Labeled putrescine as a probe in brain tumors.

The polyamine metabolism of transplanted N-nitrosomethylurea-derived rat glioma was determined with radiolabeled putrescine used as a marker for malignancy. The uptake of putrescine in vivo was complete within 5 minutes and was specific for tumor tissue. The conversion of putrescine to spermine and other metabolites by the tumor was rapid, in contrast to the case for adjacent normal brain. These results suggest that putrescine labeled with carbon-11 may be used as a positron-emission tomographic tracer for the selective metabolic imaging of brain tumor and may be used in an appropriate model as a marker for tumor growth rate.

Negative symptoms and hypofrontality in chronic schizophrenia.

Frontal lobe dysfunction is widely suspected to underlie negative symptoms of schizophrenia. This hypothesis is based largely on long-standing observations of the similarities between the effects of frontal lobe lesions and negative symptoms. However, there is little direct evidence specifically for such an association in schizophrenic patients. We measured the relationship between decreased relative prefrontal cortex glucose metabolism (hypofrontality) using positron emission tomography and evaluated the severity of negative symptoms in 20 chronic schizophrenics who underwent scanning while not receiving neuroleptic drugs. We found a close relationship between negative symptoms and prefrontal hypometabolism, particularly in the right dorsolateral convexity. This association was regionally specific. Furthermore, there was no evidence that this relationship was an artifact of age, cerebral atrophy, or severity of positive symptoms.

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.

Acute d-amphetamine challenge in schizophrenia: effects on cerebral glucose utilization and clinical symptomatology.

The effects of d-amphetamine (0.5 mg/kg orally) on regional cerebral glucose utilization were measured with positron emission tomography (PET) in 17 schizophrenics (along with a placebo-control group of an additional six schizophrenic patients). The acute d-amphetamine challenge tended to decrease glucose utilization throughout much of the brain, with a regional effect that was statistically significant in the left temporal cortex. There was no apparent relationship between the effects of amphetamine-induced changes in regional cerebral metabolism and psychotic symptom exacerbation. An exploratory analysis suggested that features characteristic of Crow's type II syndrome were significant predictors of cerebral hyporesponsivity to stimulant challenge, however.

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.

The spectral signature method for the analysis of PET brain images.

We introduce the concept of the metabolic centroid spectrum as the feature space to characterize the distribution of metabolic activity in three-dimensional brains. The method computes the metabolic centroid of a brain subvolume for each increment of metabolic activity occurring in the whole brain. The result is the metabolic spectral signature, a continuous three-dimensional curve whose shape reflects the distribution of metabolic rates in the brain. The method's sensitivity to metabolic distribution asymmetries is greatly increased over that of the metabolic centroid method, while retaining its advantages; it is almost invariant to head size, head positioning, photon scatter, and the positron emission tomography (PET) camera's full width at half-maximum. It does not require magnetic resonance, computed tomography, or x-ray images. To test the method we analyzed the metabolic PET images of 40 normal subjects and 20 schizophrenics. The results show a unification of several metabolic characteristics of schizophrenic brains, such as laterality, hypofrontality, cortical/subcortical abnormalities, and overall brain hypometabolism, which were identified by different laboratories in separate studies using differing methodologies. Here they are presented by a single automatic objective method.

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.

Brain organization in schizophrenia.

Brain metabolism was measured with positron emission tomography and [11C]deoxyglucose during baseline and during a visual task in 12 normal subjects and 18 schizophrenic patients. Global measures of metabolism for 11 brain regions were transformed into relative values by dividing them by the metabolic value for whole brain. Factor analysis was accomplished on the matrix of intercorrelations among the relative regional values for the normal and for the schizophrenic patients under baseline and under the task. Four factors that revealed independently varying metabolism in frontal, occipital, left-versus-right hemisphere, and subcortical structures were obtained. The frontal and subcortical factors discriminated between normal subjects and schizophrenic patients, whereas the occipital factor discriminated between baseline and task. Although activity in these individual regions varied significantly, it was the pattern of differences in regional metabolic activity that best discriminated between diagnostic groups and testing conditions.

The metabolic centroid method for PET brain image analysis.

The method of centroids is an approach to the analysis of three-dimensional whole-brain positron emission tomography (PET) metabolic images. It utilizes the brain's geometric centroid and metabolic centroid so as to objectively characterize the central tendency of the distribution of metabolic activity in the brain. The method characterizes the three-dimensional PET metabolic image in terms of four parameters: the coordinates of the metabolic centroid and the mean metabolic rate of the whole brain. These parameters are not sensitive to spatially uniform random noise or to the position of the subject's head within a uniform PET camera field of view. The method has been applied to 40 normal subjects, 22 schizophrenics who were treated with neuroleptics, and 20 schizophrenics who were neuroleptic-free. The mean metabolic centroid of the normal subjects was found to be superior to the mean geometric centroid of the brain. The mean metabolic centroid of chronic schizophrenics is lower and more posterior to the mean geometric centroid than is that of normals. This difference is greater in medicated than in unmedicated schizophrenics. The posterior and downward displacement of the mean metabolic centroid is consistent with the concepts of hypofrontality, hyperactivity of subcortical structures, and neuroleptic effect in schizophrenics.

