Diagnostic Pharmacokinetics: how brain-derived biomarkers distribute through the human body, and how this affects their diagnostic significance - the case of S100B

Robert Murcko, Nicola Marchi, Damian Bailey, Damir Janigro

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    Abstract

    Blood biomarkers of neurological diseases are often employed to rule out or confirm the presence of significant intracranial or cerebrovascular pathology or for the differential diagnosis of conditions with similar presentations (e.g., hemorrhagic vs. embolic stroke). More widespread utilization of biomarkers related to brain health is hampered by our incomplete understanding of the kinetic properties, release patterns, and excretion of molecules derived from the brain. This is, in particular, true for S100B, an astrocyte-derived protein released across the blood-brain barrier (BBB). We developed an open-source pharmacokinetic computer model that allows investigations of a biomarker’s movement across the body, the sources of a biomarker’s release, and its elimination. This model was derived from a general in silico model of drug pharmacokinetics adapted for protein biomarkers. We improved the model's predictive value by adding realistic blood flow values, organ levels of S100B, lymphatic and glymphatic circulation, and glomerular filtration for excretion in urine. Three key variables control biomarker levels in blood or saliva: blood-brain barrier permeability, the S100B partition into peripheral organs, and the cellular levels of S100B in astrocytes. A small contribution to steady-state levels of glymphatic drainage was also observed; this mechanism contributed to the uptake of organs of circulating S100B. Additionally, this open-source model can also mimic the kinetic behavior of other markers, such as GFAP or NF-L. Our results show that S100B, after uptake by various organs from the systemic circulation, can be released back into systemic fluids at levels that do not significantly affect the clinical significance of venous blood or salivary levels after an episode of BBB disruption.
    Original languageEnglish
    Article number32
    Number of pages20
    JournalFluids and Barriers of the CNS
    Volume19
    DOIs
    Publication statusPublished - 11 May 2022

    Keywords

    • computer model
    • MATLAB
    • Simbiology
    • astrocytes
    • physiologically-based pharmacokinetic model
    • glymphatics
    • extracranial sources
    • traumatic brain injury
    • brain barriers
    • saliva

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