Impairment of nonverbal recognition in Alzheimer disease: a PET O-15 study.

OBJECTIVE: To characterize deficits in nonverbal recognition memory and functional brain changes associated with these deficits in Alzheimer disease (AD). METHODS: Using O-15 PET, we studied 11 patients with AD and 17 cognitively intact elders during the combined encoding and retrieval periods of a nonverbal recognition task. Both task conditions involved recognition of line drawings of abstract shapes. In both conditions, subjects were first presented a list of shapes as study items, and then a list as test items, containing items from the study list and foils. In the titrated demand condition, the shape study list size (SLS) was adjusted prior to imaging so that each subject performed at approximately 75% recognition accuracy; difficulty during PET scanning in this condition was approximately matched across subjects. A control task was used in which SLS = 1 shape. RESULTS: During performance of the titrated demand condition, SLS averaged 4.55 (+/-1.86) shapes for patients with AD and 7.53 (+/-4.81) for healthy elderly subjects (p = 0.031). However, both groups of subjects were closely matched on performance in the titrated demand condition during PET scanning with 72.17% (+/-7.98%) correct for patients with AD and 72.25% (+/-7.03%) for elders (p = 0.979). PET results demonstrated that patients with AD showed greater mean differences between the titrated demand condition and control in areas including the left fusiform and inferior frontal regions (Brodmann areas 19 and 45). CONCLUSIONS: Relative fusiform and inferior frontal differences may reflect the Alzheimer disease (AD) patients' compensatory engagement of alternate brain regions. The strategy used by patients with AD is likely to be a general mechanism of compensation, rather than task-specific.

rCBF/SPECT in the evaluation of inner-city minority patients with a history of impaired memory: a pilot blind read pre- and poststudy.

Eight patients (seven women), mean +/- SD T1 age 68.57 +/- 12.43 years, average educational level 5.83 +/- 3.70 years, had two Tc-99m ECD SPECT examinations separated by an average 8.49 +/- 5.59 months. Patients were imaged using standard Harlem Hospital acquisition and processing protocols with approximately 30 mCi of ECD on a Prism 3000 triple head gamma camera. Images were interpreted by an independent reader blinded to the patients' clinical history and imaging date. T1 psychiatric diagnosis was seven Alzheimer's dementia (AD) and one depression. Eight T1 images were interpreted as abnormal, six indicative of AD. Binomial 95% two-tail confidence interval for T1 agreement between diagnosis and interpretation was 0.25 0.63 0.92. T2 diagnosis was seven AD and one none. Seven T2 images were abnormal and indicative of AD, and one was normal. T2 confidence interval was 0.34 0.75 0.97. These findings suggest SPECT's value in assessing AD in uneducated socioeconomically disadvantaged geriatric patients.

Single photon emission CT and positron emission tomography in the evaluation of neurologic disease.

Widely available SPECT allows imaging of certain critical components of neurotransmission, providing clinically and experimentally significant information. Future efforts may be directed toward developing innovative techniques to delineate dynamic neurochemical changes in vivo.

Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression.

BACKGROUND: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D(2) receptor availability and amphetamine-induced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. METHODS: The striatal equilibrium specific to nonspecific partition coefficient (V(3)") of the D(2) receptor antagonist [(123)I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. RESULTS: No significant differences were observed in preamphetamine D(2) receptor availability between depressed patients (0.73 +/- 0.08) and control subjects (0.78 +/- 0.10, p =.23). Amphetamine-induced reduction in [(123)I]IBZM V(3)" (DeltaV(3)") was similar in depressed patients (-9.8 +/- 5.5%) and control subjects (-7.8 +/- 2.5%, p =.32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [(123)I]IBZM DeltaV(3)". CONCLUSIONS: This study did not replicate previously reported alterations in striatal D(2) receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.

Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum.

