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Table of Contents    
Year : 2017  |  Volume : 65  |  Issue : 4  |  Page : 767-769

Correlation of biomarkers with cognitive deficits in young adults with mild traumatic brain injury

Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication5-Jul-2017

Correspondence Address:
Deepak Gupta
Department of Neurosurgery, Neurosciences Centre and JPN Apex Trauma Centre, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/neuroindia.NI_524_17

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How to cite this article:
Gupta D, Raheja A. Correlation of biomarkers with cognitive deficits in young adults with mild traumatic brain injury. Neurol India 2017;65:767-9

How to cite this URL:
Gupta D, Raheja A. Correlation of biomarkers with cognitive deficits in young adults with mild traumatic brain injury. Neurol India [serial online] 2017 [cited 2020 Oct 21];65:767-9. Available from:

The authors have performed a prospective observational study to evaluate the diagnostic role of acute phase serum biomarkers in patients with mild traumatic brain injury (mTBI), and their potential impact on the short-term neuropsychological outcome at the end of 3 months. There is no true “gold-standard” for the early diagnosis of mTBI. There may still be utility in considering the possibility that patients with elevated biomarkers may have sustained actual brain injury despite having a negative computed tomographic (CT) scan. Over the last two decades, there has been an increasing interest in several serum proteins that could potentially predict the presence of brain injury resulting from head trauma. These proteins are released as a result of blunt or rapid deceleration forces to the head that cause injury to the neurons and supporting glial cells. The most widely studied biomarker for this purpose is S100B, a protein that is released after astroglial injury. It has been suggested that the S100B biomarker level below a threshold level can safely eliminate the need to obtain a CT scan in patients with mTBI.

More recently, other biomarkers have begun to receive more attention for their potential role in detecting brain injury. These include glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1). GFAP is a protein expressed in astroglial cells, but unlike S100B, GFAP is not found in significant amounts in extracerebral cells. Previous studies have demonstrated that elevated levels of GFAP in patients with mTBI are associated with abnormal findings on imaging of the brain. Their presence can predict the need for a surgical intervention, and is able to differentiate between patients in motor vehicle accidents with pure orthopedic injuries and those who have sustained a mTBI.

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a deubiquitinase present in neurons. Elevated serum levels of this protein have been correlated with brain injury and clinical outcome. There is some evidence for GFAP but only little evidence for UCH-L1, regarding the early diagnostic utility of these biomarkers in patients with mTBI. Given the limitations of S100B as an ideal single biomarker for pre-CT screening of patients with mTBI, other biomarkers, such as GFAP and UCH-L1, are useful in screening for the presence of acute intracranial lesions among patients with mTBI.

The authors in the present study have analyzed the serum biomarker, calcium binding protein B (S100 β and UCH-L1) in this study. To ascertain the diagnostic value of these two serum biomarkers in mTBI, they used a case control design with 20 participants in each group. The study population comprised of 20 adult mTBI patients (with their ages ranging from 19-40 years) presenting within 6 hours of injury to their neurotrauma centre; while, the control group included age, gender and education status matched healthy volunteers. They failed to demonstrate any statistically significant difference in the serum biomarker levels among the two study groups; however, they suggested a trend towards higher serum biomarker levels in mTBI patients.

The second objective of the study was to assess the presence/absence of cognitive decline in the traumatic cohort when compared to the healthy volunteers, as well as to establish the correlation of serum biomarker levels with the short-term neuropsychological outcome in the traumatic head injury cohort. Using a panel of indigenously developed battery of neuropsychological tests for head injured patients, the authors demonstrated the presence of cognitive decline in the population that had sustained trauma. They also demonstrated the presence of a correlation between the S100 β and UCH-L1 biomarker levels, and the selective domains of neuropsychological outcome including working memory, verbal learning, verbal fluency, and visual memory. They also noted a positive correlation between the concentration of biomarkers released into the blood stream and the extent of neuropsychological impairment at a 3 month follow-up.

