In vivo determination of the kinetic parameters of glucose transport in the human brain using 11C-methyl-d-glucose (CMG) and dynamic positron emission tomography (dPET)

A method was developed to measure simultaneously (1) the rate constants for glucose influex and glucose efflux, and (2) the Michaelis-Menten constant (K _M ) and maximal velocity (V _max) for glucose transport across the blood-brain barrier (BBB) in any selected brain area. Moreover, on the basis of a mathematical model, the local perfusion rate (LPR) and local unidirectional glucose transport rate (LUGTR) are calculated in terms of parameters of the time-activity curves registered over different brain regions; ¹¹C-methyl-d-glucose (CMG) is used as an indicator. The transaxial distribution of activity in the organism is registered using dynamic positron-emission tomography (dPET). The method was used in 4 normal subjects and 50 patients with ischemic brain disease. In normals, the rate constant for CMG efflux was found to be 0.25±0.04 min^-1 in the cortex and 0.12±0.02 min^-1 in white matter. In the cortex, the K _M was found to be 6.42 mol/g and the V _max was 2.46 mol/g per minute. The LUGTR ranged from 0.43 to 0.6 mol/g per minute in the cortex, and from 0.09 to 0.12 mol/g per minute in white matter. The LPR was calculated to be 0.80–0.98 ml/g per minute for the cortex and 0.2–0.4 ml/g per minute for white matter. In patients with stroke, the ischemic defects appeared to be larger in CMG scans than in computed x-ray tomography (CT) scans. Prolonged reversible ischemic neurological deficit was associated with a significant fall in the LUGTR but no change in the LPR in the corresponding cerebral cortex. Normal LUGTR and significantly decreased LPR were registered in a patient with progressive occlusion of the middle cerebral artery. In a patient with transient ischemic attacks, a slightly reduced LPR and a disproportionally reduced LUGTR were observed before operation. After extra- and intrac-ranial bypass surgery, the LPR became normal, whereas the LUGTR increased but did not achieve normal values.     

Insulin sensitivity of protein and glucose metabolism in overweight female adolescents with type 1 diabetes mellitus: positive modulation by physical exercise

Abstract Impairment of insulin sensitivity of glucose metabolism, a prominent feature of type 1 diabetes (DM), is also well documented in adolescence and obesity. Overweight is frequently present during adolescence in females. Spurt in growth is significantly reduced during puberty in females with type 1 DM, while it is normal in males. In this study we assessed the effect of the coexistence of type 1 DM, adolescence, overweight, and their possible interference with growth. Moreover, we evaluated whether dietetic control associated with physical exercise improved insulin sensitivity in adolescence. The study enrolled 11 female adolescents and young adults (aged 18.5±0.6 years), affected by type 1 DM for 8.3±0.9 years, who were overweight (BMI, 27.3±0.8 kg/m²) and receiving conventional insulin therapy (0.78±0.10 U/kg day). We used the euglycemic hyperinsulinemic clamp technique coupled to [²H₂]glucose and [¹³C]leucine infusion. The results show a striking increase in insulin resistance of glucose metabolism: the suppression of endogenous glucose production (EGP) was 59% in comparison to 90%–100% recorded by others at similar insulin levels in subjects at different periods of life. Insulin resistance in type 1 DM overweight adolescents was also present on protein metabolism: the postabsorptive plasma leucine (146.9±10.1 M) and the endogenous leucine flux (ELF, 88.8±4.5 µmol/kg min) were higher than in healthy controls. The suppression of ELF during hyperinsulinemia was defective in diabetic adolescents (27%, p<0.001) with respect to controls (36%). Only three of the 11 overweight diabetic subjects completed the 6-month physical exercise and diet program, and showed improvement of insulin sensitivity at the final evaluation. The EGP suppression by insulin shifted from 41% to 79%; ELF suppression increased from 26% to 34%. All the parameters of glucose metabolism correlated with the weight loss (BMI reduction from 27.8±1.9 to 25.6±1.2 kg/m²). In conclusion, overweight female adolescents with type 1 DM have an impaired insulin action on glucose and protein metabolism. Physical exercise and correct dietary regimen positively influence insulin sensitivity. The present preliminary data are relevant for an improved control of glucose homeostasis and a normal growth in adolescence.     

