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January 25, 2005; 64 (2) Articles

Physical activity and the association with sporadic ALS

J. H. Veldink, S. Kalmijn, G. J. Groeneveld, M. J. Titulaer, J. H.J. Wokke, L. H. van den Berg
First published January 24, 2005, DOI: https://doi.org/10.1212/01.WNL.0000149513.82332.5C
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Abstract

Objective: To assess whether lifetime physical activity during work and leisure time is associated with an increased risk of developing ALS and to determine the association between physical activity and duration or age at onset of disease.

Methods: Patients referred to our clinic during the 1-year period 2001 to 2002 who had definite, probable, or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in the study. A case-control study was performed taking into account all occupational and leisure time activities of patients (n = 219) and controls (n = 254). Multivariate analysis included confounding factors (sex, age, level of education, body mass index, alcohol use, and smoking). Three quantitative measures of cumulative physical activity were calculated: until 1 year before the onset of disease (total physical activity), the last 10 years before the onset of disease (late physical activity), and until the age of 25 (early physical activity). In addition, a systematic review of all published data is presented.

Results: Smoking and alcohol use were independently associated with ALS (current smoking increased risk, OR = 1.8, 95% CI = 1.0 to 3.0, p = 0.03, ever/current alcohol use decreased risk, OR = 0.6, 95% CI = 0.3 to 0.9, p = 0.04). No significant association with occupational or leisure time physical activity was found (all ORs ≤ 1.7), which was in agreement with most studies with the highest level of evidence in the systematic review. Higher leisure time activities were associated with an earlier age at onset: activity levels before age of 25 (p < 0.001, 7 years earlier), and activity during the last 10 years (p < 0.001, 3 years earlier).

Conclusions: There is no association between physical activity and the risk of developing ALS.

Sporadic ALS is believed to be multifactorial in origin with modifying genes and environmental agents affecting its clinical expression.1 Excessive physical activity has been suggested as a risk factor for developing ALS. Theoretically, physical activity fits the main hypotheses regarding the pathogenesis of ALS: increased oxidative stress and glutamate excitotoxicity. Physical activity can alter the balance between free radical formation and radical scavenger systems, leading to oxidative stress.2 Furthermore, physical activity fits into the concept of excitotoxicity hypothesizing that in susceptible subjects overstimulation of motor neurons enhances motor neuron death.3

Previous studies that examined the relationship between physical activity and the risk of developing ALS produced conflicting results.4–6 Methodologic differences, including a poor definition of ALS before the introduction of the El Escorial criteria,7 small sample sizes, and variable definitions of physical activity all contributed to these conflicting results. Furthermore, since ALS is a disease with a variable clinical expression, some risk factors might only be associated with specific clinical subtypes, for example young onset ALS or slowly progressive ALS. We therefore performed an exploratory analysis examining the possible relationship with specific clinical features, including the age at onset of disease and the progression of disease, which has not been investigated previously.

The present study is a large case-control study using a qualitative and quantitative approach for assessing physical activity, taking into account all jobs and leisure time activities of patients and controls and adjusting for confounding factors. In addition, a systematic review is presented of all published data.

Methods.

Patients.

The University Hospitals in Amsterdam and Utrecht are national referral centers for ALS in the Netherlands. All patients included in this study were incident cases who visited our clinics for diagnostic purposes during the 1-year period 2001 to 2002. Every patient who visited our clinic during this period and who had definite, probable, or possible ALS according to El Escorial criteria,7 without a familial history of ALS, was asked to participate in the study. Because patients with suspected ALS may represent a collection of other syndromes, only patients with both upper and lower motor neuron involvement were included.8 According to this procedure 280 patients with sporadic ALS were identified and were sent a questionnaire, 219 of which were returned (78%). The following clinical data were obtained: age at onset of disease, duration of disease, and type of onset. Duration of disease was used for the survival analysis and defined as the interval between onset of muscle weakness and death from any cause, tracheostomy, or persistent assisted ventilation. The 61 patients who did not return the questionnaire did not differ significantly from the 219 included patients with respect to sex, age at onset, duration of disease, and type of onset.

