Trace metal signatures in cerebrospinal fluid (CSF): Insights from an amyotrophic lateral sclerosis (ALS) hotspot on Mount Etna (Sicily, Italy)

Chronic exposure to trace metals has been increasingly recognized as a possible factor influencing the risk of amyotrophic lateral sclerosis (ALS). In the province of Catania, on the eastern slopes of Mount Etna, epidemiological investigations have highlighted the presence of a high-incidence cluster of the disease. Against this backdrop, the present study was designed to explore whether the concentrations of trace elements in cerebrospinal fluid (CSF) differ between ALS patients residing in this high-incidence area (In-Cluster) and those living in regions with lower incidence (Out-Cluster). For trace element analysis, CSF was analyzed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Fourteen metals (Al, V, Mn, Co, Ni, Cu, Zn, As, Cd, Hg, Pb, Fe, Se, Mg) were quantified in standard and KED modes. No single metal concentration differed significantly between In-Cluster and Out-Cluster groups. However, In-Cluster patients frequently showed higher upper quartiles for Al, Mn, As, Hg, and Se, suggesting broader variability. Ratio analysis highlighted significant differences between groups, with higher Al/Cu ratios observed in In-Cluster patients. Sex-stratified analysis further revealed increased Mn-based ratios in females, with a significantly elevated Mn/Pb ratio. These patterns indicate possible dysregulation of trace metal homeostasis linked to environmental exposure. In conclusion, although statistical significance was limited, our findings suggest that chronic volcanic ash exposure may contribute to subtle imbalances between neurotoxic and neuroprotective elements in CSF, potentially influencing ALS susceptibility. Further studies integrating environmental monitoring, speciation analysis, and larger cohorts are needed to clarify the role of trace metals in ALS pathogenesis.