Can nitrogen-13 ammonia kinetic modeling define myocardial viability independent of fluorine-18 fluorodeoxyglucose?

OBJECTIVES: The hypothesis of this study was that evaluation of myocardial flow and metabolism using nitrogen-13 (N-13) ammonia kinetic modeling with dynamic positron emission tomographic (PET) imaging could identify regions of myocardial scar and viable myocardium as defined by fluorine-18 fluorodeoxyglucose (F-18 FDG) PET. BACKGROUND: Uptake of most perfusion tracers depends on both perfusion and metabolic retention in tissue. This characteristic has limited their ability to differentiate myocardial scar from viable tissue. The kinetic modeling of N-13 ammonia permits quantification of blood flow and separation of the metabolic component of its uptake, which may permit differentiation of scar from viable tissue. METHODS: Sixteen patients, > 3 months after myocardial infarction, underwent dynamic N-13 ammonia and F-18 FDG PET imaging. Regions of reduced and normal perfusion were defined on static N-13 ammonia images. Patients were classified into two groups (group I [ischemic viable], n = 6; group II [scar], n = 10) on the basis of percent of maximal F-18 FDG uptake in hypoperfused segments. Nitrogen-13 ammonia kinetic modeling was applied to dynamic PET data, and rate constants were determined. Flow was defined by K1; volume of distribution (VD = K1/k2) of N-13 ammonia was used as an indirect indication of metabolic retention. RESULTS: Fluorine-18 FDG uptake was reduced in patients with scar compared with normal patients with ischemic viable zones (ischemic viable 93 +/- 27% [mean +/- SD]; scar 37 +/- 16%, p < or = 0.01). Using N-13 ammonia kinetic modeling, flow and VD were reduced in the hypoperfused regions of patients with scar (ischemic viable flow: 0.65 +/- 0.20 ml/min per g, scar: 0.36 +/- 0.16 ml/min per g, p < or = 0.01; VD: 3.9 +/- 1.3 and 2.0 +/- 1.07 ml/g, respectively, p < or = 0.01). For detection of viable myocardium in these patients, the sensitivity and specificity were 100% and 80% for N-13 ammonia PET flow > 0.45 ml/min per g; 100% and 70% for VD > 2.0 ml/g; and 100% and 90% for both flow > 0.45 ml/min per g and VD > 2.0 ml/g, respectively. The positive and negative predictive values for the latter approach were 86% and 100%, respectively. CONCLUSIONS: In this cohort, patients having regions with flow < or = 0.45 ml/min per g or VD < or = 2.0 ml/g had scar. Viable myocardium had both flow > 0.45 ml/min per g and VD > 2.0 ml/g. Nitrogen-13 ammonia kinetic modeling permits determination of blood flow and metabolic integrity in patients with previous myocardial infarction and can help differentiate between scar and ischemic but viable myocardium.

Regional distribution and kinetics of [18F]6-flurodopamine as a measure of cardiac sympathetic activity in humans.