Stability of α-[11C]methyl-l-tryptophan brain trapping in healthy male volunteers

Purpose The purpose of this study was to assess the reproducibility in healthy volunteers of -[¹¹C]methyl-l-tryptophan ([¹¹C]MT) brain trapping imaging with positron emission tomography (PET), using volumes of interest (VOIs) and voxel-based image analysis.Methods Six right-handed healthy male volunteers (34.3±10.9 years) with a negative family history for psychiatric disorders were scanned twice in the resting condition, 22±17 days apart. An unbiased semiautomatic segmentation of the brain was used to define VOIs. The trapping constant K* (ml g^–1 min^–1) for [¹¹C]MT was calculated for the whole brain and seven brain regions using the graphical method for irreversible tracers. In addition, parametric maps of K* were obtained from dynamic scans using the same method. Comparison of test and retest K* functional images was performed using SPM99. Students paired t statistic was applied for comparisons of [¹¹C]MT brain trapping in a priori selected VOIs.Results [¹¹C]MT brain trapping in VOIs showed a mean variability 2.6±1.8% (0.3–5%) for absolute and 1.5±2.1% (1.4–4.1%) for normalized K*. Intraclass correlations between test and retest conditions were 0.61±0.34 for absolute K* values and 0.73±0.20 for K* values normalized by global mean. SPM99 analysis using a height threshold of p=0.05 (two tailed) and an extent threshold of 100 voxels showed no significant differences between scans.Conclusion Rest measurements in healthy male volunteers of the trapping constant for [¹¹C]MT, using PET, appeared to be stable during an average interval of 3 weeks.     

Effect of glucose and insulin infusion on the myocardial extraction of a radioiodinated methyl-substituted fatty acid

We investigated the one-way. AV extraction of 14-iodophenyl-tetradecanoic acid (BMTDA) in the canine heart under fasting conditions and during infusion of glucose plus insulin in eight anesthetized greyhound dogs. Myocardial extraction measurements were made with dual tracer approach, using Tc-99m albumin as reference tracer. Prior to, and during, infusion of 10% glucose and 25 units of regular insulin, heart rate, blood pressure, plasma glucose, insulin and free fatty acid levels were measured. Myocardial blood flow was determined using Sn-113 and Ru-103 radioactive microspheres. The mean extraction fraction of BMTDA was 0.38±SEM 0.06 at baseline and increased to 0.44±0.06 during hyperglycemia plus insulin (P<0.025). Plasma glucose and insulin were higher during the infusion (P<0.01) while plasma free fatty acids significantly declined (P<0.01). There were no changes in hemodynamics or myocardial blood flow during the infusion. We conclude that glucose and insulin infusion result in increased firstpass extraction fraction of radioiodinated BMTDA unaccompanied by changes in coronary flow or hemodynamics, implying an insulin-mediated augmented transport of BMTDA.Presented in part at the 57th Scientific Sessions, American Heart Association, 12–15 November 1984, Miami, Florida, USA; supported in part from a grant from the JP Healey Endowment and the Division of Cardiovascular Medicine (UMMC)     

Clearance of thallium-201 from the peripheral blood: Comparison of immediate and standard thallium-201 reinjection

