Abstract
Although mild traumatic brain injury (mTBI), or concussion, is not typically associated with abnormalities on computed tomography (CT), it nevertheless causes persistent cognitive dysfunction for many patients. Consequently, new prognostic methods for mTBI are needed to identify at risk cases, especially at an early and potentially treatable stage. Here, we quantified plasma levels of the neurodegeneration biomarker calpain-cleaved αII-spectrin N-terminal fragment (SNTF) from 38 participants with CT-negative mTBI, orthopedic injury (OI), and normal uninjured controls (UCs) (age range 12–30 years), and compared them with findings from diffusion tensor imaging (DTI) and long-term cognitive assessment. SNTF levels were at least twice the lower limit of detection in 7 of 17 mTBI cases and in 3 of 13 OI cases, but in none of the UCs. An elevation in plasma SNTF corresponded with significant differences in fractional anisotropy and the apparent diffusion coefficient in the corpus callosum and uncinate fasciculus measured by DTI. Furthermore, increased plasma SNTF on the day of injury correlated significantly with cognitive impairment that persisted for at least 3 months, both across all study participants and also among the mTBI cases by themselves. The elevation in plasma SNTF in the subset of OI cases, accompanied by corresponding white matter and cognitive abnormalities, raises the possibility of identifying undiagnosed cases of mTBI. These data suggest that the blood level of SNTF on the day of a CT-negative mTBI may identify a subset of patients at risk of white matter damage and persistent disability. SNTF could have prognostic and diagnostic utilities in the assessment and treatment of mTBI.
Highlights
Mild traumatic brain injury, alternatively referred to as concussion, is the most common neurological injury and affects over 1.5 million children and adults each year in the United States alone, and hundreds of thousands of military personnel worldwide [1, 2]. mTBI is typically undetectable with computed tomography (CT), yet can elicit long-term and clinically significant brain dysfunction in ∼15–30% of cases [3,4,5,6]
Whereas a number of brain-enriched proteins have been evaluated before as candidate prognostic markers for cases of mTBI with negligible CT findings, including the astrocyte-enriched S100β and glial fibrillary acidic protein (GFAP) along with the neuron-enriched neuron-specific enolase (NSE), cleaved tau, a C-terminal fragment of αIIspectrin termed SBDP145, and ubiquitin Cterminal hydrolase L1 (UCH-L1), none has demonstrated a prognostic relationship with structural signs for white matter injury or functional signs for impaired cognition [17, 22, 23, 52]
In contrast to the prior findings with other marker candidates, our results raise the possibility that the blood level of Spectrin N-terminal fragment (SNTF) and potentially other neurodegeneration biomarkers sampled in the acute period after CT-negative mTBI might help identify at an www.frontiersin.org early and potentially treatable stage a subset of cases at risk of developing white matter tract structural damage and long-term disability
Summary
Mild traumatic brain injury (mTBI), alternatively referred to as concussion, is the most common neurological injury and affects over 1.5 million children and adults each year in the United States alone, and hundreds of thousands of military personnel worldwide [1, 2]. mTBI is typically undetectable with computed tomography (CT), yet can elicit long-term and clinically significant brain dysfunction in ∼15–30% of cases [3,4,5,6]. Histopathological and biomechanical findings in experimental animal models and human cases that have come to autopsy suggest that the main underlying structural correlate for long-term functional impairment after mTBI is diffuse axonal injury (DAI) resulting from head rotational acceleration at the moment of injury [6,7,8,9,10]. Developing neuroradiological methods, such as diffusion tensor imaging (DTI), have shown promise for the detection of white matter structural abnormalities after mTBI, but collectively these studies have yielded inconsistent results [11, 12]. Blood levels of the astrocyte-enriched proteins S100β and glial fibrillary acidic protein (GFAP), along with www.frontiersin.org
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