Alternative substrate metabolism depends on cerebral metabolic state following traumatic brain injury.
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ABSTRACT:
SUBMITTER: Greco T
PROVIDER: S-EPMC8168752 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Adaptive metabolic response to injury includes the utilization of alternative energy substrates - such as ketone bodies (KB) - to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI; n = 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and β-hydroxybutyrate). Nutrition - from fasting vs. stable nutrition state - was associated with a significant decrease of brain KB (34.7 [10th-90th percentiles 10.7-189] µmol/L vs. 13.1 [6.5-64.3] µmol/L, p < 0.001) and blood KB (668 [168.4-3824.9] vs. 129.4 [82.6-1033.8] µmol/L, p < 0.01). Blood KB correlated with brain KB (Spearman's rho 0.56, p = 0.0013). Continuous feeding with medium-chain triglycerides-enriched enteral nutrition did not increase blood KB, and provided a modest increase in blood and brain free medium chain fatty acids. Higher brain KB at the acute TBI phase correlated with age and brain lactate, pyruvate and glutamate, but not brain glucose. These novel findings suggest that nutritional ketosis was the main determinant of cerebral KB metabolism following TBI. Age and cerebral metabolic distress contributed to brain KB supporting the hypothesis that ketones might act as alternative energy substrates to glucose. Further studies testing KB supplementation after TBI are warranted.
| S-EPMC6928557 | biostudies-literature
Project description:Optimal glycaemic targets for patients with severe traumatic brain injury remain unclear. The primary objective of this microdialysis study was to compare cerebral metabolism with strict versus conventional glycaemic control.We performed a prospective single-centre randomised controlled within-subject crossover study of 20 adult patients admitted to an academic neurointensive care unit with severe traumatic brain injury. Patients underwent randomised, consecutive 24-h periods of strict (4-7 mmol/L; 72-126 mg/dl) and conventional (<10 mmol/L; 180 mg/dl) glycaemic control with microdialysis measurements performed hourly. The first 12 h of each study period was designated as a 'washout' period, with the subsequent 12 h being the period of interest.Cerebral glucose was lower during strict glycaemia than with conventional control (mean 1.05 [95% CI 0.58-1.51] mmol/L versus 1.28 [0.81-1.74] mmol/L; P?=?0.03), as was lactate (3.07 [2.44-3.70] versus 3.56 [2.81-4.30]; P?<?0.001). There were no significant differences in pyruvate or the lactate/pyruvate ratio between treatment phases. Strict glycaemia increased the frequency of low cerebral glucose (<?0.8 mmol/L; OR 1.91 [95% CI 1.01-3.65]; P?<?0.05); however, there were no differences in the frequency of critically low glucose (<?0.2 mmol/L) or critically elevated lactate/pyruvate ratio between phases.Compared with conventional glycaemic targets, strict blood glucose control was associated with lower mean levels of cerebral glucose and an increased frequency of abnormally low glucose levels. These data support conventional glycaemic targets following traumatic brain injury.ISRCTN, ISRCTN19146279 . Retrospectively registered on 2 May 2014.
| S-EPMC5784688 | biostudies-other
Project description:Traumatic brain injury (TBI) results in a cerebral metabolic crisis that contributes to poor neurologic outcome. The aim of this study was to characterize changes in oxidative glucose metabolism in early periods after injury in the brains of immature animals. At 5 h after controlled cortical impact TBI or sham surgery to the left cortex, 21-22 day old rats were injected intraperitoneally with [1,6-13C]glucose and brains removed 15, 30 and 60 min later and studied by ex vivo 13C-NMR spectroscopy. Oxidative metabolism, determined by incorporation of 13C into glutamate, glutamine and GABA over 15-60 min, was significantly delayed in both hemispheres of brain from TBI rats. The most striking delay was in labeling of the C4 position of glutamate from neuronal metabolism of glucose in the injured, ipsilateral hemisphere which peaked at 60 min, compared with the contralateral and sham-operated brains, where metabolism peaked at 30 and 15 min, respectively. Our findings indicate that (i) neuronal-specific oxidative metabolism of glucose at 5-6 h after TBI is delayed in both injured and contralateral sides compared with sham brain; (ii) labeling from metabolism of glucose via the pyruvate carboxylase pathway in astrocytes was also initially delayed in both sides of TBI brain compared with sham brain; (iii) despite this delayed incorporation, at 6 h after TBI, both sides of the brain showed apparent increased neuronal and glial metabolism, reflecting accumulation of labeled metabolites, suggesting impaired malate aspartate shuttle activity. The presence of delayed metabolism, followed by accumulation of labeled compounds is evidence of severe alterations in homeostasis that could impair mitochondrial metabolism in both ipsilateral and contralateral sides of brain after TBI. However, ongoing oxidative metabolism in mitochondria in injured brain suggests that there is a window of opportunity for therapeutic intervention up to at least 6 h after injury.