As several reinjection procedures have shown encouraging results in terms of imaging, we investigated whether the kinetics of thallium-201 would differ between the standard stress-redistribution-reinjection approach and the stress-immediate reinjection approach. In 53 consecutive patients with undiagnosed chest pain, 75 MBq (2 mCi)²⁰¹Tl was injected at maximal exercise. In 26 of these patients (group I), 37 MBq (1 mCi)²⁰¹Tl was reinjected immediately after completing the exercise images (the immediate reinjection procedure) and in 27 patients (group II), 37 MBq (1 mCi)²⁰¹Tl was reinjected after completing 3-h redistribution images (the standard reinjection procedure). Mean peak²⁰¹Tl blood activity after exercise was 17.7±12.5 kBq/ml (4.8±3.4 mCi/ml) for group I versus 16.4±9.2 kBq/ml (4.4±2.5 mCi/ml) for group II (NS). The relative increase in²⁰¹Tl blood activity after reinjection of half the initial dose [37 MBq (1 mCi)] exceeded 50% of the initial peak in both groups. The relative amount of²⁰¹Tl delivered to the myocardium was assessed by the area under the curve after both exercise and reinjection, and was 117%±72% for group I and 112%±73% for group II (NS). Blood clearance of²⁰¹Tl was at least biexponential. Mean early decay constants (₁) after exercise and reinjection were 0.30±0.18 min^–1 and 0.22±0.046 min^–1 respectively for group I (T _1/2 2.3 min and 3.2 min respectively, NS), and 0.30±0.12 min^–1 and 0.24±0.07 min^–1 respectively for group II (T _1/2 2.3 min and 2.9 min respectively, NS). For both procedures no significant differences were found between ₁ after exercise and ₁ after injection. The mean late clearance (₂) from the blood was 0.032±0.056 min^–1 and 0.012±0.012 min^–1 respectively for group I (T _1/2 21.6 min and 57.7 min respectively, NS), and 0.036±0.030 min^–1 and 0.014±0.014 min^–1 respectively for group II (T _1/2 19.3 min and 49.5 min respectively, NS). Also, no significant differences were found between ₂ after exercise for both groups and between ₂ after reinjection for both groups. We conclude that reinjection of 37 MBq (1 mCi)²⁰¹Tl (half the initial dose) results in a relative increase in the initial peak and a relative increase in the amount of²⁰¹Tl delivered to the myocardium of more than 50% for both the standard and the immediate reinjection procedure. The clearance of²⁰¹Tl from the blood was not influenced by exercise or by the time of reinjection. Based on²⁰¹Tl kinetics as measured in the peripheral blood, there is no reason to postpone reinjection until 3–4 h following exercise.     

Quantitative analysis of myocardial glucose utilization in patients with left ventricular dysfunction by means of 18F-FDG dynamic positron tomography and three-compartment analysis

Purpose Myocardial glucose utilization (MGU) is altered in various heart diseases. The aim of this study was to quantitatively assess regional myocardial glucose utilization in patients with left ventricular (LV) dysfunction by dynamic ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET).Methods A total of 18 subjects were studied, including ten with LV dysfunction (seven with idiopathic dilated cardiomyopathy and three with aortic regurgitation; NYHA II in 8 and III in 2) and eight healthy normal volunteers. Patients with diabetes mellitus were excluded. A dynamic PET study was performed for 40 min following the injection of 370 MBq of FDG after 50-g glucose loading. On the basis of a three-compartment model, MGU, K₁, k₂, and k₃ were computed on a pixel by pixel basis to generate LV myocardial parametric maps. FDG standardized uptake value (SUV) was also calculated using static images obtained 40 min after FDG injection. These metabolic values were compared with myocardial flow distribution (%Flow), LVEF, LV volumes, and LV wall thickening (WT) determined by gated myocardial single-photon emission computed tomography using QGS software in eight myocardial segments.Results MGU correlated positively with LV volumes and negatively with LVEF. K₁ was significantly higher in the segments of the patients than in those of the normal volunteers (0.082±0.055 vs 0.041±0.017 ml min^–1 g^–1, p<0.05), although there was no difference in MGU between the groups. On the other hand, SUV, k₂, and k₃ did not differ significantly between the groups. Among the patients, the K₁ values were significantly higher in the areas with impaired WT (%WT<17%) (0.109±0.063 vs 0.069±0.062 ml min^–1 g^–1, p<0.05) and in the areas with flow reduction (%Flow<71%) (0.112±0.076 vs 0.071±0.046 ml min^–1 g^–1, p<0.05).Conclusion These results indicate that glucose utilization was preserved in the patients with LV dysfunction, mainly due to an increase in glucose transport, particularly in the regions with severely impaired LV function. Thus, the quantitative assessment of myocardial glucose utilization by FDG dynamic PET may provide useful information for assessing the regional myocardial metabolic status in patients with LV dysfunction.     