Dopamine transmission in the ventral striatum (VST), a structure which includes the nucleus accumbens, ventral caudate, and ventral putamen, plays a critical role in the pathophysiology of psychotic states and in the reinforcing effects of virtually all drugs of abuse. The aim of this study was to assess the accuracy and precision of measurements of D(2) receptor availability in the VST obtained with positron emission tomography on the high-resolution ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, TN, U.S.A.). A method was developed for identification of the boundaries of the VST on coregistered high-resolution magnetic resonance imaging scans. Specific-to-nonspecific partition coefficient (V(3)") and binding potential (BP) of [(11)C]raclopride were measured twice in 10 subjects, using the bolus plus constant infusion method. [(11)C]Raclopride V(3)" in the VST (1.86 +/- 0.29) was significantly lower than in the dorsal caudate (DCA, 2.33 +/- 0.28) and dorsal putamen (DPU, 2.99 +/- 0.26), an observation consistent with postmortem studies. The reproducibility of V(3)" and BP were appropriate and similar in VST (V(3)" test-retest variability of 8.2% +/- 6.2%, intraclass correlation coefficient = 0.83), DCA (7.7% +/- 5.1%, 0.77), DPU (6.0% +/- 4.1%, 0.71), and striatum as a whole (6.3% +/- 4.1%, 0.78). Partial volume effects analysis revealed that activities in the VST were significantly contaminated by counts spilling over from the adjacent DCA and DPU: 70% +/- 5% of the specific binding measured in the VST originated from D(2) receptors located in the VST, whereas 12% +/- 3% and 18% +/- 3% were contributed by D(2) receptors in the DCA and DPU, respectively. Thus, accuracy of D(2) receptor measurement is improved by correction for partial voluming effects. The demonstration of an appropriate accuracy and precision of D(2) receptor measurement with [(11)C]raclopride in the VST is the first critical step toward the use of this ligand in the study of synaptic dopamine transmission at D(2) receptors in the VST using endogenous competition techniques.

The role of nuclear medicine in the evaluation of pancreatic disease.

F-18 FDG PET in patients with nonendocrine pancreatic cancer and somatostatin receptor imaging in patients with endocrine pancreatic cancer have an important role in detecting or confirming the presence of a mass in the pancreas--a crucial step in the management of these patients. Both agents also have an important role in staging and in defining which patients are good candidates for resection surgery. Somatostatin receptor imaging also has a crucial role in selecting from the various systemic therapeutic options available. I-131 MIBG therapy can be of value therapeutically, mostly palliative, in patients who demonstrate a markedly elevated concentration of tumor radioactivity.

SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study.

OBJECTIVE: Numerous studies have suggested that temporoparietal hypoperfusion seen on brain imaging with SPECT may be useful in diagnosing AD during life. However, these studies have often been limited by lack of pathologic validation and unrepresentative samples. The authors performed this study to determine whether SPECT imaging provides diagnostically useful information in addition to that obtained from a clinical examination. METHODS: Clinical data and SPECT images were collected prospectively, and patients were followed to autopsy. Clinical history, pathologic findings, and SPECT images were each evaluated by raters blind to other features, and clinical and SPECT diagnoses were compared with pathologic diagnoses. The study population consisted of 70 patients with dementia, followed to autopsy; 14 controls followed to autopsy; and 71 controls (no autopsy performed). The primary outcome was the likelihood of a pathologic diagnosis of AD given a positive clinical diagnosis, a positive SPECT diagnosis, and both. RESULTS: When all participants (patients and controls) were included in the analysis, the clinical diagnosis of "probable" AD was associated with an 84% likelihood of pathologic AD. A positive SPECT scan raised the likelihood of AD to 92%, whereas a negative SPECT scan lowered the likelihood to 70%. SPECT was more useful when the clinical diagnosis was "possible" AD, with the likelihood of 67% without SPECT, 84% with a positive SPECT, and 52% with a negative SPECT. Similar results were found when only patients with dementia were included in the analysis. CONCLUSIONS: In the evaluation of dementia, SPECT imaging can provide clinically useful information indicating the presence of AD in addition to the information that is obtained from clinical evaluation.

Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans.

Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT(1A) receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [11C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 +/- 29% on scan 2, 38 +/- 26% on scan 3, and 64 +/- 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 +/- 5% on scan 2, 12 +/- 3% on scan 3, and 42 +/- 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT(1A) autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT(1A) agents in this application.

Schizophrenia subgroups differing in dichotic listening laterality also differ in neurometabolism and symptomatology.

Schizophrenia patients vary in right ear advantage (REA) on dichotic listening tests for assessing left hemispheric dominance for language processing. The authors examined if patients with low REA differed from other patients in symptoms and in resting brain metabolism. SPECT was conducted during visual fixation for 9 healthy control subjects and 16 schizophrenia patients: 8 with normal and 8 with diminished REA. REA-diminished patients had greater positive symptoms and lower mental status scores (all P<0.05) and had right middle temporal gyrus hypermetabolism. Both schizophrenia groups had decreased right frontal and increased medial temporal lobe metabolism vs. control subjects. REA-diminished patients had right temporal lobe hypermetabolism under a resting condition (eyes open, visual fixation). Results suggest reduced right ear (left hemisphere) advantage for dichotic word perception in schizophrenia is related to a predisposition to overactivate right temporal lobe regions and to positive symptoms. In contrast, the prefrontal-medial temporal imbalance present in both patient groups may typify the schizophrenia syndrome.

