Abstract
BackgroundSevere traumatic brain injury (TBI) is associated with blood–brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls.MethodsWe conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6–12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (QA), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort.ResultsTBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with QA, among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained ~ 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, ΔR2 = 7.4%) and complement factor B in serum (p = 0.003, ΔR2 = 9.2%) were independent outcome predictors also following step-down modelling.ConclusionsThis represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.
Highlights
Traumatic brain injury (TBI) is a common cause of death and acquired disability worldwide [1]
Lindblad et al Crit Care (2021) 25:103. This represents the largest concomitant cerebrospinal fluid (CSF) and serum proteomic profiling study so far reported in traumatic brain injury (TBI), providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts blood–brain barrier (BBB) disruption and long-term outcome
Data analysis was conducted on the 90 TBI patients and 15 healthy controls that had matched CSF and serum samples
Summary
Traumatic brain injury (TBI) is a common cause of death and acquired disability worldwide [1]. The acute, mechanically-induced BBB injury has been shown to peak at 1–3 h post-TBI [3, 4] and contribute to the inflammatory activation of (CNS) inherent cells, such as astrocytes and microglia, and in facilitating the infiltration of immune cells from the systemic circulation [5, 6] This generates an inflammatory cascade that can exacerbate BBB injury, thereby increasing the intensity of CNS neuroinflammation [7]. BBB injury and neuroinflammation propagate secondary injury pathologies, such as edema development, increased intracranial pressure, decreased cerebral perfusion, and consequent ischemia [4], presumably of importance for long-term outcome It is unclear whether these acute TBI processes are influenced by the genetic set up, but in the absence of trauma the E4 variant of apolipoprotein E (APOE4) is associated with reduced BBB function and predicts risks of cognitive decline [8]. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls
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