αII-Spectrin Breakdown Products (SBDPs): Diagnosis and Outcome in Severe Traumatic Brain Injury Patients

Abstract

In this study we assessed the clinical utility of quantitative assessments of aII-spectrin breakdown products (SBDP145 produced by calpain, and SBDP120 produced by caspase-3) in cerebrospinal fluid (CSF) as markers of brain damage and outcome after severe traumatic brain injury (TBI). We analyzed 40 adult patients with severe TBI (Glasgow Coma Scale [GCS] score 8) who underwent ventriculostomy. Patients requiring CSF drainage for other medical reasons served as controls. CSF samples were taken at admission and every 6 h thereafter for a maximum of 7 days and assessed using novel quantitative fragment-specific ELISAs for SBDPs. Outcome was assessed using the 3-month Glasgow Outcome Scale. Mean CSF levels of SBDPs were significantly higher in TBI patients than in controls at all time points examined. Different temporal release patterns of CSF SBDP145 and SBDP120 were observed. SBDP145 provided accurate diagnoses at all time points examined, while SBDP120 release was more accurate 24 h after injury. Within 24 h after injury, SBDP145 CSF concentrations significantly correlated with GCS scores, while SBDP120 levels correlated with age. SBDP levels were significantly higher in patients who died than in those who survived. SBDP145 levels (>6 ng/mL) and SBDP120 levels (>17.55 ng/mL) strongly predicted death (odds ratio 5.9 for SBDP145, and 18.34 for SBDP120). The time course of SBDPs in nonsurvivors also differed from that of survivors. These results suggest that CSF SBDP levels can predict injury severity and mortality after severe TBI, and can be useful complements to clinical assessment.

Therapy Development for Diffuse Axonal Injury

“…Among these, recent studies have suggested that aII-spectrin breakdown products SBDP150 and 145, produced by calpain cleavage, have been linked to acute neuronal necrosis, while SBDP120, produced by caspase 3, has been linked to apoptotic cell death cascades. 41,122,[125][126][127][128][129][130][131] While these aII-spectrin breakdown products have been discussed within the context of neuronal damage, it is important to note that they have been associated with both TAI/DAI and its downstream target deafferentation and synaptic loss. 38,51,[132][133][134] In addition to spectrin breakdown products, other potential markers of axonal injury include various phosphoforms of the neurofilament-H subunit as well as cleaved tau suggesting damage to the axon cytoskeleton.…”

Matrix metalloproteinase-9 in the ventricular cerebrospinal fluid 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…”

Novel Strategies for Discovery, Validation and FDA Approval of Biomarkers for Acute and Chronic Brain Injury

“…The protein is processed to breakdown products (SBDPs) of molecular weights 150 kDa (SBDP150) and 145 kDa (SBDP145) by calpain and is also cleaved to a 120-kDa product (SBDP120) by caspase-3. Calpain and caspase-3 are major executioners of necrotic and apoptotic cell death, respectively, during ischemia or TBI (Ringger et al 2004, Pineda et al 2007, Mondello et al 2010). Thus, a unique feature of this technique is the ability to concurrently detect calpain and caspase-3 proteolysis of aIIspectrin, providing crucial information on the underlying cell death mechanisms.…”

“…Thus, a unique feature of this technique is the ability to concurrently detect calpain and caspase-3 proteolysis of aIIspectrin, providing crucial information on the underlying cell death mechanisms. In addition, distinct temporal release patterns of CSF SBDP145 and SBDP120 were reported to reflect different temporal characteristics of protease activation (Mondello et al 2010 (Pineda et al 2007). Increased CSF SBDP levels were found to be significantly associated with mortality in patients with severe TBI.…”