Clare N. Gallagher

The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled microdialysis and high-resolution nuclear magnetic resonance study

Energy metabolism in the human brain is not fully understood. Classically, glucose is regarded as the major energy substrate. However, lactate (conventionally a product of anaerobic metabolism) has been proposed to act as an energy source, yet whether this occurs in man is not known. Here we show that the human brain can indeed utilize lactate as an energy source via the tricarboxylic acid cycle. We used a novel combination of (13)C-labelled cerebral microdialysis both to deliver (13)C substrates into the brain and recover (13)C metabolites from the brain, and high-resolution (13)C nuclear magnetic resonance. Microdialysis catheters were placed in the vicinity of focal lesions and in relatively less injured regions of brain, in patients with traumatic brain injury. Infusion with 2-(13)C-acetate or 3-(13)C-lactate produced (13)C signals for glutamine C4, C3 and C2, indicating tricarboxylic acid cycle operation followed by conversion of glutamate to glutamine. This is the first direct demonstration of brain utilization of lactate as an energy source in humans.

Consensus statement from the 2014 International Microdialysis Forum

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

Neuroimaging in trauma.

Purpose of reviewDevelopments in imaging following traumatic brain injury are outlined. Numerous techniques have evolved over the past several years giving us more information about the injury and prognosis for recovery. Some of these techniques are in clinical use while others are used primarily in research but have the potential to become clinically useful. Recent findingsComputed tomography (CT) scanning is the primary imaging technique for acute brain injury, giving rapid information and being part of a general trauma work up in the emergency situation. It has supplanted plain films in the immediate management of brain injury. Following stabilization, MRI is the method of choice for evaluating the full extent of brain injury. Information on diffuse axonal injury is obtained by several MRI sequences. Diffusion tensor imaging is able to show long tract damage and relates to prognosis. There are several techniques which are best suited to research in brain injury, including single photon emission CT, PET and xenon CT. SummaryCT and MRI are now the imaging techniques for acute and subacute brain injury, respectively. Diffusion tensor imaging is being developed to provide more information on structural damage in brain injury. There are several research techniques available for brain injury, particularly relating to cerebral blood flow and metabolism.

Glycolysis and the pentose phosphate pathway after human traumatic brain injury: microdialysis studies using 1,2-13C2 glucose

Increased ‘anaerobic’ glucose metabolism is observed after traumatic brain injury (TBI) attributed to increased glycolysis. An alternative route is the pentose phosphate pathway (PPP), which generates putatively protective and reparative molecules. To compare pathways we employed microdialysis to perfuse 1,2-13C2 glucose into the brains of 15 TBI patients and macroscopically normal brain in six patients undergoing surgery for benign tumors, and to simultaneously collect products for nuclear magnetic resonance (NMR) analysis. 13C enrichment for glycolytic 2,3-13C2 lactate was the median 5.4% (interquartile range (IQR) 4.6–7.5%) in TBI brain and 4.2% (2.4–4.4%) in ‘normal’ brain (P<0.01). The ratio of PPP-derived 3-13C lactate to glycolytic 2,3-13C2 lactate was median 4.9% (3.6–8.2%) in TBI brain and 6.7% (6.3–8.9%) in ‘normal’ brain. An inverse relationship was seen for PPP-glycolytic lactate ratio versus PbtO2 (r=−0.5, P=0.04) in TBI brain. Thus, glycolytic lactate production was significantly greater in TBI than ‘normal’ brain. Several TBI patients exhibited PPP—lactate elevation above the ‘normal’ range. There was proportionally greater PPP-derived lactate production with decreasing PbtO2. The study raises questions about the roles of the PPP and glycolysis after TBI, and whether they can be manipulated to achieve a better outcome. This study is the first direct comparison of glycolysis and PPP in human brain.

13C-labelled microdialysis studies of cerebral metabolism in TBI patients

Graphical abstract

A comparison of oxidative lactate metabolism in traumatically injured brain and control brain

Abstract Metabolic abnormalities occur after traumatic brain injury (TBI). Glucose is conventionally regarded as the major energy substrate, although lactate can also be an energy source. We compared 3-13C lactate metabolism in TBI with “normal” control brain and muscle, measuring 13C-glutamine enrichment to assess tricarboxylic acid (TCA) cycle metabolism. Microdialysis catheters in brains of nine patients with severe TBI, five non-TBI brain surgical patients, and five resting muscle (non-TBI) patients were perfused (24 h in brain, 8 h in muscle) with 8 mmol/L sodium 3-13C lactate. Microdialysate analysis employed ISCUS and nuclear magnetic resonance. In TBI, with 3-13C lactate perfusion, microdialysate glucose concentration increased nonsignificantly (mean +11.9%, p = 0.463), with significant increases (p = 0.028) for lactate (+174%), pyruvate (+35.8%), and lactate/pyruvate ratio (+101.8%). Microdialysate 13C-glutamine fractional enrichments (median, interquartile range) were: for C4 5.1 (0–11.1) % in TBI and 5.7 (4.6–6.8) % in control brain, for C3 0 (0–5.0) % in TBI and 0 (0–0) % in control brain, and for C2 2.9 (0–5.7) % in TBI and 1.8 (0–3.4) % in control brain. 13C-enrichments were not statistically different between TBI and control brain, showing both metabolize 3-13C lactate via TCA cycle, in contrast to muscle. Several patients with TBI exhibited 13C-glutamine enrichment above the non-TBI control range, suggesting lactate oxidative metabolism as a TBI “emergency option.”

Neurology and trauma

Neurology and trauma is a comprehensive text dealing with all aspects of neurological trauma. It is aimed at neurologists, neurosurgeons, physiatrists as well as other specialties involved in care of the neurotrauma patient. The layout of the book is easy to understand and figures are well integrated into the text. A thorough overview of the epidemiology of a variety of injury types is included. Excellent chapters on imaging and pathology introduce the reader to these technical aspects of traumatic brain injury. The text is not limited to brain injury but also includes spine and peripheral nerve, with separate sections focussed on athletic and iatrogenic injury. While the book is not aimed at patient care in the acute setting, this aspect is covered well. The neurological complications seen after acute injury both in an office setting and during rehabilitation are discussed with some detail. Overall the book is an excellent reference for those involved in patient care after neurological injury. It provides a valuable reference for those dealing with difficult complications of severe to mild injury. Sequelae of injury are covered in a comprehensive manner from epidemiology to treatment and outcome.