Ikuo Odano

A Multicenter Validation of Regional Cerebral Blood Flow Quantitation Using [123I]Iodoamphetamine and Single Photon Emission Computed Tomography

Recently, two methods have been proposed for regional cerebral blood flow (rCBF) quantitation using [123I]iodoamphetamine (IMP) and single-photon emission computed tomography (SPECT). The table look-up (TLU) method has been shown to provide both rCBF and volume of distribution, Vd, images from two SPECT scans, while a single-scan autoradiographic (ARG) technique provided rCBF using a fixed and assumed Vd. In both methods, a single blood sample was referred to calibrate the previously determined standard input function The present multicenter project was designed to evaluate the accuracy of both methods for use as clinical investigative tools. Ten independent institutions performed [123I]IMP-SPECT studies according to both methods in 76 subjects (10 normal volunteers, 32 patients with cerebrovascular disease, and 34 patients with other diseases). Calculated rCBF values were compared with those obtained by the following reference methods available in the participating institutions; [15O] H2O positron emission tomography (PET) (five institutions), [133Xe]SPECT (four institutions), and the [123I]IMP microsphere method (three institutions). Both ARG and TLU methods provided rCBF values that were significantly correlated with those measured by the [15O] H2O PET technique (p < 0.001 for all subjects; overall regression equation, y = 15.14 + 0.54×) and those measured by the [123I]IMP-microsphere method (p < 0.001 for all subjects; y = 2.0 + 0.80×). Significant correlation (p < 0.05) was observed in 18 of 24 subjects studied with the [133Xe] SPECT reference technique (overall regression equation, y = 15.0 + 0.55×). Mean cortical gray matter rCBF in a group of normal subject was 43.9 ± 3.3 and 43.4 ± 2.0 ml/min/100 g for the ARG and TLU methods, respectively. Regional Vd of [123I]IMP estimated by the TLU method was 45 ml/ml ± 20% in the normal cortical region. Close agreement between ARG and TLU rCBF values was observed (y = −3.21 + 1.07×, r = 0.97), confirming the validity of assuming a fixed Vd in the ARG method. Results of this study demonstrate that both the ARG and TLU methods accurately and reliably estimate rCBF in a variety of clinical settings.

Quantitative analyses of regional [11C]PE2I binding to the dopamine transporter in the human brain: a PET study

PurposeThe dopamine transporter (DAT) is a plasma membrane protein of central interest in the pathophysiology of neuropsychiatric disorders and is known to be a target for psychostimulant drugs. [11C]PE2I is a new radioligand which binds selectively and with moderate affinity to central DAT, as has been demonstrated in vitro by autoradiography and in vivo by positron emission tomography (PET). The aims of the present PET study were to quantify regional [11C]PE2I binding to DAT in the human brain and to compare quantitative methods with regard to suitability for applied clinical studies.MethodsOne PET measurement was performed in each of eight healthy male subjects. The binding potential (BP) values were obtained by applying kinetic compartment analysis, which uses the metabolite-corrected arterial plasma curve as an input function. They were compared with the BP values quantified by two reference tissue approaches, using cerebellum as a reference region representing free and non-specific radioligand binding.ResultsThe radioactivity concentration was highest in the striatum, lower in the midbrain and very low in the cerebellum. The regional [11C]PE2I binding could be interpreted by kinetic compartment models. However, the BP values in the striatum obtained by the compartment analyses were about 30% higher than the BP values obtained using reference tissue methods. We suggest that the difference may be explained by the inaccurate metabolite correction, small amounts of radioactive metabolites that could account for the presence of non-specific binding in the cerebellum and insufficient data acquisition time.ConclusionThe reference methods may be used to quantify [11C]PE2I binding in clinical studies, assuming that non-specific binding in the cerebellum does not vary between subjects and that an extended data acquisition time is employed. Moreover, the study corroborates the previous observation that [11C]PE2I is advantageous for PET examination of DAT binding in the midbrain, a region from which dopaminergic innervation originates and which is of central interest for the pathophysiology of several neuropsychiatric disorders.

Decrease in benzodiazepine receptor binding in a patient with Angelman syndrome detected by iodine-123 iomazenil and single-photon emission tomography