OBJECTIVES: To determine whether an increase in cardiac sympathetic activity produced by exercise or sublingual glyceryl trinitrate causes an increased rate of loss of fluorine-18 from the myocardium after intravenous [18F]6-fluorodopamine ([18F]F-DA) in normal volunteers. In addition, to determine the contribution of non-specific uptake of [18F]F-DA in the myocardium in patients with recent heart transplant. PROTOCOL: [18F]F was prepared by direct electrophilic fluorination of dopamine. Nine healthy volunteers each received 1.85 x 10(8) Bq (168-250 micrograms) [18F]F-DA over a period of 3 min and were scanned for 2 h in an ECAT 953/31 tomograph. Three controls were scanned before and after vigorous cycle exercise and two were scanned before and after sublingual glyceryl trinitrate. In addition, two patients (1 and 2 years post-heart transplant) underwent a myocardial perfusion study with ammonia labelled with nitrogen-13 followed by an [18F]F-DA study. RESULTS: There was intense uniform uptake of [18F]F-DA throughout the myocardium in the healthy volunteers. The time course of 18F in the myocardium under resting conditions fitted a biexponential function with mean half-times of 8.0 and 109 min. Vigorous exercise produced a three to fivefold increase in the rate of loss of 18F compared with that when resting. After glyceryl trinitrate, one control had a profound reduction in blood pressure (23%) and twofold increase in the rate of loss of myocardial 18F. The other control had no physiologically significant change in blood pressure, heart rate, or rate of loss of myocardial 18F. Uptake of [18F]F-DA in the two posttransplant patients was confined to a small anterobasal region adjacent to the atrioventricular groove, while blood flow, as measured with [13N] ammonia, was uniformly distributed throughout the myocardium. Partial reinnervation of the myocardium was confirmed by the presence of distinct low frequency spectral peaks of the heart rate power spectrum in both patients. CONCLUSIONS: These results suggest that the uptake of [18F]F-DA reflects the distribution of cardiac sympathetic innervation and that the rate of loss of 18F from the myocardium partially reflects spill over of noradrenaline. The technique may be useful in investigating various cardiac conditions in which the sympathetic system is compromised.

A probe for intracerebral aromatic amino-acid decarboxylase activity: distribution and kinetics of [18F]6-fluoro-L-m-tyrosine in the human brain.

Positron tomography, using [18F]6-fluoro-L-dopa as a tracer, has been used for the study of Parkinson's disease. Unfortunately, the analysis of data obtained with this agent is bedeviled because it readily forms labeled methylated metabolites that enter the brain. We have evaluated [18F]6-fluoro-L-m-tyrosine (FmT) as an alternative tracer to study intracerebral dopamine metabolism with positron tomography. Imaging studies in humans showed specific accumulation of this tracer in the dopamine-rich striatal regions. Reduced striatal uptake of the tracer was demonstrated in a patient suffering from Parkinson's disease. Increased retention of the tracer was demonstrated in a subject pretreated with the peripheral decarboxylase inhibitor carbidopa. Analysis of plasma samples for labeled metabolites of FmT revealed no methylated metabolites. Results of compartmental analysis showed that a two-compartment three rate constant model described adequately the time course of radioactivity in the striatum after an injection of FmT. The FmT decarboxylation rate constant (k21) was found to be 0.0108 min-1. Because the peripheral metabolism of FmT is simpler than that of [18F]6-fluoro-L-dopa, we propose FmT as a superior agent with which to study intracerebral dopamine metabolism in health and disease in humans.

Redistribution of myocardial blood flow with topical nitroglycerin in patients with coronary artery disease.

BACKGROUND: Unlike nonselective coronary vasodilators, nitroglycerin (GTN) is said to exert its primary vasodilatory effect on epicardial conductance vessels. Thus, in experimental models of coronary occlusion GTN appears to preferentially direct blood flow to poststenotic zones of ischemia. This phenomenon has, to date, not been tested in humans. Using positron emission tomography we examined the effect of transdermal GTN on global and regional myocardial perfusion in patients with angiographically proven coronary artery disease. METHODS AND RESULTS: Myocardial perfusion with [13N]ammonia was estimated from dynamic time-activity curves at baseline and 3 hours following application of either a 0.4 mg/h GTN skin patch (n = 10) or a placebo patch (n = 10) in a double-blind parallel design. From resliced cross-sectional images, regional flow, expressed as [13N]ammonia retention, was estimated from 216 myocardial sectors. Ischemia was defined as a significant reduction (> 2 SDs from average counts/pixel in maximally perfused zones) in [13N]ammonia retention within 10 contiguous myocardial sectors coupled with an increase or no change in counts derived from [18F]fluorodeoxyglucose. There was no change in global myocardial blood flow as expressed by [13N]ammonia retention following either placebo (0.61 +/- 0.14 to 0.62 +/- 0.12 min-1) or GTN (0.75 +/- 0.22 to 0.74 +/- 0.19 min-1). Conversely, there was a significant increase in the proportion of blood flow to the ischemic zones with GTN (73.9 +/- 12.6% to 94.9 +/- 17.8%; P < .05). No change in the distribution of blood flow to either ischemic or nonischemic zones was observed with placebo. A slight but insignificant decrease in [13N]ammonia retention in nonischemic zones was observed with GTN (1.01 +/- 0.31 to 0.93 +/- 0.26 min-1). CONCLUSIONS: This study suggests that under resting conditions topical GTN alters myocardial perfusion by preferentially increasing flow to areas of reduced perfusion with little or no change in global myocardial perfusion in patients whose angina is responsive to GTN.

