A method to quantitate the fractional extraction of rubidium-82 across the blood-brain barrier using positron emission tomography.

Previously, rubidium-82 and positron emission tomography (PET) have been used to assess qualitatively the integrity of the blood-brain barrier (BBB). In this report, a method is described to measure the fractional extraction of rubidium across the BBB using the constant intravenous infusion of rubidium-82. In addition, the continuous inhalation of oxygen-15-labelled carbon dioxide is needed to measure regional CBF, and it is also necessary to measure regional cerebral blood volume. The assumptions underlying the model are identified, and the impact of deviations from these assumptions is described. From radiation dose and statistical considerations, it is shown that for normal cerebral tissue and the PET scanner used in this study, the rubidium extraction fraction can be quantitated only for regions as large as a cerebral hemisphere. However, quantitation is also possible for smaller regions where the focal extraction of rubidium is increased.

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.

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.

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 H2(15)O (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 H2(15)O in the brain, without recourse to postulating a nonexchanging water pool.

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 approximately 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%.

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.

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.

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.

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.

Changes in pituitary responsiveness to LH-releasing hormone after acute buserelin treatment: a time-course and dose-response study.

The acute in-vivo effects of a potent LH-releasing hormone (LHRH) agonist, buserelin, on LH secretion and pituitary responsiveness to LHRH have been investigated in oestrous rats. Doses of 50, 100 and 250 ng buserelin stimulated LH release in a dose-dependent manner, the peak serum LH concentrations being measured 1 h after the treatment. Thereafter LH levels fell rapidly between 1 and 6 h and by 18 h serum LH concentrations were similar in all groups of animals. Pituitary responsiveness to a challenge with 100 ng LHRH was potentiated by 50 or 100 ng buserelin injected 1 or 2 h before the LHRH challenge. In contrast, 250 ng buserelin completely abolished the LH response to LHRH when tested 1, 2 and 4 h after treatment, but by 6 h a small but attenuated response was observed. Four hours after treatment there was no significant difference in the responses when compared with the saline-treated controls.

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 non-invasively, 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.

Regional cerebral oxygen utilization and blood flow in normal man using oxygen-15 and positron emission tomography.

Quantitative determination of regional cerebral blood flow (rCBF), regional cerebral oxygen utilization (rCMRO2) and regional oxygen extraction ratio (rOER) was performed in 11 normal volunteers by an oxygen 15 inhalation method and positron emission tomography. Regional values comparable with figures from the literature have been obtained. This non-invasive approach offers the possibility of a simultaneous quantitative evaluation of these physiological parameters in health and disease.

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 15O-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.

Measurement of lung water in dog lobes using inhaled C15O2 and injected H215O.

Indicator-dilution analysis was used in a recirculation-free isolated dog lobe preparation to compare an inhaled water tracer (C15O2) and an injected water tracer (H215O) with direct weighing as a measure of total lung water. Residue detection (counting over the lung) was compared with outflow detection (counting over the venous effluent). With outflow detection, inhaled C15O2 measured 74% and injected H215O 90% of the gravimetric lung water. In hemodynamic edema, the increase in lung water measured by residue detection of both tracers correlated well with increases in weight (r = 0.92, slope = 1.03). However, outflow detection of both tracers underestimated the lung water increase by 53% in edema (r = 0.88, slope = 0.47). Thus, in edema, equilibration of both tracers within the lung water volume is rapid, but clearance from the lung is delayed because slowly clearing water pools develop. The errors caused by inhomogeneity of perfusion distribution were investigated after pulmonary arterial injection of 34-, 50-, and 175-micrometers spheres. For the same lung weight, C15O2 transit was delayed and H215O transit accelerated greatly by the 175-micrometers spheres and slightly by the 50-micrometers spheres.

CMRO2 and CBF by the oxygen-15 inhalation technique. Results in normal volunteers and cerebrovascular patients.

The oxygen-15 inhalation technique has been applied to the quantitation of regional CBF, CMRO2 and OER with positron emission tomography. The introduction of corrections for gamma-ray attenuation, and for recirculation, has allowed us to obtain values for CBF, CMRO2 and OER in close agreement with values obtained using other techniques. In 27 normal volunteers mean CMRO2 shows values ranging from 4.98 to 3.79 ml/100/min, depending on the region evaluated. Mean CBF values range from 55.3 to 38.8 ml/100ml/min. Mean OER is more constant, ranging from 0.56 to 0.49, with a mean of 0.53 +/- 0.04, thus reflecting the close matching between metabolism and blood supply. We have further identified corrections for cerebral blood volume, which is measurable, and for water partition coefficient, which remains uncertain. In preliminary studies these corrections decrease the OER over the physiological range of flow by 10%, with a 15% lower CMRO2. The reproducibility of the results and the effects of aging have been studied. A series of 27 studies on acute ischaemic CVD are reported. The course of the clinical condition has been correlated with the quantitation of oxygen utilization and blood flow performed at different intervals from the onset of symptoms.

Measurement of regional cerebral blood flow and oxygen utilisation in patients with cerebral tumours using 15O and positron emission tomography: analytical techniques and preliminary results.

Regional cerebral blood flow and oxygen utilisation have been studied in 8 patients with brain tumours using continuous inhalation of C15O2 and 15O2 and positron emission tomography. The methods used to analyse the regional cerebral pathophysiology are presented. A relative uncoupling between oxygen consumption and blood flow was observed in all tumours as indicated by a decreased regional fractional extraction of oxygen (rOER). This suggest that a major proportion of these tumours had sufficient blood supply to meet oxygen metabolic demand. A decrease of blood flow in grey matter was found both in the affected and contralateral hemispheres of the brain. Matched reductions of flow and oxygen utilisation were observed in oedematous tissue.