Clinical Significance ofαII-Spectrin Breakdown Products in Cerebrospinal Fluid after Severe Traumatic Brain Injury

Abstract

Following traumatic brain injury (TBI), the cytoskeletal protein alpha-II-spectrin is proteolyzed by calpain and caspase-3 to signature breakdown products. To determine whether alpha -II-spectrin proteolysis is a potentially reliable biomarker for TBI in humans, the present study (1) examined levels of spectrin breakdown products (SBDPs) in cerebrospinal fluid (CSF) from adults with severe TBI and (2) examined the relationship between these levels, severity of injury, and clinical outcome. This prospective case control study enrolled 41 patients with severe TBI, defined by a Glasgow Coma Scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring. Patients without TBI requiring CSF drainage for other medical reasons served as controls. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, and 120 h following TBI and analyzed for SBDPs. Outcome was assessed using the Glasgow Outcome Score (GOS) 6 months after injury. Calpain and caspase-3 mediated SBDP levels in CSF were significantly increased in TBI patients at several time points after injury, compared to control subjects. The time course of calpain mediated SBDP150 and SBDP145 differed from that of caspase-3 mediated SBDP120 during the post-injury period examined. Mean SBDP densitometry values measured early after injury correlated with severity of injury, computed tomography (CT) scan findings, and outcome at 6 months post-injury. Taken together, these results support that alpha -II-spectrin breakdown products are potentially useful biomarker of severe TBI in humans. Our data further suggests that both necrotic/oncotic and apoptotic cell death mechanisms are activated in humans following severe TBI, but with a different time course after injury.

αII-Spectrin Breakdown Product Cerebrospinal Fluid Exposure Metrics Suggest Differences in Cellular Injury Mechanisms after Severe Traumatic Brain Injury

“…In a prospective case-control study, we recently determined that aII-spectrin proteolysis, as assessed in CSF, is a potentially reliable biomarker for severe TBI in humans (Pineda et al, 2007). This study examined changes in 150-kDa and 145-kDa aII-spectrin breakdown products (SBDPs) produced primarily by calpain (SBDP150 and SBDP145), and 120-kDa SBDPs produced by caspase-3.…”

Matrix metalloproteinase-9 in the ventricular cerebrospinal &#64258;uid correlated with the prognosis of traumatic brain injury

“…Numerous approaches have been used in the prognosis of TBI patients such as imaging examinations with computerized tomography (CT) and magnetic resonance imaging (MRI), neurological scales including Glasgow coma scale and Barthal index, as well as the monitoring of intracerebral pressure/cerebral perfusion pressure as indirect strategies (24); however, the prognostic efficacy of these tools for the prediction of TBI patient outcome is still relatively poor (18). In addition to these prognostic tools, numerous biochemical markers have been used to predict the prognosis of patients with cerebral injury, including alpha-II spectrin (14,17), tissue type plasminogen activator (1), Bcl-2 and cytochrome C (32), as well as S100B in the serum (23) and CSF…”

Biomarcadores prognósticos no traumatismo crânio-encefálico grave

“…The α-spectrin is the main action substrate of calpains and of caspase-3 cysteine proteases and products of degradation of the α-II-spectrin may also be viewed as biomarkers in the context of TBI. (41) In liquor, Pineda et al (42) recorded increased concentrations of α-IIspectrin degradation products, which correlated to severity of the injury, CT findings and functional outcome after severe TBI. The α-II-spectrin degradation product generated by action of the caspase-3 had a temporal release curve different from the calpain, suggesting that mechanisms of necrotic as well as apoptotic cell death are activated in humans after TBI, but at different points in time.…”