| S-EPMC2692097 | biostudies-literature
Project description:Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.
| S-EPMC6598636 | biostudies-literature
Project description:The postinjury period of glucose metabolic depression is accompanied by adenosine triphosphate decreases, increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase (a key glycolytic enzyme) via depletion of the cytosolic NAD pool. Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism. Preclinical studies employing both pre- and postinjury implementation of the ketogenic diet have demonstrated improved structural and functional outcome in traumatic brain injury (TBI) models, mild TBI/concussion models, and spinal cord injury. Further clinical studies are required to determine the optimal method to induce cerebral ketone metabolism in the postinjury brain, and to validate the neuroprotective benefits of ketogenic therapy in humans.
| S-EPMC4242438 | biostudies-other
Project description:Metabolic derangements following traumatic brain injury are poorly characterized. In this single-centre observational cohort study we combined 18F-FDG and multi-tracer oxygen-15 PET to comprehensively characterize the extent and spatial pattern of metabolic derangements. Twenty-six patients requiring sedation and ventilation with intracranial pressure monitoring following head injury within a Neurosciences Critical Care Unit, and 47 healthy volunteers were recruited. Eighteen volunteers were excluded for age over 60 years (n = 11), movement-related artefact (n = 3) or physiological instability during imaging (n = 4). We measured cerebral blood flow, blood volume, oxygen extraction fraction, and 18F-FDG transport into the brain (K1) and its phosphorylation (k3). We calculated oxygen metabolism, 18F-FDG influx rate constant (Ki), glucose metabolism and the oxygen/glucose metabolic ratio. Lesion core, penumbra and peri-penumbra, and normal-appearing brain, ischaemic brain volume and k3 hotspot regions were compared with plasma and microdialysis glucose in patients. Twenty-six head injury patients, median age 40 years (22 male, four female) underwent 34 combined 18F-FDG and oxygen-15 PET at early, intermediate, and late time points (within 24 h, Days 2-5, and Days 6-12 post-injury; n = 12, 8, and 14, respectively), and were compared with 20 volunteers, median age 43 years (15 male, five female) who underwent oxygen-15, and nine volunteers, median age 56 years (three male, six female) who underwent 18F-FDG PET. Higher plasma glucose was associated with higher microdialysate glucose. Blood flow and K1 were decreased in the vicinity of lesions, and closely related when blood flow was <25 ml/100 ml/min. Within normal-appearing brain, K1 was maintained despite lower blood flow than volunteers. Glucose utilization was globally reduced in comparison with volunteers (P < 0.001). k3 was variable; highest within lesions with some patients showing increases with blood flow <25 ml/100 ml/min, but falling steeply with blood flow lower than 12 ml/100 ml/min. k3 hotspots were found distant from lesions, with k3 increases associated with lower plasma glucose (Rho -0.33, P < 0.001) and microdialysis glucose (Rho -0.73, P = 0.02). k3 hotspots showed similar K1 and glucose metabolism to volunteers despite lower blood flow and oxygen metabolism (P < 0.001, both comparisons); oxygen extraction fraction increases consistent with ischaemia were uncommon. We show that glucose delivery was dependent on plasma glucose and cerebral blood flow. Overall glucose utilization was low, but regional increases were associated with reductions in glucose availability, blood flow and oxygen metabolism in the absence of ischaemia. Clinical management should optimize blood flow and glucose delivery and could explore the use of alternative energy substrates.
| S-EPMC8677561 | biostudies-literature
Project description:BACKGROUND:Hyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO2), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD). METHODS:This prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score?<?9 at presentation and with ICP monitoring, PbrO2, and/or microdialysis (MD) probes during ICU admission within 36?h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50?min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4-4.7?kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate. RESULTS:Eleven patients (64% males, mean age 36?±?14?years) with an initial median GCS score of 7 (IQR 3-8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO2 showed a statistically significant reduction but remained within the normal range. CONCLUSION:Moderate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation. TRIAL REGISTRATION:NCT03822026 . Registered on 30 January 2019.
