Updated Review of Neurologic Concussion Biomarkers for Time-sensitive Point-of-care Testing

Abstract

As traumatic brain injuries (TBIs) continue to rise annually, scientists are continuing to improve point-of-care (POC) testing, involved in TBI diagnosis. TBIs, having various levels of severity, are often misdiagnosed or overlooked, especially in acute mild TBI or concussion scenarios. At the POC, currently, medical professionals utilize neuroimaging, cognitive scales, and biomarker assays to diagnose concussions and other forms of TBI. However, many of these parameters hinder diagnostic value due to accessibility and time-sensitive restraints. After analyzing the profuse research surrounding time sensitive concussion biomarkers kinetics, in the National Institute of Health National Library of Medicine database, this review aims to compile all published research on concussion POC biomarkers, screened between 2022 and 2023. Commonly studied concussion POC biomarkers include ubiquitin C-terminal hydrolase L1, glial fibrillary acidic protein, visinin-like protein-1, S100 calcium-binding protein B, tau, and neurofilament light chain. Each neurologic biomarker has various implications and limitations when characterizing TBI. Novel biomarkers and multimodal paired concussion parameter models are continuously being evaluated for their respective diagnostic strengths and weaknesses.

INTRODUCTION

Traumatic brain injuries (TBIs), one of the leading causes of hospitalization and death in the United States, have continued to impact millions of patients, annually. Motor vehicle accidents, military combat, contact sports, civilian falls, and physical assaults are some of the main causes of TBI.[1,2,3,4,5] TBI rates are most common in geriatric (75 years and older), pediatric (0–4 years), and young adult (14–24 years) populations, respectively.[3,6,7] Today, TBI has become a larger topic of concern, as TBI patient populations have consistently risen over recent years.[2,3] In the context of the total U. S. population, recently, approximately 1.7 million individuals have experienced either injury, hospitalization, death, or some secondary effects of TBI.[2] As presented by Georges and Das, there has been a significant increase in diagnosed patient cases, surging from 10,958 to 344,030, between 2000 and 2015.[2] In parallel, Moore and Sandsmark reiterated further supporting the Centers for Disease Control and Prevention statistics, recording a 53% increase in related national emergency department visits between 2010 and 2019.[3] With numerous studies highlighting its effect on society, scientists continue to brainstorm ways to prevent, diagnose, treat, and potentially cure patients with lasting symptoms.[1,2,3,4,5] Evaluating the reasons for the recent increases in TBI cases, scientists have speculated several key reasons. Garza et al. hypothesize that the aging U. S. population may be the greatest influence on the increase in TBI cases, correlating the growth in the geriatric population ratio to the types of injuries that accumulate within this demographic.[1,8] In addition, while geriatric populations are the most impacted by TBI, this study further mentions that developing countries are also significantly influenced by the increased cases of motor vehicle accidents, falls, sports-related injuries, and many other similar incidents, influencing all ages.[1,3,4] Similar studies also analyze the influence of geographic barriers, monetary hurdles, and medical care accessibility. Wittevrongel et al. positively correlated concussion diagnostic rates to the accessibility of care for those categorized with high socioeconomic status.[8] Finally, with the continuous growth in diagnostic procedures, scientists also appreciate the recent advances in TBI prognosis, analyzing the various psychopathological variables that have assisted medical professionals in indicating early TBI severity patterns in patients.[9] Fighting against the rise in TBI cases, investigating accurate diagnostic tests, discovering potentially groundbreaking treatments, and improving TBI prognosis, scientists are continuing grand efforts to improve all forms of TBI point-of-care testing (POCT).[2,3,10]

TRAUMATIC BRAIN INJURY POINT-OF-CARE TESTING

While millions of individuals are impacted by various forms of TBI, each brain injury can be identified as mild, moderate, or severe injuries, along with additional classifications of penetrating and nonpenetrating characteristics.[1,2,3,7] The majority of TBI falls under the category of mild TBI (mTBI), making up around 75% of all brain injury cases.[4,11] Concussions, the classification that will be focused on in this review, are classified as nonpenetrating mTBI with no significant characteristics of structural brain damage.[3,4] In general, concussions can occur through either one mTBI impact or several subconcussive hits, overall influenced by impact severity, number of collisions, and time intervals between hits.[2,3,10,12] As many studies have shown, after experiencing either one severe concussion or multiple accumulated hits, patients can be affected by various short-term and long-term effects, including, double vision, light sensitivity, posttraumatic headaches, psychological symptoms, sleep disorders, postconcussion syndrome (PCS), and eventually, chronic traumatic encephalopathy (CTE).[6,13,14,15,16,17,18,19] Often, regardless of conventional symptoms, isolating concussions from other forms of TBI is difficult due to their heterogeneous and dynamic attributes. While highlighting penetrating characteristics can help upgrade TBI severity, it does not necessarily assist in segregating those with minute structural brain damage, concussions, or other forms of mTBI. The kinetics of brain biomarkers and the molecular plasticity of the brain, during injury, are constantly changing, displaying either hidden or clear postinjury symptoms.[17,20] As stated by Schmit et al., approximately 50% of all concussions remain undiagnosed, while an estimated 25.5%–32% of all concussions are diagnosed late.[21] In a social sense, as analyzed by many surveys and interviews, it is believed that concussion disclosure can be affected by a lack of informative knowledge, social pressures, personal intentions, sports culture, professional stigmas, or inaccessible medical support.[7,22,23,24,25] Regardless of social reasons, research has emphasized the need for quick and accurate concussion diagnoses, especially before returning to sport-related action or military combat.[5,21,22,23]

SEARCH AND SELECTION CRITERIA

Understanding the rising prevalence of concussion research and increased application of neuroproteomic biomarker diagnostics, this review aims to compile the most prevalent concussion biomarkers assessed primarily for concussion POCT, exclusively over the last year of research in the United States (2022–2023). The most prevalent commercial biomarkers were elaborated on, while novel, horizon biomarkers were mentioned for prospective future applications. The Boolean search phrases including, “Concussion Biomarkers AND Concussion point of care AND Concussion Biomarkers at Point of Care,” were all screened through the National Institute of Health (NIH) National Library of Medicine database, filtered over the 2022–2023 time frame. As expected, after screening all articles derived from each search phase, respectively, the broadest results were derived with “Concussion Biomarkers” and the narrowest with “Concussion Biomarkers at Point of Care.” In the end, after meticulously screening for topic relevance, duplicates, and publication dates of less than a year (2022–2023), a total of 149 works of literature qualified for further analysis.