A receptor mapping technique using iodine-123 iomazenil and single-photon emission tomography (SPET) was employed to examine benzodiazepine receptor binding in a patient with Angelman syndrome (AS). AS is characterized by developmental delay, seizures, inappropriate laughter and ataxic movement. In this entity there is a cytogenic deletion of the proximal long arm of chromosome 15g11–q13, where the gene encoding the GABAA receptorβ3 subunit (GABRB3) is located. Since the benzodiazepine receptor is constructed as a receptor-ionophore complex that contains the GABAA receptor, it is a suitable marker for GABA-ergic synapsis. To determine whether benzodiazepine receptor density, which indirectly indicates changes in GABAA receptor density, is altered in the brain in patients with AS, we investigated a 27-year-old woman with AS using123I-iomazenil and SPET. Receptor density was quantitatively assessed by measuring the binding potential using a simplified method. Regional cerebral blood flow was also measured withN-isopropyl-p-[123I]iodoamphetamine. We demonstrated that benzodiazepine receptor density is severely decreased in the cerebellum, and mildly decreased in the frontal and temporal cortices and basal ganglia, a result which is considered to indicate decreased GABAA receptor density in these regions. Although the deletion of GABRB3 was not observed in the present study, we indirectly demonstrated the disturbance of inhibitory neurotransmission mediated by the GABAA receptor in the investigated patient.123I-iomazenil with SPET was useful to map benzodiazepine receptors, which indicate GABAA receptor distribution and their density.

Assessment of dopamine and its metabolites in the intracellular and extracellular compartments of the rat striatum after peripheral administration ofl-[11C]DOPA

Success in the synthesis of L-3,4-[beta-11C]dihydroxyphenylalanine (L-[11C]DOPA) and its application to positron emission tomography encouraged us to perform radioactive metabolite analyses in rats in an early phase after peripheral injection of L-[11C]DOPA. Following intravenous injection of [11C]DOPA, the radioactivity associated with DOPA and its metabolites was determined in the striatum after decapitation and in striatal extracellular fluid using in vivo brain microdialysis. Without pretreatment, 70-80% of 11C-radioactivity taken up into the striatum was associated with acidic metabolites of dopamine (DA) from 2 to 30 min after administration of L-[11C]DOPA with or without 300 micrograms/kg of unlabelled L-DOPA. In contrast, 80-90% of 11C-radioactivity in the striatum was associated with DOPA and DA after pretreatment with benserazide (25 mg/kg, i.p.) followed by administration of L-[11C]DOPA with or without unlabelled L-DOPA. The radioactivity in the DOPA fraction decreased with time (from 35% of 11C-radioactivity in the striatum at 5 min to 10% at 30 min), but that in the DA fraction increased (from 57% to 68%). The 11C-radioactivity in the extracellular fluid determined by brain microdialysis was less than 0.4% of that in the whole striatum and no radioactivity was present in the DA fraction. These results suggest that, in an early phase after administration of L-[11C]DOPA, [11C]DA is the main metabolite and is localized exclusively in the intracellular compartment within this time frame.

A potential use of a 123I-labelled benzodiazepine receptor antagonist as a predictor of neuronal cell viability: comparisons with 14C-labelled 2-deoxyglucose autoradiography and histopathological examination

SUMMARYIn the treatment and therapy of patients suffering a stroke, it is very important to predict whether viable neurones, even those of poor function, remain intact in the lesions of the brain. To determine whether viable neurones of low functional activity are represented in in vivo neuroreceptor imaging, we undertook experiments in gerbils with cerebral infarction, in which we examined histological changes and the results of dual-tracer in vivo autoradiography of glucose utilization with 14C-labelled deoxyglu-cose and benzodiazepine receptor binding with 123I-labelled Ro 16–0154. The unrelated findings of cerebral glucose metabolism and benzodiazepine receptor binding were observed in the primary infarct lesion and in remote areas, including the ipsilateral striatum and thalamus.Our experiments showed that when viable neurones with low functional activity remain intact, normal in vivo binding to benzodiazepine receptors is demonstrated as hypometabolism of glucose utilization. This functional, contrast-enhanced technique with 123I-labelled Ro 16–0154 may have an important role to play in the prediction of neuronal cell viability after recent brain infarction in experimental animals and humans using single photon emission tomography (SPET).

Evaluation of cerebral blood flow in patients with idiopathic orthostatic hypotension using Tc-99m HMPAO brain SPECT during postural testing.

To determine whether regional cerebral blood flow (rCBF) would change on standing in patients with idiopathic orthostatic hypotension (IOH), Tc-99m HMPAO SPECT studies were performed during postural testing in five patients with IOH. After 10 minutes of quiet rest on a bed, the patients arose quickly and, at the same time, the radiotracer was injected intravenously. SPECT data were obtained with a ring-type SPECT scanner. Another dose of Tc-99m HMPAO was injected with the subjects in the supine position, and SPECT was performed again. Image subtraction was used to evaluate the change in rCBF caused by postural testing. In all patients, the authors observed a decrease of rCBF in the frontal cortex and basal ganglia. This preliminary study suggests that changes in rCBF occur in patients with IOH on standing, and Tc-99m HMPAO SPECT performed during postural testing may have an important role in evaluating these changes.

