Poor long-term outcomes and abnormal neurodegeneration biomarkers after military traumatic brain injury: the ADVANCE study

Background Traumatic brain injury (TBI) is common in military campaigns and is a risk factor for dementia. ArmeD SerVices TrAuma and RehabilitatioN OutComE-TBI (ADVANCE-TBI) aims to ascertain neurological outcomes in UK military personnel with major battlefield trauma, leveraging advances in quantification of axonal breakdown markers like neurofilament light (NfL), and astroglial marker glial fibrillar acidic protein (GFAP) in blood. We aimed to describe the causes, prevalence and consequences of TBI, and its fluid biomarker associations. Methods TBI history was ascertained in 1145 servicemen and veterans, of whom 579 had been exposed to major trauma. Functional and mental health assessments were administered, and blood samples were collected approximately 8 years postinjury, with plasma biomarkers quantified (n=1125) for NfL, GFAP, total tau, phospho-tau181, amyloid-beta 42 and 40. Outcomes were related to neurotrauma exposure. Results TBI was present in 16.9% (n=98) of exposed participants, with 46.9% classified as mild-probable and 53.1% classified as moderate to severe. Depression (beta=1.65, 95% CI (1.33 to 2.03)), anxiety (beta=1.65 (1.34 to 2.03)) and post-traumatic stress disorder (beta=1.30 (1.19 to 1.41)) symptoms were more common after TBI, alongside poorer 6 minute walk distance (beta=0.79 (0.74 to 0.84)) and quality of life (beta=1.27 (1.19 to 1.36), all p<0.001). Plasma GFAP was 11% (95% CI 2 to 21) higher post-TBI (p=0.013), with greater concentrations in moderate-to-severe injuries (47% higher than mild-probable (95% CI 20% to 82%, p<0.001). Unemployment was more common among those with elevated GFAP levels post-TBI, showing a 1.14-fold increase (95% CI 1.03 to 1.27, p<0.001) for every doubling in GFAP concentration. Conclusions TBI affected nearly a fifth of trauma-exposed personnel, related to worse mental health, motor and functional outcomes, as well as elevated plasma GFAP levels 8 years post-injury. This was absent after extracranial trauma, and showed a dose-response relationship with the severity of the injury.