SEARCH FOR BIOMARKERS

Neuroimaging

With high percentages of late and undisclosed concussion cases, many scientists have investigated its consequences. Studies have listed the ramifications of missing concussion diagnoses, listing overwhelming symptom burdens that last over 2 days postinjury (P < 0.001), longer recovery times, and delayed activity return timelines.[11,21] Analysis, like the review from Graham et al., emphasizes the corollary of repetitive concussions, especially in youth, linking it to increased rates of depression, suicide, posttraumatic stress disorders (PTSD), neurocognitive deficits, long-term neurodegenerative diseases, and many other unfavorable neurologic conditions.[5] Currently, to improve concussion POCT, medical professionals are brainstorming potential diagnostic tools that can identify the severity of brain injuries and optimize outcome predictions through qualitative neurologic imaging, quantitative neurocognitive scales, and biomarker assay data.[5,20,21,26,27,28] Evaluating through a qualitative perspective, computed tomography (CT) and magnetic resonance imaging (MRI) are the two most common neuroimaging procedures for TBI.[6,13] Currently, evidence positively supports utilizing CT scans for initial TBI triage and MRI for more detailed imaging, 24–48 h postinjury.[27,29,30] However, regardless of their beneficial data, both CT and MRI only illustrate gross structural brain damage, blind to psychological, cognitive, molecular, and minute neurologic symptoms, all of which are critical for classifying the severity of injury.[27,29] In addition, when dealing with acute patients, neuroimaging is often time-consuming, extortionate, inaccessible, and sometimes ineffective for discriminating mild injuries from major brain injuries.[20,27,29] Highlighting the limitations in time consumption, CT scans can often delay brain injury reports by 3 h, undermining the accuracy of injury severity in certain situations.[20,31] This also downplays the need for immediate CT scans in many acute scenarios, especially when many studies highlight the consequences of altered patient outcomes caused by protocol delays within the first 48 h of injury.[14,20] Analyzing the cost of treatment and injury, it is also estimated that TBI management costs approximately over $40 billion, with neuroimaging accounting for significant proportions of the expenses.[14,20] In comparison to CT scans, MRI seems to produce 10%–20% more detailed readings, highlighting contusions, hematomas, hemorrhages, and other structural abnormalities.[20] While MRI is favored over CT scans for TBI diagnostics, the expenses for MRI are profoundly higher, and accessibility to MRI machines is limited, especially when dealing with military and sports-related TBI.[19,31,33,34,35] In retrospect, as analyzed by Dennis et al., while more recent neuroimaging has provided valuable insights into TBI diagnosis, translating neuroimaging data to clinical care is difficult due to the heterogeneity of TBI severity and the lack of clinical studies that support normative outcome data.[20,30,32,33,34]

Neurologic screening tools

Examining through a quantitative, macroscopic lens, there have also been many numerical neuropsychomotor scales that have assisted professionals in classifying brain injury severity, especially distinguishing potential concussion symptoms in various cases. Some common scale scores include the vestibular ocular motor screening (VOMS) assessments, Standardized Assessment of Concussions (SACs), Sports Concussion Assessment Tool 3 (SCAT3), Military Acute Concussion Evaluation, Concussion Challenge Assessment, King-Devick tests, Rotterdam CT score, Marshall classification system, and numerous other neurologic assessments.[5,15,35,36,37,38] While there may be a plethora of assessments, many tests like the near point of convergence test, a VOMS scale, only produce broad results, distinguishing musculoskeletal injuries from brain injuries and failing to highlight concussion symptoms when used independently.[15,35,39] In addition, many tests such as the SCAT3 (P < 0.001) and SAC (P = 0.03) have significantly different symptom and severity scores for opposite genders, demonstrating no standardization for clinical application.[40,41] On the contrary, while many scales are inadequate in clearly diagnosing concussions, one of the most consistent scoring systems utilized includes the Glasgow Coma Scale (GCS), which measures neurocognitive aspects of consciousness, factoring eye movement (4 points), verbal communication (5 points), and motor response (6 points).[5,42] The most updated GCS scores label patients with either mild (13–15 points), moderate (9–12 points), or severe (3–8 points) TBI, categorizing the impact of injury and classifying patients for their next steps to time-sensitive treatment.[5,20,42] Although the GCS has been proven to help predict mortality and severity, many studies have found gray areas in its scoring distributions.[42,43] First, as analyzed by Jain et al., the GCS scoring system heavily emphasizes the motor response of patients, as it significantly indicates a more severe TBI. In hindsight, this scoring method restrains GCS from accurately classifying a milder TBI, which demonstrates stronger signs of ocular and verbal deficits.[44] Another ceiling for the GCS scoring system is highlighted in an early study by Mena et al., who contraindicated today’s GCS scoring boundaries, supporting that a GCS score of 13 predicted mortality rates for moderate TBI more significantly than mTBI.[42] In continuation, Nair et al. further discuss multiple studies illustrating how equivalent GCS scores can lead to variable outcomes, regardless of the initial characterized points.[43] Similar studies also discuss how even certain molecular biomarker indications, like rises in myelin basic protein (MBP) concentrations, contraindicate with GCS scoring categorizations at certain time points of diagnosis.[45] As concluded by Jain and Iverson and many other scientists, research supports that GCS and other scoring systems should not be the sole autonomous factor utilized for predicting TBI severity and patient outcomes and rather should be utilized in multifactorial models, paired with other parameters for more accurate patient outcome predictions.[28,44]

Molecular biomarkers

Finally, in addition to neuroimaging and quantitative scoring systems, recent studies have focused primarily on neurologic biomarkers and their kinetics throughout TBI and its diagnosis. A variety of neurologic biomarkers is found in blood, serum, cerebrospinal fluid (CSF), saliva, and similar mediums. Each biomarker has its own critical windows for detection during point of care (POC) and fluctuates at various time points. Aiming to determine the most consistent biomarker presentation patterns, biomarker concentrations are being evaluated in minutes, hours, days, months, and years after injury.[20,27,44,46,47] While CSF seems to have the most abundant and reliable biomarkers, scientists are also investigating alternative biofluid sampling procedures, aiming to find more accessible and noninvasive diagnostic procedures.[47] In the most updated studies, the most commercialized biomarkers in diagnosing and prognosing TBI include ubiquitin C terminal hydrolase L1 (UCHL 1), Visinin like protein 1 (VLP 1), S100 calcium binding protein B (S100B), glial fibrillary acidic protein (GFAP), tau, and neurofilament light chain (NfL).[27,48,49] Currently, utilizing the i-STAT TBI Plasma test, GFAP and UCHL-1 have been named the first biomarkers to be commercially approved for concussion testing by the United States Food and Drug Administration (FDA).[50,51] As such a modern advancement and little conclusive data, scientists hope that biomarker research will continue to improve clinical and legal classifications of mTBI and concussions.[52] In addition to protein biomarkers, scientists like Yilmaz et al.[53] also tested the potential of metabolomic profiles testing biomarkers such as taurine, creatinine, adenine, dimethylamine, histidine, N-acetylaspartate, and glucose 1-phosphate. For a holistic point of view, scientists believe that pairing multiple reliable neurologic biomarkers will help classify concussions from severe TBI and efficiently predict prognosis at POC.[2,27] In contrast to neuroimaging and cognitive assessments, biomarkers are time-sensitive neurologic parameters and provide a deeper insight into the state of the injury on a molecular level.[20,27] Many scientists, like Zimmer et al., have also evaluated the cost-effective benefits of pairing diagnostic biomarkers and limiting unnecessary neuroimaging for many acute TBI cases.[54,55,56] Overall, with continuous efforts and overwhelming research, studying various neurologic POC TBI biomarkers, this review aims to highlight those most studied, specifically in the last year of concussion research. Already successful in many studies, it has been supported that biomarkers can be paired together, some along with neuroimaging and quantitative scales, for potentially novel concussion diagnosis and POC protocols.

