ArticlesAnalysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study
Introduction
Amyotrophic lateral sclerosis is a neurodegenerative disease that mainly affects upper and lower motor neurons. It shows complex inheritance: about 5% of people with amyotrophic lateral sclerosis have a family history of the disease or frontotemporal dementia in a first degree relative and up to 20% have an affected relative in more extensive population-based family studies.1
Amyotrophic lateral sclerosis has several intriguing features (many shared with other neurodegenerative diseases) that remain unexplained. First, amyotrophic lateral sclerosis is an adult-onset disorder, even in individuals born with a gene mutation that increases the risk of the disease. Although such a mutation is carried from birth, many people remain healthy into old age and do not develop the disease.2 Others remain completely healthy until disease onset seems to begin suddenly (typically between the age of 50 and 70 years), and progresses rapidly.3 It is unknown why a pathological genetic change present from birth is expressed only in adult life, in some people but not others, even for high-penetrance mutations (eg, in the SOD1 gene), and why, when the mutation is expressed, the pathological process progresses rapidly. Furthermore, several amyotrophic lateral sclerosis genes show pleiotropy, in which the same gene mutation can result in different phenotypes. For example, individuals with expansion of a hexanucleotide repeat in the C9orf72 gene can remain healthy, or might develop amyotrophic lateral sclerosis, frontotemporal dementia, or amyotrophic lateral sclerosis–frontotemporal dementia. The same mutation might also predispose to schizophrenia, depression, and Parkinson's disease1 but in every case the burden seems to be specific to a particular subgroup of cells. Additionally, amyotrophic lateral sclerosis seems to start in one neural region and spread,4 but no genetic or environmental factor has yet been found to decide the site of onset.
Several of these characteristics are shared with cancer, which suggests that, despite the differences between cancer and neurodegeneration (eg, cancer is an uncontrolled proliferation of cells, whereas neurodegeneration is the result of the death of cells),5 other shared features remain to be discovered.
Since the 1950s, multistep models have been applied to the study of population patterns of cancer and, although the level of mathematical support remains a matter of debate, they have yielded insights into the likely causes of cancer and in some cases the identification of the steps involved.6, 7, 8, 9, 10 These models generally show that a plot of epithelial cancer incidence against age has an exponential pattern; incidence is proportional to age raised to the power six. This association is consistent with the hypothesis that these cancers are the end result of seven successive mutations.8, 9, 10, 11 Different patterns are reported with some specific cancers—eg, breast cancer, in which cell replication at particular stages of life might have an important role.
Like cancer, amyotrophic lateral sclerosis might be a multistep process in which several sequential steps are needed. For example, a high-penetrance disease-causing mutation would still need the accumulation of the remaining steps to result in disease, which would take time. This scenario would explain both the adult onset and the finding that not every individual carrying a mutation develops disease.
Multistep models have not been used previously in the study of neurodegenerative disease. Therefore, we used a model originally applied to cancer epidemiology to test the hypothesis that amyotrophic lateral sclerosis is a multistep process.
Section snippets
Model
We used the approach outlined by Armitage and Doll.11 Briefly, if one assumes that amyotrophic lateral sclerosis is caused in one step, the incidence in a particular year, i, will be proportional to the risk of having undergone that specific step in that year; this risk, u, will depend on the level of exposure to the relevant disease-causing factor. However, without knowledge of that factor and the exposure level, the incidence will be proportional to the average background risk, u, of this
Results
The five amyotrophic lateral sclerosis population registers gave similar values for the overall incidence of amyotrophic lateral sclerosis and within each age group. Table 1 shows results for each population register.
There was a linear relationship between log incidence and log age in all five population registers (figure 1, appendix): England r2=0·95, Ireland r2=0·99, Italy r2=0·95, the Netherlands r2=0·99, Scotland r2=0·97, and overall r2=0·99, entirely consistent with a multistep model.
All
Discussion
We noted a linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis, consistent with a multistep model of disease. This association is also consistent with other models,9 but our findings cannot be taken as definitive proof that amyotrophic lateral sclerosis results from a multistep process (panel). However, our findings provide support for this initial hypothesis, and suggest that it should be explored further. If the model is correct, then the slope
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