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Causes and consequences of alterations in cerebral glucose metabolism in Traumatic Brain Injury

Periodic Reporting for period 1 - GOMB-TBI (Causes and consequences of alterations in cerebral glucose metabolism in Traumatic Brain Injury)

Reporting period: 2015-11-01 to 2016-10-31

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults, although the incidence in the elderly is also increasing. It is estimated that around 7.7 million people are living with TBI related disability in the European Union alone. Derangements in cerebral glucose metabolism are common after traumatic brain injury (TBI). Although some of these metabolic changes can be attributed to a switch to anaerobic glycolysis in the presence of classical ischaemia, this is not the principal mechanism. Instead the underlying pathophysiology is more heterogenic and complex, as glucose metabolism depends on glucose delivery (blood flow), glucose uptake, finally phosphorylation and also glucose availability (plasma glucose). 18F-FDG Positron Emmision Tomography (PET) allows imaging of regional glucose metabolism and non-invasive assessment of the different kinetic glucose parameters. Combining this imaging technique with data from plasma glucose and interstitial brain glucose measured by microdialysis, allows assessemnt of the pathophysiology. Improving our understanding of the derangements in glucose metabolism after TBI may contribute to developing proper treatment to prevent secondary injury, which is key in improving outcome. The aim of this study therefore was to interrogate the underlying pathophysiological mechanisms responsible for such changes in cerebral glucose metabolism. Using combined 18F-fluorodeoxyglucose (18FDG) and oxygen-15 (15O) whole brain positron emission tomography (PET), the main objective is to study how derangements in 18FDG kinetic parameters relate to visible TBI lesions and changes in cerebral blood flow (CBF), oxygen metabolism (CMRO2), oxygen extraction fraction (OEF), plasma glucose and microdialysis glucose.

Specific objectives
1) Investigate the relationship between oxygen and glucose metabolism in injured and non-injured brain regions after TBI using 15O and 18FDG PET imaging.
2) Investigate the relationship between plasma glucose, microdialysis glucose and cerebral glucose metabolism
3) Investigate the temporal evolution of alterations in cerebral metabolism using serial 15O and 18FDG PET.

For this project we analysed data from 26 patients with TBI (4 women, 22 men) who underwent 34 combined 18FDG and 15O PET scans. All patients were recruited and included at the Neuro Critical Care Unit (NCCU) in Addenbrooke’s Hospital, (Cambridge, UK). As reference groups we included 10 healthy volunteers who underwent 15O PET and 9 healthy volunteers who underwent 18FDG PET scans. All PET scans were performed with approval of the Cambridge Research Ethics Committee and Administration of Radioactive Substances Advisory Committee. Written informed consent for TBI patients was obtained from next of kin before study inclusion. Twenty-six TBI patients underwent combined 15O and FDG-PET on 34 occasions; 10 and 18 healthy volunteers (controls) underwent 15O and FDG-PET respectively. FDG rate constants were determined with an irreversible two-compartment model: transport across BBB (K1,k2), hexokinase activity (k3), and influx rate (Ki). Regions of interest were defined for haemorrhagic lesion (core), hypodense tissue (penumbra), 1 cm border zone of normal appearing tissue (peri-penumbra), and remote normal appearing tissue (normal). Plasma and microdialysis glucose were recorded.


In patients, glucose delivery (K1) was dependent on supply with significantly lower values occurring below a threshold cerebral blood flow (CBF) of 25ml/100ml/min. K1 was particularly driven by CBF within lesion core (R=0.87,p<0.001) where CBF values were lower. Changes in hexokinase activity (k3) were variable across the injured brain and not driven by CBF. While k3 hot-spots were found close to lesions they were often found within non-lesion brain with normal K1, and in the absence of increases in OEF consistent with cerebral ischaemia. Increases in k3 were associated with low microdialysis glucose (R=-0.73,p=0.016).


The results have been presented at
- The annual University of Cambridge Neuroscience meeting 2016, Cambridge UK
- The annual Neurocritical Care Meeting (Neurocritical Care Society) 2016, National Harbour, USA
- The annual SNACC (society for Neuroscience in Anesthesiology and Critical Care) meeting 2016, Chicago, USA

Further presentations and manuscripts are being prepared.
During this project the findings that extend beyond the current state of the art are:
- Impaired glucose transport (K1) is related to a decrease in Cerebral Blood Flow (CBF) after TBI, especially in lesion core and penumbra at lower flow rates.
- In contrast, derangements in hexokinase activity (k3) are more variable and do not depend on CBF, unless critically low. Although there is a general decrease in k3 activity and glucose metabolism in TBI patients as compared to healthy controls, increased activity was found mostly away from contusions.
- We demonstrated a method to identify these hot-spots using the upper 95% confidence interval limit for k3 from normal appearing brain in TBI patients.
- We further assessed the underlying physiology and concluded that although there are some signs of increased metabolic demand in the hot-spots, there is no evidence for classic ischaemia.
- Finally, low plasma glucose and especially low microdialysis glucose may contribute to metabolic derangements, as lower glucose increases k3 and Ki activity, indicating metabolic stress.

The is the first study to show the changes in glucose metabolism after TBI, investigating the complete pathway from glucose availability in plasma, delivery, availability in the interstitium, transport into the cell and phosphorylation. These findings indicate that optimizing blood flow and plasma glucose may be the first steps in maintaining adequate glucose delivery, especially to the injured brain. Further studies should also investigate the relation between hot spots with increased hexokinase activity and late structural changes. The method we developed to identify hot-spots is an effective way to do this.
CT scan, 18FDG and 15O kinetic parameters obtained in a 36-year old male with severe TBI