Concussion protein biomarkers at point-of-care testing

Before diving into the various imminent POC concussion biomarkers, highlighted by recent studies, it is important to understand where these biomarkers originate from and how they deposit into their respective biofluids. First, describing the mechanism of TBI, it has been documented that during injury, intracranial pressure typically augments through increased cerebral blood flow and possibly induces cerebrovascular damage throughout the brain.[47,57,58,59,60] At intersections like the blood–brain barrier (BBB), the body naturally compensates for injury through neuroinflammation, collecting circulating blood and CSF to provide nutrients, oxygen, and support. During nutrient exchange and circulation, indicative biomarkers concentrate in biofluids such as CSF, blood serum, urine, saliva, tears, and much more.[27,47,59] When describing the various protein biomarkers, it is important to discuss each protein’s origin of release [Figure 1]. First, there are neural cell-body proteins, which include UCHL-1 and VLP-1, commonly released in CSF, blood, or saliva during injury.[48,61] Additional proteins, classified as glial markers, encompass indicators such as S100-B calcium-binding protein and GFAP, accumulating throughout the body through astroglial cell damage and BBB disturbance.[48,61,62] Finally, there are axonal biomarkers, such as tau, NfL, and MBP, most often collected in peripheral blood, urine, and CSF, all indicative of repetitive concussions, severe TBI, axonal damage, necrosis, or prolonged tauopathy conditions, such as CTE and Alzheimer’s disease (AD).[48,61,62] UCHL-1, VLP-1, S100B, GFAP, tau, NfL, and various other biomarkers together act as characteristic biomarkers for brain injury POCT, all heavily studied with various and unclear implications. These biomarkers fluctuate at various intervals during TBI and together are potentially effective for creating a kinetic model for TBI diagnosis.[61,62,63] Their concentrations long after injury are also beneficial as they correlate to many neurobehavioral outcomes, such as depression, anxiety, and PTSD.[64] While UCHL-1 and GFAP are the only commercially approved biomarkers, VLP-1, S100B, tau, and NfL have been around and studied repetitively over the last two decades.[47,51] Despite the abundance of supporting data, it must also be acknowledged that although there are many common biomarkers and patterns, as discussed in this analysis, each individual’s physiology and unique situation can present with distinctive symptoms, exclusive biomarker presentations, and alternative condition outcomes longitudinally [Table 1].[29,48,61,62,63,64]

Figure 1.

Listing the most studied concussion biomarkers, it is important to highlight from where each biomarker emerges. During TBI, scientists have observed the kinetics of biomarkers primarily stemming from neural cell bodies, axonal sheets, and astroglia cells. UCHL-1, VLP-1, and NSE, originating in the cell body, usually deposit in CSF, blood, or saliva, after brain injury. Astroglia markers, like GFAP and S100B, are found in similar biofluids, concentrated throughout the CNS, often emerging in conditions outside of TBI. Finally, axonal markers, including tau, NfL, and MBP, disintegrate from the axon and myelin sheath, usually indicative of severe injury or long-term neurodegeneration. Together the protein kinetics of all these biomarkers are key in TBI POCT, and each can potentially assist in different aspects of concussion diagnosis

Table 1.

Prominent concussion diagnostic protein biomarkers at point of care (2022–2023)

Biomarker		Biofluid medium		Conclusions		Statistical significance		Source
UCHL-1		1,2Blood		1Blood UCHL-1 concentrations were strongly associated with CT + lesions		1AUC=0.82		Papa et al., 2022[65]
		1,2Blood		2POC UCHL-1 can differentiate CT + lesions and structural abnormalities within the first 8 h of TBI		2AUC=0.779		Wang et al., 2023[66]
VLP-1		1Blood		1Dependent on injury severity and the respective sports played, blood ubVILIP-1 concentrations increase significantly within 30 min of sport-related concussions		1P=0.014		Wu et al., 2022[72]
S100B		1,2Blood		1Among the blood-based biomarkers studied in rugby concussion patients, S100B was characterized to have a significant capacity to differentiate resolutive and nonresolutive concussions within 36 h of injury		1P=0.006		Oris et al., 2023[75]
		1,2Blood		2Incorporating a multimodal model, age, Charlson index scores, institutional status, hemoglobin, platelet, and blood S100B concentrations, together significantly correlated with patient mortality		2P<0.05		Yuguero et al., 2023[77]
		3Serum		3Serum S100B concentrations displayed a strong ability to rule out TICH in low-risk, mild brain injuries		4NPV: 100% PPV: 10.1%		Faisal et al., 2023[73]
		4Plasma		4Plasma S100B concentrations can reduce unnecessary CT scans, by significantly predicting the presence of intracranial lesions in mTBI patients		4NPV: 93% PPV: 16.3% Sensitivity: 93.2%		H Hopman et al., 2023[74]
GFAP		1,2Blood		1Blood GFAP concentrations were strongly associated with CT + lesions presentation		1AUC=0.84		Papa et al., 2022[65]
		1,2Blood		2Blood GFAP concentrations, collected in the first 24 h of mTBI, positively correlate with PTA* and reduced risk of PTSD**		2Correlation between GFAP and PTA*: ρ=0.35, P<0.001, OR=0.85**		Kulbe et al., 2022[81]
Tau		1Plasma		1In retired contact sport athletes, p-tau181 concentrations* were significantly higher, and related white matter integrity** was significantly lower		1P=0.02* P=0.003**		Vasilevskaya et al., 2022[91]
NfL chain		1-6Serum		1Serum NfL concentrations were found significantly higher in mTBI cases, such as sport-related concussions		1P=0.0015		Karantali et al., 2022[98]
		1-6Serum		2When comparing professional soccer athletes versus nonathletic controls, data supported no significant differences in serum NfL concentrations, indicating that high levels of exercise do not influence NfL		2P=0.957		Cornali et al., 2022[99]
		1-6Serum		3In a cohort of collegiate women polo athletes, experiencing concussion and accumulated subconcussive impacts, serum NfL concentrations were significantly correlated with head impact exposure		3P=0.957		Huibregtse et al., 2023[101]
		1-6Serum		4Serum pNF-H chain significantly increases between 2 and 4 h of injury and subsides around 6-h postinjury		P<0.001d		Karesioglu et al., 2022[103]
		1-6Serum		5In a two-hit induced-mTBI rat model, after one mTBI incident, serum NfL concentrations strongly correlated with reinjury or neurologic vulnerability toward a potential second mTBI* Patients with more than two neurologic symptoms, post-mTBI, were categorized to have significantly higher brain injury severity in comparison to those with two or fewer neurologic signs**		P=0.0044*, e AUC=0.73** P=0.009		O’Brien et al., 2023[105]
		1-6Serum		6Serum NfL demonstrated a significantly poor ability to predict CT + intracranial lesions in mTBI patients* However, after mTBI, serum NfL has a significant ability to categorize patients with neurologic disorders**, strongly associating with neurodegenerative characteristics		AUC=0.58*,f AUC=0.87**		Kahouadji et al., 2022[102]

