Normal values and within-subject variability of cardiac I-123 MIBG scintigraphy in healthy individuals: Implications for clinical studies

BACKGROUND: Although several myocardial iodine 123 metaiodobenzylguanidine (MIBG) indices are increasingly used to detect alterations in myocardial sympathetic activity in various forms of cardiac pathology, published measurements of normal values and within-subject variability are lacking. METHODS AND RESULTS: Twenty-five healthy volunteers underwent planar and single photon emission computed tomography (SPECT) imaging. Heart-mediastinum ratio (H/M) and myocardial washout were calculated from planar images comparing three different methods for the assessment of myocardial activity: (1) global region over the myocardium (cavity included), (2) global region over the myocardium (cavity excluded), and (3) fixed small myocardial region. Segmental (relative) uptake and washout were assessed by SPECT. For all MIBG indices, the interindividual variation was the lowest for methods 1 and 2. In SPECT this variation was low for relative segmental uptake compared with washout. In 9 subjects a second MIBG scintigraphy was performed after 3 months. The within-subject variability of H/M and washout assessed by planar methods 1 and 2 was 5%, whereas it was approximately 9% for planar method 3. For relative segmental uptake from SPECT, this variability was 5%. CONCLUSION: MIBG H/M (planar) and relative segmental uptake (SPECT) show a low interindividual and within-subject variability. This enables the detection of small (regional) variations in myocardial sympathetic nervous function, especially to monitor the effect of therapeutic interventions in patients with various cardiac diseases.     

Characterisation of [<Superscript>123</Superscript>I]iomazenil distribution in a rat model of focal cerebral ischaemia in relation to histopathological findings

Iodine-123 labelled iomazenil ([¹²³I]IMZ) has been reported to be a useful marker of neuronal viability. The brain distribution of [¹²³I]IMZ, however, has not been correlated with the pathophysiological response in detail after an ischaemic insult. To characterise [¹²³I]IMZ as a marker of neuronal viability, we compared its brain distribution with cyclooxygenase-2 (COX-2) expression, DNA fragmentation and cellular integrity. [¹²³I]IMZ and [¹²⁵I]IMP were injected into rats with focal cerebral ischaemia for the purpose of dual-tracer autoradiography. COX-2 and microtubule-associated protein-2 (MAP-2, a marker of cellular integrity) were immunostained. In situ DNA polymerase-I-dependent dUTP incorporation into damaged DNA was used as an indicator of DNA fragmentation. Lesion to normal ratios (LNRs) for [¹²³I]IMP and [¹²⁵I]IMZ were calculated. [¹²³I]IMZ accumulation was preserved in several regions with impaired [¹²³I]IMP accumulation. COX-2 expression was occasionally observed, whereas neither DNA fragmentation nor MAP-2 denaturation was detected in these regions. DNA fragmentation and impaired MAP-2 immunostaining were observed only in the regions with reduced LNRs for both tracers. The LNR for [¹²³I]IMZ was significantly lower in regions with impaired MAP-2 immunostaining (0.120±0.152, P<0.0001), in regions positive for dUTP incorporation (0.488±0.166, P<0.0001) and in regions positive for COX-2 expression (0.626±0.186, P<0.001) than in histologically normal regions (0.784±0.213). Thus, neuronal DNA is still intact and cellular integrity is maintained in the ischaemic regions with preserved [¹²³I]IMZ accumulation. The impairment of [¹²³I]IMZ accumulation precedes DNA fragmentation and denaturation of cellular integrity. These results provide the molecular basis of [¹²³I]IMZ distribution.     

Three-dimensional display in staging hemodynamic brain ischemia for JET study: Objective evaluation using SEE analysis and 3D-SSP display

The Japanese EC-IC bypass trial (JET study) was established to evaluate the validity of MCA-STA anastomosis in intracranial arterial occlusive disease aiming at stroke prevention. This study must use an objective method to reliably estimate hemodynamic brain ischemia. We devised a method of objectively classifying the severity of hemodynamic ischemia using quantitatively analytical and display software, stereotactic extraction estimation for stereotactic brain coordinates and three-dimensional stereotactic surface projections (3D-SSP). We analyzed data from 16 patients registered in the JET study. Our method offers quantitative information and 3-dimensional displays of the CBF at rest and after Diamox challenge, vascular reserve and the severity of the hemodynamic brain ischemia. We compared the maximal projection counts with ROI data from tomographic images in the anterior commissure-posterior commissure plane. The maximal counts data correlated closely with the ROI data of rest and with Diamox SPECT images (both p < 0.0001). The slopes of the linear regression line were 1.15 and 1.12, respectively. The results of this study indicated that our method could simply and objectively evaluate the severity of impaired brain circulation. This procedure should support the evaluation of hemodynamic ischemia in the JET study although validation is required by several institutions using more study subjects.     

