Discovery and validation of temporal patterns involved in human brain ketometabolism in cerebral microdialysis fluids of traumatic brain injury patients.

Eiden, Michael; Christinat, Nicolas; Chakrabarti, Anirikh; Sonnay, Sarah; Miroz, John-Paul; Cuenoud, Bernard; Oddo, Mauro; Masoodi, Mojgan (2019). Discovery and validation of temporal patterns involved in human brain ketometabolism in cerebral microdialysis fluids of traumatic brain injury patients. EBioMedicine, 44, pp. 607-617. Elsevier 10.1016/j.ebiom.2019.05.054

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BACKGROUND Traumatic brain injury (TBI) is recognized as a metabolic disease, characterized by acute cerebral glucose hypo-metabolism. Adaptive metabolic responses to TBI involve the utilization of alternative energy substrates, such as ketone bodies. Cerebral microdialysis (CMD) has evolved as an accurate technique allowing continuous sampling of brain extracellular fluid and assessment of regional cerebral metabolism. We present the successful application of a combined hypothesis- and data-driven metabolomics approach using repeated CMD sampling obtained routinely at patient bedside. Investigating two patient cohorts (n = 26 and n = 12), we identified clinically relevant metabolic patterns at the acute post-TBI critical care phase. METHODS Clinical and CMD metabolomics data were integrated and analysed using in silico and data modelling approaches. We used both unsupervised and supervised multivariate analysis techniques to investigate structures within the time series and associations with patient outcome. FINDINGS The multivariate metabolite time series exhibited two characteristic brain metabolic states that were attributed to changes in key metabolites: valine, 4-methyl-2-oxovaleric acid (4-MOV), isobeta-hydroxybutyrate (iso-bHB), tyrosyine, and 2-ketoisovaleric acid (2-KIV). These identified cerebral metabolic states differed significantly with respect to standard clinical values. We validated our findings in a second cohort using a classification model trained on the cerebral metabolic states. We demonstrated that short-term (therapeutic intensity level (TIL)) and mid-term patient outcome (6-month Glasgow Outcome Score (GOS)) can be predicted from the time series characteristics. INTERPRETATION We identified two specific cerebral metabolic patterns that are closely linked to ketometabolism and were associated with both TIL and GOS. Our findings support the view that advanced metabolomics approaches combined with CMD may be applied in real-time to predict short-term treatment intensity and long-term patient outcome.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Masoodi, Mojgan

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2352-3964

Publisher:

Elsevier

Language:

English

Submitter:

Mojgan Masoodi

Date Deposited:

14 Nov 2019 08:04

Last Modified:

14 Nov 2019 08:04

Publisher DOI:

10.1016/j.ebiom.2019.05.054

PubMed ID:

31202815

Uncontrolled Keywords:

Cerebral microdialysis Ketometabolism Metabolic state Traumatic brain injury

BORIS DOI:

10.7892/boris.134954

URI:

https://boris.unibe.ch/id/eprint/134954

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