Fluid markers of traumatic brain injury
Introduction
Moderate to severe traumatic brain injury (TBI), in which there are intracranial bleedings and/or mass lesions in the brain parenchyma after a blow to the head, is easily diagnosed by clinical examination and standard neuroimaging techniques. However, mild TBI or concussion (defined as a head trauma resulting in brief loss of consciousness and/or alteration of mental state; the two terms are used interchangeably) is much harder to objectively detect and presents an everyday challenge in emergency care units globally. Concussion causes no gross pathology, such as hemorrhage, and no abnormalities on conventional computed tomography scans of the brain (McCrory et al., 2009), but rather rapid-onset neuronal dysfunction that resolves in a spontaneous manner over a few days to a few weeks. The dysfunction is at least partly caused by direct damage to axons and other structures in the central nervous system (CNS). Approximately 15% of concussion patients suffer persisting cognitive dysfunction (Roe et al., 2009, Williams et al., 2010) and diffuse axonal injury (DAI) appears to be the most important underlying pathology in such cases (Kirov et al., 2013). Further, it has been shown that repetitive concussions increase the risk of chronic traumatic encephalopathy (CTE), a condition described in boxers and other sports athletes, as well as in military veterans, characterized by chronic and sometimes progressive neurological and/or psychiatric symptoms following repetitive brain injury (Stein et al., 2014). Fluid markers of neuronal, axonal and astroglial damage would be valuable to diagnose concussion in patients with head trauma, to predict short- and long-term clinical outcome and to tell when the brain has recovered from the TBI.
In this review, we start by discussing the different fluids that may be used as samples to determine markers of TBI. We thereafter discuss technical aspects of biomarker analyses. We then review the literature published so far on candidate biomarkers for mild TBI. Finally, we discuss the special case of CTE and emphasize the need of biomarker development for this disease entity. To obtain the data, we searched PubMed for English language articles on mild TBI and CTE using the keyword “traumatic brain injury” together with other keywords including: “concussion”, “chronic traumatic encephalopathy”, “biomarkers”, “CSF”, “blood”, “saliva”, “urine”, “tears”, “tau”, “neurofilament light”, and several other keywords relevant to every section. We largely selected publications in the past 5 years, but did not exclude important older publications. Selection criteria also included a judgment on the novelty of studies and their relevance for the well-informed researcher/clinician.
Section snippets
Cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear fluid that surrounds the brain and provides mechanical support. It also carries nutrients and signaling molecules to neurons and helps in disposing metabolites that are further cleared into the blood via arachnoid villi in the intracranial dural sinuses and at the cranial and spinal nerve root sheaths. The total CSF volume is around 150 mL and the production and clearance rates are around 20 mL per hour. CSF is easily sampled through a lumbar puncture.
Measurement techniques
Most fluid markers of CNS injury are proteins or protein fragments. Such proteins may be visualized on Western blots in which proteins in the sample are separated on a gel, transferred to a membrane and visualized using labeled antibodies to the protein of interest. This technique is often sensitive but not really quantitative and is not suitable for use in clinical laboratory practice.
Enzyme-linked immunosorbent assay (ELISA) and variants thereof have become established as the method of choice
Fluid markers of acute mild traumatic brain injury
Candidate fluid markers of acute mild TBI are summarized in Table 1.
Chronic traumatic encephalopathy
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma (Stein et al., 2014). Although initially believed to affect only boxers, the at-risk population has expanded to encompass a much wider demographic, including American football players, ice hockey players, wrestlers, and military veterans. This expansion has garnered considerable media attention and public concern for the potential neurodegenerative effects of head trauma. There are no
Could markers of mild TBI/concussion help prevent CTE?
The primary goal of biomarker research in TBI is not to develop techniques to identify moderate to severe brain injury, as such already exist, but rather to identify molecular changes in mild TBI/concussion to tell if the brain was injured by a hit to the head and to monitor the recovery process. Most current research suggests that the risk of long-term symptoms following concussion is highest in individuals who have received repetitive concussions before the brain has had a chance to recover (
Conflicts of interest
Drs. Zetterberg and Blennow are listed as co-inventors on a US patent application for plasma tau as a brain injury marker. Dr. Blennow has served on advisory boards for Eli Lilly, Kyowa Kirin Pharma, Pfizer, and Roche. No other disclosures were reported.
Acknowledgments
Work in the authors' laboratories is supported by the Swedish Research Council, the Swedish State Support for Clinical Research, the Torsten Söderberg Foundation, the Knut and Alice Wallenberg Foundation and the Wolfson Foundation.
References (33)
- et al.
Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke
Neurosci. Lett.
(2001) - et al.
Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: results of a pilot study
Resuscitation
(2013) - et al.
PET scanning of brain tau in retired national football league players: preliminary findings
Am. J. Geriatr. Psychiatry
(2013) - et al.
Cerebrospinal fluid and plasma biomarkers in Alzheimer disease
Nat. Rev. Neurol.
(2010) - et al.
Ultrasensitive detection techniques pave the way to mechanism
Nat. Med.
(2015) - et al.
The role of calpain-mediated spectrin proteolysis in traumatically induced axonal injury
J. Neuropathol. Exp. Neurol.
(1999) Boxing and the brain
BMJ
(1989)- et al.
Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers
Nat. Rev. Neurol.
(2013) - et al.
Salivary alpha-synuclein and DJ-1: potential biomarkers for Parkinson's disease
Brain
(2011) - et al.
Axonal pathology in traumatic brain injury
Exp. Neurol.
(2012)