Metabolic mapping of functional activity in human subjects with the [18F]fluorodeoxyglucose technique.

The 2-[18F]fluoro-2-deoxy-D-glucose technique was used to measure regional cerebral glucose utilization by human subjects during functional activation. Normal male volunteers subjected to one or more sensory stimuli (tactile, visual, or auditory) exhibited focal increases in glucose metabolism in response to the stimulus. Unilateral visual hemifield stimulation caused the contralateral striate cortex to become more metabolically active than the striate cortex ipsilateral to the stimulated hemifield. Similarly, stroking the fingers and hand of one arm with brush produced an increase in metabolism in the contralateral postcentral gyrus, compared with the homologous ipsilateral region. The auditory stimulus, which consisted of a monaurally presented factual story caused an increase in glucose metabolism in the auditory cortex in the hemisphere contralateral to the stimulated ear. These results demonstrate that the technique is capable of providing functional maps in vivo related to both body region and submodality of sensory information in the human brain.

Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET.

The regional distributions of monoamine oxidase (MAO) types A and B have been identified in human brain in vivo with intravenously injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and positron emission tomography. The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in one subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO B for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.

Regional brain glucose metabolism in chronic schizophrenia. A positron emission transaxial tomographic study.

Thirteen diagnosed schizophrenics and 11 normal controls were studied with a method using the PETT III positron emission tomograph (PET) and fluorodeoxyglucose labeled with fluorine 18. Each subject also had a computed tomographic (CT) scan. For each subject, two brain levels, one through the basal ganglia and one through the semioval center, were analyzed for the mean regional metabolic glucose rate. Specifically, relationships between frontal and posterior regions were evaluated. The CT scans of matching levels were superimposed on the functional PET images to provide anatomic criteria for region of interest selection. While no whole-slice metabolic differences were apparent between groups, schizophrenics had significantly lower activity in the frontal lobes, relative to posterior regions. The medicated and drug-free groups did not differ from one another in these regards. Trait v state dependency of the phenomenon was analyzed, and several technological limitations were considered.

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 more 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 run 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% and 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.

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 Alzheimer's 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.

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 Alzheimer's 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.

Positron emission tomography studies of normal aging: a replication of PET III and 18-FDG using PET VI and 11-CDG.

Using PET VI and 11-CDG we replicated our earlier PET III and 18-FDG normal aging findings. Examination of young and old normal volunteers revealed the absence of any absolute regional age-related changes in glucose utilization. For the combined sample (N = 81) we did find evidence to suggest a relative hypofrontal change with increasing age. A strong relationship between age and ventricular size (CT) was also found. These findings suggest the preserved glucose metabolism of the resting aging brain in the presence of structural atrophic changes.

Effects of chronic cocaine abuse on postsynaptic dopamine receptors.

To assess the effects of chronic cocaine intoxication on dopamine receptors in human subjects, the authors evaluated [18F]N-methylspiroperidol binding using positron emission tomography in 10 cocaine abusers and 10 normal control subjects. Cocaine abusers who had been detoxified for 1 week or less showed significantly lower values for uptake of [18F]N-methylspiroperidol in striatum than the normal subjects, whereas the cocaine abusers who had been detoxified for 1 month showed values comparable to those obtained from normal subjects. The authors conclude that postsynaptic dopamine receptor availability decreases with chronic cocaine abuse but may recover after a drug-free interval.

Effect of reserpine on regional cerebral glucose metabolism in control and migraine subjects.

The regional cerebral metabolic rate of glucose metabolism (RCMRGlu) in five headache and six control subjects was measured with positron emission tomography (PET) using the tracer 2-deoxy-D-[1-11C] glucose before and after the administration of reserpine. The short half-life of the carbon 11 tracer made possible a test-retest paradigm wherein each subject served as his own control in assessing the effect of reserpine on RCMRGlu. Thus, measurements were first performed with subjects at rest and subsequently at 1 1/2 hours after the parenteral administration of reserpine (rest-reserpine). In control subjects without history of migraine, reserpine did not induce headache, and, furthermore, PET measurements 1 1/2 hours after drug administration consistently showed a global increase in RCMRGlu over resting values similar to that observed in a normal control (rest-rest) group not receiving reserpine. By contrast, four of the five subjects with migraine began to experience a mild unilateral headache or visual disturbances 1 1/2 hours after reserpine, at which time PET scanning showed a 5% to 30% decline in RCMRGlu below the values that had been measured before reserpine injection, all well outside of the 99% confidence limits of normal variation separately determined on 25 control subjects (rest-rest). There was no apparent laterality, and subjects with a history of either common or classic migraine responded in a similar manner. The difference in percent change in RCMRGlu following administration of reserpine observed in these four subjects with migraine headaches was significantly different over all regions of interest as compared with all six control subjects receiving the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Alteration of regional cerebral glucose metabolic rate in non-Korsakoff chronic alcoholism.

