Introduction:
Speciation analysis — the determination of chemical forms of trace elements alongside total content — is a powerful tool in bioanalytical chemistry and clinical medicine. Research by A.V. Skalny et al.¹ using ICP-HPLC in studies of Parkinson’s disease (PD) and animal models^2,3 demonstrates that alterations in metal distribution between high-molecular-mass (protein) and low-molecular-mass (amino acid) complexes constitute critical pathological biomarkers. In contrast, total elemental levels frequently remain within reference ranges despite underlying disease.

Results:
In healthy subjects, copper is primarily bound to ceruloplasmin (94.8%), with a smaller fraction associated with albumin (4.3%) and negligible amounts present as low-molecular-mass (LMM) species. Manganese is principally bound to transferrin (49.7%), with minor proportions complexed with albumin (2.7%) or present as hydroxyacid complexes (26%). In PD patients, ceruloplasmin-bound copper is significantly reduced, and LMM copper species are detectable. Additionally, manganese–albumin complexes exhibit a more than fourfold increase. These results redefine physiological normality not as a static concentration range, but as a dynamic equilibrium among specific chemical species, dependent on tissue type, biological system, and physiological status. This paradigm shift enables the derivation of novel diagnostic indices for clinical assessment such as set of minimum necessary and sufficient similar coefficients (markers) can be included in the calculation and outpatient clinical control: Labile Copper Index (ILM): (Cu-LMM / Cu-Ceruloplasmin). The norm is <1.5%, the excess is >2.5% is a marker of the risk of neurodegeneration and oxidative stress, as well as a pronounced risk of rheumatoid arthritis or the Coefficient of manganese redistribution (KPM): (Mn-Albumin / Mn-Transferrin). The ratio 0.05–0.25 is higher than the norm — the risk of toxic accumulation of Mn in the central nervous system and the Zinc-albumin ratio (CAC): (Zn-Albumin / Zn-LMM) - decrease in this ratio reflects impaired albumin transport function and inflammatory status, associated with metabolic syndrome.

Conclusion:
This approach can be extended to other essential trace elements. For selenium, for instance, the ratio of selenoprotein P (SELENOP) to non-specific selenium compounds serves as a functional indicator; a shift toward non-specific forms denotes deficiency. Disruption of these speciated patterns—termed “speciation imbalance” — represents an early and often reversible manifestation of physiological dysfunction, preceding detectable changes in total element content, which typically reflect prolonged pathology. The application of speciation analysis holds significant promise for broader applications beyond PD, including Alzheimer’s disease (via metal-amyloid interactions), Wilson’s disease (copper metabolism), cardiovascular diseases (oxidative stress), and oncology (altered metalloprotein metabolism in tumors).