Most medical specialities rely on their own unique biomarkers, whether measuring prostate cancer burden with PSA or cardiac muscle damage with troponin. Now, neurology is assembling an arsenal of its own.

A biomarker is a measurable biological signal that tells us something about a disease or injury process. In TBI, biomarker proteins like GFAP and UCH-L1, released from damaged astrocytes and neurons, have already made their mark. In the United States, blood tests for these markers are FDA-cleared to help rule out the need for acute CT scans in mild TBI.

This is excellent for emergency department triage, reducing unnecessary radiation, and speeding up management. But CT rule-out is only one part of the problem. A normal scan does not guarantee a rapid recovery, just as an initially severe presentation doesn’t preclude an excellent outcome with the right rehabilitation.

In a previous article, we addressed how the traditional labels of “mild, moderate, and severe”, based almost largely on the Glasgow Coma Scale, are increasingly viewed as too blunt. Acknowledging this, the 2025 NIH-NINDS TBI Classification Initiative proposed the CBI-M framework, arguing that TBI must be characterised using Clinical findings, Biomarkers, Imaging, and patient-specific Modifiers.

This is where one biomarker in particular takes the spotlight.

The Rise of NfL

Neurofilament light chain (NfL) is a structural protein found in neurons, primarily within long myelinated axons. This is critical because traumatic axonal injury is a major driver of long-term disability, yet it frequently evades standard imaging.

Historically, NfL was a cerebrospinal fluid (CSF) biomarker, making it completely impractical for routine or repeated acute head injury assessment. The game-changer was the development of ultrasensitive assay platforms (such as single-molecule arrays) capable of measuring minute concentrations of NfL in serum or plasma. Suddenly, researchers weren’t just asking if a protein was present; they were asking if a blood test, measured repeatedly, could map a patient’s recovery trajectory.

Biomarkers Across Specialities

To understand the trajectory of NfL, we need only look at cardiology. Decades ago, clinicians evaluating chest pain relied on crude, non-specific markers like AST and LDH before moving to CK-MB. The eventual arrival of cardiac troponins, and later, high-sensitivity troponin assays, fundamentally shifted practice. Troponin didn’t replace the ECG, the patient’s history, or clinical judgement; it sharpened them by providing a quantifiable biological signal of myocardial injury.

NfL is following a similar path. Like troponin, which can elevate in pulmonary embolism, sepsis, or renal impairment, NfL is not perfectly disease-specific. Its true value lies not in a binary “brain injury yes/no” diagnosis, but in helping clinicians understand the nature, severity, and trajectory of neuroaxonal damage.

A Feature, Not a Flaw

Different biomarkers answer different clinical questions because they follow distinct kinetic profiles. While GFAP and UCH-L1 spike rapidly after injury to aid acute triage, NfL rises slowly. Serum NfL continues to climb over days and weeks post-injury, with peak levels reported around 20–30 days in moderate-to-severe TBI.

This slow kinetic profile is a feature, not a flaw. A sustained, evolving elevation tells us something arguably more important than acute triage: the ongoing burden of axonal injury, neurobiological stress, and the likely long-term outcome.

Prognosis and Proof

The optimism surrounding NfL is grounded in increasingly robust longitudinal data. As early as 2016, a foundational proof-of-concept study found that high initial serum NfL levels powerfully predicted poor 12-month clinical outcomes in severe TBI, achieving a near-perfect diagnostic separation between injured patients and healthy controls (Shahim et al., 2016).

More recently, research tracking chronic TBI recovery has highlighted NfL’s unique ability to monitor long-term neurodegeneration. A 2022 study tracking patients for over five years found that elevated NfL measured roughly eight months post-injury accurately predicted ongoing white matter and overall brain volume loss (Newcombe et al., 2022). This aligns with 2024 data showing that persistently high plasma NfL at an average of nine months post-injury directly correlates with worse functional outcomes (Tuure et al., 2024).

These individual milestones are synthesised in a 2026 systematic review and meta-analysis of 14 studies (comprising 2,905 participants), which confirmed that higher NfL concentrations are significantly associated with unfavourable long-term neurological outcomes following moderate-to-severe TBI.

For patients, this biological anchoring could prompt earlier neurorehabilitation, targeted specialist follow-up, and more realistic return-to-work planning. For claimants and solicitors, the implications are equally profound. Biomarkers could feasibly be used to assess whether an impact caused meaningful damage and whether ongoing symptoms are plausibly linked to the injury.

While biomarkers will not automatically prove causation or replace expert clinical assessment, objective biological data is a powerful tool when a claimant is forced to prove an “invisible” injury. Crucially, it may help distinguish between absence of evidence and evidence of absence.

Looking Ahead

We have focused on NfL because it tracks axonal injury, often the primary driver of long-term disability. But NfL is unlikely to be the final word.

The future of TBI assessment is not a single “magic bullet” blood test. We are moving towards multimodal panels where an array of biomarkers (NfL, GFAP, UCH-L1, tau, and inflammatory proteins) are measured at strategic time intervals. Ultimately, these will be synthesised into prognostic scoring systems, offering a highly accurate biological classification of the injury.

Evaluating traumatic brain injury has always meant navigating the grey areas of blunt clinical labels. With the rise of serum biomarkers, the true trajectory of recovery is finally coming to light.

References

Bazarian, J. J., Biberthaler, P., Welch, R. D., Lewis, L. M., Barzo, P., Bogner-Flatz, V., … & Jagoda, A. S. (2018). Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. The Lancet Neurology, 17(9), 782-789.

Manley, G. T., Dams-O’Connor, K., Alosco, M. L., Awwad, H. O., Bazarian, J. J., Bragge, P., … & Yurgelun-Todd, D. (2025). A new characterisation of acute traumatic brain injury: the NIH-NINDS TBI Classification and Nomenclature Initiative. The Lancet Neurology, 24(6), 512-523.

Newcombe, V. F., Ashton, N. J., Posti, J. P., Glocker, B., Manktelow, A., Chatfield, D. A., … & Menon, D. K. (2022). Post-acute blood biomarkers and disease progression in traumatic brain injury. Brain, 145(6), 2064-2076.

Shahim, P., Gren, M., Liman, V., Andreasson, U., Norgren, N., Tegner, Y., … & Blennow, K. (2016). Serum neurofilament light protein predicts clinical outcome in traumatic brain injury. Scientific reports, 6(1), 36791.

Tuure, J., Mohammadian, M., Tenovuo, O., Blennow, K., Hossain, I., Hutchinson, P., … & Posti, J. P. (2024). Late blood levels of neurofilament light correlate with outcome in patients with traumatic brain injury. Journal of Neurotrauma, 41(3-4), 359-368.

Wang, K. K., Barton, D. J., McQuillan, L. E., Kobeissy, F., Cai, G., Xu, H., … & Wagner, A. K. (2024). Parallel cerebrospinal fluid and serum temporal profile assessment of axonal injury biomarkers neurofilament-light chain and phosphorylated neurofilament-heavy chain: associations with patient outcome in moderate-severe traumatic brain injury. Journal of Neurotrauma, 41(13-14), 1609-1627.

Bouras, M., Pageau, M., Gagnon, M. A., Costerousse, O., Demers, K., Grenier-Gagnon, A., … & Canadian Traumatic Brain Injury Research Consortium. (2026). Association between neurofilament light chain concentrations and outcomes in patients with moderate to severe traumatic brain injury: a systematic review and meta-analysis. Critical Care.