Controls.

Patients were sent three identical questionnaires. One questionnaire was to be completed by the patient and the other two by control subjects. Every patient was asked to approach two individuals who fulfilled the following criteria: 1) should not be their spouse or partner, 2) should preferably not differ from them in age by more than 5 years, 3) should preferably be of the same sex. As many patients indicated that they were not able to find two suitable persons, 254 healthy controls could be included. All questionnaires remained anonymous, and all data were entered in a blinded fashion.

The questionnaire.

The questionnaire was divided into two sections: the first section contained questions regarding age, sex, level of education, smoking, alcohol use, and anthropometric characteristics. The second section contained questions regarding lifetime physical activity: participants were asked to recollect all their jobs and to describe the various activities they had to perform during these jobs. They were also asked to list all their sports and hobbies, the period during which they performed these activities, and for how many hours per week. The reference period for all variables ended 1 year before the onset of muscle weakness or bulbar signs, to avoid a possible influence of subclinical disease on the factors of interest. The end of the reference period for controls was the moment they completed the questionnaire.

All reported activities were quantified based on the Compendium of Physical Activities, a coding scheme for classifying physical activity according to rate of energy expenditure.9 The Compendium was developed to enhance the comparability of results across studies using self-reports of physical activity. Activities are classified by purpose (i.e., sports, occupation, self-care), the specific type of activity, and its intensity, expressed as a metabolic equivalent (MET). The definition of an MET is the ratio of work metabolic rate to a standard resting metabolic rate of 1 kcal × kg−1 body weight × h−1; 1 MET is considered to be the resting metabolic rate while sitting quietly. For example, a person bicycling at a 4 MET value expends 4 kcal × kcal × kg−1 body weight × h−1. MET levels for specific activities as reported in the Compendium were established by reviewing published and unpublished studies that measured the energy cost of human physical activities.9 The compendium has recently been updated and now describes 605 specific human activities.10

The assignment of MET scores enabled us to calculate and compare three different cumulative scores of all reported activities (MET × hours/week × years): cumulative activity until the age of 25 (early physical activity), cumulative activity during the period 10 years before the reference year (late physical activity), and total cumulative activity until the reference year (total physical activity).

Participants were also asked whether they were engaged in sports as a youngster or as an adult or whether they had ever performed an extreme form of physical activity. Examples of extreme physical activity were marathon running, skating tours exceeding 200 km, extensive bicycling tours, high-level mountaineering, and long-distance swimming.

The institutional ethical committee of the University Medical Center Utrecht approved the study protocol.

Systematic review.

To identify studies on physical activity as a risk factor for ALS, a PubMed/Medline search from 1966 to 2003 was performed. Keywords used in our search were “amyotrophic,” “ALS,” “motor neuron(e) disease,” “MND,” “risk factor,” and “physical activity.” In addition, the reference lists of all relevant publications were checked for other studies. According to this procedure, 23 studies were identified reporting on physical activity in relation to ALS or variants thereof.4–6,11–30 These studies were evaluated according to the following characteristics: qualitative or quantitative data, physical activity investigated before (biologic) onset of disease, study design and (adjusted) statistical analysis, sources of bias and confounding, number of patients and, if applicable, number of controls, response rates, and number of comparisons (multiple testing). Recently, a classification for etiologic studies in ALS was proposed.31 Based on the aforementioned criteria, we were able to assign a level of evidence to each study and to present a critical review.

Statistical analysis.

Differences in categorical factors between patients and controls were determined with the χ2 test. Differences in continuous variables were computed using the Mann–Whitney U test. Physical activity was categorized into quartiles based on the data of controls. Multivariate logistic regression was used to determine independent ORs for the association between physical activity and ALS with the lowest quartile of physical activity as the reference category. These four-level variables were also entered into the model as continuous variables to determine whether a linear trend was present. The multivariate model always included sex, age (at onset for patients, current age for controls), level of education (low, middle, high), smoking (never, ever, current), alcohol use (never, ever/current), and premorbid body mass index (BMI). In addition, sex specific associations were examined by adding an interaction term of the quartiles of physical activity as a continuous variable with sex to the model.

