Jon D. Heather

Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography: theory, procedure, and normal values.

A method is described for quantifying regional cerebral blood flow (rCBF), oxygen extraction (rOER), and oxygen utilization (rCMRO2) in man noninvasivey, using inhaled 15O-labeled CO2 and O2 and positron emission tomography. The theoretical considerations and practical aspects are described. The results of rCBF, rCMRO2, and rOER for gray and white matter in normal volunteers are presented. The significance and limitations of the results are discussed. The method appears suitable for the study of human cerebral aerobic metabolism and blood flow under differing physiological conditions and in a wide variety of neurological disorders.

Localisation in PET images: direct fitting of the intercommissural (AC-PC) line.

A technique is described for estimating the position of the intercommisural line (AC–PC line) directly from landmarks on positron emission tomographic (PET) images, namely the ventral aspects of the anterior and posterior corpus callosum, the thalamus, and occipital pole. The relationship of this estimate to the true AC–PC line, fitted through the centres of the anterior and posterior commissures, showed minimal vertical and angular displacement when measured on magnetic resonance imaging (MRI) scans. Using regression analysis, the ease and reliability of fitting to these points was found to be high. This directly derived AC–PC line estimate was validated in terms of the assumptions used in the method of Fox et al. The ratio of distance between the AC–PC line and a line passing through the base of the inion (GI line) to total brain height was 0.21, as predicted. The technique has been further validated by localizing focal activation of the sensorimotor cortex. The technique is discussed in terms of absolute limits to localization of structures in the brain using noninvasive tomographic techniques in general and PET in particular.

In vivo Measurement of Regional Cerebral Haematocrit Using Positron Emission Tomography

A method is described for measuring the regional cerebral-to-large vessel haematocrit ratio using inhalation of carbon-11-labelled carbon monoxide and the intravenous injection of carbon-11-labelled methyl-albumin in combination with positron emission tomography. The mean value in a series of nine subjects was 0.69. This is ∼20% lower than the value of 0.85 previously reported. It is concluded that previous measurements of regional cerebral blood volume using a haematocrit ratio of 0.85 will have underestimated the value of regional cerebral blood volume by 20%.

Combination of Dynamic and Integral Methods for Generating Reproducible Functional CBF Images

A new method to measure regional CBF is presented, applying both dynamic and integral analyses to a dynamic sequence of positron emission tomographic scans collected during and following the administration of H215O (inhalation of C15O2). The dynamic analysis is used to correct continuously monitored arterial whole-blood activity for delay and dispersion relative to tissue scans. An integral analysis including corrections for this delay and dispersion is then used to calculate CBF on a pixel-by-pixel basis. Normal values and reproducibility over a 2-h period are presented, together with the results of validation and simulation studies. The results indicate that the single–tissue compartment model adequately describes the distribution of H215O in the brain, without recourse to postulating a nonexchanging water pool.

Correction for the Presence of Intravascular Oxygen-15 in the Steady-State Technique for Measuring Regional Oxygen Extraction Ratio in the Brain: 2. Results in Normal Subjects and Brain Tumour and Stroke Patients

Values of regional cerebral oxygen extraction ratio and oxygen utilisation obtained with the oxygen-15 steady-state inhalation technique have been found to be overestimated due to the signal from intravascular oxygen-15. A previously described method to correct for this intravascular component has been applied to a series of studies on normal subjects, and on brain tumour and stroke patients. With this correction the regional cerebral oxygen extraction ratio in normals becomes comparable to the global values previously reported with arteriovenous sampling techniques. Within the lesions of brain tumour and stroke patients, the corrections have been found to be variable and often substantial. It is concluded that failure to apply this correction may result in major errors in the values for regional oxygen extraction ratio and oxygen utilisation. This is especially true when the regional blood flow and oxygen extraction ratio of a tissue is low and regional blood volume is high.

Dexamethasone treatment of brain tumor patients: effects on regional cerebral blood flow, blood volume, and oxygen utilization.

Regional values for cerebral blood flow, blood volume, oxygen extraction fraction, and oxygen utilization were measured, using PET, in 10 brain tumor patients before and after treatment with dexamethasone. Dexamethasone treatment decreased cerebral blood flow and blood volume and increased the fractional extraction of oxygen throughout the brain without affecting oxygen utilization. Dexamethasone probably causes direct vasoconstriction of cerebral blood vessels.

Measurement of Glucose Utilisation with [18F]2-Fluoro-2-Deoxy-D-Glucose: A Comparison of Different Analytical Methods

A number of different analytical methods were applied to dynamic scans obtained with [18F]2-fluoro-2-deoxy-d-glucose and positron emission tomography. In particular, methods applying three, four, standard, or no rate constants were compared in four studies on three normal subjects. In addition, regional cerebral blood flow, oxygen utilisation, and blood volume were measured using the oxygen-15 steady-state inhalation technique. There was a large difference between values of glucose utilisation obtained with the various analytical methods, in particular between methods using three or four rate constants. This difference was not due to contamination of the tracer with [18F]2-fluoro-2-deoxy-d-mannose. For dynamic techniques, the separate measurement of regional cerebral blood volume was essential. Static techniques (single scans with standard or no rate constants) were best related to dynamic techniques utilising four rate constants. From the results, it followed, however, that these static techniques can only be applied clinically if relatively large disturbances of glucose metabolism and no changes in rate constants are anticipated. The lumped constant was assessed from the combined measurement of oxygen and glucose utilisation and was higher than previously reported.

Measurement of cerebral blood flow using bolus inhalation of C15O2 and positron emission tomography: description of the method and its comparison with the C15O2 continuous inhalation method.

This article describes a rapid method for the regional measurement of cerebral blood flow using a single breath of C15O2 and positron emission tomography. The technique is based on the bolus distribution principle and utilises a reference table for the calculation of flow. Seven subjects were studied using both this method and the C15O2 continuous inhalation steady-state technique. The single-breath method gave flow values 20% higher than those obtained using the steady-state method. A simulation study was performed in an attempt to define the reasons for the difference between the two techniques. Estimations were made of identified sources of error in the measurement of regional cerebral blood flow using the single-breath technique and compared with results from a similar study previously described for the steady-state technique. However, further comparative studies will be necessary to satisfactorily explain the difference between both techniques.

A statistical study of the steady state technique for measuring regional cerebral blood flow and oxygen utilisation using 15O.

Regional cerebral blood flow and oxygen utilisation can be measured using positron emission tomography and the continuous inhalation of 13O-labelled carbon dioxide and molecular oxygen. However, there is concern about the propagation of errors in this technique. This arises from statistical uncertainties, inherent in the transmission and emission scans, being amplified in the steady state model used for calculating the physiological parameters. The magnitude of this effect has been studied using a series of repeat transmission and emission phantom measurements in which pixel count densities equivalent to those seen in the clinical data were recorded. These measurements have been used to determine the final propagated errors that occur in the calculated values of regional cerebral blood flow, oxygen extraction fraction, and oxygen utilisation rate.

The C15O2 Build-up Technique to Measure Regional Cerebral Blood Flow and Volume of Distribution of Water:

A new method to measure regional CBF (rCBF) and volume of distribution of water is presented. It centres on recording the tissue build-up and retention of 15O-labelled water during the continuous inhalation of 15O-labelled carbon dioxide. Simultaneously, the arterial concentration is continuously monitored, and corrections for delay and dispersion in the recorded response are made by curve fitting. The values for the volume of distribution of water obtained in four normal subjects were close to reported in vitro values. Using the same fixed distribution volumes for both build-up and steady-state studies resulted in comparable rCBF values for both techniques.