Factors affecting myocardial 2-[F-18]fluoro-2-deoxy-d-glucose uptake in positron emission tomography studies of normal humans

The goal of this study was to identify the anatomic and physiologic factors affecting left ventricular myocardial 2-[F-18]fluoro-2-deoxy-d-glucose (FDG) uptake and myocardial glucose utilization rates (MRGlc) in normal humans. Eighteen healthy male volunteers were studied in the fasting state (4–19 h) and 16 after oral glucose loading (100 g dextrose) with positron emission tomography (PET) and FDG. Substrate and hormone concentrations were measured in each study. The kinetics of myocardial FDG uptake were evaluated using both a three-compartment model and Patlak graphical analysis. Systolic blood pressures and rate pressure products were similar in the fasting and postglucose states. MRGlc averaged 0.24±0.17 mol/min/g in fasting subjects and rose to 0.69±0.11 mol/min/g after glucose loading. Phosphorylation rate constant, k₃, and MRGlc were linearly related (P < 0.001). Increases in MRGIc following glucose loading were correlated with plasma glucose, insulin and free fatty acid concentrations, ratios of insulin to glucagon levels, and influx rate constants of FDG. Glucose loading improved the diagnostic image quality due to more rapid clearance of tracer from blood and higher myocardial FDG uptake. When MRGlc, glucose and insulin concentrations, and insulin to glucagon ratios exceeded 0.2 mol/min/g, 100 mg/dl, 19 U/ml, and 0.2 U/pg, respectively, myocardial uptake of FDG was always adequate for diagnostic use. FDG image quality and MRGlc were similar after relatively short (6 ±2 h) and overnight (16 ± 2 h) fasting. Significant (P<0.05) regional heterogeneity of myocardial FDG uptake and MRGlc was observed in both the fasting and the postglucose studies. MRGlc and FDG uptake values in the posterolateral wall were higher than those in the anterior wall and septum. Thus, both 6-h and overnight fasts resulted in similarly low myocardial glucose utilization rates. While MRGlc and myocardial FDG uptake depended on plasma glucose, free fatty acid, and insulin concentrations, the results also suggest an additional dependency on plasma glucagon levels. Regional heterogeneities in myocardial FDG uptake and MRGlc are evident and independent of the subjects' dietary state. These regional heterogeneities need to be considered in studies of patients with cardiac disease.Laboratory of Biomedical and Environmental Sciences operated for the US Department of Energy by the University of California under Contract DE-FC03-87ER60615Correspondence to: Y Choi     

Tetrahydrobiopterin restores impaired coronary microvascular dysfunction in hypercholesterolaemia

