Serum transthyretin monomer as a possible marker of blood-to-CSF barrier disruption.
The CNS is shielded from systemic influences by two separate barriers, the blood-brain barrier (BBB) and the blood-to-CSF barrier. Failure of either barrier bears profound significance in the etiology and diagnosis of several neurological diseases. Furthermore, selective opening of BBB tight junctions provides an opportunity for delivery of otherwise BBB impermeant drugs. Peripheral assessment of BBB opening can be achieved by detection in blood of brain-specific proteins that extravasate when these endothelial junctions are breached. We developed a proteomic approach to discover clusters of CNS-specific proteins with extravasation into serum that correlates with BBB openings. Protein profiles from blood samples obtained from patients undergoing iatrogenic BBB disruption (BBBD) with intra-arterial hyperosmotic mannitol were compared with pre-BBB opening serum. A low molecular weight protein (14 kDa) identified by mass spectroscopy as transthyretin (TTR) consistently correlated with BBBD. Protein gel electrophoresis and immunodetection confirmed that TTR was indeed extravasated in its monomeric form when CNS barriers were breached. The time course of TTR extravasation was compared with release from the brain of another BBB integrity marker, S-100beta (11 kDa). Kinetic analysis revealed that the appearance of S-100beta, presumably originating from perivascular astrocytic end feet, preceded extravasation of TTR by several minutes. Because TTR is localized primarily in choroid plexus and, as a soluble monomer, in CSF, we concluded that although S-100beta is a marker of BBB integrity, TTR instead may be a peripheral tracer of blood-to-cerebrospinal barrier.
Marchi
Nicola
N
Division of Cerebrovascular Research, Cleveland Clinic Foundation, Cleveland, Ohio 44196, USA.
Fazio
Vince
V
Cucullo
Luca
L
Kight
Kelly
K
Masaryk
Thomas
T
Barnett
Gene
G
Vogelbaum
Michael
M
Kinter
Michael
M
Rasmussen
Peter
P
Mayberg
Marc R
MR
Janigro
Damir
D
Volgelbaum
M
M
D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid; D001798:Blood Proteins / Q000032:analysis; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D001932:Brain Neoplasms / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy; D002556:Cerebrospinal Fluid Proteins / Q000032:analysis; D015180:Electrophoresis, Gel, Two-Dimensional; D006242:Haptoglobins / Q000032:analysis; D006801:Humans; D007261:Infusions, Intra-Arterial; D008223:Lymphoma / Q000097:blood* / Q000000981:diagnostic imaging / Q000188:drug therapy; D008353:Mannitol / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage; D009414:Nerve Growth Factors; D010751:Phosphopyruvate Hydratase / Q000097:blood; D011228:Prealbumin / Q000032:analysis* / Q000134:cerebrospinal fluid; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014057:Tomography, X-Ray Computed
D015415:Biomarkers; D001798:Blood Proteins; D002556:Cerebrospinal Fluid Proteins; D006242:Haptoglobins; D009414:Nerve Growth Factors; D011228:Prealbumin; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D008353:Mannitol; D010751:Phosphopyruvate Hydratase; D008727:Methotrexate