That chronic alcoholism yields devastating effects to the central nervous systems of its victims is well known, but the actual physiologic mechanisms underlying that deterioration have yet to be completely identified. What is also known is that many chronic alcoholics seem to recover brain function after a protracted period of abstinence, but the actual mechanisms of that restoration are also not well understood. Using positron emission tomography with the tracer 11C-2-deoxy-D-glucose as a probe to measure regional cerebral metabolic rate of glucose (RCMRGlu), we compared the magnitudes of glucose consumption in 44 brain regions between a group of newly abstinent chronic alcoholics without Korsakoff's psychosis and a control group of normal nonalcoholic subjects whose range of age was that of the alcoholic group. We found that RCMRGlu measurements in the brains of alcoholics were significantly lower than in the brains of the control group, and that there were many fewer significant interregional correlations in the brains of the alcoholics than in the brains of the control group. We also found no significant correlation between age and global metabolic rate of glucose in either group. However, even though the number of alcoholic subjects was too few to allow a reliable statistical comparison, the measurements suggest that chronic alcoholics over the age of 50 years suffer a greater decrease of RCMRGlu values than do their counterparts under the age of 50 years. While resting in a bland environment, neither alcoholic nor control subjects were found to have significant differences in RCMRGlu values between their brain hemispheres. In contrast to this similarity, normal dextrous subjects responded to a nonverbal auditory stimulus by increasing the metabolic rate of glucose in their right hemispheres while eight of nine chronic alcoholics did not. The results of this pilot study point to arguments that the alcoholic brain metabolizes glucose at a lower rate than do normal brains, that there are fewer region-to-region functional relationships in the alcoholic brain than in the normal brain, and that alcoholics may be impaired in right hemispheric processing. In subsequent investigations, we will measure the metabolic changes that follow abstinence, if any, by tracking subjects throughout an interval of rehabilitation. Also, we intend to test the findings of this study by measuring greater numbers of alcoholic subjects to separate the consequences of measurement variability, age, and chance from the underlying biologic processes that seem to be affected by chronic alcoholism.

The radiation dosimetry of 2 [F-18]fluoro-2-deoxy-D-glucose in man.

Bladder and brain time-activity measurements in humans were performed after the intravenous administration of 2-[F-18]fluoro-2-deoxy-D-glucose. Radiation doses were calculated using the MIRD schema. The bladder wall received an average of 440 mrad/mCi (s.e. 76) in ten subjects who voided at 2 hr after administration of tracer. If these subjects had voided at 1 hr, the bladder-wall dose would have been reduced to 220 mrad/mCi. The brain received an average of 81 mrad/mCi in eight subjects. The doses to other organs, calculated from published dog biodistribution data, are between 50 and 85 mrad/mCi except for spleen and heart, which both received 160 mrad/mCi. These time-activity measurements for the critical organ in the human avoid the assumptions made in using animal biodistribution data for human dosimetry calculations.

Improved delineation of human dopamine receptors using [18F]-N-methylspiroperidol and PET.

