Serum Trace-Element Profiles and Exploratory Composite Indices in Multiple System Atrophy: A Case-Control Study

Background/Objectives: Circulating trace-element differences have been reported in neurodegenerative disorders, but data in multiple system atrophy (MSA) are scarce. We compared eleven trace elements and two operationally defined exploratory composite indices between patients with MSA and controls. Methods: This case-control study included 30 patients with MSA and 30 frequency-matched controls. Eleven elements were quantified by ICP-MS. The raw Metal Burden Index (MBI; mean of aluminum, lead, cadmium, manganese, and arsenic) and Neurotoxic Metal Score (NMS) were calculated. Component-level decomposition was performed, and an aluminum-excluded index and component-standardized MBI (MBIz) were evaluated as sensitivity analyses. Results: Patients with MSA had higher aluminum and copper and lower iron and zinc than controls (all p < 0.001, Bonferroni-corrected; absolute Cohen's d = 3.39-3.85). The raw MBI was higher in MSA (p < 0.001, d = 1.38) and remained associated with MSA status after age/sex adjustment (OR = 5.50, 95% CI 2.25-13.47 per 1-SD increase). Aluminum accounted for 114.6% of the MBI difference; the aluminum-excluded index did not differ. MBIz was higher in MSA (p < 0.001, d = 0.95). Exploratory ROC analyses showed apparent separation for raw MBI, aluminum, and copper without establishing validated diagnostic thresholds. No statistically significant correlations with disease severity or duration were observed; estimates were imprecise. Conclusions: MSA was associated with higher serum aluminum and copper and lower iron and zinc. The raw MBI predominantly reflected the aluminum signal; its incremental value beyond individual elements remains unproven. Findings require validation in disease-control and multicenter cohorts.