Biomarker evidence for mild central nervous system injury after surgically-induced circulation arrest

• Published in: Brain research 2008-06, Vol.1213, p.1-11
• Main Authors: Siman, Robert, Roberts, Victoria L, McNeil, Elizabeth, Dang, Antony, Bavaria, Joseph E, Ramchandren, Sindhu, McGarvey, Michael
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - metabolism; Acute CNS damage; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Biomarkers - metabolism; Calpain; Cardiopulmonary Bypass - adverse effects; Central Nervous System Diseases - etiology; Central Nervous System Diseases - metabolism; Circulation arrest; Circulatory Arrest, Deep Hypothermia Induced - adverse effects; Enzyme-Linked Immunosorbent Assay - methods; Female; Humans; Ischemia; Male; Medical sciences; Middle Aged; Neurofilament Proteins - cerebrospinal fluid; Neurology; Spectrin - metabolism; Surrogate marker; Time Factors; Ubiquitin Thiolesterase - cerebrospinal fluid; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2008.03.034

Abstract Previously, we identified 14-3-3 β and ζ isoforms and proteolytic fragments of α-spectrin as proteins released from degenerating neurons that also rise markedly in cerebrospinal fluid (CSF) following experimental brain injury or ischemia in rodents, but these proteins have not been studied before as potential biomarkers for ischemic central nervous system injury in humans. Here we describe longitudinal analysis of these proteins along with the neuron-enriched hypophosphorylated neurofilament H (pNFH) and the deubiquitinating enzyme UCH-L1 in lumbar CSF samples from 19 surgical cases of aortic aneurysm repair, 7 involving cardiopulmonary bypass with deep hypothermic circulatory arrest (DHCA). CSF levels of the proteins were near the lower limit of detection by Western blot or enzyme-linked fluorescence immunoassay at the onset of surgical procedures, but increased substantially in a subset of cases, typically within 12–24 h. All cases involving DHCA were characterized by > 3-fold elevations in CSF levels of the two 14-3-3 isoforms, UCH-L1, and pNFH. Six of 7 also exhibited marked increases in α-spectrin fragments generated by calpain, a protease known to trigger necrotic neurodegeneration. Among cases involving aortic cross-clamping but not DHCA, the proteins rose in CSF preferentially in the subset experiencing acute neurological complications. Our results suggest the neuron-enriched 14-3-3β, 14-3-3ζ, pNFH, UCH-L1, and calpain-cleaved α-spectrin may serve as a panel of biomarkers with clinical potential for the detection and management of ischemic central nervous system injury, including for mild damage associated with surgically-induced circulation arrest.