UCHL-1: Ubiquitin C-terminal hydrolase L1, VLP-1: Visinin-like protein-1, S100B: S100 calcium-binding protein B, GFAP: Glial fibrillary acidic protein, NfL: Neurofilament light, TICH: Traumatic intracranial hemorrhage, NPV: Negative predictive value, PPV: Positive predictive value, PTA: Posttraumatic amnesia, p-tau181: Plasma phosphorylated tau-181, pNF-H: Phosphorylated NfL heavy, POC: Point of care, TBI: Traumatic brain injury, mTBI: Mild TBI, CT: Computer tomography, AUC: Area under the curve, OR: Odds ratio

Ubiquitin C-terminal hydrolase L1

Throughout the studies evaluated over the past year, UCHL-1 stood out as one of the most studied concussion biomarkers. As a neural cell body biomarker, it has been previously tested as a potential criterion for various TBI diagnostics and officially been approved as a commercial biomarker in plasma concussion testing.[47,51] However, regardless of its strengths, its efficiency in differentiating concussions and mTBI is still being tested.[48,61] To further investigate the efficacy of UCHL-1, Papa et al. conducted one clinical study on a cohort of all verified concussion patients, controlling GCS scores and time of injury. Here, this experiment concluded that UCHL-1 concentrations (P = 0.025) were strong indicators for injury severity, especially when significantly associated with CT + lesion profiles (area under the curve [AUC] = 0.82). In addition, UCHL-1 proved to be a successful prediction tool for detrimental 3-month postinjury outcomes, regardless of CT lesion presentations. Interpreting these results, UCHL-1 concentrations could potentially replace the need for unnecessary CT scans, in severe injuries, and beneficially contribute to long-term prognostic models.[65] Similarly, Wang et al. compared the greater diagnostic efficiency of UCHL-1 (AUC = 0.779) to neuron-specific enolase (NSE) (AUC = 0.684), specifically when evaluating TBI subjects. Despite the often-contraindicating data from false-positive and false-negative neuroimaging scans, it was determined that UCHL-1 was significantly more effective in detecting structural brain damage, isolating moderate-and-severe TBI cases within the first 8 h of injury at POC.[66] In synopsis, UCHL-1 seems to be a proven potential biomarker for detecting moderate-to-severe TBI, regardless of juxtaposing neuroimaging data.[65,66] In contrast, while UCHL-1 seems to be a highly favored TBI biomarker, its boundaries for concussion diagnosis must also be noted. UCHL-1 has a strong ability to detect structural brain damage and CT + lesions; however, more parameters are necessary to further differentiate concussions from more severe TBI.[65,66] As many studies have shown, blood UCHL-1 concentrations are consistently detectable as early as within 1 h of TBI, signaling structural brain damage, but regardless, many have rejected its diagnostic power due to the high variability among tested subjects (P > 0.05).[67,68,69] Supporting these claims, Harrell et al. discreetly displayed UCHL-1 as having significant variability between genders (P = 0.007) and no significant diagnostic powers for isolating concussions (P > 0.05) from other brain injuries.[67] Overall, while having many strengths in detecting structural brain damage, without extrinsic neuroimaging, the diagnostic power of UCHL-1 is limited and must be further tested for more effective utilization in concussion POC.[65,66,67,68,69]

Visinin-like protein-1

Another CSF neuronal body biomarker, VLP-1, has also been heavily tested and hypothesized as a potential index parameter for distinguishing concussion from other TBI cases.[48,61] As previously researched, VLP-1 has been defined as comparable to tau in foreshadowing cognitive impairment, dementia, and early-stage AD.[70] Although a horizon biomarker not heavily utilized in the realms of concussion or mTBI diagnostics, VLP-1 can already possibly filter out cases of moderate-to-severe TBI, tauopathies, and other long-term neurodegenerative diseases.[70,71] As supported by many studies, VLP-1 is evidently involved in the mechanism of brain injury, but its window of detection and severity index is still being studied.[70,71,72] To look deeper into the role of VLP-1 in the early mechanisms of mTBI and concussions, Wu et al. conducted a prospective cohort study focusing solely on sports-related concussions and mTBI patients. In this study, it was concluded that ubiquitinated visinin-like protein-1 (uVLP-1) could be detected as immediately as 30 min postdiagnosis, merely measured through a finger-stick blood sample using a lateral flow device. Longitudinal data in the same study also found significant increases in uVLP-1 immediately after concussions (P = 0.02), along with positive correlations between uVLP-1 concentrations and injury severity (P = 0.014).[72] Overall, this demonstrated that uVLP and posttransitionally modified biomarkers can sometimes provide insights into the mechanisms of mTBI and act as more specific biomarkers toward concussion diagnosis.[72] Specifically interpreting the relevance of uVLP-1 as a biomarker, data have shown promise of its potential as an easily accessible, noninvasive, cost-effective, and time-efficient concussion POCT tool, especially convenient in a sports or military setting.[70,71,72]

