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.

The role of single photon emission computed tomography brain imaging with 99mTc-bicisate in the localization and definition of mechanism of ischemic stroke.

99mTc-bicisate (99mTc-ECD) is a new brain perfusion imaging agent formulated from a radiochemically stable kit (Neurolite). A multicenter trial was conducted to determine the sensitivity and specificity of single photon emission computed tomography (SPECT) imaging with 99mTc-bicisate in the localization of ischemic stroke; 170 subjects were enrolled, 128 patients with stroke and 42 controls. Imaging results from 148 subjects (107 stroke patients and 41 controls) were considered evaluable. In the evaluable subjects, SPECT brain imaging with 99mTc-bicisate (21.0 +/- 2.5 mCi) was interpreted without clinical information and was compared with a final assessment using all clinical, diagnostic, and laboratory procedures except the 99mTc-bicisate SPECT results. 99mTc-bicisate was safe and well-tolerated. SPECT imaging with 99mTc-bicisate demonstrated a specificity of 98% and a sensitivity of 86% for localization of strokes (kappa, 0.75; 95% confidence interval, 0.64-0.86). Results were unchanged over time and were similar for all stroke mechanisms except for lacunar disease (sensitivity, 58%). In a secondary analysis, a normal image or small, deep (e.g., subcortical) perfusion defect was highly predictive of a lacunar mechanism. Defects involving the cortical surface were strongly associated with nonlacunar mechanisms. SPECT imaging with 99mTc-bicisate is a sensitive marker in the localization of perfusion defects associated with ischemic stroke and may assist in the determination of the underlying mechanism of a stroke.

Cerebral single-photon emission computed tomography abnormalities in human immunodeficiency virus type 1-infected gay men without cognitive impairment.

OBJECTIVE: To determine whether technetium Tc99m exametazime single-photon computed emission tomography (SPECT) can distinguish gay human immunodeficiency virus (HIV)-positive subjects, both with and without mild cognitive impairment, from gay HIV-negative control subjects. DESIGN: Twenty HIV-positive subjects (12 without cognitive impairment and eight with mild cognitive impairment) and 10 HIV-negative subjects underwent neurological, neuropsychological, magnetic resonance imaging, and technetium Tc 99m exametazime SPECT examinations. SETTING: Subjects were recruited from a natural history study of gay men with HIV infection. PATIENTS: Subjects from the cohort who had previously participated in a magnetic resonance imaging study were selected for the SPECT study. MAIN OUTCOME MEASURES: The SPECT scans were rated as abnormal if focal defects, confirmed by a horizontal profile analysis, were seen. RESULTS: Sixty-seven percent of HIV-positive subjects without cognitive impairment, 88% of HIV-positive subjects with mild cognitive impairment, and 20% of HIV-negative subjects had abnormal SPECT scans (P < .05 for both HIV-positive groups when each group was compared with HIV-negative subjects). CONCLUSION: Compared with gay HIV-negative control subjects, focal SPECT defects are seen with an increased frequency in HIV-positive gay men without cognitive impairment and in HIV-positive gay men with mild cognitive impairment.

A comparison of cerebral SPECT abnormalities in HIV-positive homosexual men with and without cognitive impairment.

