R. P. Beaney

Glucose Utilization In Vivo by Human Pulmonary Neoplasms

Neoplastic tissue in general shows a high rate of glucose consumption under both anaerobic and aerobic conditions. Using positron emission tomography (PET) we measured the rate of uptake of the glucose analogue 18fluoro‐2‐deoxy‐D‐glucose (18FDG) in 12 patients with carcinoma of the lung. The tumor types were six squamous cell, two large cell, two oat cell, one adenocarcinoma, and one undifferentiated carcinoma. In each patient a transaxial plane was selected that contained the bulk of the tumor tissue. Regional density and blood volume were measured. Following the intravenous injection of 18FDG, the rates of uptake in the tumor and normal lung tissue were assessed from sequential scans over 1 hour. In each patient the rate of uptake of 18FDG in the tumor tissue was significantly increased relative to normal lung tissue. For the group the rate of uptake by the tumor was 211.4 ± 69.4 ml/100 g/hr (mean ± SD) compared to 31.9 ± 13.2 in the contralataral lung (P < 0.05). The tumor‐to‐normal tissue ratio of 6.6 (range, 2.7 to 14.6) was higher than previously reported ratios for brain and liver tumors. In contrast to brain tumors there was little correlation between tumor type and rate of 18FDG uptake. Measurements of glucose metabolism taken in vivo in human pulmonary tumors may lead to advances in screening, staging, and therapy.

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%.

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.

Quantitative Measurement of Blood—Brain Barrier Permeability Using Rubidium-82 and Positron Emission Tomography

In normal brain, the blood–brain barrier (BBB) is highly impermeable to K+ cations, their transport being controlled by ATPases situated in the endothelial cell membranes. 82Rb+ is a positron-emitting analogue of K+ with a half-life of 75 s. Using a steady-state model and positron emission tomography, quantitative extraction data for 82Rb+ transport across the BBB have been obtained both in normal human subjects and in a variety of conditions of cerebral pathology. A mean cerebral Rb extraction of 2.1% was found for normal subjects, corresponding to a mean value of 1.1 × 10−6 cm s−1 for 82Rb+ cation permeability across the BBB. No increase in cerebral Rb extraction was observed for patients with diffusely raised intracranial pressure secondary to obstructive hydrocephalus and benign intracranial hypertension, or for patients with multiple sclerosis or cerebral systemic lupus erythematosus. Cerebral tumours that were enhanced on computed tomography scanning showed a significant increase in local Rb uptake. No correlation between tumour size, or grade of glioma, and tumour Rb extraction was found. Nonenhancing tumours showed no increase in local Rb extraction, and regions of perifocal tumour oedema also had Rb extraction values in the normal range. It is concluded that increased Rb extraction occurs only where tight junction integrity in the BBB breaks down locally, that is, in the microcirculation of enhancing tumours but not in that of perifocal regions of tumour oedema or nonenhancing tumours.

Blood flow and oxygen utilisation in the contralateral cerebral cortex of patients with untreated intracranial tumours as studied by positron emission tomography, with observations on the effect of decompressive surgery.

Using positron emission tomography, regional cerebral blood flow and oxygen utilisation were measured in the contralateral cortex of 14 patients with a variety of intracranial tumours. A comparison was made with cortical values derived from 14 normal controls. Compared with normal subjects, patients with brain tumours had a significant reduction in oxygen utilisation and blood flow in their contralateral cortex. Decompression resulting from craniotomy and biopsy, led to a partial reversal of this cerebral hypofunction.

Glucose Transport across the Blood—Brain Barrier in Normal Human Subjects and Patients with Cerebral Tumours Studied Using [11C]3-O-Methyl-D-Glucose and Positron Emission Tomography