Clinical usefulness of iodine-123-MIBG scintigraphy for patients with neuroblastoma detected by a mass screening survey

The purpose of this study was to evaluate the usefulness in a clinical setting of iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy, planar and single photon emission computed tomography (SPECT) images, in patients with neuroblastoma as detected by a mass screening survey. METHODS: 123I-MIBG planar whole body images, and regional SPECT images of patients with neuroblastoma in 51 studies were reviewed. They were all detected by a mass screening survey performed in the 6th month after birth using vanil mandelic acid (VMA), and homovanillic acid (HVA) and the neuroblastoma had been confirmed by surgery. Scintigraphy was performed 24 hours after injection of 111 MBq of 123I-MIBG. We assessed the accuracy of the planar whole body images in order to demonstrate the extent of the lesion and the correlation between the degree and extent of the lesions of 123I-MIBG accumulation and clinical staging with tumor markers, such as urinary VMA, urinary HVA, serum neuron specific enolase (NSE) and serum lactate dehydrogenase (LDH). Additionally, we evaluated SPECT how useful supplemental SPECT might be in a clinical setting as compared with planar whole body images. RESULTS: 123I-MIBG planar whole body images revealed all 33 (100%) primary lesions, 4 of the 5 cases (80%) with liver metastasis, 3 of the 13 (23%) with lymph nodes metastasis and 1 of 3 (33%) with bone marrow infiltration. The extent and degree of accumulation correlated with the values of urinary VMA, urinary HVA and serum NSE. SPECT images helped to understand the positional relation in all cases and provided useful additional information for clinical staging in 7 cases. CONCLUSION: 123I-MIBG scintigraphy with planar and SPECT images is useful for evaluating patients with neuroblastoma, following detection by a mass screening survey.     

Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT₄) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT₄ receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT₄ receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT₄ receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [¹²³I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT₄ receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT₄ receptor antagonist, SB 204070, at 20 min before [¹²³I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [¹²³I]SB 207710 is an effective radioligand for imaging brain 5-HT₄ receptors in vivo.For preliminary accounts of this work, see Pike VW et al., J Nucl Med 1998; 39 (Suppl):185; Eur J Nucl Med 1999; 26:991.     

ETA receptor-mediated Ca2+ mobilisation in H9c2 cardiac cells

Expression and pharmacological properties of endothelin receptors (ETRs) were investigated in H9c2 cardiomyoblasts. The mechanism of receptor-mediated modulation of intracellular Ca(2+) concentration ([Ca(2+)](i)) was examined by measuring fluorescence increase of Fluo-3-loaded cells with flow cytometry. Binding assays showed that [125I]endothelin-1 (ET-1) bound to a single class of high affinity binding sites in cardiomyoblast membranes. Endothelin-3 (ET-3) displaced bound [125I]ET-1 in a biphasic manner, in contrast to an ET(B)-selective agonist, IRL-1620, that was ineffective. The ET(B)-selective antagonist, BQ-788, inhibited [125I]ET-1 binding in a monophasic manner and with low potency. An ET(A)-selective antagonist, BQ-123, competed [125I]ET-1 binding in a monophasic manner. This antagonist was found to be 13-fold more potent than BQ-788. Immunoblotting analysis using anti-ET(A) and -ET(B) antibodies confirmed a predominant expression of the ET(A) receptor. ET-1 induced a concentration-dependent increase of Fluo-3 fluorescence in cardiomyoblasts resuspended in buffer containing 1mM CaCl(2). Treatment of cells with antagonists, PD-145065 and BQ-123, or a phospholipase C-beta inhibitor, U-73122, abolished ET-1-mediated increases in fluorescence. The close structural analogue of U-73122, U-73343, caused a minimal effect on the concentration-response curve of ET-1. ET-3 produced no major increase of Fluo-3 fluorescence. Removal of extracellular Ca(2+) resulted in a shift to the right of the ET-1 concentration-response curve. Both the L-type voltage-operated Ca(2+) channel blocker, nifedipine, and the ryanodine receptor inhibitor, dantrolene, reduced the efficacy of ET-1. Two protein kinase C inhibitors reduced both potency and efficacy of ET-1. Our results demonstrate that ET(A) receptors are expressed and functionally coupled to rise of [Ca(2+)](i) in H9c2 cardiomyoblasts. ET-1-induced [Ca(2+)](i) increase is triggered by Ca(2+) release from intracellular inositol 1,4,5-trisphosphate-gated stores; plasma membrane Ca(2+) channels and ryanodine receptors participate in sustaining the Ca(2+) response. Regulation of channel opening by protein kinase C is also involved in the process of [Ca(2+)](i) increase.     