We performed an exploratory analysis to test four additional hypotheses concerning the possible association between clinical features (sex, type of onset, age at onset, and duration of disease) and level of physical activity. The results are shown regarding age at onset and duration of disease. Cox regression analysis was used to determine an independent association between physical activity and age at onset of ALS adjusting for the above-mentioned confounders and type of onset. The same procedure was used to determine an independent association between physical activity and duration of disease, additionally adjusting for age at onset and type of onset. Physical activity was entered into these models as a categorical variable (0 < median, 1 ≥ median). Also, a Kaplan-Meier curve was drawn comparing age at onset or duration of disease between the two levels of activity. All tests were two-sided, and a p value of < 0.05 was considered significant.

Results.

Characteristics of patients and controls.

Table 1 shows the characteristics of patients and controls, including the main potential confounding factors for the relationship between physical activity and ALS. Based on these figures, a representative sample of patients with ALS was obtained with respect to sex, but a younger age at onset and a relative predominance of spinal onset patients in our sample suggest some referral bias as compared to a recent population-based study in Ireland.32 Apparently, not every patient was able to find control subjects of the same sex because the control population showed a slight, but significant predominance of females compared to the patients. All analyses of physical activity were adjusted for sex and other potential confounding factors (age, level of education, body mass index, alcohol use, and smoking). Apparently, smoking and alcohol use were the only factors in this logistic regression model that were independently associated with ALS (current smoking, OR = 1.8, 95% CI = 1.0 to 3.0, p = 0.03, ever/current alcohol use, OR = 0.6, 95% CI = 0.3 to 0.9, p = 0.04).

View this table:

Table 1 Characteristics of ALS patients and controls

Physical activity and risk for ALS.

None of the qualitative measures of physical activity (sports, extreme physical activity, or body mass index) showed a significant association with ALS (table 2).

View this table:

Table 2 Physical activity among ALS patients and controls

Figure 1 shows the adjusted ORs for the cumulative quantitative measures of total (figure 1A), late (figure 1B), or early (figure 1C) occupational and leisure time physical activity. Also shown are the p values for the adjusted linear trend analyses. None of the adjusted ORs of the occupational data or the leisure time data were significant, and none of the ORs exceeded 1.7 (the fourth quartile of the total occupational activity, see figure 1A). All the ORs for leisure time activity were close to a value of 1.

Figure

Figure 1. Adjusted ORs for the relationship between quartiles of the total cumulative activity (A), of the cumulative activity of the last 10 years until 1 year before the onset of disease (late, B), and of the cumulative activity until the age of 25 (early, C). ORs were adjusted for sex, age (for patients, age at onset), level of education (low, middle, high), smoking (never, ever, current), and alcohol use (never, ever/current).

Physical activity and clinical features.

Multivariate Cox regression analyses were performed to determine whether physical activity was independently associated with duration of disease or age at onset. Analysis of duration of disease showed that none of the three cumulative measures of physical activity was associated with disease progression (all p values > 0.11). However, higher cumulative leisure time activities were associated with earlier age at onset: early physical activity: HR = 1.7, 95% CI = 1.3 to 2.4, p < 0.001, and late physical activity: HR = 1.6, 95% CI = 1.2 to 2.2, p < 0.001. Kaplan-Meier curves (figure 2) revealed that in subjects with higher leisure time activities before the age of 25, onset of disease was 7 years earlier (logrank test: p = 0.001), and that higher leisure time activities during the 10 years before the reference date resulted in earlier onset of disease by 3 years (logrank test: p = 0.02). Interactions with type of onset of disease or sex were not significant (all p values > 0.20). To exclude period effect or recall bias due to age differences, the same procedure was performed in controls using the filling out of the questionnaire as the event. Neither physical activity measure was related to age at event in controls (p = 0.56 and p = 0.87).

