Serum SNTF, a Surrogate Marker of Axonal Injury, Is Prognostic for Lasting Brain Dysfunction in Mild TBI Treated in the Emergency Department

Abstract

Mild traumatic brain injury (mTBI) causes persisting post-concussion syndrome for many patients without abnormalities on conventional neuroimaging. Currently, there is no method for identifying at-risk cases at an early stage for directing concussion management and treatment. SNTF is a calpain-derived N-terminal proteolytic fragment of spectrin (α II-spectrin1-1176) generated in damaged axons following mTBI. Preliminary human studies suggest that elevated blood SNTF on the day of mTBI correlates with white matter disruption and lasting brain dysfunction. Here, we further evaluated serum SNTF as a prognostic marker for persistent brain dysfunction in uncomplicated mTBI patients treated in a Level I trauma center emergency department. Compared with healthy controls (n = 40), serum SNTF increased by 92% within 24 h of mTBI (n = 95; p < 0.0001), and as a diagnostic marker exhibited 100% specificity and 37% sensitivity (AUC = 0.87). To determine whether the subset of mTBI cases positive for SNTF preferentially developed lasting brain dysfunction, serum levels on the day of mTBI were compared with multiple measures of brain performance at 90 days post-injury. Elevated serum SNTF correlated significantly with persistent impairments in cognition and sensory-motor integration, and predicted worse performance in each test on a case by case basis (AUC = 0.68 and 0.76, respectively). SNTF also predicted poorer recovery of cognitive stress function from 30 to 90 days (AUC = 0.79-0.90). These results suggest that serum SNTF, a surrogate marker for axonal injury after mTBI, may have potential for the rapid prognosis of lasting post-concussion syndrome and impaired functional recovery following CT-negative mTBI. They provide further evidence linking axonal injury to persisting brain dysfunction after uncomplicated mTBI. A SNTF blood test, either alone or combined with other markers of axonal injury, may have important utilities for research, prognosis, management and treatment of concussion.

Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death

“…Calpain activation has long been shown to be involved in the pathology of traumatic brain injury (TBI) [ 84 , 85 , 86 ]. Calpain activation results in the truncation of brain spectrin and several spectrin breakdown products (SBDPs) have been used as biomarkers for TBI in both cerebro-spinal fluid (CSF) and blood [ 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 ]. Surprisingly, none of these studies has addressed the respective roles of calpain-1 and calpain-2 either in brain pathology or in the generation of the blood biomarkers.…”

“…In good agreement with this result, the lesion volume 7 days after TBI was significantly smaller in C2CKO mice than in control mice ( Figure 4 ). Finally, we also determined the levels of calpain-cleaved αII-spectrin N-terminal fragment (SNTF), a blood biomarker shown to be present in human subjects after concussion [ 92 , 93 , 94 ], in the blood of mice subjected to TBI with or without treatment with a selective calpain-2 inhibitor ( Figure 5 ). First of all, we found that SNTF blood levels were very well correlated with the levels of calpain-2 activation in the brain; in addition, treatment of the mice with C2I 1 h after TBI prevented the increase in blood SNTF elicited by TBI.…”

Post-concussive mTBI in Student Athletes: MRI Features and Machine Learning

“…Premorbid conditions have been shown to be associated with severity of PCS; where PCS is higher in those with a personal history of mood disorders ( 38 ). On the other hand, blood biomarkers have been modestly associated with mTBI ( 41 ) and used to predict long-lasting PCS ( 44 ). Hence, premorbid conditions, blood biomarkers, and imaging findings could be combined in a multimodal test to improve the assessment of severity and length of PCS using machine-learning approaches.…”

The Role of Novel Imaging and Biofluid Biomarkers in Traumatic Axonal Injury: An Updated Review

“…The role of SBDP as a potential biomarker in mild TBI in humans has been previously investigated [ 69 ]. Regarding its prognostic role in TAI, Siman et al [ 70 ] found that the serum levels of SNTF, a cleavage of αII-spectrin1-1176, could accurately predict long-term brain dysfunction in patients with long post-concussion syndrome, an entity strongly related to axonal injury. Indeed, it has been found that post-concussion syndrome is an entity with clinical, imaging, and histopathological correlation with axonal injury, with many authors reporting that concussion syndrome is in the milder spectrum of TAI [ 71 ].…”