The Challenge of Mild Traumatic Brain Injury: Role of Biochemical Markers in Diagnosis of Brain Damage

During the past decade there has been an increasing recognition of the incidence of mild traumatic brain injury (mTBI) and a better understanding of the subtle neurological and cognitive deficits that may result from it. A substantial, albeit suboptimal, effort has been made to define diagnostic criteria for mTBI and improve diagnostic accuracy. Thus, biomarkers that can accurately and objectively detect brain injury after mTBI and, ideally, aid in clinical management are needed. In this review, we discuss the current research on serum biomarkers for mTBI including their rationale and diagnostic performances. Sensitive and specific biomarkers reflecting brain injury can provide important information regarding TBI pathophysiology and serve as candidate markers for predicting abnormal computed tomography findings and/or the development of residual deficits in patients who sustain an mTBI. We also outline the roles of biomarkers in settings of specific interest including pediatric TBI, sports concussions and military injuries, and provide perspectives on the validation of such markers for use in the clinic. Finally, emerging proteomics‐based strategies for identifying novel markers will be discussed.     

Biomarkers and acute brain injuries: interest and limits

For patients presenting with acute brain injury (such as traumatic brain injury, subarachnoid haemorrhage and stroke), the diagnosis and identification of intracerebral lesions and evaluation of the severity, prognosis and treatment efficacy can be challenging. The complexity and heterogeneity of lesions after brain injury are most probably responsible for this difficulty. Patients with apparently comparable brain lesions on imaging may have different neurological outcomes or responses to therapy. In recent years, plasmatic and cerebrospinal fluid biomarkers have emerged as possible tools to distinguish between the different pathophysiological processes. This review aims to summarise the plasmatic and cerebrospinal fluid biomarkers evaluated in subarachnoid haemorrhage, traumatic brain injury and stroke, and to clarify their related interests and limits for diagnosis and prognosis. For subarachnoid haemorrhage, particular interest has been focused on the biomarkers used to predict vasospasm and cerebral ischaemia. The efficacy of biomarkers in predicting the severity and outcome of traumatic brain injury has been stressed. The very early diagnostic performance of biomarkers and their ability to discriminate ischaemic from haemorrhagic stroke were studied.     

Blood-based diagnostics of traumatic brain injuries

Traumatic brain injury is a major health and socioeconomic problem that affects all societies. However, traditional approaches to the classification of clinical severity are the subject of debate and are being supplemented with structural and functional neuroimaging, as the need for biomarkers that reflect elements of the pathogenetic process is widely recognized. Basic science research and developments in the field of proteomics have greatly advanced our knowledge of the mechanisms involved in damage and have led to the discovery and rapid detection of new biomarkers that were not available previously. However, translating this research for patients' benefits remains a challenge. In this article, we summarize new developments, current knowledge and controversies, focusing on the potential role of these biomarkers as diagnostic, prognostic and monitoring tools of brain-injured patients.     

Cytokines and brain injury: invited review

The brain reacts to injury or disease by cascades of cellular and molecular responses. Evidence suggests that immune-inflammatory processes are key elements in the physiopathological processes associated with brain injury or damage. Cytokines are among major mediators implicated in these processes. Cytokine responses in the initial phase of brain injury might have a role in aggravating brain damage. However, in later stages, these molecular mediators might contribute to recovery or repair. Hemodynamic stabilization and optimalization of oxygen delivery to the brain remain cornerstones in the management of acute brain injury. New approaches might use anticytokine therapy to limit progression and halt or attenuate secondary brain damage. Progress toward such novel neuroprotection strategies, however, awaits better understanding of the optimal timing and dosing of those neuromodulatory therapies and better knowledge of the numerous interactions of those mediators. This also requires understanding of how and when precisely immune mechanisms shift from noxious to protective or restorative actions.     