S100B calcium-binding protein

S100B calcium-binding protein, another important commercial concussion biomarker, has recently been labeled as the most studied and clinically significant mTBI biomarker. As a glial biomarker, S100B is elaborated to be important in specifically predicting concussion recovery timelines and revealing signs of neurovascular damage.[48,61,73,74,75,76,77] Evidence from Oris et al. first confirms the potency of S100B, as it outperformed UCHL-1, GFAP, NfL, tau, and NSE (P = 0.006) in differentiating resolutive sports-related concussions from nonresolutive cases, within 36-h postinjury.[75] Another study demonstrated a similar prognostic quality, in which S100B successfully predicted mortality rates when paired with hemoglobin and platelet concentrations.[77] In addition, in terms of identifying neurovascular disturbances, evidence confirms that S100B is excellent for dismissing potential traumatic intracranial hemorrhage in mTBI patients.[73] Hopman et al. also reiterated this fact by testing S100B concentrations in 495 TBI patients and using its data to reveal approximately 94% of all traumatic intracranial lesion presentations. While cerebrovascular damage and most concussion injuries usually require neuroimaging for some sense of assurance, many believe that S100B, independently, has a high sensitivity for screening cerebral lesions (0.932).[74] Currently, more research must follow to detect the specificity of S100B toward concussion diagnosis before it can be translated to concussion POC; however, recent data have positively supported its use for future concussion prediction models and lesional screening procedures. By being able to predict mortality rates, reveal resolutive damage, and illuminate potential hemorrhages, S100B data can guide professionals to aim their focus on more acute TBI cases.[73,74,75,76,77]

Glial fibrillary acidic protein

GFAP, another well-studied glial biomarker, has historically shown promise as a potential concussion indicator due to its dominant abundance in the central nervous system (CNS).[78] In years past, research has well documented that GFAP concentrations significantly increase in TBI patients, evidently accumulating in blood serum and CSF. Scientists have specifically recorded observations on GFAP gene activation during TBI or CNS injury, predicted to be induced by astrogliosis, compensatory astroglia cell stimulation. Recently, along with UCHL-1, GFAP was officially approved by the FDA for commercial concussion protocol testing.[51] Today, studies have evaluated the various modifications of GFAP, its protease-induced breakdown products, and its limitations on differentiating mTBI.[78,79,80] To dive into the recent discoveries, Papa et al., in a concussion-focused clinical study, strongly supported the use of GFAP biomarker concentrations (P = 0.014) in predicting injury severity and potential CT + intracranial lesions (AUC = 0.84).[65] As seen with many of the other biomarkers, identifying structural abnormalities and categorizing severity are the primary steps in diagnosing concussions. Further, looking at its prognostic potential, specifically after an mTBI or concussion, Kulbe et al. observed that elevated day-of-injury plasma GFAP levels were strongly associated with neuropsychological symptoms like posttraumatic amnesia (P < 0.001) and decreased chances of PTSD.[81] As supported by the listed and a multitude of other evidence, baseline GFAP values, to some degree, seem to be able to diagnose and predict a few mTBI patient outcomes.[78,79,80,81] Viewing the limitation of GFAP, while useful in some domains, scientists have also recognized that elevated levels of this biomarker are nonspecific toward mTBI.[65,79,80] Outside of TBI, research has also described GFAP to have a high prevalence in a variety of miscellaneous diseases, such as orthopedic injuries, stroke, spinal cord injury, Alexander’s disease, inflammatory bowel diseases, and Crohn’s disease.[78,79] As GFAP does not identify exclusively with TBI, mTBI, or subconcussive characteristics, it is often hard to pinpoint patients presenting with external conditions aside from a concussion.[65,79,80] Ultimately, although its implications must be carefully construed, with its deterrents in mind, GFAP has already been proven to be a valuable concussion biomarker when paired with other parameters.[51,78,79,80,81]

Tau

Looking into the primary axonal biomarkers, tau has commercially been studied as the main sign of late-life neurodegeneration.[47,48,61,62] CTE, AD, and other tauopathies have been associated with induced TBI or excessively accumulated concussions.[82] As documented by numerous studies, after TBI, a cascade of kinases hyperphosphorylate the protein tau, introducing pathological concentrations of phosphorylated tau (p-tau).[82,83,84] Abnormal levels of p-tau disengage from the axonal microtubule proteins, aggregating into paired helical filaments and neurofibrillary tangle.[82,83,84] Late into an injury or accumulated incidents, patients present with excessive microtubule axonal disintegration, synaptic disruption, necrosis, neurodegeneration, and eventually clinical signs of dementia.[82,83,84,85,86] During TBI and concussion cases, scientists are observing common trends in total tau (t-tau), cleaved tau (c-tau), and p-tau.[87,88] The prevalence of tau is clear in neurodegeneration and severe TBI; however, there are many contraindicating studies on its role in distinguishing concussions, TBI severity, and long-term outcomes.[47,48,61,62,87,89] Devoto et al. state that p-tau plasma levels positively correlate with positive TBI neuroimaging, although its diagnostic power is unknown.[89] Bazarian et al. state that the S100B and c-tau biomarkers are both poor predictors of 3-month outcomes following mTBI, failing to correlate with PCS-questionnaire scores.[90] In other studies, analyzing serum samples in contact-sport athletes, high concentrations of p-tau181 were found to significantly indicate white matter disintegration in specific brain regions; however, this data also did not present strong prognostic prediction powers for long-term symptoms or longitudinal concussion progression patterns.[86,91]

In general, it has been noted that t-tau concentrations are low in peripheral blood and do not always correlate with CSF concentrations. To have the most informative serum samples, subjects must be evaluated specifically during the 12–24-h window of detection postinjury.[87] On a positive note, when collected within this 24-h time frame, some studies have confirmed that plasma tau can differentiate mTBI from negative controls, predict athlete return-to-play timelines, and prognose chronic symptoms in military TBI.[87,92,93,94] Foreshadowing one important long-term consequence of concussions, Lee et al. discuss how coupling t-tau, p-tau, amyloid-P peptide (Ap 1-42), and VLP-1, together, act as a strong multimodal tool for diagnosing white matter damage, dementia, and AD.[70,88] Although a well studied and utilized biomarker in other diseases, it is hard to pinpoint the clinical utilization of tau for concussion POC due to multiple contravening studies.[87] Heavily associated with long-term neurologic diseases and chronic symptoms, more data could potentially improve our knowledge of trends in tau kinetics and its relationship specifically to concussions.[29,30,44,55,87,90,91,92,93,94]