The authors have to be commended for their work that objectively analyzes the much-overlooked symptom of cognitive impairment following minor head injury, which can significantly impact the social and occupational rehabilitation of patients recovering from traumatic brain injury. However, their study suffers from a few major shortcomings including those highlighted by the authors themselves. Their study is underpowered due to the limited sample size, rendering validity of the study results questionable. The limited age range of the enrolled patients (19-40 years) and exclusion of patients with a Glasgow Coma scale (GCS) of 13, precludes the generalizability of the study results and its applicability, in general, in the realm of minor head injury. A post-injury short follow-up duration of just 3 months is another shortcoming of this study. As highlighted by the authors, a better control group could be comprised of patients who have sustained non-head injury trauma as opposed to healthy volunteers, since the extracranial injuries have also been known to cause elevations in serum biomarkers along with cognitive decline.[1]

To assess the serum biomarker levels in the acute phase of traumatic brain injury, the authors designated two sampling time periods in quick succession, with the first one within 6 hours of injury and the next one within 6-12 hours of injury. The mean time difference between the two sampling periods was ~5 hours in their study, which seems to be quite a short duration for detecting any significant differences in the impact of biomarker levels on the cognitive outcome. Instead, the authors should have spaced the sampling times much more than just a few hours, as has been performed in previous studies.[2],[3],[4] Adequately spacing the sampling time, essentially helps to identify the incidence of a persistent elevation or a delayed rise due to secondary brain injury, due to the ongoing release of astroglial (S100 β) and neuronal (UCH-L1) markers into the blood stream from the disruption of blood brain barrier (BBB).

Serum assay of astroglial biomarker - S100 β is constrained by its poor BBB permeability, short half-life (~2 hours, small sampling window), and its peripheral source of production besides the central nervous system (CNS). On the contrary, UCH-L1, a neuronal marker has better BBB permeability and a longer t 1/2 of ~8 hours. It is also much more specific for CNS as the neuraxis is responsible for its primary production.[2],[5] Since the average time for the first and second sampling in this study were 3.7 hours and 8.7 hours from the onset of injury respectively, therefore quantitative assessment of UCH-L1 might have been inappropriate during the first sampling time; while, S100 β sampling during the second sampling time period might have been too late, for appropriately measuring the levels to assess for the extent of brain injury. Sampling time period window often gets governed by the metabolic profile of the target biomarker agents. Cerebrospinal fluid (CSF) biomarker level of S100 β is a more sensitive diagnostic tool to assess for the extent of injury.[5] However, it may not be practically feasible to perform CSF studies in patients with mTBI and in healthy volunteers.

The authors have stated that despite the fact that there was no statistically significant difference between the serum biomarker levels among the two study groups (mTBI and control groups), there was a trend towards higher biomarker levels in the test group. However, on carefully looking at the mean values of biomarker levels and their corresponding P values, it becomes quite apparent that there was no difference whatsoever between the two groups. In fact, for UCH-L1 at both time periods, and for S100 β at <6 hours, the mean values were marginally more in the control group as compared to the patient group. Hence, there seems to be an apparent bias while interpreting the results. Therefore, the authors should restate the conclusions and findings of the study, and try and identify the possible reasons for not being able to find difference in serum biomarker levels between the two groups. One of the possible reasons for a negative result in this study could be the exclusion of patients with the admission GCS of 13 from the study cohort, since it is quite reasonable to think that greater the severity of injury, lower is the GCS score, and consequently, higher are the amount of glial and neuronal biomarkers released into the bloodstream as a result of BBB disruption. It could have very well affected the average serum biomarker levels in the mTBI group. Welch et al., in their study of 251 cases of TBI noted that when obtained within 6h of injury and thereafter 6 hrly for 24 hrs (maximum of 5 samples during the index visit), UCH-L1 and the combination of GFAP and UCH-L1 were very sensitive for predicting a positive CT scan of the head among patients with mild-to-moderate TBI.[6]

