Martin Reivich

THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT

Abstract— A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2‐deoxy‐D‐[14C]glucose ([14C]DG) as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose‐6‐phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2‐chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.

The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man.

A method has been developed to measure local glucose consumption in the various structures of the brain in man with three-dimensional resolution. [18F]-2-deoxy-2-fluoro-D-glucose is used as a tracer for the exchange of glucose between plasma and brain and its phosphorylatdon by hexokinase in the tissue. A mathematical model and derived operational equation are used which enable local cerebral glucose consumption to be calculated in terms of the following measurable variables. An intravenous bolus of [18F]-2-deoxy-2-fluoro-D-glucose is given and the arterial specific activity monitored for a predetermined period of from 30 to 120 minutes. Starting at 30 minutes, the activity in a series of sections through the brain is determined with three-dimensional resolution by an emission tomographic scanner. The method was used to measure local cerebral glucose consumption in two normal volunteers. The values in gray matter structures range from 5.79 mg/100 g per minute in the cerebellar cortex to 10.27 in the visual cortex, whereas, in white matter structures, the values range from 3.64 mg/100 g per minute in the corpus callosum to 4.22 in the occipital lobe. Average values for gray matter, white matter, and whole brain metabolic rates, calculated as a weighted average based on the approximate volume of each structure, are 8.05, 3.80, and 5.90 mg/100 g per minute, respectively. The value of 5.9 mg/100 g per minute compares favorably with values previously reported. Ore Res 44: 127-137, 1979

Glucose Metabolic Rate Kinetic Model Parameter Determination in Humans: The Lumped Constants and Rate Constants for [18F]Fluorodeoxyglucose and [11C]Deoxyglucose

The rate constants and lumped constants (LCs) for [18F]fluorodeoxyglucose ([18F]FDG) and [11C]deoxyglucose ([11C]DG) were determined in humans for the glucose metabolic rate kinetic model used to measure local cerebral glucose consumption. The mean values (±SE) of the LCs for [18F]FDG and [11C]DG are 0.52 ± 0.028 (n = 9) and 0.56 ± 0.043 (n = 6), respectively. The mean values (±SE) of the rate constants k*1, k*2, k*3, and k*4 for [18F]FDG for gray matter are 0.095 ± 0.005, 0.125 ± 0.002, 0.069 ± 0.002, and 0.0055 ± 0.0003, respectively. The corresponding values for white matter are 0.065 ± 0.005, 0.126 ± 0.003, 0.066 ± 0.002, and 0.0054 ± 0.0006, respectively. Using these values and previously published values for the rate constants for [11C]DG, the average whole-brain metabolic rates for glucose in normal subjects measured with [18F]FDG and [11C]DG are 5.66 ± 0.37 (n = 6) and 4.99 ± 0.23 (n = 6) mg/100 g/min, respectively. These values are not significantly different (t = 1.56, p > 0.10) and agree well with reported values in the literature determined by means of the Kety-Schmidt technique.

Elastically deforming 3D atlas to match anatomical brain images

To evaluate our system for elastically deforming a three-dimensional atlas to match anatomical brain images, six deformed versions of an atlas were generated. The deformed atlases were created by elastically mapping an anatomical brain atlas onto different MR brain image volumes. The mapping matches the edges of the ventricles and the surface of the brain; the resultant deformations are propagated through the atlas volume, deforming the remainder of the structures in the process. The atlas was then elastically matched to its deformed versions. The accuracy of the resultant matches was evaluated by determining the correspondence of 32 cortical and subcortical structures. The system on average matched the centroid of a structure to within 1 mm of its true position and fit a structure to within 11% of its true volume. The overlap between the matched and true structures, defined by the ratio between the volume of their intersection and the volume of their union, averaged 66%. When the gray-white interface was included for matching, the mean overlap improved to 78%; each structure was matched to within 0.6 mm of its true position and fit to within 6% of its true volume. Preliminary studies were also made to determine the effect of the compliance of the atlas on the resultant match.

Positron emission tomography in patients with glioma. A predictor of prognosis.

Positron emission tomography (PET) studies have been performed using 18‐F‐fluorodeoxyglucose in 29 adult subjects with primary brain tumors. Seventy‐two percent of the patients were treated previously. The glucose metabolic state in the lesions was increased in 16 patients, and was normal or decreased in 13 patients. The hypermetabolic tumors tended to behave in a more malignant fashion. Patients with hypermetabolic tumors had a median survival of 7 months after PET scan, compared to 33 months for those with hypometabolic lesions. Among the high‐grade glioma patients, the PET results separated them into a good prognosis group (hypometabolic, with 78% 1‐year survival) and a poor prognosis group (hypermetabolic, with a 29% 1‐year survival after PET). These results suggest that glucose metabolic studies may provide an independent measure of the aggressiveness of a brain tumor, and may supplement pathologic grading.