Electrophilic 18F from a Siemens 11 MeV proton-only cyclotron.

Because more and more PET centres are using small proton cyclotrons there is a renewed interest in methods for the production of electrophilic 18F by proton irradiation of [18O]O2. A method for the routine production of clinically useful quantities of [18F]F2 having a specific activity of 35 Ci/mmol has been developed and implemented using an 11 MeV proton cyclotron and [18O]O2. Based on the yield, purity, reproducibility, and specific activity of [18F]F2 this is the most efficient method reported thus far.

The distribution and kinetics of [18F]6-fluoro-3-O-methyl-L-dopa in the human brain.

The analysis of positron tomographic studies of 3,4-dihydroxyphenylethylamine (dopamine) metabolism in which [18F]6-fluoro-L-3,4-dihydroxyphenylalanine (F-dopa) is used as a tracer is confounded by the presence of [18F]6-fluoro-3-O-methyl-L-3,4-dihydroxyphenylalanine (OMFD). This labeled molecule, formed by the action of peripheral catechol-O-methyltransferase on F-dopa, crosses the blood-brain barrier and contributes to the radioactivity measured by the tomograph. Corrections for this radioactivity in the brain have been proposed. They rely upon the assumption that regional variations in the handling of this molecule by the brain are negligible. Although this assumption is pivotal for the proper quantification of dopamine metabolism using F-dopa, the distribution and kinetics of OMFD have never been studied in humans. We present results in humans that show that there is little selective regional 18F accumulation in the brain, that the distribution volume of OMFD is close to unity, and that a single, reversible compartment is adequate to model the measured time course of radioactivity after an OMFD injection. Analysis of plasma samples for labeled metabolites showed that more than 95% of the radioactivity was associated with OMFD at all times. Our results for OMFD kinetics are in accord with published results obtained in nonhuman primates and for the bidirectional transport of large neutral amino acids across the blood-brain barrier measured using a synthetic amino acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Three clinical syndromes of schizophrenia in untreated subjects: relation to brain glucose activity measured by positron emission tomography (PET).

A number of studies of chronically ill, medicated patients have found that the clinical symptoms of schizophrenia segregate into three syndromes which can be labelled poverty, disorganization, and reality distortion. It has been previously found that each of these syndromes is associated with a specific pattern of perfusion (rCBF) in paralimbic and association cortex and in related subcortical nuclei. We replicated the symptom factors in 20 untreated subjects. Utilizing positron emission tomography with 18-F-fluorodeoxyglucose as a tracer for glucose metabolism, we reconstructed a map of the entire cortical activity from 16 to 20 tomographic slices. Each of the three syndromes was associated with a different pattern of regional glucose metabolism. Findings in common with previous studies were an association of poverty with left cortical metabolic activity in prefrontal and superior parietal areas, reality distortion with left temporal activity, and disorganization with left inferior parietal lobule. This is the first report of an association between regional metabolic activity and clinical syndromes in untreated patients, strengthening previous models of distributed neural networks in this disorder.

Fluctuating cognitive abnormalities and cerebral glucose metabolism in neuropsychiatric systemic lupus erythematosus.

