Alfred P. Wolf

Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography

Positron emission tomography was used to measure local cerebral glucose utilization by the 2-[18F]fluoro-2-deoxy-D-glucose technique in 23 patients with cerebral gliomas. All 10 high-grade (III and IV) astrocytomas demonstrated a region of high activity with a glucose consumption of 7.4 ± 3.5 (SD) mg/100 gm per minute. The 13 low-grade (I and II) gliomas had a glucose metabolic rate of 4.0 ± 1.8 mg/100 gm per minute, with no distinctly visible hot spot. Thus, we found a correlation between rate of glycolysis and malignancy in primary cerebral tumors. Cerebral cortical glucose utilization was often depressed in areas adjacent to or neurally connected to the tumor site, and there was focal irregular delta wave EEG activity in these areas.

A Fluorinated Glucose Analog, 2-fluoro-2-deoxy-D-glucose (F-18): Nontoxic Tracer for Rapid Tumor Detection

Rapid uptake of F-18 FDG was observed in a variety of transplanted and spontaneous tumors in animals. The tumor uptake reached a peak by 30 min and remained relatively constant up to 60 min, with a very slow wash-out of F-18 activity from the tumor thereafter. Tumor-to-normal tissue and tumor-to-blood ratios ranged from 2.10-9.15 and 2.61-17.82, respectively, depending on the type of tumor. A scintiscan of a seminoma in a dog showed very high uptake in the viable part and lack of uptake in the necrotic mass. Toxicological studies in mice using 1000 times human tracer dose (HTD) per wk for 3 wk and in dogs using 50 times HTD per wk for 3 wk did not show any evidence of acute or chronic toxicity.

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.

Computed Tomography and Positron Emission Transaxial Tomography Evaluations of Normal Aging and Alzheimer's Disease

Young normal subjects, old normal subjects, and patients with senile dementia of the Alzheimers type (SDAT) were studied with both computed tomography (CT) and positron emission transaxial tomography (PETT). Increases in ventricular size with both aging and disease were measured. Regional glucose metabolic rate was not affected by age, but was markedly reduced in SDAT patients. These data indicate that in normal aging, structural brain changes may be more salient than biochemical changes. Although both structural and biochemical changes occur in SDAT, the biochemical changes are more marked. The results suggest that PETT is potentially more useful than CT in the in vivo diagnosis of SDAT.

Acute effects of ethanol on regional brain glucose metabolism and transport.

To evaluate the effects of ethanol in the human brain, we tested six normal subjects and six alcoholics using positron emission tomography and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) under baseline conditions and 24 hours later after ethanol administration (1 g/kg). Ethanol inhibited cortical and cerebellar glucose metabolism with relative sparing of the basal ganglia and corpus callosum. This inhibition was more pronounced in the alcoholics than in the controls. Measurement of the constants for glucose transport and utilization showed that decreased glucose metabolism was due to a reduction in glucose phosphorylation and not to a change of glucose transport into the tissue. The pattern of regional metabolic inhibition by alcohol paralleled the distribution of benzodiazepine receptors in the human brain.

The production of ultra high activity 11C-labeled hydrogen cyanide, carbon dioxide, carbon monoxide and methane via the 14N(p,α)11C reaction (XV)☆

The use of N2O2 or N2H2 pressurized gaseous systems as targets in proton bombardment makes use of the 14N(p,α) 11C reaction and allows the facile, quantitative production of H11CN, 11CO2, 11CO or 11CH4 as needed. A system is described for the production of “carrier-free”, high activity (up to 2 Ci) H11CN in an on-line process in the effluent gas stream from a cyclotron target. The target gas is a mixture of 94·5% nitrogen, 5·5% hdrogen, run at a total pressure of 11 atmospheres. The primary products are converted to 11CH4 in over 95 per cent yield by radiolysis in the target, and this, along with NH3 which is concurrently produced radiolytically, is converted quantitatively to “carrier-free” H11CN over platinum wire held at 1000°C. The radiation processes and dosimetry studies involved in the system are discussed. The product is available for use as gaseous H11CN, or in base or carrier sodium cyanide, within 10–12 min after the end of an irradiation. It has been used as such in animal studies and also in the production of carrier-free dopamine-11C and norepinephrine-11C at levels up to 30 mCi at the time of delivery for medical use. An identical target, using tank N2 with trace O2 impurity as the target gas, can be used to produce “carrier-free” 11CO2 at similar activity levels, and from this 11CO or 11CH4 can be made either on-line or by a rapid catalytic reduction.