Heat-shock proteins and molecular chaperones: implications for pathogenesis,diagnostics, and therapeutics

Summary Cells react to physical (e.g., heat) or chemical (e.g., anoxia, low pH) stressors, mounting a stress (heat-shock) response. Most genes are turned down or off, while a few are activated. The latter encode the stress or heat-shock proteins (Hsps), whose levels increase in stressed cells. Various Hsps are molecular chaperones. These, and other molecular chaperones that are not Hsps, help the other cellular proteins to achieve their native state (correct folding or functional conformation), reach their final destination (e.g., the endoplasmic reticulum or the mitochondria), resist denaturing by stressors, and regain the native state after partial denaturation. Thus the Hsps and molecular chaperones occupy the stage's center whenever and wherever there is cellular and tissue injury caused by local or systemic stressors via protein damage. This feature, their participation in protein folding and transport, and their evolutionary conservation within the three phylogenetic domains, strongly suggest a vital role for Hsps and molecular chaperones. Their importance in pathogenesis, and as diagnostic markers and prognostic indicators, is beginning to be appreciated. The role of Hsps and molecular chaperones in cell recovery from injury by a variety of noxae of clinical and surgical relevance is also being assessed. Consequently, the potential of these molecules (and corresponding genes) as targets for treatment or as therapeutic tools is emerging and is being explored. Stroke, myocadial infarction, inflammatory syndromes, infectious and parasitic diseases, autoimmune disorders, cancer, and aging are but some examples of conditions in which Hsps and molecular chaperones are being scrutinized. The era of Hsps and molecular chaperone pathology has dawned. It is likely that genetic and acquired defects of Hsp and molecular chaperone structure and function will be identified, and will play a primary, or auxiliary but determinant, role in disease.     

Fatty acid-binding proteins as plasma markers of tissue injury

BACKGROUND: One of the novel and promising plasma markers for detection of tissue injury is the family of 15 kDa cytoplasmic fatty acid-binding proteins of which various tissue-specific types occur. AIMS AND OBJECTIVES: The present status of heart-type fatty acid-binding protein (H-FABP) as a diagnostic and prognostic marker for acute and chronic cardiac injury, as well as the preliminary diagnostic use of other types of FABP for detecting injury in other organs, is reviewed. METHODS: This review is based on an overview of the literature on clinical diagnostics of various forms of organ injury, and uses additional literature on physiological aspects relevant for the interpretation of plasma marker concentrations. RESULTS: H-FABP not only proves to be an excellent early marker for cardiac injury in acute coronary syndromes, but also allows detection of minor myocardial injury in heart failure and unstable angina. Preliminary results indicate that sensitivity, rule-out power and prognostic value of H-FABP in cardiac injury surpass the performance of the standard early marker myoglobin. The liver only contains liver-type FABP (L-FABP), but co-expression of H-FABP and L-FABP occurs in the kidney. Similarly, intestinal-type FABP (I-FABP) and L-FABP are found in intestines, and brain-type FABP (B-FABP) and H-FABP occur in the brain. Preliminary but promising applications of these proteins have been demonstrated for liver rejection, viability selection of kidneys from non-heart-beating donors (NHBD), inflammatory and ischemic bowel disease, traumatic brain injury and in the prevention of muscle injury in trained athletes. CONCLUSIONS: Further study of the diagnostic and prognostic use of various FABP types is warranted, but their clinical application will require further commercialization of automated and rapid assays.     

Detection of brain injury by fatty acid-binding proteins.

The rapid detection of brain injury (neuronal damage in general) is an important parameter in the management of cerebrovascular accidents, especially in hemorrhagic and/or ischemic events. Two types of 15-kDa cytoplasmic fatty acid-binding proteins (FABPs), brain-type FABP and heart-type FABP, have recently been postulated as novel markers for brain injury detection. Here we review the possible roles of these FABPs as rapid diagnostic markers for the detection of brain injury due to cerebrovascular accident, trauma or neurodegenerative diseases. The occurrence of brain- and heart-type FABPs in segments of the human brain is also described. Although only limited amounts of data are available, brain- and heart-type FABPs show higher sensitivities and specificities than protein S100 and neuron specific enolase in the rapid detection of brain injury in stroke, trauma and neurodegenerative diseases.     

Biomarkers: optimizing treatment guidance in heart failure

Heart failure is a frequent and life-threatening syndrome which is not only the result of myocardial injury or hemodynamic overload as commonly perceived, but appears to be the result of an interplay among genetic, neurohormonal, inflammatory, and biochemical factors, collectively referred to as biomarkers. Biomarkers can become risk factors in case their therapeutic modification results in an improvement of clinical outcomes. Among those markers identified in patients with heart failure, a number appears to have direct clinical relevance in aiding diagnosis, risk stratification, monitoring therapy, and treating to targets in order to improve clinical outcomes. These include brain natriuretic peptides (e.g., BNP, NT-proBNP), inflammatory markers (e.g., hsCRP), neurohormones (e.g., aldosterone), cardiorenal markers (e.g., cycstatin C), and novel markers (e.g., galectin-3). While their utility to indicate risk is mostly well established, there are less data to establish that a treatment using biomarkers as a guidance results in better outcomes than a more generalized intensified treatment of patients with heart failure. Future directions may involve larger platforms that facilitate to simultaneously analyze hundreds of biomarkers and may help to tailor heart failure therapy on a single patient basis, considering the specific pathogenesis and prognosis. Also from a therapeutic perspective there are data that a single intervention such as aldosterone blockade may affect multiple biomarkers at the same time. Taken together the data indicate that biomarkers are evolving into a valuable addendum to the diagnostic and therapeutic armamentarium.     

Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis

PURPOSE OF REVIEW: This review highlights recent advances in cerebral microdialysis as a tool for neurochemical monitoring of patients with traumatic brain injury. RECENT FINDINGS: Progress in microdialysis research has come from validation studies of microdialysis biomarkers and clinical outcome in large cohorts of traumatic brain injury patients and by combining microdialysis with other methods, such as positron emission tomography, magnetic resonance spectroscopy, brain tissue oximetry and electrophysiology. The combination of rapid-sampling microdialysis and electrocorticography has revealed complex, transient fluctuations of microdialysis glucose and lactate and depolarization-like events that may affect the secondary injury process. The use of microdialysis to monitor global cerebral metabolic events (related to intracranial hypertension or reduced cerebral perfusion pressure for example) as opposed to focal events in peri-lesional brain tissue need to be clearly distinguished and the microdialysis catheter location verified by neuroimaging to ensure proper data interpretation. Differences in microdialysis biomarker levels between grey and white matter following traumatic brain injury need clarification. SUMMARY: Microdialysis is established as a neurochemical research tool in neurointensive care, particularly in combination with other monitoring methods, and contributes to a growing knowledge of secondary injury mechanisms in traumatic brain injury. The value of microdialysis as a tool in routine neurointensive care decision-making remains unclear.     

Pediatric traumatic brain injury: not just little adults

PURPOSE OF REVIEW: This review will update the reader on the most significant recent findings with regards to both the clinical research and basic science of pediatric traumatic brain injury. RECENT FINDINGS: The developing brain is not simply a smaller version of the mature brain. Studies have uncovered important distinctions of the younger brain after traumatic brain injury, including an increased propensity for apoptosis, age-dependent parameters for cerebral blood flow and metabolism, development-specific biomarkers, increased likelihood of early posttraumatic seizures, differential sensitivity to commonly used neuroactive medications and altered neuroplasticity during recovery from injury. Specifically, there is strong preclinical evidence for increased neuronal apoptosis in the developing brain being triggered by anesthetics and anticonvulsants, making it paramount that future studies more clearly delineate preferred agents and specific indications for use, incorporating long-term functional outcomes as well as short-term benefits. In addition, the young brain may actually benefit from therapeutic interventions that have been less effective following adult traumatic brain injury, such as decompressive craniectomy and hypothermia. SUMMARY: An increasing body of evidence demonstrates the importance of establishing age-dependent guidelines for physiological monitoring, pharmacological intervention, management of intracranial pressure and facilitating recovery of function.     

Molecular biomarkers in esophageal,gastric, and colorectal adenocarcinoma

Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment.     

Biomarkers for the diagnosis of acute kidney injury

The identification of acute kidney injury relies on tests like blood urea nitrogen and serum creatinine that were identified and incorporated into clinical practice several decades ago. This review summarizes clinical studies of newer biomarkers that may permit earlier and more accurate identification of acute kidney injury. The urine may contain sensitive and specific markers of kidney injury that are present due to either impaired tubular reabsorption and catabolism of filtered molecules or release of tubular cell proteins in response to ischemic or nephrotoxic injury. Many potential markers have been studied. Promising injury markers in the urine include N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and interleukin-18. New biomarkers of kidney injury hold the promise of substantially improving the diagnostic approach to acute kidney injury. Adequately powered clinical studies of multiple biomarkers are needed to qualify the biomarkers before they can be fully adopted in clinical practice. Once adopted, more sensitive biomarkers of acute kidney injury hold the potential to transform the care of patients with renal disease.     

