David R. Christman

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.

Positron Emission Tomography and Computed Tomography Assessments of the Aging Human Brain

The relationship between alterations in brain structure and brain function was studied in vivo in both young and elderly human subjects. Computed tomography revealed significant age-related ventricular and cortical sulcal dilatation. The cortical changes were most closely related to age. Positron emission tomography failed to show regional changes in brain glucose metabolic rate. The results suggest that the normal aging brain undergoes structural atrophic changes without incurring regional metabolic changes. Examination of the correlations between the structural and the metabolic measures revealed no significant relationships. These data are discussed with respect to the significant structure-function relationships that have been reported in Alzheimer disease.

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.

Scintigraphy with positron-emitting compounds.--I. Carbon-11 labeled thymidine and thymidylate.

Abstract The in vivo distribution of 11 C in normal and VX2 carcinoma-tumored rabbits has been observed with a gamma camera after i.v. doses of [ 11 C]thymidine or [ 11 C]thymidylate. The heart was visible immediately after injection of 11 C; the image disappeared by 5 min, indicating a rapid redistribution from the blood stream. We observed a generalized distribution of 11 C label with some notably “hotter” spots: tumor, bone marrow, liver. The liver, spleen and bone marrow were also visualized by 99 Tcm sulfur colloid injected before the [ 11 C]TdR or [ 11 C]dTMP. Injection of [ 11 C]TdR diluted with 60 times more nonradioactive TdR, 97 μmoles in all, resulted in a rapid excretion of 11 C. With 4 mCi of 11 C at injection time scintiphotos could be obtained up to 120 min.

Tissue distributions of radiopharmaceuticals labeled with positron emitters and problems in relating them to human studies

This paper discusses a few specific examples of organ distributions involving positron-emitting nuclides intended to illustrate some specific points in this area. In particular, work with 2-fluoro-2-deoxyglucose will be discussed in some detail, and its distribution in the body compared with the closely related (chemically but not biologically) 3-fluoro-3-deoxyglucose and 1-/sup 11/C-2-deoxyglucose. Other compounds labeled with these two nuclides, and with /sup 13/N and /sup 15/O will also be discussed.