Effects of age and time since injury on traumatic brain injury blood biomarkers: a TRACK-TBI study

Abstract

Older adults have the highest incidence of traumatic brain injury globally. Accurate blood-based biomarkers are needed to assist with diagnosis of patients across the spectrum of age and time post-injury. Several reports have suggested lower accuracy for blood-based biomarkers in older adults, and there is a paucity of data beyond day-1 post-injury. Our aims were to investigate age-related differences in diagnostic accuracy and 2-week evolution of 4 leading candidate blood-based traumatic brain injury biomarkers – plasma glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, S100 calcium binding protein B, and neuron specific enolase – among participants in the 18-site prospective cohort study Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI). Day-1 biomarker data were available for 2602 participants including 2151 patients with traumatic brain injury, 242 orthopedic trauma controls, and 209 healthy controls. Participants were stratified into 3 age categories (young: 17-39 years, middle-aged: 40-64 years, older: 65-90 years). We investigated age-stratified biomarker levels and biomarker discriminative abilities across 3 diagnostic groups: head CT-positive/negative; traumatic brain injury/orthopedic controls; traumatic brain injury/healthy controls. The difference in day-1 glial fibrillary acidic protein, ubiquitin carboxy-terminal hydrolase L1, and neuron specific enolase levels across most diagnostic groups was significantly smaller for older versus younger adults, resulting in a narrower range within which a traumatic brain injury diagnosis may be discriminated in older adults. Despite this, day-1 glial fibrillary acidic protein had good to excellent performance across all age-categories for discriminating all 3 diagnostic groups (area under the curve 0.84-0.96; lower limit of 95% confidence intervals all >0.78). Day-1 S100 calcium binding protein B and ubiquitin carboxy-terminal hydrolase L1 showed good discrimination of CT-positive vs. negative only among adults under age 40 years within 6 hours of injury. Longitudinal blood-based biomarker data were available for 522 hospitalized patients with traumatic brain injury and 24 hospitalized orthopedic controls. Glial fibrillary acidic protein levels maintained good to excellent discrimination across diagnostic groups until day 3 post-injury irrespective of age, until day 5 post-injury among middle-aged or younger patients, and until week 2 post-injury among young patients only. In conclusion, the blood-based glial fibrillary acidic protein assay tested here has good to excellent performance across all age-categories for discriminating key traumatic brain injury diagnostic groups to at least 3 days post-injury in this trauma center cohort. The addition of a blood-based diagnostic to the evaluation of traumatic brain injury, including geriatric traumatic brain injury, has potential to streamline diagnosis.

Management of traumatic brain injury in older adults: What you need to know

“…58 Consequently, although these biomarkers may be highly sensitive in older adults, their poor specificity prevents them from reducing the need for CT scans. 58 On the other hand, considering that older adults with complicated mild TBI are often under-triaged due to comorbid conditions and the imprecision of the initial GCS score, these biomarkers could potentially serve as a valuable tool for faster TBI confirmation and in optimizing triage and acute surgical management in older adults. [59][60][61] Further research is warranted in this rapidly advancing field, particularly regarding the role of blood biomarkers in predicting outcomes in TBI in older adults.…”

“…However, there have been limited studies assessing the impact of aging on the kinetics and clinical performance of these biomarkers. Age and neurodegenerative disease can lead to an elevated baseline level of brain injury biomarkers, independent of TBI severity 58 . Consequently, although these biomarkers may be highly sensitive in older adults, their poor specificity prevents them from reducing the need for CT scans 58 .…”

“…Age and neurodegenerative disease can lead to an elevated baseline level of brain injury biomarkers, independent of TBI severity 58 . Consequently, although these biomarkers may be highly sensitive in older adults, their poor specificity prevents them from reducing the need for CT scans 58 . On the other hand, considering that older adults with complicated mild TBI are often under-triaged due to comorbid conditions and the imprecision of the initial GCS score, these biomarkers could potentially serve as a valuable tool for faster TBI confirmation and in optimizing triage and acute surgical management in older adults 59–61 .…”

Maximizing the Clinical Value of Blood-Based Biomarkers for Mild Traumatic Brain Injury

“…The absence of representation of the pediatric concussion patient is a major gap since the developing brain is particularly susceptible to injury and prolonged sequelae [122,123]. In older persons, baseline levels of biomarkers are higher, and discriminative capability may be less or of shorter duration after injury [115,124,125]. In persons with Alzheimer's disease, GFAP levels may be elevated [126].…”

Performance of biomarkers NF-L, NSE, Tau and GFAP in blood and cerebrospinal fluid in rat for the detection of nervous system injury

“…NSE is a cell specific isoenzyme of the glycolytic enzyme enolase, highly specific for neurons and peripheral neuroendocrine cells. NSE has been used as a biomarker for neuroblastoma and traumatic brain injury (TBI) ( Isgro et al, 2015 ; Chen et al, 2022 ; Gardner et al, 2023 ). GFAP is an intermediate filament protein, unique to astrocytes, non-myelinating Schwann cells (PNS) and enteric glial cells and is mostly studied as a biomarker of TBI ( Yang and Wang, 2015 ; Gardner et al, 2023 ).…”