consumption. Cigarette smoking (ever versus never) was less common in cases than control subjects; however, this difference did not reach significance (OR = 0.69, 95% CI = 0.45 to 1.08). The OR was similar after adjustment for education, coffee drinking, and alcohol drinking and when considering smoking as past versus never. Dose–effect contrasts were made for number of cigarettes per day, number of years smoked, and pack–years smoked; none of the trends was significant. The inverse association between smoking and PD (suggestive but not significant) was restricted to PD cases with onset below age 79 years; however, we did not find a consistent trend of increasing risk with increasing age when using four age strata. Men and women had similar OR. The age at onset of PD was similar in PD cases who ever smoked (median 70 years, range 42 to 91 years) and in PD cases who never smoked (median 71.5 years, range 41 to 97 years). Pipe and cigar smoking were equally common in cases and control subjects; however, tobacco chewing or snuff use was significantly more common in control subjects than cases (OR = 0.18, 95% CI = 0.04 to 0.82).
Association between PD and cigarette smoking or other tobacco consumption in 196 cases and 196 control subjects, Olmsted County, MN, 1976–1995
Table 2 summarizes our case-control analyses for alcohol drinking. Our findings are negative overall, when considering age and sex strata and when adjusting for other exposures or confounders. However, control subjects were diagnosed with alcoholism significantly more frequently than cases (OR = 0.41, 95% CI = 0.19 to 0.89).
Association between alcohol drinking and PD in 196 cases and 196 controls: Olmsted County, MN, 1976–1995
Table 3 summarizes our case-control analyses for coffee consumption. Coffee drinking was significantly more common in control subjects than cases (OR = 0.35, 95% CI = 0.16 to 0.78), and the magnitude of the association remained unchanged after adjustment for education. In addition, we found a significant trend of decreasing risk with increasing number of cups per day (figure 1). Coffee drinking and smoking were often present in the same subjects (48% of all cases and control subjects pooled); however, coffee drinking remained significantly associated with PD after adjustment for cigarette smoking (ever versus never), alcohol drinking (ever versus never), and education (OR = 0.34, 95% CI = 0.13 to 0.87). At subgroup analyses, the association was restricted to PD cases with onset below age 72 years and to men (table 3). Onset of PD occurred at significantly later ages in PD cases who drank coffee (median 72 years, range 42 to 97 years) compared with PD cases who never drank coffee (median 64 years, range 41 to 80 years) (figure 2).
Association between PD and coffee consumption in 196 cases, 196 controls: Olmsted County, MN, 1976–1995
Figure 1. Dose–effect trend for number of cups of coffee consumed per day (p = 0.003).
Figure 2. Distribution of the age at onset of PD among cases who were exposed to coffee drinking (ever) and cases who were not (never). (A) Direct display of data. Each dot represents the age at onset in a particular case. The asterisk indicates the median. (B) Box plot representation.28 Dots outside the inner fences represent outliers. Rank sum test, p = 0.0002.
A multivariate model including not only smoking (ever versus never), coffee drinking (ever versus never), alcohol drinking (ever versus never), and education (four quartiles) but also anxiety disorders (ever versus never) and depressive disorders (ever versus never) was built. The magnitude of the associations was almost unchanged after adjustment: coffee drinking, OR = 0.32, 95% CI = 0.12 to 0.86; alcohol drinking, OR = 1.40, 95% CI = 0.67 to 2.90; smoking, OR = 0.70, 95% CI = 0.38 to 1.30.
Discussion.
Consideration of results. Our study is consistent with previous reports of an inverse association between cigarette smoking and PD as reviewed elsewhere1,29⇓; however, the association was not significant, and dose–effect analyses did not show significant trends. The only tobacco-related significant finding was for tobacco chewing or snuff use. A previous case-control study based on the same records linkage system used by us but relating to a preceding time period (1967 to 1979) also showed a suggestive but not significant inverse association between smoking and PD (OR = 0.7, 95% CI = 0.4 to 1.2).30
Our findings for coffee were significant and were confirmed by a dose–effect trend. The OR for coffee remained significant after adjustment for smoking, alcohol drinking, and education. In addition, the median age at onset of PD was 8 years older for cases who consumed coffee compared with cases who never did. Finally, we found a sizable difference in OR across strata by age and sex; the inverse association was restricted to cases with onset below age 72 years and to men. An inverse association between coffee and PD was reported by others.4-7,31⇓⇓⇓⇓
With the exception of alcoholism, our findings for alcohol consumption were negative and were consistent with some previous negative reports.31,32⇓ However, other studies showed an inverse association between alcohol consumption and PD independent of smoking.7-9⇓⇓ The reasons for these inconsistent findings remain unknown.
Our results in conjunction with data from other studies provide a pattern of findings suggestive of multiple inverse associations between certain life habits or behaviors and PD. This pattern is compatible with several hypotheses. First, these life habits may be markers of an underlying premorbid personality manifesting early in life and characterized by reduced novelty seeking.11-17⇓⇓⇓⇓⇓⇓ Individuals who will later develop PD may avoid behaviors that are habituating or negatively sanctioned by society or that may jeopardize their health. We note that our significant findings for tobacco and alcohol use refer to patterns of extreme or unusual exposure rather than to more usual exposures. Therefore, we may interpret the suggestive inverse association with cigarette smoking and the significant inverse associations with tobacco chewing or snuff use, coffee consumption, and alcoholism as nonspecific markers of an underlying personality.
Second, individuals who will later develop PD may avoid coffee or smoking because they are intolerant to their pharmacologic stimulating effects.33 For example, one or several genes could determine a pharmacologic intolerance to nicotine or caffeine and independently increase the risk of PD through a distinct mechanism. Under such a hypothesis, coffee consumption and smoking are inversely associated with PD, but they have no causal role (association due to confounding).
