Prognostic Cerebrospinal Fluid Biomarkers in Traumatic Brain Injury: An Evolving Frontier

Traumatic brain injury (TBI) remains a life-threatening concern worldwide, contributing to long-term disability and mortality. Identifying reliable prognostic biomarkers is essential for tailoring therapeutic strategies and predicting outcomes. Among various biological matrices, cerebrospinal fluid (CSF) holds promise due to its proximity to the site of injury and direct reflection of central nervous system pathology. This letter concisely overviews the most studied CSF-based prognostic biomarkers in TBI and highlights their clinical implications.

Neuronal injury markers are among the most extensively studied. Neuron-specific enolase (NSE) is released from damaged neurons, and elevated CSF levels are correlated with poor Glasgow Outcome Scores and mortality, particularly in severe TBI cases.[1] Similarly, S100B, a calcium-binding protein from astrocytes, has shown predictive value in both acute and subacute phases of injury, especially when combined with radiological and clinical parameters.[2] [3] Neurofilament light chain (NFL), indicative of axonal damage, has recently gained attention for its role in predicting long-term neurocognitive deficits.[4] Tau protein and its phosphorylated form, commonly studied in Alzheimer's disease, have also been detected at elevated levels in TBI, especially in patients progressing toward posttraumatic dementia.[5]

Inflammatory biomarkers such as interleukin (IL)-6, IL-8, and IL-1β and tumor necrosis factor-alpha are consistently elevated in severe TBI and are strongly associated with secondary injury cascades, including cerebral edema and increased intracranial pressure.[6] [7] The chemokine monocyte chemoattractant protein-1 (MCP-1) is derived from the blood–brain barrier (BBB) and has worse functional outcomes.[8]

From a vascular and metabolic standpoint, the albumin quotient (CSF/serum ratio) is a marker of BBB integrity and is frequently deranged in severe TBI, correlating with cerebral autoregulatory dysfunction.[9] Furthermore, matrix metalloproteinase-9, a protease involved in extracellular matrix remodeling, has been implicated in BBB disruption and neuroinflammation, and its presence in CSF predicts the development of intracranial hypertension.[10]

Metabolic markers such as lactate/pyruvate ratios and glutamate concentrations help detect mitochondrial dysfunction and excitotoxicity. Elevated CSF glutamate, for instance, is associated with poor neurological recovery.[11] Oxidative stress markers, including F2-isoprostanes, have also shown promise in indicating lipid peroxidation and neuronal injury severity.[12]

The application of CSF biomarkers in TBI is increasingly being explored to assist in early diagnosis, therapeutic decision-making, and prognostic evaluation. Biomarkers such as glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) have demonstrated utility in identifying neuronal and astrocytic damage, respectively, particularly in moderate-to-severe injuries.[13] Inflammatory mediators, including IL-6 and high-mobility group box 1 (HMGB1), have shown potential in detecting early secondary injury responses and BBB disruption, guiding targeted interventions.[14] Moreover, combining biomarkers into multiplex platforms enhances their predictive value. It may be particularly effective when integrated with neuroimaging and clinical scales like the Glasgow Coma Scale or Rotterdam CT score.[15]

From a prognostic perspective, elevated CSF levels of GFAP, UCH-L1, and spectrin breakdown products are significantly associated with long-term neurological deficits and increased mortality rates.[16] Additionally, metabolic derangements reflected by abnormal CSF lactate and glutamate concentrations point toward mitochondrial dysfunction and excitotoxicity, mechanisms closely tied to poor recovery trajectories.[17] Implementing these biomarkers in acute clinical workflows may facilitate early prognostication, inform family counseling, and optimize patient selection for neuroprotective trials or rehabilitative strategies to improve functional outcomes.

We outlined a table with key TBI CSF biomarkers with optimal detection timing ([Table 1]).

Table 1 Key cerebrospinal fluid (CSF) biomarkers in traumatic brain injury with timing of optimal detection

Biomarker	Source or function	Clinical use	Suggested time frame for CSF sampling
Neuron-specific enolase (NSE)	Released from injured neurons	Associated with neuronal damage and poor outcomes	6–24 hours post-injury
S100B	Derived from astrocytes	Aids in early diagnosis and severity assessment	Within first 48 hours
Neurofilament light chain (NFL)	Reflects axonal breakdown	Predicts long-term neurological impairment	Several days to weeks
Tau/phosphorylated tau	Microtubule-associated neuronal protein	Linked to chronic degeneration and cognitive decline	3 days to several weeks
Interleukin-6 (IL-6)	Pro-inflammatory cytokine	Marker of acute neuroinflammatory response	6–72 hours
TNF-α, IL-1β, IL-8	Cytokines involved in immune signaling	Indicate ongoing inflammation and edema risk	12–72 hours
Monocyte chemoattractant protein-1 (MCP-1)	Chemokine from glial cells	Suggests blood–brain barrier disruption	First 72 hours
Matrix metalloproteinase-9 (MMP-9)	Enzyme affecting vascular permeability	Linked to edema and rising intracranial pressure	1–4 days
Lactate/pyruvate ratio	Reflects metabolic stress in brain cells	Indicates mitochondrial dysfunction	12–48 hours
Glutamate	Excitatory neurotransmitter	Marker of excitotoxic injury	Within 12–48 hours
F2-isoprostanes	Byproduct of lipid oxidation	Marker of oxidative injury severity	2–3 days

While many of these biomarkers remain under investigation, several—especially S100B, NSE, and NFL—are nearing clinical applicability, particularly when used in multimodal panels. However, challenges remain in standardizing measurement, timing of collection, and establishing reference ranges.

In conclusion, CSF biomarkers offer a valuable window into the pathophysiological processes of TBI and hold substantial prognostic potential. Future studies should focus on longitudinal profiling, integration with imaging and electrophysiological tools, and developing validated biomarker panels for routine clinical use.

 

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Conflict of Interest

None declared.

• References

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Publication History

Article published online:
13 June 2025