Different brain networks mediate task performance in normal aging and AD: defining compensation.

OBJECTIVE: To determine whether the pathologic mechanisms of AD alter the brain networks subserving performance of a verbal recognition task. BACKGROUND: Functional imaging studies comparing task-related activation in AD patients and controls generally have not used network analysis and have not controlled for task difficulty. METHODS: H2 15O PET was used to measure regional cerebral blood flow in 14 patients and 11 healthy elders during the performance of a serial verbal recognition task under two conditions: low demand, with study list size (SLS) equal to one; and titrated demand, with SLS adjusted so that each subject recognized words at 75% accuracy. The Scaled Subprofile Model was used to identify networks of regionally covarying activity across these task conditions. RESULTS: In the elders, higher SLS was associated with the recruitment of a network of brain areas involving left anterior cingulate and anterior insula (R2 = 0.94; p < 0.0001). Three patients also expressed this network. In the remaining patients, higher SLS was associated with the recruitment of an alternate network consisting of left posterior temporal cortex, calcarine cortex, posterior cingulate, and the vermis (R2 = 0.81, p < 0.001). Expression of this network was unrelated to SLS in the elders and more intact AD patients. CONCLUSIONS: The patients' use of the alternate network may indicate compensation for processing deficits. The transition from the normal to the alternate network may indicate a point where brain disease has irreversibly altered brain function and thus may have important implications for therapeutic intervention.

Regional cerebral blood flow in mood disorders, V.: Effects of antidepressant medication in late-life depression.

Twenty elderly outpatients with major depression were treated with either nortriptyline or sertraline. Resting regional cerebral blood flow (rCBF) was assessed by the planar (133)Xenon inhalation technique after a medication washout and following 6- 9 weeks of antidepressant treatment. At baseline, the depressed sample had reduced rCBF in frontal cortical regions when compared with 20 matched normal-control subjects. After treatment, Responders and Nonresponders differed in the expression of a specific topographic alteration, with Responders manifesting reduced perfusion in frontal regions. These findings are consistent with this group's previous report of reduced rCBF after response to electroconvulsive therapy (ECT) and suggest a common mechanism of action.

Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia.

BACKGROUND: Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans. METHODS: In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM. RESULTS: Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023). CONCLUSIONS: The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.

In vivo quantification of brain serotonin transporters in humans using [11C]McN 5652.

UNLABELLED: Abnormal brain regional densities of serotonin (5-hydroxytryptamine [5-HT]) transporters have been reported in postmortem studies in several neuropsychiatric conditions, such as major depression and schizophrenia. trans-1,2,3,5,6,10-beta-Hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]-isoquinoline ([11C]McN 5652) is the first PET radioligand successfully developed to label 5-HT transporters in the living human brain. The purpose of this study was to develop an imaging protocol and analytic method to measure regional 5-HT transporter binding potential (BP) with [11C]McN 5652 in humans. METHODS: The arterial input function and brain uptake of (+)-[11C]McN 5652 and (-)-[11C]McN 5652, the active and inactive enantiomers, respectively, were measured in 6 healthy volunteers. RESULTS: (+)-[11C]McN 5652 concentrated in brain regions rich in 5-HT transporters (midbrain, thalamus, basal ganglia, and medial temporal lobe structures), whereas the uptake of (-)-[11C]McN 5652 was more uniformly distributed. Total distribution volumes (V(T)) were derived using kinetic 2-compartment analysis and graphic analysis. V(T) derived by both methods were highly correlated. (+)-[11C]McN 5652 regional V(T) ranged from 18 +/- 2 mL/g in the cerebellum to 46 +/- 13 mL/g in the midbrain. (-)-[11C]McN 5652 regional VT ranged from 10 +/- 2 mL/g in the cerebellum to 14 +/- 3 mL/g in the thalamus. (+)-[11C]McN 5652 V(T) were higher than (-)-[11C]McN 5652 V(T) in all regions, including the cerebellum, a region devoid of 5-HT transporters. Blocking experiments were also performed in baboons with saturating doses of citalopram and in humans with nonsaturating doses of paroxetine. Cerebellar and neocortical (+)-[11C]McN 5652 V(T) were unaffected by pretreatment with 5-HT transporter blockers. In areas of high receptor concentration (midbrain, caudate, and thalamus) 5-HT transporter blockers decreased (+)-[11C]McN 5652 V(T) to the level of cerebellum (+)-[11C]McN 5652 V(T). CONCLUSION: These experiments indicate that the use of the difference between (+)- and (-)-[11C]McN 5652 V(T) to define specific binding to 5-HT transporters leads to an overestimation of specific binding. 5-HT transporter BP was derived as the difference between the regional and cerebellar (+)-[11C]McN 5652 V(T). BP values were in good agreement with the distribution of 5-HT transporters in the human brain, except for regions of relatively low 5-HT transporter concentration, such as the prefrontal cortex, where no specific binding was detected using (+)-[11C]McN 5652. (+)-[11C]McN 5652 is an appropriate radiotracer to quantify 5-HT transporters in regions with relatively high concentration of 5-HT transporters, such as the midbrain, thalamus, and basal ganglia, and should prove useful in elucidating abnormalities of 5-HT transmission in neuropsychiatric conditions.