The brain uptake of [18F]-N-methylspiroperidol, a butyrophenone neuroleptic with high selectivity for the dopamine receptor, has been measured in three normal human volunteers using positron emission tomography for times up to 12 hr postinjection. These studies demonstrated two unique findings concerning the in vivo distribution of this neuroleptic: (a) it is tightly bound to dopamine D-2 receptors in the caudate-putamen brain regions, and (b) these regions are the only large brain structures which exhibit appreciable long-term retention. In addition, radioactivity clears rapidly from plasma, and the percentage of unchanged [18F]-N-methylspiroperidol in plasma declines rapidly. These results suggest that this compound binds irreversibly to dopamine D-2 receptors, and that there are few if any dopamine D-2 receptors in the human frontal cortex. These studies emphasize not only the importance of characterizing neurotransmitter receptors in living human brain using a ligand labeled with a positron emitting nuclide of sufficiently long half-life to allow monitoring of brain radioactivity distribution for several hours after the injection of radioligand, but also of accurately determining the amount of unchanged tracer in plasma for tracer kinetic modeling.

Is [1-11C]putrescine useful as a brain tumor marker?

Our experience with 11C-putrescine underscores the difficulty of finding a selective brain tumor tracer, uniquely incorporated by neoplastic glia or metastatic cells within brain, but not by the proliferating, nontransformed cells which constitute a normal pathophysiological reaction to various disease processes. Thirty-three patients with 36 lesions were studied with 11C-putrescine to determine the specificity of labeled putrescine for tumor tissue. The uptake of 11C-putrescine was correlated with local cerebral glucose metabolic rate in various lesions, including different types of tumors, to assess the relationship between 11C-putrescine uptake and tumor biology. Carbon-11-putrescine uptake was similar in malignant tumor and benign, non-neoplastic lesions with blood-brain barrier breakdown, illustrating the lack of tumor specificity of this tracer. Carbon-11-putrescine was not well incorporated into poorly enhancing lesions, regardless of their pathology, emphasizing the requirement of a disrupted blood-brain barrier for 11C-putrescine uptake. The ratio of 11C concentration within lesions, compared to that in a region of interest in the contralateral brain, weakly correlated with an analogous ratio for local cerebral glucose metabolic rate in various lesions. Physiological processes not unique to tumors are associated with polyamine active transport and metabolism and contribute to the lack of tumor specificity of 11C-putrescine. Carbon-11-putrescine appear to have less diagnostic utility than 18FDG in brain tumors. The potential of 11C-putrescine for evaluating the effect of antineoplastic therapy and providing prognostic information on brain tumors remains to be investigated.

Increased accumulation of 2-deoxy-2-[18F]Fluoro-D-glucose in liver metastases from colon carcinoma.

Three patients with liver metastases from colon carcinoma were studied with 2-deoxy-2-[F-18]fluoro-d-glucose (F-18-FDG) using positron emission tomography. The radioactivity in the metastatic tumor increased continuously following the injection of F-18-FDG, whereas it decreased in normal liver tissue. This resulted in the tumor to normal-liver ratio of 3.3-4.7 at 50 min after injection. The liver tumor was visualized as an increased accumulation of radioactivity in all patients, with the central area of the tumor showing less activity. These preliminary results suggest that F-18-FDG may be useful as a positive imaging agent for the detection and characterization of liver tumors.

Serial PET studies of human cerebral malignancy with [1-11C]putrescine and [1-11C]2-deoxy-D-glucose.

Serial PET measurements of [1-11C]putrescine ([11C]PUT) uptake and glucose metabolic rate (GMR) using [1-11C]2-deoxy-D-glucose ([11C]2DG) were made on eight human subjects with a radiological and, in most cases, pathological diagnosis of primary or metastatic brain tumor. Blood-to-brain influx constants (Ki) were calculated for [11C]PUT. Tumor uptake of 11C after [11C]PUT injection was unidirectional peaking at 15 min. The mean +/- s.d. Kis for [11C]PUT for tumor and normal brain tissue were 0.78 +/- 0.045 and 0.024 +/- 0.007 ml cc-1 min-1, respectively (average of ratio, 3.11) whereas the ratio of GMR for tumor and normal brain tissue was 1.2 +/- 0.5. The mean Ki for four active, high grade astrocytomas was 0.098 +/- 0.030 in contrast to 0.027 +/- 0.008 ml cc-1 min-1 for two patients with low grade astrocytoma. Active high grade astrocytomas also showed marked CT contrast enhancement and regional glucose hypermetabolism. In one subject with brain metastases, both [11C]PUT and GMR correlated with a declining clinical picture in repeated studies over a 4-mo period. PET studies with [11C]PUT provide a better signal:noise ratio than GMR measurements, are useful for locating small glycolytically hypometabolic tumors and, when used in longitudinal studies in a single subject, appear to provide an index of degree of malignancy.