Regional serotonin transporter availability and depression are correlated in Wilson’s disease

Summary. In patients with Wilsons disease (WD), depression is a frequent psychiatric symptom. In vivo neuroimaging studies suggest that depression and other neuropsychiatric disorders are associated with central serotonergic deficits. However, in vivo measurements of serotonergic neurotransmission have not until now been performed in patients with this copper deposition disorder. The present prospective study revealed that depressive symptomatology is related to an alteration of presynaptic serotonin transporters (SERT) availability as measured by [¹²³I]-2-carbomethoxy-3-(iodophenyl)tropane ([¹²³I]-CIT) and high-resolution single-photon emission computed tomography (SPECT). SERT imaging with [¹²³I]-CIT-SPECT could therefore become a useful tool for diagnosis and therapy monitoring in depressed WD patients.Received December 10, 2001; accepted March 24, 2003 Published online June 10, 2003     

The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson's disease

Objective: One of the most frequent psychiatric symptoms in patients with Wilson's disease (WD) is depression. It has been suggested that depression is associated with deficits in serotonergic neurotransmission, but, hitherto, no measurements have been performed in WD. Methods: We prospectively examined 23 adult patients (12 women, 11 men, mean age 40 years) with WD for symptoms of depression using the Hamilton rating scale for depression (HAMD). We correlated the data with the presynaptic serotonin transporter density (SERT density) in the thalamus–hypothalamus and the midbrain–pons regions measured with high resolution single-photon emission computed tomography (SPECT) 24 hours after the application of 180 MBq 2β-carbomethoxy-3β-(4 [¹²³I]iodophenyl)tropane ( [¹²³I]b-CIT). The regions of interest were determined by coregistration with a standard MRI dataset. Results: A significant negative correlation was found between HAMD and SERT density in the thalamus–hypothalamus region (r = −0.49, p = 0.02), but not in the midbrain–pons (r = −0.31, p = 0.15). Conclusions: We conclude that depression in patients with Wilson's disease is correlated with alterations of serotonergic neurotransmission in the thalamus–hypothalamus region. Received: 24 July 2002, Received in revised form: 20 November 2002, Accepted: 28 November 2002 Correspondence to Wieland Hermanns, MD     

Higher occupancy of muscarinic receptors by olanzapine than risperidone in patients with schizophrenia. A[123I]-IDEX SPECT study

RATIONALE: In vitro data have shown anticholinergic properties of the atypical antipsychotic drug olanzapine. Substantial occupancy of muscarinic receptors may be an explanation for the low incidence of extrapyramidal side effects induced by olanzapine. OBJECTIVES: To obtain an in vivo measurement of muscarinic receptor occupancy by olanzapine compared with risperidone in patients with schizophrenia stabilised on medication. METHODS: Five patients with schizophrenia treated with olanzapine and five patients treated with risperidone were studied. Muscarinic receptor occupancy in the striatum and cortex was studied in vivo with SPECT using [123I]-IDEX as a radioligand. SPECT data were compared with those of six healthy subjects. RESULTS: Patients stabilised on olanzapine showed significantly lower mean (+/-SD) striatal and cortical (1.50+/-0.21 and 1.51+/-0.22, respectively) muscarinic receptor binding ratios of [123I]-IDEX (reflecting higher levels of muscarinic receptor occupancy) than controls (3.91+/-0.61 and 3.65+/-0.70, respectively). Furthermore, [123I]-IDEX binding ratios in patients treated with risperidone were slightly lower than controls, reaching significance only in the striatum (2.99+/-0.27 versus 3.91+/-0.61, for risperidone and controls). CONCLUSIONS: The substantial occupancy of muscarinic receptors in the striatum and cortex by olanzapine may be an explanation for the low incidence and severity of extrapyramidal side effects of this antipsychotic drug. Furthermore, it may also explain the anticholinergic side effects of olanzapine.     

Melatonin as an antioxidant in retinal photoreceptors

Dark-adapted, single photoreceptors isolated from the frog retina produce reactive oxygen species (ROS) after about 1 min of illumination with saturating light that we verified by their oxidation of preloaded dihydrorhodamine 123 (DHR) into the fluorescent rhodamine 123 (RHO). In this preparation we tested the antioxidant effects of vitamin E and of melatonin. Melatonin at picomolar and low nanomolar concentrations was determined to be 100 times more potent in inhibiting the light-induced oxidative processes than was vitamin E. On the contrary, both compounds exerted potent prooxidant effects at micromolar concentrations that is above the physiological levels of melatonin. This provides evidence that physiological concentrations of melatonin in a living cell may exert protective actions against a natural oxidant stimulus (light). This helps to define the functional role of endogenous melatonin in photoreceptors, which by their physiological characteristics, are among the marked producers of ROS in the organism.