The study of levels from redox-active elements in cerebrospinal fluid of amyotrophic lateral sclerosis patients carrying disease-related gene mutations shows potential copper dyshomeostasis

Abstract

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by a loss of function of motor neurons. The etiology of this disorder is still largely unknown. Gene-environment interaction arises as a possible key factor in the development of amyotrophic lateral sclerosis. We assessed the levels of trace metals, copper (Cu), iron (Fe), and manganese (Mn), of 9 amyotrophic lateral sclerosis cases and 40 controls by measuring their content in cerebrospinal fluid. The following trace element species were quantified using ion chromatography-inductively coupled plasma mass spectrometry: univalent copper (Cu-I), divalent Cu (Cu-II), divalent Fe (Fe-II), trivalent Fe (Fe-III), divalent Mn (Mn-II), trivalent Mn (Mn-III), and also unidentified Mn species (Mn-unknown) were present in some samples. When computing the relative risks for amyotrophic lateral sclerosis through an unconditional logistic regression model, we observed a weak and imprecise positive association for iron (Fe III, adjusted odds ratio 1.48, 95% CI 0.46–4.76) and manganese (total-Mn and Mn-II; adjusted odds ratio 1.11, 95% CI 0.74–1.67, and 1.13, 95% CI 0.79–1.61, respectively). Increased risk for copper was found both in the crude analysis (odds ratio 1.14, 95% CI 0.99–1.31) and in multivariable analysis after adjusting for sex, age, and year of storage (1.09, 95% CI 0.90–1.32). Our results suggest a possible positive association between Cu and genetic amyotrophic lateral sclerosis, while they give little indication of involvement of Fe and Mn in disease, though some correlations found also for these elements deserve further investigation.