Faculty Bibliography

Positron emission tomography (PET) and the deoxyglucose method were used to determine the test-retest stability of regional cerebral glucose metabolism in 8 male schizophrenic patients and 11 normal control subjects, scanned twice under baseline (resting) conditions. Normal and schizophrenic subjects showed comparable stability of regional metabolism. When the regional values were scaled to compensate for the effects of changes in whole brain metabolism, the resulting mean regional changes were reduced to about 1-2% in both groups. This study demonstrates that the baseline resting state is an appropriate reference state for schizophrenic subjects in deoxyglucose PET experiments

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

Interactions between the dopaminergic D2 receptor system and the muscarinic cholinergic system in the corpus striatum of adult female baboons (Papio anubis) were examined using positron emission tomography (PET) combined with [18F]N-methylspiroperidol [( 18F]NMSP) (to probe D2 receptor availability) and [N-11C-methyl]benztropine (to probe muscarinic cholinergic receptor availability). Pretreatment with benztropine, a long-lasting anticholinergic drug, bilaterally reduced the incorporation of radioactivity in the corpus striatum but did not alter that observed in the cerebellum or the rate of metabolism of [18F]NMSP in plasma. Pretreatment with unlabelled NMSP, a potent dopaminergic antagonist, reduced the incorporation of [N-11C-methyl]benztropine in all brain regions, with the greatest effect being in the corpus striatum greater than cortex greater than thalamus greater than cerebellum, but did not alter the rate of metabolism of the labelled benztropine in the plasma. These reductions in the incorporation of either [18F]NMSP or [N-11C-methyl]benztropine exceeded the normal variation in tracer incorporation in repeated studies in the same animal. This study demonstrates that PET can be used as a tool for investigating interactions between neurochemically different yet functionally linked neurotransmitters systems in vivo and provides insight into the consequences of multiple pharmacologic administration

The muscarinic cholinergic system has been mapped in vivo in human and baboon brain using [N-11C-methyl]-benztropine and high resolution positron emission tomography (PET). [N-11C-methyl]-benztropine uptake was observed in frontal, parietal, occipital, and temporal cortices as well as in subcortical structures including the corpus striatum and thalamus. Uptake continued to increase in baboon and human brain in all areas over an 80 minute experimental period with the exception of the cerebellum where the accumulation of radioactivity began to decrease by 25 minutes postinjection. The ratio of incorporation of [N-11C-methyl]-benztropine between corpus striatum/cerebellum was 1.53 and 1.46 in humans and baboons, respectively, at 60 minutes. Blocking studies in baboons using the muscarinic cholinergic antagonists scopolamine and benztropine and the muscarinic cholinergic agonist pilocarpine combined with blocking studies in humans using benztropine indicate that the binding of this compound is specific for the muscarinic cholinergic system. Pretreatment with the potent dopamine reuptake blocker nomifensine produced no effect on the incorporation of radioactivity in any baboon brain region examined. Analysis of labelled plasma metabolites indicates that in humans, the rate of metabolism of [N-11C-methyl]-benztropine is slow (83.0% unchanged at 30 minutes postinjection) differing quite dramatically from the rate of metabolism observed in baboons (43.4% unchanged at 30 minutes postinjection). These data combined with postmortem studies in humans and primates demonstrate that [N-11C-methyl]-benztropine is a suitable muscarinic cholinergic ligand for use in humans and baboons with PET

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