Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study

The present study shows a borderline significant inverse dose–response relationship between total PA measured at enrolment and subsequent risk of dying from ALS. This association does not appear to be confounded or modified by age, gender, or BMI, smoking, or highest level of education attained; but it became of borderline statistical significance once introducing WHR into model. The CPAI was designed for ranking the participants according to their overall PA based on heart rate monitoring, best reflecting the amount of energy spent in physical activities [26].

This is the first prospective cohort study assessing the type and amount of PA before disease onset, and the subsequent risk of developing and dying from ALS. The finding of an inverse association between PA and risk of ALS is at odds with the majority of findings coming from case–control studies [8, 10, 12, 20].

To date, in fact, all published evidence on the association between ALS and PA comes either from case–control studies [8, 9, 20, 29], or from retrospective cohort studies [6, 7]. The former have the limitation of being prone to recall bias (which might be particularly relevant when assessing PA whose quantification is not easy, and which can be easily related by patients to a disease impairing movements). The retrospective cohort studies investigating the risk of ALS among football players have the advantage of including large numbers, but are limited to a highly selected group, and cannot fully account for potential confounders.

Possible ways in which PA may increase the risk of ALS involve oxidative stress, glutamate excitotoxicity and complex interactions with ALS susceptibility genes [30]. On the other hand, the mechanisms through which PA might protect against ALS are thought to be mediated by exercise-induced changes in motor neuron morphology, muscle-nerve interaction, glial activation, and altering levels of gene expression of anti-apoptotic proteins and neurotrophic factors [31]. The effects of exercise upon astrocytes and angiogenesis are also relevant in ALS as astrocytes play an important structural role in the maintenance of the blood–brain barrier (BBB) [32]. A disruption of the BBB in SOD1 mice was found starting in the early stages of the disease [33]. The extensive disruption of the neurovascular unit may promote the progressive loss of motor neurons, with their integrity dependent upon efficient capillary influx of nutrients and efflux of waste, as well as direct supportive interactions with astrocytes. In the brains of exercised rats, the neurovascular unit is strengthened by increased angiogenesis and astrocyte proliferation [34].

The present data suggest that reverse causality is not a likely explanation of the results: after removing ALS deaths during the first 3 years of follow up, the inverse association strengthened (albeit with a reduced sample size). The role of unemployment in contributing to the CPAI is more complex: it might represent an effect of residual confounding of socio-economic status, or an unmeasured reverse causality. However, the fact that an association of similar magnitude between CPAI and ALS mortality (albeit not significant) is obtained after excluding those subjects who were unemployed at recruitment suggests that residual confounding or reverse causality are perhaps not the most likely explanations.

The present study had lower statistical power to detect interactions, and the findings in this sense should be interpreted cautiously and regarded as hypothesis generating. Nevertheless, it is interesting that there was also a suggestion of an increased risk of ALS from vigorous PA in obese subjects (or subjects with an elevated BMI due to substantial increase of muscle mass) among those practising sports, and in young individuals. Should these be confirmed by further investigations, they may reflect some specific characteristics of these two categories, such as, for example, the use of some stimulating agents enhancing sportive performance and/or promoting weight loss [35]. Some of these compounds, such as anabolic steroids and testosterone, increasingly used and abused by athletes for enhancing performance [36], have been shown to stimulate muscle mass increase [37]. These hormones may increase ALS risk though unknown mechanisms, and may also contribute to the higher incidence of ALS in men than women [38]. This hypothesis is consistent with previous observations linking ALS risk to practising sports in general [17, 20], or being professional football players [6, 7], or varsity athletes [8, 9, 20] or professional athletes [17]. Also, a recent report from Europe describes an inverse association between PA and ALS, except for professional sport players [29, 39]. Unfortunately, we are not able to reproduce the findings on professional sport players in this setting, as this information is not available in EPIC. A cohort effect explaining the suggested increased risk among those practising vigorous PA at younger ages has already been suggested by Ascherio [13] in reference to the study by Veldink et al. [12]; this cannot be ruled out, although it seems an unlikely explanation given that it applies to vigorous activity only. The small sample size and the relative oversampling of women by design in the EPIC study do not allow powered estimates of association in both sexes, separately. Despite the p value for interaction with sex being far non-significant (p = 0.272), we cannot rule out that the present results are at least partially driven by the association in women.

Death records appear to be reliable for ascertaining ALS deaths (and hence ALS itself) in this [2] and other large population studies [40]. Nonetheless, a recent study in UK identified an error in the WHO ICD-10 Alphabetic coding Index where progressive supranuclear palsy was mistakenly given as code G12 [23]. However, a validation exercise on death records demonstrated that only 8 % of the women receiving a diagnosis of ALS were misclassified [3]. Furthermore, misclassification introduced by the use of death records instead of specialist diagnoses would likely be non-differential and thus bias the estimate towards the null; therefore the risk estimates reported here might underestimate true associations.

In summary, in this prospective study, practising more PA was associated with a reduced risk of dying from ALS. This association does not appear to be confounded or modified by age, gender, BMI, smoking and the highest level of education attained, and it is unlikely explained by reverse causation.