Third, the avoidance of smoking, and particularly of coffee, could be a marker of an underlying olfactory deficit occurring in the preclinical phase of PD.34 Individuals who will later develop PD would not experience the rewarding effect of smell involved with these consumption habits, and thus they would be less likely to become regular users. Similarly, the avoidance of smoking and coffee could be related to psychiatric conditions occurring in the preclinical phase of PD. We reported elsewhere that patients with PD were significantly more likely than control subjects to have had an anxiety disorder or a depressive disorder years before the onset of the motor symptoms of PD.26 These psychiatric disorders may have influenced the substance use habits of future PD patients. However, our multivariate analyses including anxiety disorders and depressive disorders did not modify the magnitude of the inverse association between coffee drinking or smoking and PD.
A fourth possibility is that coffee, smoking, and possibly alcohol could be inversely related to PD through a direct pharmacologic action of their chemical constituents (direct protective effect). Possible pharmacologic actions of smoking (nicotine) have been discussed extensively by others.2 Caffeine is the most widely consumed methylxanthine, and its most important pharmacologic effect at doses normally assumed through coffee drinking is an antagonistic action on the adenosine receptors.33 Interestingly, the adenosine A2A receptor modulates the nigrostriatal dopamine system, and antagonists of that receptor have been proposed as therapy for PD.35 In addition, caffeine was shown to enhance locomotor activity in rats through an adenosine antagonist mechanism.36 Experiments in mice showed that inactivation of the adenosine A2A receptor gene (knockout mice) causes reduced exploratory activity, further reduction of exploratory activity in response to caffeine (which normally is a stimulant), and increased anxiety.37 Other substances and micronutrients contained in coffee, such as niacin, could have a direct neuroprotective effect;7,38⇓ however, this hypothesis remains untested. Against a causal association between coffee, smoking, and possibly alcohol and PD is the lack of specificity. Caffeine, nicotine, and alcohol have different pharmacologic or metabolic effects on the brain.33
Consideration of methods.
Our study has a number of strengths compared with previous case-control studies of risk habits that almost invariably were not population based, used prevalent PD cases, and collected data through an interview.1 First, we included all incident cases of PD from a defined population over a defined time window and control subjects derived from the same population over the same time. Referral bias is expected to be minimal in this population-based case-control study.39 Although cases of PD that did not come to medical attention may have been missed, we showed that our case ascertainment through the records linkage system was complete and representative of the population.18 We emphasize that our control subjects were general population control subjects and they should have been affected by smoking-related diseases (or coffee- or alcohol-related diseases) with frequencies representative of the general population with the same age and sex. Second, our study design reduced the risk of prevalence–incidence bias.39 If smoking has a negative prognostic effect on survival after onset of PD (reduced survival because of smoking–PD interaction), prevalent series of PD cases may underrepresent individuals who smoked. This negative effect on survival would tend to create a spurious inverse association in a case-control comparison based on prevalent cases.40,41⇓
Third, we collected information about exposures through a retrospective review of medical records in the records linkage system; this approach reduced the risk of recall bias.39 The study did not involve any interview or recall of past events. Documentation of smoking, alcohol, and coffee consumption was generated historically as part of routine medical care and before the onset of PD in cases. Therefore, the information was independent of knowledge about subsequent disease status. Fourth, strict matching of cases and control subjects for age (and calendar year) prevented differences across groups due to secular trends in habits and behaviors.
Our study has, however, a number of limitations. First, because record abstracting of exposures for cases and control subjects was performed by a neurologist, we cannot exclude some unmasking in the data collection. This potential unmasking would increase the risk of an exposure suspicion bias.39 The concern is that the abstractor would search the records of cases more intensively than records of control subjects. Because the information abstracted for this study is clearly present in the record and does not require interpretation or clinical judgment, we do not think this was a problem. In addition, the information abstracted from the record agreed with that independently obtained from a telephone interview in a subsample of cases and control subjects (reliability study for smoking information).
Second, information about smoking, alcohol, and coffee was not available for all study subjects; however, differences in frequency of missing data between cases and control subjects were not significant. Individuals with missing data were excluded from analysis. In addition, some of our cases or control subjects may have been misclassified concerning smoking, alcohol, and coffee consumption or about the dose of exposure. Misclassification (primarily undercounting of exposures) may have resulted from inaccurate reporting (denial of use) or from inaccurate documentation in the records. However, because data on exposure were generated prospectively (historically), we may reasonably assume that the misclassifications were independent of the subsequent disease status and should have biased our analyses toward conservative findings (driving the OR toward 1.0). In addition, our reliability study comparing record information with telephone interview information about the same individuals suggests that the record documents smoking more often than the interview, thus arguing against an undercounting of exposures. On the other hand, some of our negative findings for dose–effect trends may have been due to the combined effect of missing data and possible misclassification. For example, this may explain our failure to detect a significant dose–effect trend for pack–years of smoking.
Third, our findings based on a retrospective review of records in a records linkage system could be biased if cases had a longer time of enrollment in the system than control subjects. Because the likelihood of generating habits information over life is related to the number of years in which a person has been in contact with the system, this is a potential source of bias. We investigated the duration of enrollment in the records linkage system for cases and control subjects and found no difference.
Acknowledgments
Supported by NIH grant NS33978 and made possible by the Rochester Epidemiology Project (AR30582).
Acknowledgment
The authors thank Rita Black, RN, for her assistance with data collection and Tonya Anderson for typing the manuscript.
Footnotes
-
Dr. Benedetti completed this study while on leave from the Department of Neurology, University of Verona, Italy.
-
Presented in part at the 123rd annual meeting of the American Neurological Association; Montreal, Canada; October 1998.
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