A metrological basis for traceable, reliable, and comparable determinations of biomarkers in biological samples
As Europeans live longer healthier lives, the prevalence of Alzheimer’s disease (AD), a form of dementia, is expected to increase markedly, placing an increased financial burden on the care system.
Studies have highlighted that treatment is most effective at early stages of disease progression. Early interventions can delay the onset of severe dementia symptoms, supporting a better quality of life for AD patients and their carers. Biomarkers can be used to identify AD but inaccuracies in the current methods (e.g. immunoassays or optical) for quantifying these mean that only about half of the number of AD sufferers are identified, often at advanced stages disease progression. Also, since the most established biomarkers, β-amyloid peptide, β-amyloid peptide 1-40, total tau-protein (T-tau) and hyperphosphorylated tau-protein are also elevated during normal ageing, clinicians need cut off values, to distinguish between healthy and diseased status.
In addition to these biomarkers metal and metal containing proteins, or metalloproteins are also suspected to be involved in the formation of AD tangles and plaques required assessing,
This project built on the achievements of EMRP project Metallomics to improve accuracy in measurements of AD biomarkers, by establishing reference measurement procedures for these in cerebrospinal fluid using isotope dilution (ID) analysis in combination with either mass spectrometry or Raman spectrometry.
Specifically, the project:
- Introduced procedures for potential new blood-based biomarkers.
- Developed potential reference measurement procedures based on species-specific isotope dilution mass spectrometry (SS-IDMS) for the traceable quantification of metals and metal-containing biomolecules.
- Prepared and fully characterised natural and isotopically labelled materials for further use in the development of SS-IDMS methods.
- Developed methods for measuring two aβ peptides and the protein biomarker, T-tau which included applying a SERS immunoassay sandwich approach with a sensitivity sufficient for clinical samples, making use of complex gold nanoparticles.
- Developed methods for measuring the uptake, metabolism and transport to the brain of metals and metal-containing biomolecules were developed and applied to mouse models.
- Developed and applied, in a clinical study of therapies for treating Wilson’s disease, a method for measuring copper bound the albumin (Cu-ALB) biomarker. Wilson’s disease is a rare genetic condition that leads to a build-up of copper in the liver and other tissues.
The project provided a metrological basis for the traceable, reliable and comparable determination of established and novel AD biomarkers in biological samples. As a result, reference laboratories can apply SI-traceable reference values, to make the results of clinical laboratories more reliable and provide a basis for establishing universal cut-off values for diagnosing AD.
A European Metrology Network on Traceability in Laboratory Medicine (TraceLabMed) has since been established for stakeholders in the field of laboratory diagnostics. Participating National Metrology Institutes and Designated Institutes plan to offer services based on the methods developed within this project.
Journal of Analytical Atomic Spectrometry
Journal of Biophotonics
Neurology - Neuroimmunology Neuroinflammation
BMC Research Notes