Brain imaging techniques such as MRI and PET have the potential for identifying central nervous system involvement in SLE. They may also help elucidate the mechanisms giving rise to the widely diverging manifestations of CNS involvement in SLE. This report documents an intensive longitudinal study of three women with neuropsychiatric SLE. PET and neuropsychological evaluation were both used to examine the co-occurrence of behavioural/cognitive deficits with alterations in regional brain glucose metabolism. In all three patients, FDG uptake indicated abnormalities which were not identified on CT scan, but corresponded well with localisable cognitive deficits. Changes in each patient's cognitive profile on reassessment paralleled changes on PET. These findings support the suggestion that cognitive deficits in SLE patients reflect primary CNS involvement.

Toward a brain map of auditory hallucinations.

OBJECTIVE: This study asks whether auditory hallucinations are reflected in a distinctive metabolic map of the brain. METHOD: Regional brain metabolism was measured by positron emission tomography with [18F]-fluorodeoxyglucose in 12 DSM-III schizophrenic patients who experienced auditory hallucinations during glucose uptake and 10 who did not. All patients were free of neuroleptics and 19 had never been treated with neuroleptics. Nine patients were reexamined after 1 year to assess effects of neuroleptic treatment. RESULTS: Compared with the patients who did not experience hallucinations, the patients who did experience hallucinations had significantly lower relative metabolism in auditory and Wernicke's regions and a trend toward higher metabolism in the right hemisphere homologue of Broca's region. Hallucination scores correlated positively and significantly with relative metabolism in the striatum and anterior cingulate regions. Neuroleptic treatment resulted in a significant increase in striatal metabolism and a reduced frontal-parietal ratio, which was significantly correlated with a decrease in hallucination scores. CONCLUSIONS: Auditory hallucinations involve language regions of the cortex in a pattern similar to that seen in normal subjects listening to their own voices but different in that left prefrontal regions are not activated. The striatum plays a critical role in auditory hallucinations.

Apomorphine effects on brain metabolism in neuroleptic-naive schizophrenic patients.

Since neuroleptic treatment produces a significant increase in striatal metabolism relative to cortical metabolism, we wished to determine whether the dopamine agonist apomorphine (APO) might have the opposite effect, and whether it would discriminate schizophrenic patients from healthy controls. Eleven neuroleptic-naive schizophrenic patients (diagnosed according to DSM-III) and eight normal subjects were compared with respect to cerebral accumulation of 18F-fluorodeoxyglucose measured by positron emission tomography following APO, 0.75 mg/70 kg (weight adjusted), or saline. Relative striatal glucose metabolism decreased significantly after APO in schizophrenic patients but not in control subjects. Post hoc analysis of data in 12 other regions revealed that relative superior temporal metabolism decreased very slightly, but significantly, in schizophrenic patients but not in control subjects after APO, and that the posterior frontal region increased in control subjects but not in the patient group.

Posterior cortical dementia with alexia: neurobehavioural, MRI, and PET findings.

A progressive disorder of relatively focal but asymmetric biposterior dysfunction is described in a 54 year old right handed male. Initial clinical features included letter-by-letter alexia, visual anomia, acalculia, mild agraphia, constructional apraxia, and visuospatial compromise. Serial testing demonstrated relentless deterioration with additional development of transcortical sensory aphasia, Gerstmann's tetrad, and severe visuoperceptual impairment. Amnesia was not an early clinical feature. Judgment, personality, insight, and awareness remained preserved throughout most of the clinical course. Extinction in the right visual field to bilateral stimulation was the sole neurological abnormality. Early CT was normal and late MRI showed asymmetrical bioccipitoparietal atrophy with greater involvement of the left hemisphere. Results from positron emission tomography (PET) showed bilaterally asymmetric (left greater than right) occipitotemporoparietal hypometabolism. The metabolic decrement was strikingly asymmetric with a 50% reduction in glucose consumption confined to the left occipital cortex. The picture of occipitotemporoparietal compromise verified by MRI, PET, and neurobehavioural testing would be unusual for such degenerative dementias as Alzheimer's (AD) and Pick's disease, although atypical AD with predominant occipital lobe involvement cannot be excluded. This case supports the concepts of posterior cortical dementia (PCD) as a clinically distinct entity and for the first time documents its corresponding metabolic deficit using PET.