OBJECTIVE: To determine whether technetium Tc 99m exametazime (HMPAO) single-photon emission computed tomography (SPECT) can distinguish between human immunodeficiency virus (HIV)-positive homosexual men with normal neuropsychologic test results and HIV-positive homosexual men with abnormal neuropsychologic test results. DESIGN: Neurologic, neuropsychologic, magnetic resonance imaging, and Tc 99m HMPAO SPECT examinations were performed on 10 HIV-positive homosexual men without cognitive impairment and five HIV-positive homosexual men with cognitive impairment. PATIENTS: Human immunodeficiency virus-positive homosexual men from New York City were recruited for the study. MAIN OUTCOME MEASURES: Findings on SPECT scans were evaluated qualitatively for focal defects, heterogeneity of the cortical margin, white matter hypoperfusion, and decreased global cortical uptake. All SPECT focal defects were coregistered with magnetic resonance images; SPECT heterogeneity and global cortical uptake were also measured quantitatively. RESULTS: Coregistration with magnetic resonance imaging revealed that 63% of the focal SPECT defects corresponded to brain gyri and 37% corresponded to sulci. There was no significant difference in the frequency of qualitative or quantitative SPECT abnormalities between HIV-positive homosexual men ith and without cognitive impairment. However, after examining individual neuropsychologic test factors, impaired motor speed performance was associated with decreased quantitative global cerebral uptake. CONCLUSIONS: Qualitative SPECT abnormalities are not increased in frequency in HIV-positive homosexual men with global cognitive impairment compared with those in HIV-positive homosexual men without cognitive impairment. Impaired motor speed performance may be associated with decreased quantitative global cerebral uptake.

SPECT liver imaging using an iterative attenuation correction algorithm and an external flood source.

The results obtained from the inclusion of a new intrinsic attenuation correction algorithm into a protocol for SPECT liver imaging are presented in this study. A total of six patients were evaluated with this protocol. The new algorithm uses a transmission tomographic acquisition that is obtained before a standard emission tomograph, and requires the use of an external flood source. The transmission tomograph results in an attenuation image, or map, of the patient. The attenuation map then serves as input into the final intrinsic correction algorithm, that also uses data from a standard emission acquisition. The results of the six patients studied show that the algorithm can correct for attenuation effects without degrading image quality. In all the cases studied, the attenuation corrected images made the cases easier to interpret than did the images obtained without attenuation correction.

A count-based algorithm for attenuation-corrected volume determination using data from an external flood source.

We discuss the basic features of a count-based algorithm for attenuation-corrected volume determination, for use with planar gamma camera images. The attenuation correction is arrived at by combining the results of two 180 degrees opposed images with a transmission image obtained with an external flood source. A sample of the imaged radioactive volume is used to convert the attenuation-corrected count to an absolute volume. The algorithm is best suited to the measurement of small to medium-sized volumes of uniform activity, such as are encountered in cardiac blood-pool imaging.

Single-photon emission computed tomography in human immunodeficiency virus encephalopathy: a preliminary report.

Depression or psychosis in a previously asymptomatic individual infected with the human immunodeficiency virus (HIV) may be psychogenic, related to brain involvement by the HIV or both. Although prognosis and treatment differ depending on etiology, computed tomography (CT) and magnetic resonance imaging (MRI) are usually unrevealing in early HIV encephalopathy and therefore cannot differentiate it from psychogenic conditions. Thirty of 32 patients (94%) with HIV encephalopathy had single-photon emission computed tomography (SPECT) findings that differed from the findings in 15 patients with non-HIV psychoses and 6 controls. SPECT showed multifocal cortical and subcortical areas of hypoperfusion. In 4 cases, cognitive improvement after 6-8 weeks of zidovudine (AZT) therapy was reflected in amelioration of SPECT findings. CT remained unchanged. SPECT may be a useful technique for the evaluation of HIV encephalopathy.

Cerebral SPECT imaging: effect on clinical management.

This study, performed in 94 consecutive patients referred for evaluation, demonstrates the clinical utility of cerebral SPECT imaging. In a significant percentage of patients (47%), the additional information provided by SPECT resulted in an alteration in clinical management. Long-term follow-up will be necessary to determine the effect of these management decisions on patient outcome.

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.

Colorectal cancer imaging with iodine-123-labeled CEA monoclonal antibody fragments.