The average scores in trail making tests 1 and 2 were significantly higher in the patient group as compared to the control group. Similarly, UCH-L1 serum levels within 6 hours of injury were positively correlated with Rey's auditory verbal learning test (rho = 0.529, P = 0.05); and, UCH-L1 serum levels within 6-12 hours of injury, correlated positively with the spatial span testing working and verbal memory (rho = 0.650, P< 0.01). These findings with a positive correlation between the biomarker levels and the test scores suggest that patients with a higher load of serum biomarkers released from CNS fared better in their neuropsychological assessment. This contradictory finding needs to be rationally explained with an appropriate and a plausible explanation. Getting a baseline neuropsychological assessment performed at the time of the initial admission might have helped to answer some of these aberrant observations at a 3 month follow-up. Besides this, the authors' attempt to correlate the variations in serum biomarker levels with the short-term neuropsychological outcome may have be inappropriate in the present context, given the fact that there was no evidence of statistically significant elevation of biomarker levels in mTBI patients as compared to healthy volunteers.

Both S100B and GFAP have been studied in patients with mild-to-moderate TBI, with the former being extensively evaluated. For UCH-L1, however, only limited information, particularly related to the early screening for CT abnormalities, is available in patients with mild-to-moderate TBI.

The analysis in this study has primarily focused on establishing the association of admission serum biomarker levels with the neuropsychological outcome. Whether the observations made in this study are just a mere coincidence or actually have a cause and effect relation will be difficult to establish. Hence, a logistic regression analysis taking all the relevant confounding factors into account would have been a better statistical approach to delineate the factors truly predicting outcome. Lastly, the radiological findings should also have been correlated with biomarker levels, since the S100 β level is known to correlate with contusions, and the UCH-L1 levels is described to correlate with the diffuse axonal injury pattern of imaging findings. Getting a magnetic resonance imaging of the brain in patients who have sustained a TBI would have also provided some novel insights into the persistent changes in the brain areas attributed to regulating the corresponding cognitive functions.[7],[8] Therefore, a true clinical, radiological, and biochemical correlation would have been a much more rationale approach to understand the mechanisms of cognitive decline in patients with mTBI.

  References Top

Dey S, Gangadharan J, Deepika A, Kumar JK, Christopher R, Ramesh SS, et al. Correlation of ubiquitin C terminal hydrolase and S100β with cognitive deficits in young adults with mild traumatic brain injury. Neurol India 2017;65:761-66.  Back to cited text no. 1
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Papa L, Brophy GM, Welch RD, Lewis LM, Braga CF, Tan CN, et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol 2016;73:551-60.  Back to cited text no. 2
Posti JP, Hossain I, Takala RS, Liedes H, Newcombe V, Outtrim J, et al. Glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 are not specific biomarkers for mild CT-negative traumatic brain injury. J Neurotrauma 2017. doi: 10.1089/neu. 2016.4442.  Back to cited text no. 3
Kleindienst A, Ross Bullock M. A critical analysis of the role of the neurotrophic protein S100B in acute brain injury. J Neurotrauma 2006;23:1185-200.  Back to cited text no. 4
Li J, Yu C, Sun Y, Li Y. Serum ubiquitin C-terminal hydrolase L1 as a biomarker for traumatic brain injury: A systematic review and meta-analysis. Am J Emerg Med 2015;33:1191-6.  Back to cited text no. 5
Welch RD, Ayaz SI, Lewis LM, Unden J, Chen JY, Mika VH, et al. Ability of serum glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, and S100B to differentiate normal and abnormal head computed tomography findings in patients with suspected mild or moderate traumatic brain injury. J Neurotrauma. 2016;33:203-14.  Back to cited text no. 6
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[PUBMED]  [Full text]  
Massenburg BB, Veetil DK, Raykar NP, Agrawal A, Roy N, Gerdin M. A systematic review of quantitative research on traumatic brain injury in India. Neurol India 2017;65:305-14  Back to cited text no. 8


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