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

Abstract

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.

Contra-Directional Expression of Plasma Superoxide Dismutase with Lipoprotein Cholesterol and High-Sensitivity C-reactive Protein as Important Markers of Parkinson’s Disease Severity

“…Several lines of evidence already indicated that abnormalities in lipid metabolism are involved in the pathophysiological process of PD (Chung et al, 2019;Xicoy et al, 2019). A previous study demonstrated that dyslipidemia is causally related to BBB impairment and plasma HDL cholesterol were the lipids most associated with BBB integrity (Bowman et al, 2012;Deng et al, 2018;Eiden et al, 2019;Miao et al, 2019). α-synuclein is a small protein abundantly expressed in the brain.…”

Lipid Mediators in Critically Ill Patients: A Step Towards Precision Medicine

“…Major trauma is a leading cause of morbidity and mortality around the globe (86,87). Severe traumatic injury has a considerable impact on the immune and metabolic system (88,89) and leads to a posttraumatic cascade of inflammatory changes (90)(91)(92)(93). Therefore, lipid mediators have been proposed as prognostic markers in trauma patients (67,68,94).…”

Exploring Valine Metabolism in Astrocytic and Liver Cells: Lesson from Clinical Observation in TBI Patients for Nutritional Intervention

“…Traumatic brain injury (TBI) is associated with high economic costs and clinical burden. It is characterized by abnormal brain energy metabolism and the utilization of alternative energy substrates to glucose could be beneficial [ 1 , 2 ]. In a recent clinical study performed on TBI patients, we identified valine, β-hydroxyisobutyrate (ibHB) and 2-ketoisovaleric acid (2-KIV) as three of the main predictors of TBI outcome [ 2 ].…”

“…It is characterized by abnormal brain energy metabolism and the utilization of alternative energy substrates to glucose could be beneficial [ 1 , 2 ]. In a recent clinical study performed on TBI patients, we identified valine, β-hydroxyisobutyrate (ibHB) and 2-ketoisovaleric acid (2-KIV) as three of the main predictors of TBI outcome [ 2 ]. In particular, we reported a significant association between cerebral microdialysis (CMD) ibHB, CMD 2-KIV (the precursor of ibHB) and CMD valine with short-term outcome (therapy intensity level (TIL)) [ 2 ].…”

“…In a recent clinical study performed on TBI patients, we identified valine, β-hydroxyisobutyrate (ibHB) and 2-ketoisovaleric acid (2-KIV) as three of the main predictors of TBI outcome [ 2 ]. In particular, we reported a significant association between cerebral microdialysis (CMD) ibHB, CMD 2-KIV (the precursor of ibHB) and CMD valine with short-term outcome (therapy intensity level (TIL)) [ 2 ]. Interestingly, another clinical study reported lower levels of valine in plasma of TBI patients [ 3 ] and, in a mouse model of TBI, the concentration of valine in the hippocampus was reduced to half as compared to control [ 4 ], suggesting that the level of the metabolite might be related to the pathology.…”