Neurofilament light chain

A successive, critical axonal biomarker, NfL, is the final commercially researched biomarker discussed in this review, also observed to distinguish concussions and potential long-term consequences.[95,96] The mechanism of NfL resurgence during TBI is described to occur with neuroaxonal damage, releasing into CSF and interacting with the BBB.[88] While the details of its mechanism in CSF and serum are still in study, it has been confirmed that its concentrations during injury, in both, are correlated.[95,96,97] At large, there has been a multitude of studies on the relationship between NfL, athletic activity, and concussions. As supported by Karantali et al., NfL significantly elevates during sport-related activity or exercise.[48,61,98] Cornali et al. confirmed this claim by observing differentiable NfL concentrations in soccer players compared to control subjects participating in no athletics.[99] Aware of the potential for false positives, scientists must acknowledge that athletic participation can influence NfL levels without concussion or TBI. Regardless, with strong data supporting its diagnostic power, its ability to subcategorize TBI continues to be researched.[100,101,102,103,104,105]

To compare the relevance of NfL in concussion POCT, Shahim et al. discuss its ability to differentiate mTBI patients from moderate (P < 0.001) to severe TBI cases (P = 0.048), while also providing valuable correlations to neuroimaging and functional Glasgow Outcome scores.[95] Furthermore, related to TBI severity, a similar analysis confirmed that NfL concentrations significantly correlate with head impact exposure (P = 0.016), another factor of TBI severity.[101] Finally, observing the kinetic trends relating to NfL, Karesioglu et al. associate concussions to serum phosphorylated neurofilament heavy chain, documenting substantially significant increases 2–4-h postinjury and subsidence precisely 6 h afterward.[92] As a time-sensitive indicator of mTBI, relating to severity, neuroimaging results, and cognitive outcome scores, NfL seems to be a promising biomarker for future concussion diagnostics.[95,101,103] Talking about its prognostic capacity, NfL seems useful as it remains elevated in serum, longstanding sports concussions, postconcussion symptoms, and cognitive deficit recovery.[104] Its longitudinal parameters were found valuable for detecting repetitive head injury (RHI) and foreshadowing reinjury vulnerability, essential for return-to-activity timelines.[105] Shahim et al. emphasize that NfL greatly overshadows many biomarkers, such as tau, S100B, and NSE, in identifying sports concussions, PCS, and long-term patient outcomes at the POC.[96] Currently, statistics clearly distinguish the potency of NfL, but its translation to clinical practice is still hindered due to the limited studies highlighting baseline NfL concentrations and its correlations specifically to concussions, brain damage, and recovery.[99,100,104] Contradicting conclusions also limit its proficiency, as some describe NfL to be a poor POC biomarker for early, time-sensitive mTBI diagnosis, and rather a more discrete sign for long-term symptoms, neurodegeneration, and age-related neuropathology.[102] Ultimately, with varying described powers of NfL, extensive clinical research must follow before NfL-biomarker diagnostics translate to acute clinical POC TBI diagnostics.[95,96,98,99,100,101,102,103,104,105]

Horizon biomolecular markers

In the last year, an overwhelming amount of research has already been presented highlighting the kinetic characteristics of biomarkers, such as UCHL-1, VLP-1, S100B, GFAP, tau, and NfL; nonetheless, each biomarker’s limitations have been documented, and there is much more to research before their translations to concussion POC.[27,48,49,106] Supplementary to those concussion biomarkers heavily tested and discussed in this study, there are many ongoing investigations on numerous other horizon biomolecular markers and parameter pairings.[107,108] As reiterated throughout this paper and many others, to convert this knowledge to standardized clinical care, scientists should continue to document the limitations of each biomarker and organize larger clinical studies, pairing multiple parameters for generalizable and normative population data.[20,29,30,44,55]

One of the more minimally studied mTBI and concussion biomarkers, includes, amyloid beta peptides (Ap peptides), which has been classified as highly specific toward brain damage, necrosis, nerve damage, CTE, and neurodegenerative diseases.[20,29,30,44,55] Currently, there is some obscurity on the implications of its concentrations; however, Boutté et al. recently confirmed that Ap-peptide isoforms, like Ap 1-40 and Ap 1-42, remain, especially elevated in peripheral blood, hours to months after concussions.[109] Similarly, Vorn et al. and Vasilevskaya et al. highlight other novel protein indicators, supporting plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) as accurate diagnostic biomarkers for detecting concussions as early as 6-h postinjury (AUC = 1.000).[110,111] Finally, Kvist et al. discuss the potential diagnostic power of glycan-binding lectin proteins, which also seem to have significant fluctuation patterns postconcussion.[112] While only further investigations will fulfill the limited knowledge on the POC potential of all these new protein biomarkers, these preliminary results support that they are all to some degree ambiguously associated with mTBI, concussions, and subconcussive patient cases.[109,111]

Further screening other horizon biomarkers, hormones have been another center of focus. Cortisol, a stress-induced steroid hormone, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, hypothetically has been associated with mTBI recovery and recompensation.[113,114,115] Daneva et al. observed significant sudden increases in cortisol and arterial pressure in the early, acute phases of mTBI.[113] Another experiment further elaborated cortisol’s mechanism by studying pediatric ice hockey concussion cases, observing significant decreases in cortisol days after the sports-induced concussions (P = 0.009).[114] Evaluating the kinetic fluctuations in hormones could be valuable in determining the different phases of TBI.[113,114,115] Additional advantages of cortisol are also discussed with its presentation in saliva, beneficial for future noninvasive concussion POCT procedures.[114] Through support from these studies and others, cortisol levels could potentially be monitored postconcussions and possibly act as a gauge for activity return timelines.[114,115] Acknowledging the positive qualities of hormone biomarkers, Tabor et al. and Villegas et al. also concluded contraire, stating that cortisol levels do not directly correlate with injury severity or gender-related symptoms. Hence, although hormones, like cortisol, may provide valuable insights, professionals must have a holistic perspective before making assertive conclusions.[114,115]

Discussing other modern diagnostic platforms, immunological and inflammatory biomarkers are another novel, time-sensitive pathway being evaluated.[116,117] Gard et al.[118] and Thomas et al.,[119] respectively, observed the predicted increases in pro-inflammatory CSF cytokines (interleukin [IL]-2, IL-6, TNF-a, IL-15, TNF-P, vascular endothelial growth factor, eotaxin, IP-10, TARC, and von Willebrand Factor) after mTBI, confirming the consequential effects of neuroinflammation postinjury.[118,119,120,121] Recent studies have also noted the fluxes in antibodies and cytokines during TBI, associating its timely shifts to specific protein biomarker disintegrations.[105] Istanbouli et al.[116] similarly observed exponentially increasing immunoglobulin G (IgG) and IgM concentration trends, days to months after TBI, associated with autoimmune reactions to GFAP, myelin oligodendrocyte glycoprotein, and myelin-associated glycoprotein accumulations. Furthermore, Khosh-Fetrat et al.[117] discovered that cytokines, like IL-10, can differentiate CT + mTBI cases as early as 90 min after hospital admission. Subsequently, Eagle et al. observed increases in high-sensitivity C-reactive protein and IL-6 in mTBI patients, specifically classified as obese.[122] In addition to the abundance of protein biomarkers currently being tested, cytokines, antibodies, chemokines, and other immunologic factors could supplement future concussion POCT.[116,117,120,123]