Radiopharmaceuticals XXVII. 18F-labeled 2-deoxy-2-fluoro-d-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals.

18F-2-Deoxy-2-fluoro-D-glucose (18FDG) is rapidly extracted by the mouse heart, and the radioactivity in heart (3-4% per organ) remains relatively constant for 2 hr post injection. The brain uptake (2-3% per organ) remained relatively constant throughout the time course of the study. Liver, lungs, kidneys, small intestine, and blood all showed a rapid clearance of radioactivity after injection of 18FDG. At 120 min the heart-to-lung ratio was 12 and heart-to-liver ratio was 32. Urinary excretion of activity was approximately 16% of the injected dose at 60 min. The uptake of radioactivity by dog heart following the intravenous administration of 18FDG was 2.8-4.1% at 60 min and 2.4% at 135 min; it was regionally distributed, the areas of highest activity being the left ventricle and the interventricular septum. The brain activity was 2.1-3.5% at 120 min, with a ratio of gray matter-to-white matter of 2-3:1. Urinary excretion in dogs was 16% and 50% of the injected dose at 60 and 135 min. The chemical form of the activity in the urine, although unidentified, was not 18F-. Cross-sectional images of the myocardium of the dog after intravenous injection of 18FDG were obtained using emission tomography.

Radioactive phosphorus uptake test. An in vitro analysis of choroidal melanoma and ocular tissues.

The concentration of radioactive phosphorus in uveal melanoma and normal parts of the eye was determined in vitro in 14 eyes. The eyes were enucleated after a positive 32P uptake test. Portions of the melanoma as well as normal choroid, retina, sclera, lens, and vitreous were analyzed. The 32P uptake test had been performed at various intervals after intravenous administration of 32P from 24 to 556 hr. The in vitro uptake of 32P was compared to cell type, tumor volume, time of testing, percent uptake measured clinically, and specific activity. The only positive correlation was between percent uptake measured clinically and 32P concentration (dpm/gm). A higher concentration of phosphorus in melanoma resulted when carrier-free 32P was used. A negative correlation existed between number of hours from injection to clinical measurement of percent uptake, although melanoma to normal choroid ratios did not change from 24 to 72 hr. No correlation was found between uptake and tumor volume. The sample was small; however, we saw no correlation between 32P uptake and degree of malignancy.

Mapping of functional activity in brain with 18F-fluoro-deoxyglucose.

The efficacy of using the 18F-fluoro-deoxyglucose (18F-DG) for measuring regional cerebral glucose utilization in man during functional activation is demonstrated. Normal male volunteers subjected to sensory stimuli (visual, auditory, tactile) exhibited focal increases in glucose metabolism in response to the stimulus. Unilateral visual hemifield stimulation caused the contralateral striate cortex to become more active metabolically than the striate cortex ipsilateral to the stimulated hemifield. Similarly, stroking of the fingers and hand of one arm with a brush produced an increase in metabolism in the contralateral postcentral gyrus compared to the homologous ipsilateral region. The auditory stimulus, which consisted of monaural listening to either a meaningful or nonmeaningful story, caused an increase in glucose metabolism in the right temporal cortex independent of which ear was stimulated. These results demonstrate that the 18F-DG technique is capable of providing functional maps in vivo in the human brain.

Human primary visual cortex topography imaged via positron tomography.

The visuotopic structure of primary visual cortex was studied in a group of 7 human volunteers using positron emission transaxial tomography (PETT) and 18F-labeled 2-deoxy-2-fluoro-D-glucose ( [18F]DG). A computer animation was constructed with a spatial structure which was matched to estimates of human cortical magnification factor and to striate cortex stimulus preferences. A lateralized cortical 'checker-board' pattern of [18F]DG was stimulated in primary visual cortex by having subjects view this computer animation following i.v. injection of [18F]DG. The spatial structure of the stimulus was designed to produce an easily recognizable 'signature' in a series of 9 serial PETT scans obtained from each of a group of 7 volunteers. The predicted lateralized topographic 'signature' was observed in 6 of 7 subjects. Applications of this method for further PETT studies of human visual cortex are discussed.