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.

Blunted change in cerebral glucose utilization after haloperidol treatment in schizophrenic patients with prominent negative symptoms.

OBJECTIVE: The purpose of this report was to determine 1) the effects of chronic haloperidol treatment on cerebral metabolism in schizophrenic patients, 2) the relation between negative symptoms and haloperidol-induced regional changes in cerebral glucose utilization, and 3) the relation between metabolic change and clinical antipsychotic effect. METHOD: Cerebral glucose utilization, as determined by position emission tomography (PET), was studied in 18 male schizophrenic subjects before and after chronic treatment with haloperidol at a standardized plasma level. RESULTS: Overall, haloperidol caused a widespread decrease in absolute cerebral glucose metabolism. The cerebral metabolic response to haloperidol was blunted in patients with high pretreatment negative symptom scores. CONCLUSIONS: Taken together with the results from a previously reported PET study of the effects of an acute amphetamine challenge (in which 14 of the current subjects participated), these data suggest that the negative symptom complex is associated with diminished cerebral response to change in dopaminergic activity. This deficit cannot be solely accounted for by structural differences.

Effect of a haloperidol challenge on regional brain metabolism in neuroleptic-responsive and nonresponsive schizophrenic patients.

OBJECTIVE: The CNS metabolic response to a neuroleptic challenge in treatment-responsive and nonresponsive schizophrenic patients was measured in order to examine the relation between treatment outcome and the capacity to alter neurochemical function in response to acute receptor blockade. METHOD: Positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) were used to measure regional cerebral metabolism in seven schizophrenic patients judged to have been responsive to drug treatment previously and seven nonresponsive schizophrenic patients after a drug-free period of at least 3 weeks (baseline) and again 12 hours after administration of 5.0 mg of haloperidol. RESULTS: The haloperidol challenge caused widespread decreases in absolute metabolism in the nonresponsive patients but not the responsive patients. These group differences reflect the findings on the second (challenge) scans, since metabolic values at baseline were not statistically different in the two groups. The pattern of decreased metabolic activity in the nonresponders after the haloperidol challenge is similar to that previously observed in normal subjects. CONCLUSIONS: The metabolic response to drug challenge separates treatment responders from nonresponders and normal subjects. The results suggest that subtyping of schizophrenia (and other psychiatric disorders) can be achieved by measuring the physiologic response to a pharmacologic challenge in vivo with chemical brain-imaging techniques.

Persistence of cerebral metabolic abnormalities in chronic schizophrenia as determined by positron emission tomography.

Local cerebral metabolic rates were determined by positron emission tomography and the deoxyglucose method in a group of 10 chronic schizophrenic subjects before and after somatic treatment and in eight normal subjects. Before treatment, schizophrenic subjects had markedly lower absolute metabolic activity than did normal controls in both frontal and temporal regions and a trend toward relative hyperactivity in the basal ganglia area. After treatment, their metabolic rates approached those seen in normal subjects in nearly all regions except frontal. Persistence of diminished frontal metabolism was manifested as significant relative hypofrontality. These findings suggest specific loci of aberrant cerebral functioning in chronic schizophrenia and the utility of positron emission tomography in characterizing these abnormalities.

Phenomenological correlates of metabolic activity in 18 patients with chronic schizophrenia.

Using [11C]-deoxy-D-glucose and positron emission tomography (PET), the authors measured brain metabolism in 18 patients with chronic schizophrenia to assess which of the metabolic measures from two test conditions was more closely related to the patients' differing clinical characteristics. The two conditions were resting and activation, and an eye tracking task was used. Patients with more negative symptoms showed lower global metabolic rates and more severe hypofrontality than did the patients with fewer negative symptoms. Differences among the patients were distinguished by the task: sicker patients failed to show a metabolic activation response. These findings suggest that cerebral metabolic patterns reflect clinical characteristics of schizophrenic patients.

Low frontal glucose utilization in chronic schizophrenia: a replication study.

Frontal/posterior ratios of cerebral glucose metabolism as determined by positron emission tomography were significantly lower in 13 chronic schizophrenic patients than in eight normal control subjects, as were absolute metabolic rates in both the frontal and posterior regions. The differences were not accounted for by cerebral atrophy.

Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia.