Finally, in light of the strengths of proteins, hormones, and immunological neurologic indicators, scientists have finally also shifted their focus to the roots of all biology, researching genetic biomarkers.[124,125,126,127] Gene-regulating markers, like miRNA, have been observed to shift regularly, distinguishing acute and chronic neuropathology.[125,127] Similar to some of the other markers discussed, its concentration in saliva also makes it a promising target for noninvasive POCT.[125,126] To further support its efficacy in concussion research, a case-controlled study by Hicks et al.[125] tested the strength of various miRNA biomarkers, finding 11 which could significantly discriminate between concussed and nonconcussed subjects (P < 0.05). When tested in numerous studies evaluating heterogeneous population ages, Hiskens et al. noted its potency for standardization, recording approximately 188 miRNA having TBI diagnostic capabilities and 30 overlapping in multiple studies.[126] Additional recent investigations by Mitra et al. successfully linked markers, such as plasma miR423-3p, specifically to mTBI 6-h postinjury.[128] Continuing excessive research and pairing this knowledge with the surfeit of other mentioned concussion biomarkers, professionals could potentially utilize miRNA and other genetic indicators to have a deeper comprehension of TBI mechanisms and improved concussion POCT.[124,125,126,127]

Limitations and the future of traumatic brain injury biomarker research

Through extensive research on the various biomolecular pathways involved in TBI, scientists believe that they have observed some similar patterns. However, many reviews have also described TBI to have a heterogeneous nature, factoring different mechanisms of injury, individual physiology, personalized symptoms, and unique outcomes.[29,129,130,131] Despite the demonstrated interest toward the various concussion biomarkers, many studies fail to analyze variable interactions and proper comparison tests to effectively evaluate each biomarker’s efficacy.[132] A few limitations to consider include the medium of biomarker collection, the accessibility of different mediums, variability in injury mechanisms, and the influence of confounding variables.[48,62,129,130,131]

Overall, to have the most proximate view of the various TBI biomarkers, within the brain, CSF seems to be the most obvious biofluid medium.[47] However, CSF located in the cranial space and spinal cord is difficult to access in the majority of concussion and mTBI cases due to the lack of penetrative injury or leaking fluids.[48,62] Considering the cost of CSF extraction and accessibility, in most studies, CSF biomarkers are only studied in postmortem patients, limiting our perspective on in vivo biomarker levels.[47,48,62] As mentioned throughout this review and many articles, blood, serum, and saliva are some of the more common in vivo, noninvasive biofluid mediums, currently being tested for TBI diagnostics.[47,48,62] Mavroudis et al.[17] elaborate on the cost-effective benefits of testing noninvasive biofluids by compiling successful evidence on the combination of clinical parameters with salivary TBI biomarkers. In rebuttal, supported by multiple studies, blood, serum, and salivary biomarker concentrations often do not match CSF concentrations after repetitive concussions.[133,134] Overall, the time of biofluid collection is also important as extensive time between collections has shown to create a lack of association between biomarkers and their medium.[135] Evaluating the accessibility, economic, and correlative characteristics of different biofluids will all be essential factors to consider when screening for the next wave of concussion biomarkers.[47,48,62,133,134]

Furthermore, in a clinical setting, when analyzing concussion biomarker implications, medical professionals must be wary of the influences of external factors such as patient age, gender, environmental factors, and mechanism of injury, leading to unstandardized data.[99,101,125,136,137,138,139,140,141,142,143,144,145,146,147,148] For example, in a cross-sectional study, Tabor et al. first emphasize the evasive association between age, gender, puberty, and biomarker concentration patterns, especially in important proteins, such as GFAP, UCHL-1, and tau.[148] Gardner et al.[140] reiterate this conclusion, in a TRACK-TBI study, reiterating that age directly hinders the strength of GFAP in illuminating intracranial CT scan outcome in mTBI. Finally, in one experiment, when collecting biomarker data in the elderly population, there were delusive reports of no significant correlations between biomarkers and TBI, in confirmed, concussed retired athletes.[147] Looking further into the environmental factors, such as patient consumption, Huibregtse et al. highlight the significant influence of hormonal contraceptives, like progesterone, influencing NfL and GFAP concentrations, postconcussion.[101] Correspondingly, altering many concussion diagnosis parameters, many studies have also highlighted the dual impact of alcohol consumption, leading to exacerbated neurologic dysfunction and ancillary mTBI biomarker presentations.[136,139] Mutually exclusive from TBI, past patient history, including previous diagnoses like ADHD and AD can individually present with similar unstable biomarker concentrations.[149,150] Finally, considering the effect of the mechanism of injury, scientists are aware that each TBI case presents different biomarker data and its own unique barriers.[90,108,124,125,126,127,128] For one example, scientists and medical professionals must be aware of the effects of exercise on biomarker kinetics. Many studies analyzing sports-related concussions have demonstrated that physical exercise, even without concussive injuries, can alone affect some protein and genetic biomarker concentrations.[99,125,137,145,146] Bazarian et al. support this claim by finding significant decreases in blood serum GFAP (P < 0.0001) and significant increases in blood serum UCHL-1 (P = 0.016), in subjects performing aerobic and resistance training, regardless of controlled white matter integrity and concussion absence.[137] Equivalently, Hicks et al. also demonstrated that a few miRNA genetic biomarkers, such as miR-532-5p and miR-182-5p, can decrease (P < 0.05), simply through physical exertion.[125] In parallel, it has been hypothesized that warfare-induced blast injuries, uncommon to most individuals, may also have their own unknown mechanistic effects on biomarker concentrations.[138,141] Overall, with the multitude of environmental influences, it is emphasized that extensive normative clinical data and multimodal prediction models can impinge the marks of many confounding variables, leading to generalizable results and the most accurate biomarker implications.[20,27,28,29,44,46,151,152]