125I-iomazeniI binding shows stress- and/or diazepam-induced reductions in mouse brain: Supporting data for123I-iomazenil SPECT study of anxiety disorders

Effects of repeated swim stress on the binding of125I-iomazenil were examined in the brains of diazepam-treated and non-treated mice. The mice were orally administered diazepam or vehicle (0.5% ethylene glycol) and subjected to daily swim stress (at 20°C for 10 min) for seven consecutive days. The distribution and the amount of125I-iomazenil binding were analyzed autoradiographically afterin vivo andin vitro binding experiments. Repeated swim stress decreased thein vivo binding in the hippocampus (p < 0.05) and cerebral cortex (p < 0.05) of vehicle-treated mice but caused no significant changes in diazepam-treated mice. Subchronic treatment with diazepam decreased thein vivo binding approximately 50% in all brain regions examined (p < 0.01). Thein vitro experiment, however, revealed no significant changes except in the hippocampus, where a small but significant decrease in the binding was observed after subchronic treatment with diazepam (p < 0.01). The stress- or diazepam-induced reductions seem to represent alterations in thein vivo environment related to125I-iomazenil binding. These results suggest that we can investigate the pathophysiology of stress and anxiety with123I-iomazenil SPECT. Care must be taken concerning the effects of benzodiazepines.

A new method of regional cerebral blood flow measurement using one-point arterial sampling based on the microsphere model with N-isopropyl- p -[123i]-iodoamphetamine Spect

We developed a new method for quantitative measurement of regional cerebral blood flow (rCBF) using one-point arterial sampling with N-isopropyI-p-[123I]-iodoamphetamine (123I-IMP) and single photon emission computed tomography (SPECT) based on the microsphere model. Although the conventional microsphere method requires both the continuous withdrawal of arterial blood (integral of Ca(t)) and treatment of the blood with octanol to obtain the fraction of true tracer activity in the integral of Ca(t) (N), the new method does not require these two procedures. We examined 14 patients to analyse the correlation between the integral of Ca(t)N and a small arterial sample obtained at one time point [one-point Ca(t)] after the injection of 123I-IMP without octanol treatment. The integral of Ca(t)N was calculated from one point Ca(t) using the regression line of the correlation. An error of 8.1% in the calculated value compared to the actual value of the integral of Ca(t)N, could be inferred from one-point Ca(t) obtained at 6 min after the injection. Then regional cerebral blood flow was measured by the method and a significant correlation was obtained with rCBF measured using the 133Xe inhalation method (r=0.773). The one-point Ca(t) method provides fast, easy, accurate and non-invasive measurement of rCBF without inserting catheters and without treatment of arterial blood with octanol.

Regional cerebral blood flow measured with N-isopropyl-p-[123I]iodoamphetamine single-photon emission tomography in patients with Joseph disease

Regional cerebral blood flow (rCBF) was measured in five Japanese patients who were clinically diagnosed as having Joseph disease, also called Machado-Joseph disease or Azorean disease, using N-isopropyl p-[123I]iodoamphetamine (IMP) and single-photon emission tomography (SPET). Cerebellar atrophy was evaluated by a five-step rating scale as defined on X-ray computed tomography (X-CT). Compared with ten age-matched normal controls (mean cerebellar CBF ± SD: 66.9 ± 6.6 ml/100 g/min), rCBF in patients with Joseph disease was significantly decreased in the cerebellum (mean ± SD: 50.2 ± 7.3 m1/100 g/min). No significant relationship, however, was found between the decrease in rCBF in the cerebellum and the degree of cerebellar atrophy on X-CT. rCBF in the cerebellum was minimally decreased in one patient who had severe cerebellar atrophy and in two patients with moderate atrophy. These data may support the findings that Purkinje cells in the cerebellum are almost normal in Joseph disease, and that the granular and molecular layers remain intact in spite of cortical atrophy of the cerebellum. It is concluded that [123I]-IMP SPET is able to identify pathological and metabolic changes in the cerebellum that do not appear on X-CT or magnetic resonance imaging, and thus is useful for the diagnosis of Joseph disease.

Radio‐guided sentinel node mapping in patients with superficial esophageal carcinoma: Feasibility study

The aim of this study was to assess whether the sentinel node concept could be applicable to clinically early carcinoma of the esophagus. We studied ten consecutive cT1N0 patients who underwent radical esophagectomy with regional lymph node dissection. On the day before surgery, 99m‐Tc tin colloid was injected endoscopically around the primary tumor. Lymphoscintigraphy was also performed about three hours after injection. Immediately after surgery, the radioactivity of all dissected lymph nodes was measured with a hand‐held gamma probe. The radioactivity and the metastatic status assessed by routine histopathologic examination were compared. A total of six patients had hot spots detected by lymphoscintigraphy, of which the detection rate was 60% (6 of 10). The ex vivo hot node detection rate was 90% (9 of 10). Three patients were found to have metastatic nodes. In one patient, sentinel node mapping failed to identify any hot spot or hot node. In the other two patients, the metastatic nodes did not correspond to hot nodes. The accuracy of hot node status was 77.8% (7 of 9), and the false‐negative rate was 100% (2 of 2). The present study showed that radio‐guided sentinel node detection is insufficiently reliable at present due to the high false‐negative rate and low accuracy.