Background: Blood biomarkers of neurovascular damage are used clinically to diagnose the presence severity or\nabsence of neurological diseases, but data interpretation is confounded by a limited understanding of their dependence\non variables other than the disease condition itself. These include half-life in blood, molecular weight, and\nmarker-specific biophysical properties, as well as the effects of glomerular filtration, age, gender, and ethnicity. To\nstudy these factors, and to provide a method for markersââ?¬â?¢ analyses, we developed a kinetic model that allows the\nintegrated interpretation of these properties.\nMethods: The pharmacokinetic behaviors of S100B (monomer and homodimer), Glial Fibrillary Acidic Protein and\nUbiquitin C-Terminal Hydrolase L1 were modeled using relevant chemical and physical properties; modeling results\nwere validated by comparison with data obtained from healthy subjects or individuals affected by neurological diseases.\nBrain imaging data were used to model passage of biomarkers across the bloodââ?¬â??brain barrier.\nResults: Our results show the following: (1) changes in biomarker serum levels due to age or disease progression are\naccounted for by differences in kidney filtration; (2) a significant change in the brain-to-blood volumetric ratio, which\nis characteristic of infant and adult development, contributes to variation in blood concentration of biomarkers; (3)\nthe effects of extracranial contribution at steady-state are predicted in our model to be less important than suspected,\nwhile the contribution of bloodââ?¬â??brain barrier disruption is confirmed as a significant factor in controlling markersââ?¬â?¢\nappearance in blood, where the biomarkers are typically detected; (4) the contribution of skin to the marker S100B\nblood levels depends on a direct correlation with pigmentation and not ethnicity; the contribution of extracranial\nsources for other markers requires further investigation.\nConclusions: We developed a multi-compartment, pharmacokinetic model that integrates the biophysical properties\nof a given brain molecule and predicts its time-dependent concentration in blood, for populations of varying\nphysical and anatomical characteristics. This model emphasizes the importance of the bloodââ?¬â??brain barrier as a gatekeeper\nfor markersââ?¬â?¢ blood appearance and, ultimately, for rational clinical use of peripherally-detected brain protein.
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