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Caroline Lindblad
Karolinska Institutet
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4952-8597
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Severe 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.
Methods: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Scale, 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.
Results: TBI patients had an upregulation of structural 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.
Conclusions: This 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.
Keywords
traumatic brain injury, protein biomarkers, proteomics, neuroinflammation, blood-brain barrier, apolipoprotein E4, Glasgow Outcome Scale, human
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CURRENT STATUS: Published
View the published article at Critical Care.
No community comments so far
Editorial decision: Accept
On 09 Feb, 2021
Reviewer #2 agreed
On 08 Feb, 2021
Review #2 received
Received 08 Feb, 2021
Review #1 received
Received 04 Feb, 2021
Reviewer #1 agreed
On 20 Jan, 2021
Editor assigned
On 19 Jan, 2021
Reviewers invited
Invitations sent on 19 Jan, 2021
Submission checks complete
On 19 Jan, 2021
Editor invited
On 19 Jan, 2021
Version 1
Posted 29 Oct, 2020
No comments provided
Editorial decision: Major revision
On 02 Dec, 2020
Review #3 received
Received 30 Nov, 2020
Review #2 received
Received 26 Nov, 2020
Reviewer #3 agreed
On 15 Nov, 2020
Reviewer #2 agreed
On 15 Nov, 2020
Review #1 received
Received 10 Nov, 2020
Reviewers invited
Invitations sent on 27 Oct, 2020
Reviewer #1 agreed
On 27 Oct, 2020
Editor invited
On 22 Oct, 2020
Editor assigned
On 21 Oct, 2020
Submission checks complete
On 20 Oct, 2020
First submitted
On 19 Oct, 2020
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PDF Downloads: ...
HTML Views: ...
Subject Areas
Critical Care & Emergency Medicine
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A new preprint design is coming!
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See the published version of this preprint at Critical Care.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Caroline Lindblad
Karolinska Institutet
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4952-8597
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Critical Care.
No community comments so far
Editorial decision: Accept
On 09 Feb, 2021
Reviewer #2 agreed
On 08 Feb, 2021
Review #2 received
Received 08 Feb, 2021
Review #1 received
Received 04 Feb, 2021
Reviewer #1 agreed
On 20 Jan, 2021
Editor assigned
On 19 Jan, 2021
Reviewers invited
Invitations sent on 19 Jan, 2021
Submission checks complete
On 19 Jan, 2021
Editor invited
On 19 Jan, 2021
Version 1
Posted 29 Oct, 2020
No comments provided
Editorial decision: Major revision
On 02 Dec, 2020
Review #3 received
Received 30 Nov, 2020
Review #2 received
Received 26 Nov, 2020
Reviewer #3 agreed
On 15 Nov, 2020
Reviewer #2 agreed
On 15 Nov, 2020
Review #1 received
Received 10 Nov, 2020
Reviewers invited
Invitations sent on 27 Oct, 2020
Reviewer #1 agreed
On 27 Oct, 2020
Editor invited
On 22 Oct, 2020
Editor assigned
On 21 Oct, 2020
Submission checks complete
On 20 Oct, 2020
First submitted
On 19 Oct, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Critical Care & Emergency Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Critical Care.
Background: Severe 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.
Methods: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Scale, 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.
Results: TBI patients had an upregulation of structural 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.
Conclusions: This 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.
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
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