Because CNS neuroleptic concentration cannot be directly measured in patients, the relation between clinical response and extent of dopamine receptor blockade is unknown. This relationship is critical in ascertaining whether nonresponse to neuroleptics is the result merely of inadequate CNS drug levels or of more basic biological differences in pathophysiology. Using [18F]N-methylspiroperidol and positron emission tomography, the authors assessed dopamine receptor occupancy in 10 schizophrenic patients before and after treatment with haloperidol. Responders and nonresponders had virtually identical indices of [18F]N-methylspiroperidol uptake after treatment, indicating that failure to respond clinically was not a function of neuroleptic uptake or binding in the CNS.

Low cerebellar metabolism in medicated patients with chronic schizophrenia.

Because of the frequent association of cerebellar structural defects with schizophrenia, the authors reanalyzed the metabolic brain images of patients with chronic schizophrenia to assess if they had abnormalities in cerebellar metabolism. They used carbon-11-2-deoxyglucose and positron emission tomography to study 18 medicated patients with chronic schizophrenia and 12 normal comparison subjects. Patients with schizophrenia showed significantly lower absolute and relative metabolism in the cerebellum than normal subjects.

Effects of haloperidol challenge on regional cerebral glucose utilization in normal human subjects.

OBJECTIVE: Positron emission tomography and the fluorodeoxyglucose (FDG) method were used to determine the brain's metabolic response to neuroleptic challenge in a normal, disease-free state. METHOD: FDG measurements were obtained before and 12 hours after administration of 5 mg of haloperidol to 12 young normal men. These values were compared with test-retest FDG measures obtained from nine normal male control subjects who received no drug intervention. RESULTS: After haloperidol administration, the haloperidol subjects showed significantly lower glucose utilization in the neocortex, limbic cortex, thalamus, and caudate nucleus but not in the putamen or cerebellum. After adjustment for global effects, significant reductions were still evident in the frontal, occipital, and anterior cingulate cortex, whereas the putamen and cerebellum showed significant increases. CONCLUSIONS: This study, measuring the brain's metabolic response to acute receptor blockade, is a first step in the development of an assay of CNS pharmacological activity. By determining the response to neuroleptic challenge in a normal state, the study establishes a comparison group for determining response to challenge in various psychiatric conditions.

Serotonergic modulation of dopamine measured with [11C]raclopride and PET in normal human subjects.

OBJECTIVE: This study was undertaken to measure serotonergic modulation of dopamine in vivo by using positron emission tomography (PET), a radiotracer for the striatal dopamine D2 receptor ([11C]raclopride), and a pharmacologic challenge of the serotonin system (d,l-fenfluramine). METHOD: Two PET studies using [11C]raclopride were performed in 11 normal male subjects before administration of the serotonin-releasing agent and reuptake inhibitor fenfluramine (60 mg p.o.) and 3 hours afterward. A graphical analysis method was used with the [11C]raclopride data to derive the distribution volume of D2 receptors. Plasma levels of fenfluramine, norfenfluramine, homovanillic acid (HVA), cortisol, and prolactin were determined. RESULTS: Levels of fenfluramine and prolactin were elevated 2 hours after fenfluramine administration and remained significantly elevated during the second scan, while levels of HVA and cortisol were not altered significantly during the time of scanning. A significant decrease in the specific binding (striatum) and the nonspecific binding subtracted from the specific binding (striatum minus cerebellum) of [11C]raclopride was observed. The rate of metabolism of [11C]raclopride and the nonspecific binding (cerebellum) were not significantly altered by the fenfluramine intervention. CONCLUSIONS: The observed decrease in [11C]raclopride binding is consistent with an increase in dopamine concentrations and with the ability of serotonin to stimulate dopamine activity. The ability to measure serotonergic modulation of dopamine in vivo may have implications for the study of etiologic and therapeutic mechanisms in schizophrenia, major depressive disorder, obsessive-compulsive disorder, and substance abuse.

Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates.

The pharmacologic treatment of many neuropsychiatric disorders (Alzheimer's disease, schizophrenia, depressive illness) has been targeted at the central hypothesis that defects in a single neurotransmitter system underlie the pathophysiology of the disease state. With the recognition that such treatments have not been efficacious consistently, recent drug development has been directed at altering other functionally linked neurotransmitters involved in these diseases. Using positron emission tomography, we have noninvasively investigated the effects of two noncholinergic drugs on the release of acetylcholine. By examining the effects of gamma-vinyl gamma-aminobutyric acid (GABA) (a GABA transaminase inhibitor) or altanserin (a serotonergic antagonist) on the regional binding of 11C-benztropine in the primate brain (Papio anubis), we demonstrated that drugs acting upon either GABAergic or serotonergic neurons produce profound regional changes in acetylcholine release. These findings indicate that the mechanisms of action and the subsequent therapeutic efficacy of these centrally acting drugs may be linked to their multitransmitter effects. This application of positron emission tomography represents an extremely promising experimental approach that can be directed towards elucidating abnormalities in neurotransmitter modulation relevant to disease progression and pharmacologic treatment.