title: Improving the clinical management of traumatic brain injury through the pharmacokinetic modeling of peripheral blood biomarkers.
abstract: BACKGROUND
  Blood biomarkers of neurovascular damage are used clinically to diagnose the presence severity or absence of neurological diseases, but data interpretation is confounded by a limited understanding of their dependence on variables other than the disease condition itself. These include half-life in blood, molecular weight, and marker-specific biophysical properties, as well as the effects of glomerular filtration, age, gender, and ethnicity. To study these factors, and to provide a method for markers' analyses, we developed a kinetic model that allows the integrated interpretation of these properties.
  
  
  METHODS
  The pharmacokinetic behaviors of S100B (monomer and homodimer), Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 were modeled using relevant chemical and physical properties; modeling results were validated by comparison with data obtained from healthy subjects or individuals affected by neurological diseases. Brain imaging data were used to model passage of biomarkers across the blood-brain barrier.
  
  
  RESULTS
  Our results show the following: (1) changes in biomarker serum levels due to age or disease progression are accounted for by differences in kidney filtration; (2) a significant change in the brain-to-blood volumetric ratio, which is characteristic of infant and adult development, contributes to variation in blood concentration of biomarkers; (3) the effects of extracranial contribution at steady-state are predicted in our model to be less important than suspected, while the contribution of blood-brain barrier disruption is confirmed as a significant factor in controlling markers' appearance in blood, where the biomarkers are typically detected; (4) the contribution of skin to the marker S100B blood levels depends on a direct correlation with pigmentation and not ethnicity; the contribution of extracranial sources for other markers requires further investigation.
  
  
  CONCLUSIONS
  We developed a multi-compartment, pharmacokinetic model that integrates the biophysical properties of a given brain molecule and predicts its time-dependent concentration in blood, for populations of varying physical and anatomical characteristics. This model emphasizes the importance of the blood-brain barrier as a gatekeeper for markers' blood appearance and, ultimately, for rational clinical use of peripherally-detected brain protein.
authors.affiliation: Flocel Inc., Cleveland, OH, 44103, USA.|The Ohio State University, Columbus, OH, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Dadas
authors.affiliation: Flocel Inc., Cleveland, OH, 44103, USA.|John Carroll University, University Heights, OH, USA.
authors.forename: Jolewis
authors.initials: J
authors.lastname: Washington
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Institut de Génomique Fonctionnelle, Université Montpellier, Montpellier, France.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
authors.affiliation: Flocel Inc., Cleveland, OH, 44103, USA. djanigro@flocel.com.|Case Western Reserve University, Cleveland, OH, USA. djanigro@flocel.com.
authors.forename: Damir
authors.identifier: http://orcid.org/0000-0002-9645-0318
authors.initials: D
authors.lastname: Janigro
mesh_terms: D000375:Aging / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D000070642:Brain Injuries, Traumatic / Q000097:blood* / Q000628:therapy; D019468:Disease Management; D018450:Disease Progression; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000097:blood*; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D011446:Prospective Studies; D044469:Racial Groups; D064568:S100 Calcium Binding Protein beta Subunit / Q000097:blood*; D012621:Seasons; D012867:Skin / Q000378:metabolism; D012880:Skin Pigmentation / Q000502:physiology; D043222:Ubiquitin Thiolesterase / Q000097:blood*
chemical_list: D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D064568:S100 Calcium Binding Protein beta Subunit; C579160:S100B protein, human; C482860:UCHL1 protein, human; D043222:Ubiquitin Thiolesterase
keywords: Glomerular filtration; Physiologically-based pharmacokinetic model; Precision medicine; Serum markers; Traumatic brain injury