Elsevier

NeuroImage

Volume 61, Issue 2, June 2012, Pages 492-504
NeuroImage

Review
Oxygen metabolism, oxygen extraction and positron emission tomography: Historical perspective and impact on basic and clinical neuroscience

https://doi.org/10.1016/j.neuroimage.2011.12.036Get rights and content

Abstract

Oxygen utilization is central to the human brain's high metabolic rate. Measurement of this fundamental process, in both disease and health, has been a focus of research attention over the last 35 years. This review plots the course of the use of oxygen-15 to study regional cerebral oxygen extraction and metabolism using Positron Emission Tomography (PET) in disease and in health. The scientific discoveries and resulting conceptual changes to both basic and clinical neuroscience, as well as the new methodological approaches brought about by this area of research, are also summarized. We conclude with a brief overview of the current status of oxygen-15 PET in neuroscience, along with our visions for future developments and applications.

Highlights

► Oxygen-15 has been used to measure regional cerebral oxygen metabolism and extraction. ► Its use for researching a range of brain disorders and normal functions is reviewed. ► Focally increased oxygen extraction fraction indicates regional cerebral ischemia. ► Oxygen extraction fraction decreases in physiological cerebral activation. ► 15O-PET has revolutionized several key physiological and pathophysiological concepts.

Introduction

Oxygen-15 (15O) is a positron emitting radioisotope which can be used as a specific imaging biomarker or ‘tracer’ for measuring tissue oxygen extraction and metabolism. It has a short half life of 2.1 min, which suits the comparable time scale of oxygen utilization processes in vivo. Here we chart methodologies developed to use this tracer for studying regional cerebral oxygen extraction. We begin by covering early non-PET work, which used invasive methods and qualitative planar imaging. This led to the use of PET, which provided not only tomographic readouts of the distribution of oxygen extraction and metabolism in the human and animal brain, but also quantification of regional cerebral tracer concentrations. From this data, absolute values of regional cerebral oxygen extraction fraction (OEF) and the cerebral metabolic rate for oxygen (CMRO2), together with cerebral blood flow (CBF), could be calculated. Such quantitative data was directly comprehendible and appreciated by the basic and clinical neuroscientific communities. The key stimulus to measuring regional OEF was to study flow-metabolism uncoupling (mismatching) — a process which was thought to be present in certain brain disorders including cerebrovascular disease. Key research findings using these methodologies are summarized. The resulting conceptual and procedural changes upon basic and clinical neuroscience are also outlined. In many ways the application of oxygen-15 PET to human brain research has led to the use of other PET tracers to investigate neuronal function, including glucose metabolism and hypoxia, which are related to oxygen metabolism and discussed in context. We conclude by making the case that oxygen-15 PET is still the gold standard method for measuring regional cerebral OEF and CMRO2, and will continue to be a major player in the area of physiological brain imaging in the clinical and experimental settings.

Section snippets

Initial global measurements of cerebral oxygen extraction and metabolism

The first measurements of cerebral oxygen extraction and metabolism were undertaken by serial assays of arterial and cerebral venous blood. Nitrous oxide was used as an inert, freely diffusible tracer. From the oxygen contents and nitrous oxide concentration curves of arterial and venous blood, a mean value for the brain's single pass OEF and a mean value for CBF in ml/g tissue/min was calculated. Multiplying OEF, CBF, and the arterial blood's oxygen content provided a measurement of the mean

Early regional cerebral function based on measurements of perfusion

Because of the functional regional anatomy of the human brain and the focal nature of many cerebral diseases, the 1960's saw active interest in studying regional cerebral function based on measurement of regional perfusion, initially in animals using ex vivo autoradiography (Freygang and Sokoloff, 1958). Translated to man in vivo, this approach involved using radiolabeled inert, freely diffusible agents, such as xenon-133, and radiation detectors placed in arrays over the brain to image the

Measuring regional cerebral oxygen extraction and metabolism using oxygen-15

The early cerebral perfusion studies provided the stimulus to undertake similar measurements of regional cerebral metabolism. The interest here was to investigate mismatching between the physiological functions of perfusion and metabolism. Mismatching whereby CBF is in excess of metabolic demand was inferred to be present in certain brain pathologies, particularly in cerebrovascular disease (coined the “luxury perfusion syndrome”; (Lassen, 1966)), and was expected to be directly observable by

The use of oxygen-15 PET in stroke and cerebrovascular disease

The oxygen-15 PET method has the unique ability to provide quantitative mapping of the supply and use of oxygen, and information on the balance between the two i.e. the OEF. As these are the main pathophysiological variables involved in cerebral ischemia, it was immediately applied to cerebrovascular diseases and stroke, initially in patients and later in animal models, with critically important results that profoundly altered clinical practice.

Other clinical applications of the oxygen-15 PET method

The Hammersmith researchers extended the application of oxygen-15 PET to a range of neurological and psychiatric conditions including Parkinson's disease (Wolfson et al., 1985), epilepsy (Bernardi et al., 1983, Gallhofer et al., 1985) and dementia, with the latter notably showing preserved flow-metabolism coupling (Frackowiak et al., 1981). Multiple Sclerosis (Brooks et al., 1984), hydrocephalus (Brooks et al., 1985, Brooks et al., 1986), sickle cell anemia (Herold et al., 1986), schizophrenia (

Dynamic PET studies of regional oxygen extraction and metabolism using oxygen-15

The steady state method was particularly attractive as it made use of the first generation of commercial PET scanners, such as the ECAT which was restricted to recording just one trans-axial 20 mm-thick plane at a time. This meant that the patient needed to be moved axially through the tomography to cover a significant area of brain tissue. As PET scanner technology advanced to simultaneous recording of multiple trans-axial planes, ultimately covering the whole brain, it became possible to

The oxygen-15 PET method in the new millennium

Although the bulk of brain research using oxygen-15 to image OEF and CMRO2 was undertaken in the 1980's and 1990's, applications are on-going in Cambridge. This includes studies of head injury patients investigating secondary tissue ischemia (Coles et al., 2004, Hutchinson et al., 2002, Nortje et al., 2008) and of carotid disease patients, showing that internal watershed infarction could result not only from hemodynamic compromise but also from microembolism originating in the inflamed carotid

Conceptual changes and new methodological approaches resulting from oxygen-15 PET imaging research

In addition to the significant conceptual changes to cerebrovascular pathophysiology and clinical management brought about by research using oxygen-15 PET, applications of this method have had major impact on a number of other conceptual and methodological domains.

The current status of oxygen-15 PET

Oxygen-15 remains a specific imaging biomarker for studying oxygen utilization, irrespective of the underlying pathology. This is contrary to the use of 18F-FDG for imaging glucose metabolism, the transport of which is known to deviate from that of natural glucose under certain pathological conditions. Oxygen-15 PET methodology is still considered the gold standard for measuring regional cerebral oxygen extraction and metabolism, against which other more readily available, indirect methods may

Continuing to use the oxygen-15 PET methodology to validate more readily available imaging methodology

This could be used for functional MRI methods which shows promise to quantitatively image regional OEF. Validation such as this is especially important in pathological situations where methodology developed in normal brain may become inaccurate in diseased tissue. Although this application mainly involves studies in the clinical setting, validation in experimental models may also be considered, especially since recent improvements in spatial resolution of small animal PET scanners make the

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    Review article commissioned as part of a series to celebrate the 20th Anniversary of Neuroimage.

    1

    Formerly at the UK's Medical Research Council's Cyclotron Unit, Hammersmith Hospital, Imperial College, London and the Wolfson Molecular Imaging Centre, The University of Manchester, UK.

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