Investigating the characteristics and correlates of systemic inflammation after traumatic brain injury: the TBI-BraINFLAMM study

Abstract

Introduction: A significant environmental risk factor for neurodegenerative disease is traumatic brain injury (TBI). However, it is not clear how TBI results in ongoing chronic neurodegeneration. Animal studies show that systemic inflammation is signalled to the brain. This can result in sustained and aggressive microglial activation, which in turn is associated with widespread neurodegeneration. We aim to evaluate systemic inflammation as a mediator of ongoing neurodegeneration after TBI.

Methods and analysis: TBI-braINFLAMM will combine data already collected from two large prospective TBI studies. The CREACTIVE study, a broad consortium which enrolled >8000 patients with TBI to have CT scans and blood samples in the hyperacute period, has data available from 854 patients. The BIO-AX-TBI study recruited 311 patients to have acute CT scans, longitudinal blood samples and longitudinal MRI brain scans. The BIO-AX-TBI study also has data from 102 healthy and 24 non-TBI trauma controls, comprising blood samples (both control groups) and MRI scans (healthy controls only). All blood samples from BIO-AX-TBI and CREACTIVE have already been tested for neuronal injury markers (GFAP, tau and NfL), and CREACTIVE blood samples have been tested for inflammatory cytokines. We will additionally test inflammatory cytokine levels from the already collected longitudinal blood samples in the BIO-AX-TBI study, as well as matched microdialysate and blood samples taken during the acute period from a subgroup of patients with TBI (n=18).We will use this unique dataset to characterise post-TBI systemic inflammation, and its relationships with injury severity and ongoing neurodegeneration.

Ethics and dissemination: Ethical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (17/LO/2066). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of larger observational and experimental medicine studies assessing the role and management of post-TBI systemic inflammation.

Keywords: Dementia; NEUROLOGY; Neurological injury; TRAUMA MANAGEMENT.

Figure 1

Schematic of neurodegeneration after traumatic brain injury (TBI). Neuronal loss after TBI is a combination of the fixed damage from the initial injury, coupled with ongoing loss from progressive neurodegeneration. The static damage from the initial injury can be assessed by blood biomarkers and acute CT (A). Neurodegeneration can be visualised in vivo by changes in grey and white matter structure on longitudinal MRI (B) and through chronically elevated neuronal injury biomarkers (C). This project will investigate the relationship between injury and systemic inflammation in the acute and chronic phase (D) and the extent to which it contributes to ongoing neurodegeneration.

Figure 2

Schematic showing TBI patient data available and to be acquired for this study. Blue indicates the data are already acquired, and red indicates data to be acquired during this study. D0−5=period from day of injury to 5 days after injury. D0−10=period from day of injury to 10 days after injury. D10−6w=period covering 10 days to 6 weeks after injury. 6m/12m=6 months/12 months. TBI, traumatic brain injury.

Figure 3

In this directed acyclic graph, injury severity and extent are hypothesised to cause both early (up to 6 weeks) and late (6+ months) systemic inflammation, as well as directly influence neurodegeneration. Additionally, late systemic inflammation is hypothesised to partly mediate the relationship between injury severity and extent and neurodegeneration. Red denotes processes, blue indicates events and green denotes outcome measures. FA, fractional anisotropy; GM, grey matter; WM, white matter.