The kinetics of the regional cerebral uptake of [11C]3-O-methyl-d-glucose ([11C]MeG), a competitive inhibitor of d-glucose transport, have been studied in normal human subjects and patients with cerebral tumours using positron emission tomography (PET). Concomitant measurement of regional cerebral blood volume and blood flow enabled corrections for the contribution of intravascular tracer signal in PET scans to be carried out and regional unidirectional cerebral [11C]MeG extractions to be determined. A three-compartment model containing an arterial plasma and two cerebral compartments was required to produce satisfactory fits to experimental regional cerebral [11C]MeG uptake data. Under fasting, resting conditions, normal controls had mean unidirectional whole-brain, cortical, and white matter [11C]MeG extractions of 14, 13, and 17%, respectively. Mean values of k1 and k2, first-order rate constants describing forward and back transport, respectively, of tracer into the first cerebral compartment, were similar for [11C]MeG and [18F]2-fluoro-2-deoxy-d-glucose (18FDG), a second competitive inhibitor of d-glucose transport, k3, a rate constant describing FDG phosphorylation, was 20 times higher for cortical FDG uptake than the k3 fitted for [11C]MeG cortical uptake. Glioma [11C]MeG extractions ranged from normal levels of 12% to raised levels of 30%. Transport of [11C]MeG in and out of contralateral cortical tissue was significantly depressed in patients with gliomas. It is concluded that under fasting, resting conditions, regional cerebral glucose extraction remains relatively uniform throughout normal brain tissue. Gliomas, however, may have raised levels of glucose extraction. The nature of the second cerebral compartment required to describe [11C]MeG uptake is unclear, but it could represent either a useless phosphorylation–dephosphorylation cycle or nonspecific tracer uptake by a cerebral sub-compartment.

Measurement of regional cerebral pH in human subjects using continuous inhalation of 11CO2 and positron emission tomography.

The cerebral pH of four normal human subjects has been measured using continuous inhalation of 11CO2 and positron emission tomography (PET). 11CO2 was administered to each subject at a constant rate for 15 min, during which time serial arterial plasma 11C levels were determined and serial 11C cerebral uptake PET scans were performed at a fixed axial tomographic level. 11C uptake kinetics were analysed using a three-compartment model. Rate constants have been estimated for the free exchange of 11CO2 between plasma and cerebral compartments for each subject, and their cerebral pH calculated. Whole brain pH values ranged from 6.96 to 7.05, and no significant pH difference between regions containing predominantly grey or white matter was noted. Best fits to 11C uptake data were achieved by effectively neglecting the metabolic fixation of 11C by cerebral tissue. The purpose of this study was to test the feasibility of pH measurement using the 11CO2 continuous inhalation technique. It is concluded from the results and the error analysis that continuous 11CO2 inhalation combined with PET is potentially a simple and useful method for determining regional cerebral pH.

Regional cerebral oxygen utilization, blood flow, and blood volume in benign intracranial hypertension studied by positron emission tomography

Using PET, we measured regional cerebral oxygen utilization, oxygen extraction, blood flow, and blood volume in five patients with benign intracranial hypertension. No significant differences in regional cerebral function were found between the patients and 15 age-matched normal controls. Cerebral decompression with a lumboperitoneal shunt produced little? change in regional cerebral function in one patient studied serially. The raised CSF pressure of benign intracranial hypertension is therefore not associated with any significant deterioration in cerebral oxygen metabolism or hemodynamics.

Studies on regional cerebral haematocrit and blood flow in patients with cerebral tumours using positron emission tomography.

Regional cerebral haematocrit has been measured in seven patients with brain tumours, and in one normal subject, using positron emission tomography (PET). Red cell and plasma volumes of distribution were assessed using 11CO and [methyl-11C]albumin, respectively. Haematocrit values were compared with values of regional cerebral blood flow (rCBF) measured using steady-state inhalation of C15O2. Only two of the seven cerebral tumours studied showed any increase in uptake of [methyl-11C]albumin over 45 min. Values of r, the regional ratio of cerebral small-to-large vessel haematocrit, varied from 0.52 to 0.84 for the seven tumours studied. No correlation between r and tumour blood flow was observed. The normal subject yielded an r value of 0.69 for the mean whole brain small-to-large vessel haematocrit ratio. No significant difference between gray and white matter r values was found. The contralateral hemispheres of the seven tumour patients studied yielded an overall mean r value of 0.71 +/- 0.05. We conclude that it is reasonable to assume an r value of 0.7 in tomographic calculations of regional cerebral blood volume (rCBV) from red cell or plasma volumes of distribution in normal brain. Such an assumption for tumours, however, may lead to errors of 35% in estimated rCBV.