title: alphaII-Spectrin breakdown product cerebrospinal fluid exposure metrics suggest differences in cellular injury mechanisms after severe traumatic brain injury.
abstract: Traumatic brain injury (TBI) produces alphaII-spectrin breakdown products (SBDPs) that are potential biomarkers for TBI. To further understand these biomarkers, the present study examined (1) the exposure and kinetic characteristics of SBDPs in cerebrospinal fluid (CSF) of adults with severe TBI, and (2) the relationship between these exposure and kinetic metrics and severity of injury. This clinical database study analyzed CSF concentrations of 150-, 145-, and 120-kDa SBDPs in 38 severe TBI patients. Area under the curve (AUC), mean residence time (MRT), maximum concentration (C(max)), time to maximum concentration (T(max)), and half-life (t(1/2)) were determined for each SBDP. Markers of calpain proteolysis (SBDP150 and SBDP145) had a greater median AUC and C(max) and a shorter MRT than SBDP120, produced by caspase-3 proteolysis in the CSF in TBI patients ( p < 0.001). AUC and MRT for SBDP150 and SBDP15 were significantly greater in patients with worse Glasgow Coma Scale (GCS) scores at 24 h after injury compared to those whose GCS scores improved (AUC p=0.013, MRT p=0.001; AUC p=0.009, MRT p=0.021, respectively). A positive correlation was found between patients with longer elevations in intracranial pressure (ICP) measurements of 25mmHg or higher and those with a greater AUC and MRT for all three biomarkers. This is the first study to show that the biomarkers of proteolysis differentially associated with calpain and caspase-3 activity have distinct CSF exposure profiles following TBI that suggest a prominent role for calpain activity. Further studies are being conducted to determine if exposure and kinetic metrics for biofluid-based biomarkers can predict clinical outcome.
authors.affiliation: Departments of Pharmacy and Neurosurgery, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia 23298-0533, USA. gbrophy@vcu.edu
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Brophy
authors.forename: Jose A
authors.initials: JA
authors.lastname: Pineda
authors.forename: Linda
authors.initials: L
authors.lastname: Papa
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Lewis
authors.forename: Alex B
authors.initials: AB
authors.lastname: Valadka
authors.forename: H Julia
authors.initials: HJ
authors.lastname: Hannay
authors.forename: Shelley C
authors.initials: SC
authors.lastname: Heaton
authors.forename: Jason A
authors.initials: JA
authors.lastname: Demery
authors.forename: Ming Cheng
authors.initials: MC
authors.lastname: Liu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Tepas
authors.forename: Andrea
authors.initials: A
authors.lastname: Gabrielli
authors.forename: Steven
authors.initials: S
authors.lastname: Robicsek
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Robertson
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hayes
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D001930:Brain Injuries / Q000134:cerebrospinal fluid* / Q000503:physiopathology*; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D019586:Intracranial Hypertension / Q000134:cerebrospinal fluid / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000134:cerebrospinal fluid* / Q000503:physiopathology*; D010446:Peptide Fragments / Q000032:analysis / Q000134:cerebrospinal fluid; D010447:Peptide Hydrolases / Q000378:metabolism; D011237:Predictive Value of Tests; D013049:Spectrin / Q000032:analysis / Q000134:cerebrospinal fluid*; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; D013049:Spectrin; D010447:Peptide Hydrolases; D002154:Calpain; D053148:Caspase 3