Acute traumatic brain injury (TBI) is associated with substantial metabolic abnormalities, both centrally and in the periphery. We have previously reported extensive changes in the circulating metabolome resulting from TBI, including changes proportional to disease severity and associated with patient outcomes. The observed metabolome changes in TBI likely reflect several pathophysiological mechanisms supporting the concept that TBI is a systemic disease after the primary injury. However, one of the main metabolic changes we have observed following a TBI are changes in lipids, including the structural lipids that are known to be present in the myelin in the brain. Here, we conducted a study to investigate the relationship between traumatic microstructural changes in white matter seen on magnetic resonance imaging (MRI) and quantitative lipidomic changes in the blood in a subset of patients with TBI recruited to the MRI sub-study of the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. In total, there were 103 patients who had both a magnetic resonance imaging (MRI) scan and serum samples available for analysis. From serum, 201 known lipids were quantified. Diffusion tensor fitting generated fractional anisotropy (FA) and mean diffusivity (MD) maps for the MRI scans, in addition to volumetric data. Association matrices and partial correlation networks were built to elucidate the connections between the lipid groups and the maps. We found that there are distinct directions of associations between the neuroimage data (FA and MD sets) and the concentrations of circulating lipids after injury. The FA and MD values were in inverse relationship with the severity of TBI (higher MD values, lower FA). We also observed that the lipid associations to FA and MD show different metabolic signatures. Lysophosphatidylcholines (LPC) associate mostly with FA while sphingomyelins (SM) associate with MD. Only phosphatidylcholines( PC) have strong associations with both as well as with the volumetric data. Finally, we found that the lipid changes are not associated with the number of regions with abnormalities. In conclusion, we have identified groups of lipids which assocate with specific MRI imaging metrics following TBI. There appears to be consistent patterns of lipid changes associating with the specific microstructure changes in the CNS white matter. There is also a pattern of lipids with regional specficity, suggesting that blood-based lipidomics may provide an insight into the underlying disease mechanisms in TBI.

The authors have declared no competing interest.

CENTER-TBI was supported by the European Union 7th Framework program (grant no. 602150), with additional project support from OneMind (US), the Hannelore Kohl Foundation (DE), NeuroTrauma Sciences (US), and Integra Neurosciences. The metabolomics study was supported by a grant from Swedish Research Council to M.O. (grant no. 2018-02629). V.F.J.N. was supported by a National Institute for Health and Care Research (NIHR) Advanced Fellowship and by an Academy of Medical Sciences / The Health Foundation Clinician Scientist Fellowship. The study was also supported by funding from the Academy of Finland to J.P.P. (grant no. 17379) and a grant from Maire Taponen Foundation to J.P.P. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. S.R. was supported by a Wellcome Trust PhD Fellowship (grant no. 222213/Z/20/Z)

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The CENTER-TBI study recruited 4509 patients from 18 European countries and Israel (https://www.center-tbi.eu/, registered at clinicaltrials.gov NCT02210221). The CENTER-TBI database contains data from 65 centers whose data were collected between December 19, 2014, and December 17, 2017. Ethical approval was obtained by each site in accordance with their local regulations (for details see https://www.center-tbi.eu/project/ethical-approval). Informed consent was obtained from all study participants or their legal representatives/relatives according to the local regulations of each center.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Data are accessible based on submission of a data access request through the CENTER-TBI website: https://www.center-tbi.eu/data. CENTER-TBI is committed to data sharing, and in particular to responsible further use of the data. Hereto, we have a data sharing statement in place: https://www.center-tbi.eu/data/sharing. The CENTER-TBI Management Committee, in collaboration with the General Assembly, established the Data Sharing policy and Publication and Authorship Guidelines to assure correct and appropriate use of the data as the dataset is hugely complex and requires help of experts from the Data Curation Team or Bio-Statistical Team for correct use. This means that we encourage researchers to contact the CENTER-TBI team for any research plans and the Data Curation Team for any help in appropriate use of the data, including sharing of scripts. The complete Manual for data access is also available online: https://www.center-tbi.eu/files/SOP-Manual-DAPR-20181101.pdf