Evaluating Chagas disease progression and cure through blood-derived biomarkers: a systematic review

This article reviews the usefulness of various types of blood-derived biomarkers that are currently being studied to predict the progression of Chagas disease in patients with the indeterminate form, to assess the efficacy of antiparasitic drugs and to identify early cardiac and gastrointestinal damage. The authors used a search strategy based on MEDLINE, Cochrane Library Register for systematic review, EmBase, Global Health and LILACS databases. Out of 1716 screened articles, only 166 articles were eligible for final inclusion. The authors classified the biomarkers according to their biochemical structure and primary biological activity in four groups: i) markers of inflammation and cellular injury, ii) metabolic biomakers, iii) prothrombotic biomarkers and iv) markers derived from specific antigens of the parasite. Several potential biomarkers might have clinical potential for the detection of early cardiopathy. Such capacity is imperative in order to detect high-risk patients who require intensive monitoring and earlier therapy. Prospective studies with longer follow-ups are needed for the appraisal of biomarkers assessing clinical or microbiological cure after therapy. At the same time, studies evaluating more than one biomarker are useful to compare the efficacy among them given the lack of a recognized gold standard.     

Regional ischemia after head injury

PURPOSE OF REVIEW: To examine the evidence of regional cerebral ischemia after traumatic brain injury. RECENT FINDINGS: This review describes the mechanisms responsible for secondary brain injury and the similarities between traumatic and ischemic neuronal cell death. Cerebral ischemia is defined, and the difficulties of quantifying the burden of cerebral ischemia in the context of clinical head injury are presented. Recent clinical data obtained from monitoring brain tissue oxygenation, tissue metabolites using microdialysis, and cerebral blood flow, blood volume, oxygen metabolism, and oxygen extraction fraction using oxygen-15 positron emission tomography are discussed. These data highlight that significant episodes of regional ischemia occur within the acute phase after injury and are associated with poor outcome. Although various monitoring tools are capable of detecting significant episodes of regional ischemia, each of the currently available techniques is limited in its clinical application. SUMMARY: There is increasing evidence to suggest that a small but significant volume of brain tissue is at risk of ischemic injury after trauma. Future studies should examine the pathophysiology underlying such ischemia and how monitoring techniques can be used to direct appropriate therapy and influence outcome.     

Mild traumatic brain injury: is diffusion imaging ready for primetime in forensic medicine?

ABSTRACT: Mild traumatic brain injury (MTBI) is difficult to accurately assess with conventional imaging because such approaches usually fail to detect any evidence of brain damage. Recent studies of MTBI patients using diffusion-weighted imaging and diffusion tensor imaging suggest that these techniques have the potential to help grade tissue damage severity, track its development, and provide prognostic markers for clinical outcome. Although these results are promising and indicate that the forensic diagnosis of MTBI might eventually benefit from the use of diffusion-weighted imaging and diffusion tensor imaging, healthy skepticism and caution should be exercised with regard to interpreting their meaning because there is no consensus about which methods of data analysis to use and very few investigations have been conducted, of which most have been small in sample size and examined patients at only one time point after injury.     

Quantitative cardiovascular magnetic resonance for molecular imaging

Cardiovascular magnetic resonance (CMR) molecular imaging aims to identify and map the expression of important biomarkers on a cellular scale utilizing contrast agents that are specifically targeted to the biochemical signatures of disease and are capable of generating sufficient image contrast. In some cases, the contrast agents may be designed to carry a drug payload or to be sensitive to important physiological factors, such as pH, temperature or oxygenation. In this review, examples will be presented that utilize a number of different molecular imaging quantification techniques, including measuring signal changes, calculating the area of contrast enhancement, mapping relaxation time changes or direct detection of contrast agents through multi-nuclear imaging or spectroscopy. The clinical application of CMR molecular imaging could offer far reaching benefits to patient populations, including early detection of therapeutic response, localizing ruptured atherosclerotic plaques, stratifying patients based on biochemical disease markers, tissue-specific drug delivery, confirmation and quantification of end-organ drug uptake, and noninvasive monitoring of disease recurrence. Eventually, such agents may play a leading role in reducing the human burden of cardiovascular disease, by providing early diagnosis, noninvasive monitoring and effective therapy with reduced side effects.     

Functional neuroimaging and cognitive rehabilitation for people with traumatic brain injury

Cognitive deficits are a common consequence of traumatic brain injury. Although such deficits are amenable to rehabilitation, methods for individualizing cognitive interventions are still unrefined. Functional neuroimaging methods such as positron emission tomography and functional magnetic resonance imaging are emerging as possible technologies for measuring and monitoring the cerebral consequences of plasticity associated with brain injury and for evaluating the effectiveness of rehabilitation interventions. Functional neuroimaging may even enable more customized and efficient selection, design, or adaptation of individual cognitive rehabilitation programs. We review the current literature on functional neuroimaging after traumatic brain injury, relating these findings to cognitive rehabilitation. Overall, functional neuroimaging after traumatic brain injury has shown reliable differences in brain activity within several regions of frontal cortex, partly but not uniformly consistent with neuropsychological and structural findings in traumatic brain injury. We also outline a number of promising research opportunities for applying functional neuroimaging in traumatic brain injury settings, along with associated challenges.     

