Cardiovascular disease, psychiatric diagnosis and sex-differences in the multi-step hypothesis of ALS

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  • Fleur C Garton, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
  • ,
  • Betina B Trabjerg
  • Naomi R Wray, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
  • ,
  • Esben Agerbo

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) risk increases with age and a linear log-incidence and log-age relationship is interpreted to suggest that five-six factors are involved in disease onset. The factors remain unidentified, except that fewer steps are predicted for those carrying a known ALS-causing mutation.

METHODS: Men, those with a psychiatric disorder or cardiovascular disease diagnosis (CVD) have an increased relative-risk of ALS. Using the Danish population registries (ALS diagnosis year 1980-2017) we tested whether these factors would decrease the predicted steps to disease.

RESULTS: Consistent with previous reports, we find a linear log-incidence and log-age ALS-onset relationship (N=4,385, regression coefficient b=4.6, 95%CI 4.3-4.9, R2 =0.99). This did not differ when considering ALS cases with a prior psychiatric diagnosis (N=391, b=4.6 (95%CI 4.0-5.1)) Surprisingly, it was higher (+1.5 steps, p=2.3x10-5 ) for those with a prior CVD diagnosis (N=901, b=6.1 (95%CI 5.4-6.8)). A test to investigate if this effect was maintained in those with CVD in the population (to control for competing risk of death) demonstrated an increased baseline risk and fewer steps to disease (b=1.8, 95%CI 1.2-2.3, p=4.6x10-21 ) (consistent with a positive association of CVD and ALS). Assessing sex-differences (our data and meta-analysed, N=22,495) supports half-a-step fewer for men (-0.4, 95%CI±0.24, p=0.00031) without support for contributing differences explained by menopause.

CONCLUSIONS: Any factor associated with ALS disease onset may be relevant for understanding disease pathogenesis and/or counselling. Modelling disease incidence with age demonstrates some insight into relevant risk factors, however, the outcome can differ if competing risks are considered.

OriginalsprogEngelsk
TidsskriftEuropean Journal of Neurology
ISSN1351-5101
DOI
StatusE-pub ahead of print - 25 sep. 2020

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