Positron emission tomography study of pindolol occupancy of 5-HT(1A) receptors in humans: preliminary analyses.

Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT(1A) receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT(1A) antagonist [carbonyl-(11)C]WAY-100635 or [carbonyl-(11)C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexa necarboxamide abbreviated as [(11)C]WAY-100635. Pindolol dose-dependently decreased [(11)C]WAY-100635 BP. Combining all the regions, occupancy was 20 +/- 8% at scan 2, 14 +/- 8% at scan 3, and 44 +/- 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT(1A) receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT(1A) receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT(1A) autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT(1A) agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.

Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-11C]WAY-100635 in humans: comparison of arterial and reference tisssue input functions.

Serotonin 5-HT(1A) receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT(1A) receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-(11)C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT(1A) receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT(1A) receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 +/- 0.14 (mean +/- SD of 15 regions) and 0.84 +/- 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 +/- 0.28, 0.47 +/- 0.28, and 0.55 +/- 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test-retest reproducibility, lower vulnerability to experimental noise, and absence of bias.

Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.

The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D(2) receptor. We measured in vivo occupancy of striatal D(2) receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D(2) receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (19% +/- 11%) compared with control subjects (9% +/- 7%, P = 0.003). The increased occupancy of D(2) receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D(2) receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.

Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans: validation and reproducibility.

To evaluate the postulated role of extrastriatal D1 receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [11C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D1 receptor. The goal of this study was to develop and evaluate methods to derive D1 receptor parameters in striatal and extrastriatal regions of the human brain with [11C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k3/k4). Both kinetic and graphic analyses provided BP and k3/k4 values in good agreement with the known distribution of D1 receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k3/k4 by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90+/-0.06 (mean +/- SD of 12 regions) and 0.84+/-0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72+/-0.17 and 0.58+/-0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [11C]NNC 112 uptake provides an appropriate method with which to derive D1 receptor parameters in regions with both high (striatal) and low (extrastriatal) D1 receptor density.

SPECT study of visual fixation in schizophrenia and comparison subjects.

BACKGROUND: The consistent association of impaired eye movements and schizophrenia suggests a relationship between the neurobiology of the illness and visual pursuit systems. Visual fixation (VF), an eye "movement" task at zero velocity, is the simplest such abnormality in schizophrenia patients and their relatives. METHODS: We used a VF task for a functional imaging study. Six neuroleptic-free schizophrenia patients and eight gender and mean age matched comparison subjects had SPECT scans with 20 mCi of Tc99-HMPAO, during VF on a simple blue line intersection. MEDX data saved in ANALYZE format for SPM 95 was used to generate paired t-test statistical data for display in Talairach space, with rCBF changes given as Z-scores. RESULTS: Patients, compared to controls, had increased rCBF in both the parahippocampal gyrus (bilaterally) and in the right fusiform gyrus. They had decreased rCBF in the left frontal cortex, including medial and superior frontal gyri and anterior cingulate. Overall, compared to controls, patients had medial temporal lobe hyperperfusion along with left prefrontal hypoperfusion. CONCLUSIONS: These findings are consistent with the hypothesized imbalance between the medial temporal and frontal lobes that is postulated for schizophrenia. It was of interest that the relative rCBF differences between schizophrenia patients and controls in this small sample were observable with this cognitively non-demanding visual fixation task.

PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756.

NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.