| S-EPMC6375161 | biostudies-literature
Project description:Following traumatic brain injury (TBI), raised cerebral lactate/pyruvate ratio (LPR) reflects impaired energy metabolism. Raised LPR correlates with poor outcome and mortality following TBI. We prospectively recruited patients with TBI requiring neurocritical care and multimodal monitoring, and utilised a tiered management protocol targeting LPR. We identified patients with persistent raised LPR despite adequate cerebral glucose and oxygen provision, which we clinically classified as cerebral 'mitochondrial dysfunction' (MD). In patients with TBI and MD, we administered disodium 2,3-13C2 succinate (12 mmol/L) by retrodialysis into the monitored region of the brain. We recovered 13C-labelled metabolites by microdialysis and utilised nuclear magnetic resonance spectroscopy (NMR) for identification and quantification.Of 33 patients with complete monitoring, 73% had MD at some point during monitoring. In 5 patients with multimodality-defined MD, succinate administration resulted in reduced LPR(-12%) and raised brain glucose(+17%). NMR of microdialysates demonstrated that the exogenous 13C-labelled succinate was metabolised intracellularly via the tricarboxylic acid cycle. By targeting LPR using a tiered clinical algorithm incorporating intracranial pressure, brain tissue oxygenation and microdialysis parameters, we identified MD in TBI patients requiring neurointensive care. In these, focal succinate administration improved energy metabolism, evidenced by reduction in LPR. Succinate merits further investigation for TBI therapy.
| S-EPMC8721534 | biostudies-literature
Project description:BackgroundPeople with traumatic brain injury (TBI) often experience fatigue, but an understanding of the neural underpinnings of fatigue following TBI is still lacking. This study used resting-state functional magnetic resonance imaging (rs-fMRI) to examine associations between functional connectivity (FC) changes and task-induced changes in subjective fatigue in people with moderate-severe TBI.MethodsSixteen people with moderate-severe TBI and 17 matched healthy controls (HC) performed an adaptive N-back task (working memory task) to induce cognitive fatigue. Before and after the task they rated their state fatigue level and underwent rs-fMRI. Seed-to-voxel analyses with seeds in areas involved in cognitive fatigue, namely the striatum and default mode network (DMN) including, medial prefrontal cortex and posterior cingulate cortex, were performed.ResultsThe adaptive N-back task was effective in inducing fatigue in both groups. Subjective task-induced fatigue was positively associated with FC between striatum and precuneus in people with TBI, while there was a negative association in HC. In contrast, subjective task-induced fatigue was negatively associated with FC between striatum and cerebellum in the TBI group, while there was no association in HC. Similar associations between task-induced subjective fatigue and DMN FC were found across the groups.ConclusionsOur results suggest that the subjective experience of fatigue was linked to DMN connectivity in both groups and was differently associated with striatal connectivity in people with moderate-severe TBI compared to HC. Defining fatigue-induced neuronal network changes is pertinent to the development of treatments that target abnormal neuronal activity after TBI.
| S-EPMC8749448 | biostudies-literature
Project description:BackgroundTo determine whether depressive symptoms in traumatic brain injury (TBI) patients were associated with altered resting-state functional connectivity (rs-fc) or voxel-based morphology in brain regions involved in emotional regulation and associated with depression.MethodsIn the present study, we examined 79 patients (57 males; age range = 17-70 years, M ± s.d. = 38 ± 16.13; BDI-II, M ± s.d. = 9.84 ± 8.67) with TBI. We used structural MRI and resting-state fMRI to examine whether there was a relationship between depression, as measured with the Beck Depression Inventory (BDI-II), and the voxel-based morphology or functional connectivity in regions previously identified as involved in emotional regulation in patients following TBI. Patients were at least 4 months post-TBI (M ± s.d. = 15.13 ± 11.67 months) and the severity of the injury included mild to severe cases [Glasgow Coma Scale (GCS), M ± s.d. = 6.87 ± 3.31].ResultsOur results showed that BDI-II scores were unrelated to voxel-based morphology in the examined regions. We found a positive association between depression scores and rs-fc between limbic regions and cognitive control regions. Conversely, there was a negative association between depression scores and rs-fc between limbic and frontal regions involved in emotion regulation.ConclusionThese findings lead to a better understanding of the exact mechanisms that contribute to depression following TBI and better inform treatment decisions.
| S-EPMC10123829 | biostudies-literature