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Can physical activity induce excitoxicity and increase the risk of ALS?
Even from the time of the earliest descriptions of ALS, environmental causation was considered possible. For example, Charcot mentioned that a third of his patients considered exposure to cold and damp was responsible, and he singled out one man who had sustained a fractured clavicle a few months before the onset of the disease.1 Trauma, occupational or sports-related physical activity, cigarette smoking, exposure to electromagnetic fields or electric shocks, military service and exposure to environmental lead or organic solvents have all been reported to increase the risk of acquiring ALS.2 3 However, many of these studies are based on small case numbers, or have been criticised on other methodological grounds and, for now, only an association with smoking history, pesticide exposure and dietary factors, especially premorbid fat intake have been consistent, although at a low level of risk.3 4 A moderate alcohol intake could even be protective.3 The major risk factors for the disease are increasing age, certain genetic mutations and male gender. The story regarding physical activity and ALS risk, originally based on a few case histories such as that of Lou Gehrig, an iconic US baseball player, and a number of high-level professional football players5 in Italy and the UK, is consistent but has proved difficult to define. However, it has come to attention again with the application of improved epidemiological methodologies.
In their JNNP paper, Visser et al 6 report a study in three European countries based on analysis of 1557 sets of ALS patient data and 2922 control data sets. This study provides Class one evidence for a positive association between the history of physical activity, both in leisure time (OR 1.07, P=0.01) and in occupational activities (OR 1.06, P<0.0005), and risk for the development of ALS. The history of physical activity was assessed by a structured questionnaire, mostly administered face-to-face to patients but in some cases to their family members, which contained questions designed to disguise the objective of the enquiry. Data on lifetime cigarette smoking and alcohol exposure, and other potential environmental toxins, was collected. The educational level of each participant was assessed. For the analysis the physical activity information was converted to a metabolic equivalent for each patient using a standardised methodology. The association of physical activity with ALS risk remained when all other potential risk factors, including the c9orf72 genetic status, were excluded, although ALS patients smoked more cigarettes and drank less alcohol than controls. Importantly, the risk of ALS increased linearly with increasing physical activity. The authors recall that concordance between handedness and site of onset of ALS has been described,7 but their data did not allow an assessment of any possible relation between type of physical activity and site of onset of disease. They raise a question, which is actually very long-standing, concerning the possible additional effect of trauma, perhaps including surgical trauma, as a confounding factor.8 Some other, undetected associated factor, linked in some fashion with occupational or leisure physical activity remains a possibility, although no such obvious environmental or biological candidates have emerged within this study. Recall bias or investigator bias seems unlikely given the wide nature of the study, especially considering previous evidence supportive of a risk associated with physical activity.2 3 Other currently inexplicable considerations include a possible trade-off between cardiovascular risk and ALS risk.
Where does this information lead us with regard to environmental factors and ALS? There are no simple answers. Although it is tempting to construct an hypothesis linking physical activity with increased CNS excitotoxicity in susceptible persons and, therefore, an increased risk for the onset of ALS, a disorder long recognised to be associated with CNS excitotoxicity,9 any such suggestion is, at present, purely hypothetical. Nonetheless, the data are intriguing and deserve closer investigation on a case-by-case basis.10
Contributors I am the sole author and no illustrations.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.
Data sharing statement Not relevant.
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