Multimodal concussion models

Shifting this discussion toward the success of numerous multimodal concussion parameter pairings published this year, noticeable efforts are being made to enhance the interpretation of biomarker kinetics and other clinical data. With high variability, throughout many global biomarker studies and international concussion guidelines, multimodal diagnostic tools are necessary for reliable concussion identification.[20,27,28,29,34,46,152,153] Understanding the neuroplasticity of the brain, diagnosticians must consider the multivariate significance of extracranial injuries, age, and environmental variables.[1,36] As demonstrated by many experts, investigations continue to evaluate and pair novel biomarkers, quantitative pathological parameters, physiological statistics, and novel neuroimaging to together form the blueprint for the most effective diagnostic and prognostic concussion tools.[20,29,30,44,55,63,154,155,156,157,158,159,160,161,162,163]

Unfolding some specific examples of potential multimodal biomarker tools, one basic example has been introduced in the French and United States medical systems, pairing GFAP and UCHL-1 concentrations to identify concussions and mTBI.[51,56,161] As profitably hypothesized, linking these protein biomarker parameters was concluded to be more cost-effective and outcome efficient in comparison to independent and paired evaluations of CT scans and S100B biomarker concentrations.[56] Similarly, another effective multivariable biomarker tool includes the Cox proportional hazards model, combining S100B concentrations, platelet levels, hemoglobin concentrations, and Charlson Comorbidity scores to successfully predict mTBI mortality.[77] Finally, specifically aimed toward pediatric TBI (pTBI), Munoz Pareja et al. successfully dichotomized mild-and-moderate TBI patients between 0 and 18 months of age, simply analyzing GCS, GFAP, NfL, UCHL-1, S100B, tau, and p-tau.[164] While multiple biomarkers themselves provide valuable diagnostic power, as seen in these studies, scientists are continuing to improve these models for different demographics by adding numerous other clinical parameters.[20,29,30,44,55] Continuing into more complex multimodal models, some studies have merged sequences of biomarker data, electrophysiology, neuroimaging, and cognitive scores to accurately diagnose and predict concussive characteristics.[63,154,155,161,162,163] In one example, Parker et al.[161] successfully bridged cortical depolarization and TGFP inflammatory biomarker concentrations to diagnose BBB disruption and potential mTBI. In a prognostic model, in the last year, Ritter et al.[163] published a similar multivariable technique, collecting plasma tau, plasma NfL, MRI images, and cognitive test scores, to anticipate long-term effects of concussion and potential traumatic encephalopathy syndrome. Reaffirming the cost-effective, accessible, and efficient evaluation methods of similar multimodal methods, Roy et al.[162] confirm the benefits of evaluating cognitive, sensory, cerebrovascular, and biomarker data, when diagnosing military blast injuries. For future tools, longitudinal studies continue to collect multivariable data, planning to correlate elevated biomarker patterns, shifting cognitive test results, and long-term concussion symptoms.[63] In summary, a multitude of studies should continue to develop, pairing biomarker data with related clinical parameters, aiming to create the most dependable concussion diagnostic tools.[63,154,155,161,162,163]

Building on top of many multivariable prediction tools, a few studies in the last year further contributed data on the incorporation of human vital sign trends throughout concussions.[160,165,166,167,168] Some studies correlate concussion patient diagnoses to physiological reactions, such as temporary oculomotor deficits, neurovascular hypoxia, significant decreases in heart rate, and diminished systolic blood pressure variability.[149,165,167,169] In addition, Miner and Harper extend this multimodal concept by combining neurocognitive tests and exercise stress tests to monitor physiological improvements, postconcussion.[160] Overall, vital signs, such as heart rate and blood pressure, are different for various demographics; however, normalized data and generalizable trends are also being analyzed for biomarker pairing and future standardized protocols.[29,166,168] Extending outward into a few neuroimaging parameter pairings through more defined microvascular imaging techniques, professionals believe that they can now evaluate trends in chronic and acute TBI, correlating mTBI with white matter hyperintensities, cerebral microbleeds, and other cerebrovascular characteristics.[170,171,172,173] One important neuroimaging statistical pair discussed includes mean diffusivity and mean kurtosis, both key MRI metrics for differentiating patients with RHIs and potential concussions.[132,174] Susceptible-weighted imaging, quantitative susceptible mapping, and artificial intelligence have also recently been paired together to detect microvascular injury and microstructural abnormalities, often detected in mTBI.[132,171] As novel biomarker parameters and pairing continue to resurface for future multimodal models, innovative neuroimaging techniques will also evolve to improve concussion POCT.[132,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186]

CONCLUSION

With TBI being one of the leading causes of death in the United States and worldwide, medical researchers have been focusing on improving the speed, efficiency, and accuracy of diagnostic tools for concussions and various TBI severities. Due to the glaring gray areas in TBI severity classifications and time-sensitive prognostic implications, scientists and medical professionals have continued their work on immediate POCT and multivariable biomarkers models.

Utilizing the NIH National Library of Medicine PubMed database, this review summarized the most notably studied diagnostic concussion biomarkers utilized in TBI testing. Keywords of “Concussion Biomarkers,” “Concussion Point of Care,” and “Concussion Biomarkers at Point of Care,” were all surveyed over the 2022–2023 time frame to attain the most comprehensive articles. Neuroimaging, neurologic screening tools, and numerous molecular biomarkers were discussed to benefit TBI diagnosis. Some commonly tested and horizon TBI biomarkers at POCT include UCHL-1, VLP-1, S100B, GFAP, tau, NfL, EPB41, SNCA, cytokines, antibodies, chemokines, miRNA, and manifold of others, all at different time-point postinjury.

Finally, despite the abundance of significant biomarkers and significant trends within concussion patients, there are still some obvious weaknesses even within various multimodal concussion POC models. First, professionals must always be aware of the bias toward concussion diagnosis and blindness toward other health concerns, each directly correlating with various biomarker data. Similarly, studies often solely evaluate the effectiveness of biomarkers on long-term postconcussive symptoms, failing to focus on time-sensitive concussion cases. In addition, another challenge may include poor prognostic powers, essential for predicting extended cognitive scores and persisting postconcussion symptoms. With potentially varying diagnostic results and unstandardized predictive power, it must be heavily emphasized to continue clinical research on large-scale cohorts to continue the translation of biomarker POC diagnostics.

In conclusion, combined with the progression of independent biomarker research, for a more comprehensive diagnostic model, there is still much more analysis to be done for the future of multimodal paired-parameter concussion POCT and overall improved TBI diagnosis protocols.

Research quality and ethics statement

The authors followed applicable EQUATOR Network (https://www.equator-network.org/) guidelines, during the conduct of this article.

Conflicts of interest

One of the authors SG is a member of the editorial board of this journal.

Funding Statement

Nil.