Cardiac troponins in renal failure – time for an optimistic consensus?

Elevated cardiac troponin concentrations are now accepted as the gold standard biochemical markers for the diagnosis of myocardial damage in patients with unstable coronary syndromes, having also a demonstrated value in early risk stratification and in adopting different therapeutic strategies. The specificity and sensitivity of cardiac troponins for diagnosis of acute coronary diseases in renal failure have been a point of confusion over the past decade, mainly because of moderate elevations of these cardiac biomarkers, commonly observed in patients with chronic renal dysfunction and without any significant myocardial damage. This review discusses the cardiac troponins, their biochemistry, their currently accepted cut-off values and their real significance in chronic renal failure (CRF), concluding that troponins maintain their diagnostic and prognostic values in patients with CRF, being predictive not only of cardiovascular mortality but also of general mortality in this patient group.     

Microsensor and microdialysis technology. Advanced techniques in the management of severe head injury

Neuroscientists continue the search for the "magic bullet" that will prevent the deleterious effects of primary and secondary brain injury. Indirect measurement of the effects of primary and secondary brain injury through the study of ICP- or CPP-directed management, CBF monitoring, Sjo2 monitoring, and TCD monitoring has led to improved care of persons with brain injury. Although the findings from brain injury research using microsensor and microdialysis technology are only preliminary and extensive research is still needed, these technologies have dramatically expanded knowledge about brain injury at the cellular level. Extended neuromonitoring is poised to enter a new and exciting phase because of the growth in knowledge regarding the cellular events associated with brain injury. The recent approval of NeuroTrend by the FDA will further promote this growth. Applications of the technology have already expanded to include uses beyond the management of traumatic brain injury. Microsensor and microdialysis technology is being used intraoperatively to determine "safe" temporary clipping times for aneurysm surgery and is also being used within the critical care setting to improve the monitoring and management of subarachnoid hemorrhage patients who are experiencing vasospasm. The ultimate application of this new technology is to improve long-term outcomes for patients with brain injury through the reduction of secondary brain injury. If that goal is to be accomplished, then it will be important for nurses caring for patients with brain injury to become immersed in this exciting new phase in brain injury monitoring. Nurses must obtain a comprehensive knowledge base of brain injury pathophysiology and how extended neuromonitoring can lead to improved outcomes. Technical proficiency will also be important to ensure that treatment and research conclusions are based on accurate data. Finally and perhaps most importantly, it will be critical for nurses to participate in and develop research studies that explore the impact of interventions, especially nursing care activities, on the injured brain if these exciting new advances are to be translated into tangible benefits for brain-injured patients.     

An update on diagnostic and prognostic biomarkers for traumatic brain injury

Introduction: Traumatic brain injury (TBI) is a major worldwide neurological disorder of epidemic proportions. To date, there are still no FDA-approved therapies to treat any forms of TBI. Encouragingly, there are emerging data showing that biofluid-based TBI biomarker tests have the potential to diagnose the presence of TBI of different severities including concussion, and to predict outcome.

Areas covered: The authors provide an update on the current knowledge of TBI biomarkers, including protein biomarkers for neuronal cell body injury (UCH-L1, NSE), astroglial injury (GFAP, S100B), neuronal cell death (αII-spectrin breakdown products), axonal injury (NF proteins), white matter injury (MBP), post-injury neurodegeneration (total Tau and phospho-Tau), post-injury autoimmune response (brain antigen-targeting autoantibodies), and other emerging non-protein biomarkers. The authors discuss biomarker evidence in TBI diagnosis, outcome prognosis and possible identification of post-TBI neurodegernative diseases (e.g. chronic traumatic encephalopathy and Alzheimer’s disease), and as theranostic tools in pre-clinical and clinical settings.

Expert commentary: A spectrum of biomarkers is now at or near the stage of formal clinical validation of their diagnostic and prognostic utilities in the management of TBI of varied severities including concussions. TBI biomarkers could serve as a theranostic tool in facilitating drug development and treatment monitoring.