This prospective, randomized multicenter study in 62 patients was designed to evaluate the efficacy and safety of radioimmunodetection (RAID) with 123I-labeled fragments, F(ab')2 and Fab', of IMMU-4, an anti-CEA monoclonal antibody (Immu-RAID-CEA). It was found that ImmuRAID-CEA was safe and disclosed colorectal cancer sites at least 1 cm in size. The positive predictive value by lesions was 77% initially, and increased to 91% after 7 mo of follow-up. Only one patient developed a low level of HAMA. In 17 patients with 32 surgically confirmed lesions, there were 9% true-positive lesions for CT when RAID was false-negative, and 22% for RAID when CT was false-negative. Either CT or RAID detected all 32 lesions. In this small series, therefore, RAID was shown to complement CT findings by confirming suspected tumors and disclosing new lesions which had previously been occult.

Functional brain imaging in the evaluation of psychiatric illness.

In the past century, the field of psychiatry has undergone major changes. During this time, significant advancements in both diagnosis and treatment have occurred. Medical brain imaging using structural and functional brain imaging techniques have contributed, in part, to a better basic understanding of psychiatric disease and to an improving diagnostic approach. Computed tomography and magnetic resonance imaging have supplied limited, but useful insight regarding structural alterations in schizophrenia and the affective disorders. Position emission tomography imaging has already made a major contribution in the assessment of schizophrenia and affective disorders. Single-photon emission computed tomography (SPECT), which is currently more widely available, should contribute more to psychiatric disease evaluation in the future. Recent advances in SPECT technology in the areas of improved instrumentation--such as multidetector and ring detector systems and new radiopharmaceuticals including new rCBF markers and receptor site imaging agents--have contributed to significant improvements in the SPECT imaging technique. At the present time, SPECT has been shown to be feasible and useful in the evaluation of acute and chronic psychiatric and demented states. As SPECT technology continues to evolve, further refinements in this diagnostic capability can be anticipated.

Interventions and functional brain imaging.

Assessment of regional cerebral blood flow (rCBF) is useful in the evaluation of cerebral vascular disease. However, a single resting study has limitations in that a normal rCBF may be present with diminished cerebral vascular flow reserve and regions of decreased rCBF may be seen with diaschisis or selective neuronal loss and an intact vascular supply. To help differentiate these conditions a stress rCBF study can be obtained following the administration of vasodilatory stimulus. The topic of this review is the discussion of single photon emission computed tomography (SPECT) and vascular intervention, primarily, acetazolamide (Diamox, Lederle Laboratory Division, Pearl River, NY) augmented SPECT in the evaluation of cerebral vascular disease.

Abdominal SPECT imaging.

Over the past several years, abdominal single photon emission computed tomography (SPECT) imaging has evolved from a research tool to an important clinical imaging modality that is helpful in the diagnostic assessment of a wide variety of disorders involving the abdominal viscera. Although liver-spleen imaging is the most popular of the abdominal SPECT procedures, blood pool imaging is becoming much more widely utilized for the evaluation of cavernous hemangiomas of the liver as well as other vascular abnormalities in the abdomen. Adjunctive indium leukocyte and gallium SPECT studies are also proving to be of value in the assessment of a variety of infectious and neoplastic diseases. As more experience is acquired in this area, SPECT should become the primary imaging modality for both gallium and indium white blood cells in many institutions. Renal SPECT, on the other hand, has only recently been used as a clinical imaging modality for the assessment of such parameters as renal depth and volume. The exact role of renal SPECT as a clinical tool is, therefore, yet to be determined.

Brain SPECT imaging and psychiatry.

To provide a basis for using neuroSPECT (single photon emission computerized tomography) in the evaluation of psychiatric disorders, this presentation will focus on recent developments in this field. Newer advances in cerebral SPECT instrumentation and radiopharmaceuticals and the potential impact on the evaluation of psychiatric patients will be discussed.

Spect brain imaging in neurologic disease.

In recent years cerebral SPECT imaging is rapidly evolving as a clinical tool in the evaluation of a variety of neurologic disorders. In large part, the major advances in brain imaging which have occurred in the last four years are related to new developments in instrumentation and radiopharmaceuticals. In particular, the increased availability of multidetector and dedicated ring detector systems has given rise to improved image resolution and more rapid patient throughput. Advances in the field of radiopharmaceutical development, particularly as it pertains to perfusion brain SPECT agents, has also contributed to the advances in the field. As a result of these developments, there has been an expanded interest in and use of brain SPECT imaging procedures in the evaluation of cerebrovascular disease, dementia, epilepsy, and head trauma.

