Biomarkers for TBI

A biomarker is a measurable biological indicator — a molecule, gene, or characteristic that can be objectively measured and evaluated as an indicator of a biological process, pathological condition, or response to treatment. In the context of traumatic brain injury (TBI), biomarkers are substances released into the bloodstream following neuronal damage, glial cell injury, or disruption of the blood-brain barrier. Blood-based TBI biomarkers offer a potentially objective, quantifiable window into the biological reality of brain injury — complementing clinical observation, symptom reporting, and neuroimaging.

The most clinically advanced blood-based TBI biomarkers are proteins: GFAP (Glial Fibrillary Acidic Protein) and UCH-L1 (Ubiquitin C-terminal Hydrolase-L1). The Abbott i-STAT TBI test measuring GFAP and UCH-L1 in venous whole blood is FDA-cleared for use in adults with suspected mTBI in emergency settings, and is now available in some clinical environments. S100B is widely used in Europe as a triage tool to guide CT imaging decisions in suspected mTBI. Neurofilament light chain (NfL) is an emerging biomarker with growing research support, particularly for chronic and repetitive injury contexts. These protein biomarkers have established acute utility but have limitations in mild TBI sensitivity, subacute assessment, and longitudinal monitoring.

CT and MRI are essential tools in TBI management, but they have significant limitations — particularly in mild TBI. CT is highly sensitive for detecting acute haemorrhage and structural injury requiring neurosurgical intervention, but it is frequently normal in mild TBI (concussion), even when significant neurological symptoms are present. Conventional MRI is more sensitive than CT for detecting diffuse axonal injury and microstructural changes, but it is expensive, time-consuming, and not available in field or sideline settings. Advanced MRI techniques (DTI, SWI, fMRI) can detect subtle changes in mTBI but are research tools rather than routine clinical instruments. Blood-based biomarkers are being developed to provide an objective biological signal that complements imaging — particularly in the large proportion of mTBI cases where imaging is normal.

The blood-brain barrier (BBB) is a highly selective semipermeable border formed by specialised endothelial cells lining the cerebral vasculature. Under normal conditions, it tightly regulates the passage of substances between the bloodstream and the brain, protecting the central nervous system from pathogens and maintaining the precise chemical environment required for neural function. TBI — even mild TBI — can disrupt the integrity of the BBB, allowing brain-specific molecules (proteins, nucleic acids, and other cellular contents) to leak into the peripheral bloodstream. This BBB disruption is one of the key mechanisms by which brain-derived biomarkers become detectable in blood following injury.

Current protein biomarkers such as GFAP and UCH-L1 have established utility in the acute phase of mTBI assessment (typically within 12 hours of injury) but have limitations in several areas: sensitivity in very mild TBI; utility beyond the acute window (subacute and chronic phases); monitoring biological recovery over time; and applicability in populations with pre-existing neurological conditions or repeated head injury exposure. Additionally, most current biomarker tests require venous blood collection and laboratory or near-patient testing infrastructure, limiting their use in field, sideline, and resource-limited settings. GLIA’s research is investigating whether a microRNA panel can address some of these gaps — though this remains under development.

Point-of-care (PoC) testing refers to diagnostic testing performed at or near the location of patient care — rather than in a centralised laboratory. In the context of TBI, PoC testing could enable blood-based biomarker assessment on the sports sideline, in a military field setting, in an emergency department without laboratory infrastructure, or in a remote or resource-limited environment. PoC TBI testing would require a compact, rapid, easy-to-use device capable of processing a small blood sample (ideally from a finger-stick) and delivering a result within a clinically useful timeframe. GLIA is developing a PoC platform for its miRNA panel, though this remains investigational and is not yet approved for clinical use.

Current return-to-play (sport) and return-to-duty (military) protocols following suspected TBI or concussion rely primarily on symptom resolution and clinical assessment. The fundamental limitation of symptom-based protocols is that symptom resolution does not necessarily reflect underlying biological recovery — athletes and military personnel may be symptom-free while biological injury processes are still active. Blood-based biomarkers that reflect the biological state of the brain — rather than subjective symptom reporting — could potentially provide an objective complement to clinical assessment in return-to-activity decisions. This is an area of active research; no blood-based biomarker has yet been validated for return-to-play or return-to-duty decision-making.

The terms ‘concussion’ and ‘mild TBI’ (mTBI) are often used interchangeably, but there are nuances in their usage across clinical and research contexts. Concussion is a clinical diagnosis based on the presence of specific symptoms following a head impact or acceleration-deceleration event — it is typically used in sport and community settings. Mild TBI is a broader clinical classification based on initial injury severity indicators (Glasgow Coma Scale score, loss of consciousness duration, post-traumatic amnesia duration), used in emergency and research settings. All concussions are mild TBIs, but not all mild TBIs are described as concussions in every clinical context. Both terms describe a spectrum of injury severity, and both present significant diagnostic challenges due to the frequent absence of abnormalities on standard imaging.