A Computerized System for the Elastic Matching of Deformed Radiographic Images to Idealized Atlas Images

A system of computer programs is described which, for the first time, is able to use computerized tomographic data to automatically locate, measure, and describe anatomical structures of interest with accuracy and consistency. Input to the system consists of any digitized radiographic data. Computer assisted tomographic (CAT) scans of the head were used in this first implementation. Using these data and a predefined atlas picture representing an idealized view of the average normal image, an individualized atlas was created. From the individualized atlas, structure size, density, location displacement, and distortion may be calculated. The individualized atlas created using high resolution data, such as the CAT scan, may then be directly superimposed on pictures obtained using lower resolution modalities, such as positron emission tomographic scan images. This allows the precise location of structures poorly visualized by the secondary imaging modality. This system is capable of using either two- or three-dimensional data.

Cognitive task effects on hemispheric blood flow in humans: Evidence for individual differences in hemispheric activation.

Evidence from two indirect measures of hemispheric activity, EEG α and conjugate lateral eye movements, has pointed to the existence of individual differences in hemispheric activation. Results from a more direct indicator of hemispheric activity, regional cerebral blood flow as measured by the 133Xe inhalation method, show that such individual differences can be detected in the distribution of blood in the two hemispheres and that the amount of increase in blood flow in the right relative to the left hemisphere is correlated with performance on a spatial task. These results corroborate and extend the findings from the EEG and eye movement studies and suggest that the dimension of individual differences in hemispheric activation may exert significant influence on cognitive performance and on problem-solving strategies.

Local glucose utilization in acute focal cerebral ischemia Local dysmetabolism and diaschisis

By means of an autoradiographic technique employing 14C-2-deoxyglucose, abnormalities of local brain glucose utilization were studied 90 minutes following occlusion of the left middle cerebral and common carotid arteries in a series of pentobarbital-anesthetized cats. Sham-insulted control animals exhibited a normal pattern of regional glucose utilization. In animals with vascular occlusion, a zone of greatly suppressed glucose utilization occupied the caudate nucleus of the ischemic hemisphere, with variable extension, and was surrounded by a narrow rim of increased local brain glucose utilization, suggesting the occurrence of enhanced anaerobic glycolysis in the latter zones. The cerebral cortex, which was less constantly affected, showed alternating regions of increased and decreased glucose utilization. Quantitation of local brain glucose utilization values from the contralateral nonischemic hemisphere revealed a mild suppression of cortical glucose utilization relative to the control animals. This may be the metabolic equivalent of diaschisis.

The effect of anxiety on cortical cerebral blood flow and metabolism.

The relation between anxiety and cortical activity was compared in two samples of normal volunteers. One group was studied with the noninvasive xenon-133 inhalation technique for measuring cerebral blood flow (CBF) and the other with positron emission tomography (PET) using 18Flurodeoxyglucose (18FDG) for measuring cerebral metabolic rates (CMR) for glucose. The inhalation technique produced less anxiety than the PET procedure, and for low anxiety subjects, there was a linear increase in CBF with anxiety. For higher anxiety subjects, however, there was a linear decrease in CBF with increased anxiety. The PET group manifested a linear decrease in CMR with increased anxiety. The results indicate that anxiety can have systematic effects on cortical activity, and this should be taken into consideration when comparing data from different procedures. They also suggest a physiologic explanation of a fundamental behavioral law that stipulates a curvilinear, inverted-U relationship between anxiety and performance.

Predictors of outcome after anterior temporal lobectomy Positron emission tomography

We assessed the relationship between temporal lobe metabolism measured quantitatively and qualitatively with PET using [18F]-fluorodeoxyglucose (FDG) and postoperative seizure frequency after anterior temporal lobectomy. Forty-three patients with refractory partial epilepsy had anterior temporal lobectomy and preoperative assessment with PET-FDG. Qualitative PET analysis was performed visually by two blinded observers, and quantitative PET analysis was performed using an anatomic template for six control and six temporal lobe subregions, deriving an asymmetry index for each region. Seizure outcome was assessed 1 year after surgery; patients were classified as being seizure-free or as having persistent seizures. Qualitative data were analyzed using Fishers exact test and the t test, and quantitative data were analyzed using a repeated-measures ANOVA. Thirty-two patients (74%) were seizure-free at follow-up, and 11 had persistent seizures, although most improved. Twenty-nine of 35 patients (83%) with restricted temporal lobe hypometabolism by visual analysis were seizure-free, compared with three of eight patients (37.5%) with normal scans or multilobar hypometabolism. Quantitative analysis revealed that an asymmetry of mesial temporal lobe glucose consumption (uncal region) correlated with improved surgical outcome (p < 0.02). We developed a logistic regression model to predict individual outcome based on the asymmetry in uncal metabolism. Lateral temporal metabolism did not correlate with outcome. We conclude that both visual PET analysis and quantitative PET analysis predict outcome after temporal lobectomy, although quantitative measures offer more precise information.