Figure

Figure 2. Kaplan-Meier curves comparing high vs low level leisure time activities in relation to age at onset.

Systematic review.

Table 3 shows a summary of the review of the 23 studies identified concerning physical activity and the risk of developing ALS, including the current study.4–6,11–30 Half of all studies have reported a possible relationship between physical activity and ALS or variants thereof.4,5,12,13,16–18,22,23,26,29 Table 3 also shows that the higher the class of evidence, the lower the percentage of positive studies. Most importantly, the only study that was assigned a class II level of evidence did not show a positive association between physical activity and the risk of developing ALS.6 Furthermore, no previous study investigated the possible relationship between physical activity and duration of disease or age at onset.

View this table:

Table 3 Class of evidence for physical activity as a risk factor for ALS

Discussion.

In the present study we used a qualitative and quantitative approach to determine whether physical activity is associated with the risk of developing ALS or with duration of disease or age at onset. Several measures of physical activity were not associated with the risk of developing ALS; however, increased leisure time activities were strongly associated with earlier age at onset. These results suggest that in a population at risk of developing ALS for reasons other than physical activity, a higher level of premorbid leisure time activities accelerates the onset of the disease.

Previous studies investigating physical activity in relation to ALS have been marred by several problems. Before 1994, a lack of clinical criteria for ALS led to heterogeneous study populations. Furthermore, the use of indirect measurements of physical activity—e.g., lower social economic class as an indicator of hard physical labor—led to confounding and incomplete assessment of activity levels. Also, residual confounding invalidated most studies because of unadjusted analyses and absence of controls. All studies that showed a possible relationship between physical activity and the risk of ALS were of class III evidence or lower, meaning that bias and confounding may have partly accounted for the findings. One study of class II evidence6 that also used the Compendium of Physical Activities to quantify physical activity used a population-based design, which reduces the chance of bias, and took into account possible confounders. Importantly, this study showed a lack of association between physical activity and the risk of developing ALS, similar to the results of the current study.

Our results showed that higher leisure time activities were related to an earlier age at onset in ALS. This relationship has not been investigated previously in ALS. The mechanism of physical activity as a disease modifier possibly relates to the two main hypotheses regarding the pathogenesis of ALS, i.e., increased oxidative stress and glutamate excitotoxicity.33 Physical activity could lead to enhanced motor neuron degeneration because of further stimulation of motor neurons in a pre-existent excitotoxic environment. Furthermore, physical activity may lead to increased motor neuron death because physical activity can alter the balance between free radical formation and radical scavenger systems leading to increased oxidative stress, depending on the intensity of activity.2 Nevertheless, other exposures during leisure time activities, independent from level of physical activity, might also explain the association with younger onset ALS. Independent replication of this result is needed to determine the significance of this association.

Possibly, we were unable to detect a clear association between physical activity and the risk of developing ALS because the effects of physical activity are small or because we did not adjust for unknown confounders. Since the majority of controls were acquaintances of patients, overmatching might have occurred, leading to reduced statistical power. Also, the use of a questionnaire might have introduced recall bias. However, we were able to replicate the finding that smoking was independently associated with the risk of developing ALS. In a recent evidence-based review, smoking emerged as the only “more likely than not” risk factor for ALS.31

Footnotes

  • Supported by a grant from ZonMw, The Netherlands Organization for Health Research and Development.

    Received February 5, 2004. Accepted in final form October 5, 2004.

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Letters: Rapid online correspondence

  • Reply to Ascherio
    • Jan H. Veldink, UMCU, Heidelberglaan 100 3584 CX Utrecht, The Netherlands
    • Sandra Kalmijn, Leonard H. van den Berg
    Submitted April 16, 2005
  • Physical activity and the association with sporadic ALS
    • Alberto Ascherio, Harvard School of Public Health, Depat. of Nutrition, HSPH, 665 Huntington Ave, Boston, MA 02115
    Submitted April 16, 2005
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