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.

Diagnosis and monitoring of cerebral hyperfusion after carotid endarterectomy with single photon emission computed tomography: case report.

OBJECTIVE AND IMPORTANCE: Focal neurological deficits after carotid endarterectomy may result from ischemia or hyperperfusion. The usefulness of single photon emission computed tomography (SPECT) for differentiating between these two mechanisms has not been previously emphasized. CLINICAL PRESENTATION: An 83-year-old man experienced dysarthria and left-sided weakness immediately after undergoing endarterectomy of the right internal carotid artery. The results of computed tomography of the head were normal, and transcranial Doppler sonography showed symmetrically elevated velocities in both middle cerebral arteries. On the 1st postoperative day, the patient's deficits worsened in parallel with spontaneous increases in blood pressure, and blood pressure reduction with labetalol resulted in clinical improvement. INTERVENTION: On the 2nd postoperative day, technetium-99-hexametazime SPECT demonstrated markedly increased flow in the right basal ganglia and inferior frontal cortex, confirming the diagnosis of cerebral hyperperfusion. The patient's deficits continued to improve with antihypertensive therapy, and SPECT performed 7 and 48 days after surgery showed gradual normalization of the focal hyperemia. CONCLUSION: SPECT can be used to diagnose and monitor cerebral hyperperfusion after carotid endarterectomy and may be of particular value for differentiating hyperperfusion from ischemia when characteristic computed tomographic and transcranial Doppler sonographic findings are absent.

In vivo biodistribution of a radiotracer for imaging serotonin-1A receptor sites with PET:[11C]LY274601.

LY274601 [R-(+)8-thiomethyl-2-(di-n-propyl-amino)tetralin], a full agonist of the 5-HT1A receptor with high affinity and selectivity, was labeled with 11C and 3H, and its in vivo behavior was studied to evaluate [11C]LY274601 as a PET radiotracer for imaging 5-HT1A receptor sites in living brain. Following intravenous tail injection into mice, [11C]LY274601 showed high blood-brain barrier permeability and accumulated in regions known to have high densities of 5-HT1A receptor sites such as the brain stem including the raphe nuclei. The binding of the radiotracer in target tissues is blocked by pre-injection of the 5-HT1A receptor selective ligand 8-OH-DPAT (1 mg/kg, s.c.), suggesting that the binding is specific to 5-HT1A receptor sites. Using ex vivo autoradiography, the target tissues such as hippocampus CA1-4 fields, piriform cortex, dorsal raphe nucleus and lateral septum were visualized as hot spots. These tissues were observed to have binding 2-2.7 times greater than the cerebellum. The distribution of the radiotracer agrees well with the distribution of 5-HT1A receptors revealed by in vitro autoradiography with [3H]8-OH-DPAT. However, the radiotracer was metabolized quickly and cleared from target tissues with a half life of approximately 15 min. [11C]LY274601 showed high non-specific binding in regions with low number of 5-HT1A receptor sites such as cerebellum.

The role of SPECT brain imaging in assessing psychopathology in the medically ill.

Cerebral single photon emission computed tomography (SPECT), a method of functional brain imaging, measures cerebral blood flow and metabolism. This paper describes the imaging procedure and several cases where cerebral SPECT was of use in the differential diagnosis of medically ill patients who also presented with psychopathology. SPECT patterns in cerebrovascular disease, dementia, focal epilepsy, and AIDS are at present the best described and seem to be the most specific. Often changes in regional cerebral blood flow are seen before structural changes become apparent on CT or MRI. Cerebral SPECT can add valuable diagnostic information in assessing psychopathology in the medically ill and can often lead to changes in treatment.

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.