Multi-elemental fingerprinting of the human brain: distribution of toxic, essential, and rare earth elements across neocortical, limbic, and subcortical regions.

This study investigates the regional accumulation of toxic, essential, and rare earth elements (REEs) in 42 human brain samples across neocortical, limbic, and subcortical regions. Using ICP-MS and multivariate frameworks, we demonstrate that elemental ratios (specifically Fe/Mg and Fe/Zn) provided stronger regional discrimination than absolute concentrations, with PCA explaining 51% versus 34% of variance, effectively capturing the brain's stoichiometric architecture. Mn and Fe exhibited the strongest regional gradients, with median concentrations in subcortical nuclei approximately two-fold higher than in the neocortex, consistent with DMT1-mediated transport and established tropism for dopaminergic structures. Elevated Mn in the limbic continuum supports a hybrid accumulation scenario combining systemic and olfactory pathways, while Fe enrichment in subcortical regions reflects its physiological role in dopamine metabolism rather than olfactory transport. Elevated Fe/Zn and Fe/Mg ratios in subcortical structures, driven by localised Fe surges rather than depletion of neuroprotective cofactors, suggest a relative weakening of antioxidant defense's and potential predisposition to ferroptotic neurodegeneration. Cd showed preferential accumulation in subcortical structures, consistent with Ca²⁺ mimicry-mediated neuronal entry and age-related blood-brain barrier degradation, with low limbic concentrations arguing against a dominant olfactory route for this element. Lanthanides accumulated as a unified geochemical block. 96% of their total variance was captured by a single principal component, with most REEs exhibiting identical significance levels (pBH = 0.0107). A spatial segregation was identified between light REEs enriched in subcortical nuclei via calcium channel mimicry and heavy REEs preferentially distributed in limbic structures, suggesting dual entry routes. The disappearance of regional differences in relative-profile space (CLR) points toward a non-selective lanthanide accumulation mechanism, potentially involving axonal pathways or vascular niches. The neocortex emerged as the most chemically distinct compartment, maintaining a unique elemental baseline compared to limbic and subcortical structures. These findings underscore the importance of anatomical stratification in neurotoxicological risk assessments, with particular relevance to the etiopathogenesis of neurodegenerative diseases associated with metal dyshomeostasis in the basal ganglia.