Regional brain metabolism during auditory hallucinations in chronic schizophrenia.

Regions of the brain involved in language and attention were studied using [18F]-fluorodeoxy-glucose in PET. In nine chronic DSM-III schizophrenic patients who had persistent auditory hallucinations, ten who had recovered from hallucinations and ten normal controls. In none of the regions examined was metabolic activity significantly different in hallucinating patients compared with that in other groups. However, a pattern of seven significant correlations of metabolic activity between language regions and between frontal and parietal cortex characterised the hallucinating but not the other groups. Three of the seven correlations were significantly greater in hallucinating patients than in the two other groups, and six were greater in hallucinating patients than controls. Metabolism in Broca's region and its right-hemisphere homologue correlated positively and significantly in the hallucinating group, as it did in anterior cingulate and left superior temporal areas, and in right frontal and parietal areas. Hallucination ratings correlated with metabolism in the anterior cingulate region.

New 18F tracers for the investigation of brain functions.

Advances in the synthetic methodology of radiofluorination have increased the number of clinically useful 18F labeled tracers for positron emission tomography of the brain. It is now possible to measure in vivo with 18F tracers regional cerebral blood flow (18F-fluoromethane), dopamine metabolism (6-18F-fluoro-L-dopa) and dopamine D-2 receptor density (N-18F-fluoroethylspiperone). At present 18F tracers are being developed that will, in the near future, make accessible to investigation cerebral serotonin metabolism, serotonin receptor density, melatonin receptor density, activity of L-aromatic acid decarboxylase, and protein synthesis rate.

Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia.

Frontal and parietal lobe metabolism was measured by [18F] fluorodeoxyglucose positron emission tomography in 8 never-medicated DSM-III schizophrenic patients and in 10 control subjects. Patients were in a psychotic episode at the time of this scan. Seven of eight had been ill less than 2 years and had only mild neurocognitive impairment. Frontal lobe glucose metabolism was significantly greater in schizophrenic patients than in controls. This finding differs from that of hypofrontality reported in chronic patients previously treated with neuroleptics. Relative glucose metabolism in the interior parietal lobe was significantly lower in schizophrenic patients than in controls. The frontal/parietal ratios were significantly greater in patients than in controls.

Patterns of cerebral glucose metabolism using 18FDG and positron tomography in the neurologic investigation of the full term newborn infant.

18F fluorodeoxyglucose (18FDG) and positron tomography (PT) were used in 20 full term babies with seizures or hypotonia to describe regional cerebral glucose metabolism. Among babies with seizures, birth asphyxia was the most common cause. PT was performed at age 6-17 days. One hour before PT, 18FDG (50-100 microCi/kg) was injected intravenously. Ten or more PT sections were obtained in each infant. The areas of the brain that were metabolically the most active were the cortex and the thalami. Six cortical areas and a white matter reference area were selected for analysis of relative rates of glucose metabolism as indicated by relative rates of fluorine-18 activity. Cortical fluorine-18 activity was highest in the pericentral (sensorimotor) regions and lowest in the frontal regions. The overall cortex/white matter ratio for fluorine-18 activity averaged 1.78 +/- 0.44 (SD). Four patterns of regional cerebral glucose metabolism were distinguished: 1) bilateral symmetry, 2) loss of metabolic definition, 3) hemispheral asymmetry, 4) focal hyper- or hypometabolism. Patterns 1) and 2) correlated with a history of birth asphyxia, a diagnosis of hypoxic-ischemic encephalopathy and the absence of focal echoes on cranial ultrasound. Hypodense areas on CT could be associated with either high or low fluorine-18 relative activity on PT. The prognostic significance of the presently reported patterns of cerebral glucose metabolism remains to be determined.