Reproducibility of cerebral glucose metabolic measurements in resting human subjects.

Positron emission tomography with 11C-2-deoxyglucose was used to determine the test-retest variability of regional cerebral glucose metabolism in 22 young normal right-handed men scanned twice in a 24-h period under baseline (resting) conditions. To assess the effects of scan order and time of day on variability, 12 subjects were scanned in the morning and afternoon of the same day (a.m.-p.m.) and 10 in the reverse order (p.m.-a.m.) with a night in between. The effect of anxiety on metabolism was also assessed. Seventy-three percent of the total subject group showed changes in whole brain metabolism from the first to the second measurement of 10% or less, with comparable changes in various cortical and subcortical regions. When a scaling factor was used to equate the whole brain metabolism in the two scans for each individual, the resulting average regional changes for each group were no mote than 1%. This suggests that the proportion of the whole brain metabolism utilized regionally is stable in a group of subjects over time. Both groups of subjects had lower morning than afternoon metabolism, but the differences were slight in the p.m.-a.m. group. One measure of anxiety (pulse at fun 1) was correlated with run 1 metabolism and with the percentage of change from run 1 to run 2. No significant run 2 correlations were observed. This is the first study to measure test-retest variability in cerebral glucose metabolism in a large sample of young normal subjects. It demonstrates that the deoxyglucose method yields low Intrasubject variability and high stability over a 24-h period.

Use of 2-deoxy-D[1-11C]glucose for the determination of local cerebral glucose metabolism in humans: variation within and between subjects.

The deoxyglucose technique for the measurement of local cerebral glucose metabolism (LCMRgl) has been widely applied in animals utilizing 14C-deoxyglucose and in humans employing 18F-fluorodeoxyglucose. Repeat studies in humans over a relatively brief period of time have not been possible because of the 110-min half-life of fluorine-18. With the synthesis of 11C-deoxyglucose it has now become possible to utilize this short-lived (20 min) tracer for the measurement of LCMRgl and to determine its variability within subjects over a 2-h period. The kinetic rate constants for 11C-deoxyglucose were determined for gray and white matter and found to be very similar to those for 18F-fluorodeoxyglucose, suggesting that these two analogues of glucose have similar affinities for the facilitated transport system and are similar substrates for hexokinase in the brain. The coefficient of variation of repeated measurements of LCMRgl in a series of six normal subjects was 5.5% to 8.7% for various gray matter structures and 9.7% to 14.0% for white matter structures. The pattern of cerebral metabolic rates is relatively constant in a given individual when the conditions of the study are unchanged. The ability to make repeat measurements in the same subject reduces the variance due to between-subject differences, allowing smaller changes in LCMRgl to be detected with confidence.

Positron emission tomography in the study of aging and senile dementia.

(18)F-2-deoxy-2-fluoro-D-glucose ((18)FDG) is a positron emitting tracer for rate of glucose utilization in brain. When used in conjunction with positron emission tomography (PET), the PET-FDG technique permits in vivo quantitation of regional brain metabolism in man. We have applied this technique to the study of regional brain function in normal aging and senile dementia. Preliminary results for 7 patients with senile dementia of the Alzheimers type (SDAT) and 3 elderly normal subjects indicated a large, statistically significant (p < 0.01) diminution in rate of glucose utilization in SDAT. Furthermore, the degree of diminution in metabolic activity in SDAT was highly correlated with objective measures of degree of cognitive impairment. These results demonstrate the feasibility and potential utility of the PET-FDG technique for studying regional brain function in normal aging and dementia.

Serial [18F]N-methylspiroperidol PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients

An indirect approach to the relationship among drug dose, plasma level, and the competition between a labeled neuroleptic drug [18F]N-methylspiroperidol (18F-NMS) for binding sites in striatal tissue in normal and schizophrenic subjects is described. The slope of the line plotting the ratio of activity in the striatum (As) to activity in the cerebellum (Ac) versus time up to 5 hr postinjection of 18F-NMS is taken as a marker of site occupancy. An inverse relation between labeled competitor uptake and drug plasma level has been demonstrated for the classes of antipsychotic drug studied. Striatal uptake studies showed a progressive increase in all subjects following drug withdrawal up to 156 hr postwithdrawal. Uptake and clearance of 18F-NMS in cerebellar tissue was not appreciably affected by antipsychotic medication or drug withdrawal.