This is part 1 of a 4-part series from the 27th International symposium on ALS/MND. See also part 2 here.
Insights into the causes of ALS may come from study of the “exposome,” the totality of environmental exposures over the lifespan, according to Roel Vermeulen from the University of Utrecht, The Netherlands. Vermeulen gave the opening lecture at the 27th International Symposium on ALS/MND, which took place 7-9 December in Dublin, Ireland.
“Forty to fifty percent of ALS may be environmental in origin,” Vermeulen said, based on studies of the disease in twins. This is in line with several major diseases, according to the World Health Organization Global Burden of Disease Project, which estimates that environmental, metabolic, and behavioral factors, and their interactions, provide about 40% of the attributable burden of disease in both diabetes and heart disease.
Despite this, the only environmental factor for which there is currently robust evidence for risk of ALS is smoking, Vermeulen said, with an increased risk associated with both more years a person has smoked and fewer years since a person quit. There is a long list of other factors for which he considered the evidence inconclusive but suggestive, including head trauma, physical activity, military service, and heavy metal exposure. Newer data have begun to suggest an occupational risk from high-intensity electrical fields, he said, and an unpublished study from The Netherlands indicates an increased risk from chronic exposure to air pollution, specifically nitrogen oxides and fine particulates.
Vermeulen argued that current study approaches, largely based on single risk factors and traditional epidemiological research methods, have limited the field, because risk factors may interact. “We have to switch to examining the totality of exposure,” he said. That totality should include urban vs. rural dwelling, climate, financial status, education, occupational history, social capital and social stress, as well as nutritional status and toxin exposures. This concept has been dubbed the “exposome,” and understanding it is likely to be critical to making progress in understanding non-genetic sources of ALS risk, he said.
Implementing exposome analysis can be done by combining data from multiple sources, including wearable devices (e.g., ones that measure physical activity), GIS and satellite data (for climate, air pollution, and toxin sources), and commercial databases (such as phone use). Metabolomics techniques to measure more than 20,000 small molecules in the blood are a possible way to detect exposure to environmental compounds, though he noted that this approach is likely to be limited by short half-lives of may compounds.
Scientists are already implementing this type of approach. Orla Hardiman of Trinity College in Dublin, Ireland, and colleagues are beginning to study the complete occupational and residence histories of over 1,000 ALS patients to search for common exposure patterns. Compounds of special interest may emerge from the collaborative NeuroLINCS study, which is examining the effects of chemical perturbation on control and ALS cell lines, using transcriptomics, proteomics, and epigenomics.
It is increasingly clear that exposures early in life, including in utero, can have effects on health that manifest much later in life. The effect of those exposures may be recorded in epigenetic changes. Such changes are most robustly documented for smoking, in which exposure has been linked to hypermethylation of more than 700 sites. After a smoker quits, many sites gradually revert to their pre-smoking methylation status. Thus, Vermeulen said, the pattern of residual methylation can serve as an independent marker of time since quitting. “This type of approach can easily be applied to the ALS field,” he added, to better characterize time since exposure for cigarette smoke.
Further analysis of the epigenome is likely to reveal other changes that may be associated with other exposures. Further information on exposome research can be found here.
“I am excited to see where this approach leads us,” commented Richard Bedlack of Duke University in Durham, North Carolina. “The single most important unresolved question in ALS is why the sporadic form of it happens in the first place, and the concept of the exposome may explain why we have not yet found evidence for a single environmental risk factor that explains very many cases.”