Epidemiologic studies of amytrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. The causes of ALS remain largely unknown more than 140 years after the disease was first described. The overall aims of this thesis were to describe the temporal trend of ALS incidence in Sweden during the recent years and the aggregation of ALS in families, and to investigate potential roles of early life exposure as well as blood lead concentration on the risk of ALS.

In Paper I, we described the temporal trend of ALS incidence in Sweden between 1991 and 2005, and demonstrated the incidence variations according to several major demographic factors. We found an approximately 2% annual increase of ALS incidence during the study period. The incidence increased in all age groups except those younger than 50 years. This trend was only significant among people born in Sweden. Compared to those born in April-June, individuals born in October-December were at a slightly higher risk of ALS.

In Paper II, we assessed the familial aggregation of ALS in Sweden by comparing the risk of ALS among families of ALS patients to the general Swedish population. We found that the siblings of ALS patients had a 17-fold risk and the children a 9-fold risk of ALS, compared with the reference group. Siblings and children had a greater excess risk if the proband was diagnosed at a younger age, and the excess risk decreased with increasing age at diagnosis of the proband. Co-twins of ALS probands had a relative risk of 32. Spouses of ALS patients had no significantly increased risk.

In Paper III, we investigated whether early life exposures, namely, maternal age at delivery and number of siblings, were associated with an altered risk of ALS during 1987-2005 in Sweden. Low maternal age (≤20 years) and high maternal age (≥41 years) were both associated with a higher risk of ALS. The relative risk of ALS increased slightly with increasing number of younger siblings. Children whose first younger sibling was born after the age of 6 years had the greatest relative risk. Exposure to older siblings was not associated with the risk of ALS.

In Paper IV, we evaluated the association of blood lead level with ALS risk accounting for bone turnover. We conducted a case-control study including 184 ALS cases identified from the National Registry of Veterans with ALS and 194 veteran controls. Blood lead levels were statistically higher among cases compared to controls. A doubling of blood lead was associated with a 1.9-fold risk of ALS after adjustment for age and bone turnover status. The K59N polymorphism in ALAD gene did not modify the lead-ALS association.

In conclusion, by using data from Sweden and the United States, we showed that ALS incidence has been increasing in Sweden, the first-degree relatives of ALS patients have a higher risk of ALS compared to others, and early life exposure (seasonality of birth, maternal age, and exposure to siblings) as well as lead exposure might influence the risk of ALS.

List of scientific papers

I. Fang F, Valdimarsdóttir U, Bellocco R, Ronnevi LO, Sparén P, Fall K, Ye W (2009). "Amyotrophic lateral sclerosis in Sweden, 1991-2005." Arch Neurol 66(4): 515-9
https://pubmed.ncbi.nlm.nih.gov/19364937

II. Fang F, Kamel F, Lichtenstein P, Bellocco R, Sparén P, Sandler DP, Ye W (2009). "Familial aggregation of amyotrophic lateral sclerosis." Ann Neurol 66(1): 94-9
https://pubmed.ncbi.nlm.nih.gov/19670447

III. Fang F, Kamel F, Sandler DP, Sparén P, Ye W (2008). "Maternal age, exposure to siblings, and risk of amyotrophic lateral sclerosis." Am J Epidemiol 167(11): 1281-6. Epub 2008 Mar 25
https://pubmed.ncbi.nlm.nih.gov/18367467

IV. Fang F, Kwee LC, Allen KD, Umbach DM, Ye W, Watson M, Keller J, Oddone EZ, Sandler DP, Schmidt S, Kamel F (2010). "Association of blood lead with risk of amyotrophic lateral sclerosis." (Submitted)