Designing and implementing an international online case-control study of risk factors for amyotrophic lateral sclerosis (ALS)

Little is known about the contribution of environmental factors to the etiology of ALS. I have developed an online case-control epidemiological questionnaire that contains 165 questions about risk factors for ALS, called “ALS Quest”. ALS Quest is anonymous and web-based, allowing for rapid collection and analysis of data, and is available in 28 languages. ALS patients and controls are recruited primarily via ALS Associations and social media. 1,177 respondents have to date completed the questionnaire. The methods used to design ALS Quest have been published, and, using data from the questionnaire, I have investigated the following four topics (with one publication for each topic). 1. Changes in the ratio of index:ring finger lengths, related to raised prenatal testosterone levels, had been suggested to occur in ALS. The large ALS Quest finger length dataset showed that the index:ring ratio was the same in ALS and control respondents, indicating that this widely-reported hypothesis is unlikely to be correct. 2. Personality type could underlie the selection of lifestyle factors that could put people at risk for ALS. Indeed, ALS respondents were found to be more agreeable, less neurotic, more conscientious and more extraverted than controls, which could relate, for example, to a greater tendency to smoke (a postulated risk factor for ALS). These findings can also explain the frequent observation that people with ALS are particularly “nice”. Personality could also potentially be linked to ALS via one or more genetic variants. 3. Many clinicians and people with ALS consider that stress could be a trigger for the disease. On the contrary, our ALS respondents did not have more stress-inducing life event or occupational stressors, and were more resilient, than controls. Resilience is largely genetically determined, so this opens a new avenue for ALS research. 4. Mercury has long been suspected to be a neurotoxin that could contribute to ALS. However, common sources of mercury exposure (consumption of fish and number of mercury-containing dental fillings) were similar in ALS and control groups. One item of interest is that ALS respondents consumed more shellfish, which are high in BMAA, a postulated risk factor for ALS. In summary, ALS Quest has proved to be a valuable resource to study risk factors in ALS and will continue to recruit respondents for international comparisons of risk factors

A Comparison of Mercury Exposure from Seafood Consumption and Dental Amalgam Fillings in People with and without Amyotrophic Lateral Sclerosis (ALS): An International Online Case-Control Study

Exposures to toxic metals such as mercury have been suggested to be risk factors for amyotrophic lateral sclerosis (ALS). Human intake of mercury commonly occurs via consumption of seafood or from mercury-containing amalgam dental restorations (‘mercury fillings’). We therefore compared mercury exposures from these sources in 401 ALS and 452 non-ALS respondents, using an internationally-available online questionnaire that asked respondents how often they ate seafood and what their favourite types of seafoods were. Respondents were also asked to record numbers of current or former mercury fillings. ALS and non-ALS respondents did not differ in their frequency of seafood consumption or in monthly mercury intake from favourite seafoods. Both groups had similar numbers of current, as well as former, mercury fillings. In conclusion, this study found no evidence that mercury exposure from eating seafood, or from mercury dental fillings, was associated with the risk of developing ALS. Therefore, if mercury does play a role in the pathogenesis of ALS, other sources of exposure to mercury in the environment or workplace need to be considered. Alternatively, a susceptibility to mercury toxicity in ALS, such as genetic or epigenetic variations, multiple toxic metal interactions, or selenium deficiency, may be present

Is psychological stress a predisposing factor for amyotrophic lateral sclerosis (ALS)? An online international case-control study of premorbid life events, occupational stress, resilience and anxiety.

Psychological stress has been suggested to be relevant to the pathogenesis of neurodegenerative disorders, possibly via the generation of oxygen free radicals. We therefore sought to determine whether people with amyotrophic lateral sclerosis (ALS) had been subjected to more potentially stressful life events or occupations than controls, and whether they had differences in resilience or trait anxiety that would moderate their responses to these stressors. An online anonymous multilingual questionnaire was used to collect data on significant life events from people with and without ALS, using items from a modified Social Readjustment Rating Scale and from self-described significant events, which were combined to create a Life Events Inventory. Inventory scores were subdivided into 0-20 years and 21-40 years age ranges, and for the preceding 2, 5 and 10 years. Respondents also rated levels of stress experienced during different occupations. Resilience was measured using the Connor-Davidson Resilience Scale, and trait anxiety with a modified Geriatric Anxiety Inventory. Scores were compared using nonparametric statistics. Data from 400 ALS (251 male, 149 female) and 450 control (130 male, 320 female) respondents aged 40 years and over showed that Life Events Inventory scores were similar in male ALS respondents and controls, but lower in female ALS respondents than female controls for the preceding 5-year and 10-year periods. Occupational stress did not differ between ALS respondents and controls. Both male and female ALS respondents had higher resilience scores than controls. Anxiety scores did not differ between ALS and control groups. In conclusion, people with ALS reported no raised levels of potentially stressful premorbid life events or occupational stress, and did not have reduced levels of resilience, or increased levels of anxiety, that would augment the deleterious effects of stressors. On the contrary, ALS respondents had higher resilience than controls, though this conclusion relies on ALS respondents recalling their premorbid status. These results do not support the hypothesis that psychological stress from significant life events or occupational stress plays a role in the pathogenesis of ALS