Purpose Tetrahydrobiopterin (BH₄) is an essential co-factor for the synthesis of nitric oxide (NO), and BH₄ deficiency may cause impaired NO synthase (NOS) activity. We studied whether BH₄ deficiency contributes to the coronary microcirculatory dysfunction observed in patients with hypercholesterolaemia.Methods Myocardial blood flow (MBF; ml min^–1 g^–1) was measured at rest, during adenosine-induced (140 g kg^–1 min^–1 over 7 min) hyperaemia (mainly non-endothelium dependent) and immediately after supine bicycle exercise (endothelium-dependent) stress in ten healthy volunteers and in nine hypercholesterolaemic subjects using ¹⁵O-labelled water and positron emission tomography. Measurements were repeated 60 min later, after intravenous infusion of BH₄ (10 mg kg^–1 body weight over 30 min). Adenosine-induced hyperaemic MBF is considered to represent (near) maximal flow. Flow reserve utilisation was calculated as the ratio of exercise-induced to adenosine-induced hyperaemic MBF and expressed as percent to indicate how much of the maximal (adenosine-induced) hyperaemia can be achieved by bicycle stress.Results BH₄ increased exercise-induced hyperaemia in controls (2.96±0.58 vs 3.41±0.73 ml min^–1 g^–1, p<0.05) and hypercholesterolaemic subjects (2.47±0.78 vs 2.70±0.72 ml min^–1 g^–1, p<0.01) but had no influence on MBF at rest or during adenosine-induced hyperaemia in controls (4.52±1.10 vs 4.85±0.45 ml min^–1 g^–1, p=NS) or hypercholesterolaemic subjects (4.86±1.18 vs 4.53±0.93 ml min^–1 g^–1, p=NS). Flow reserve utilisation remained unchanged in controls (70±17% vs 71±19%, p=NS) but increased significantly in hypercholesterolaemic subjects (53±15% vs 66±14%, p<0.05).Conclusion BH₄ restores flow reserve utilisation of the coronary microcirculation in hypercholesterolaemic subjects, suggesting that BH₄ deficiency may contribute to coronary microcirculatory dysfunction in hypercholesterolaemia.The first two authors have contributed equally to the present project.An erratum to this article can be found at     

Incidence of stunned, hibernating and scarred myocardium in ischaemic cardiomyopathy

Purpose Different criteria to identify residual viability in chronically dysfunctioning myocardium in patients with coronary artery disease (CAD) can be derived by the combined assessment of myocardial blood flow (MBF) and glucose utilisation (MRG) using positron emission tomography (PET). The aim of this study was to evaluate, in a large number of patients, the prevalence of these different patterns by purely quantitative means.Methods One hundred and sixteen consecutive patients with ischaemic cardiomyopathy (LVEF 40%) underwent resting 2D echocardiography to assess regional contractile function (16-segment model). PET with ¹⁵O-labelled water (H₂¹⁵O) and ¹⁸F-fluorodeoxyglucose (FDG) was used to quantify MBF and MRG during hyperinsulinaemic euglycaemic clamp. Dysfunctional segments with normal MBF (0.6 ml min^–1 g^–1) were classified as stunned, and segments with reduced MBF (<0.6 ml min^–1 g^–1) as hibernating if MRG was 0.25 mol min^–1 g^–1. Segments with reduced MBF and MRG <0.20 mol min^–1 g^–1 were classified as transmural scars and segments with reduced MBF and MRG between 0.20 and 0.25 mol min^–1 g^–1 as non-transmural scars.Results Eight hundred and thirty-four (46%) segments were dysfunctional. Of these, 601 (72%) were chronically stunned, with 368 (61%) having normal MRG (0.47±0.20 mol min^–1 g^–1) and 233 (39%) reduced MRG (0.16±0.05 mol min^–1 g^–1). Seventy-four (9%) segments with reduced MBF had preserved MRG (0.40±0.18 mol min^–1 g^–1) and were classified as hibernating myocardium. In addition, 15% of segments were classified as transmural and 4% as non-transmural scar. The mean MBF was highest in stunned myocardium (0.95±0.32 ml min^–1 g^–1), intermediate in hibernating myocardium and non-transmural scars (0.47±0.09 ml min^–1 g^–1 and 0.48±0.08 ml min^–1 g^–1, respectively), and lowest in transmural scars (0.40±0.14 ml min^–1 g^–1, P<0.01). MRG was comparable in hibernating and stunned myocardium with preserved MRG (0.40±0.19 mol min^–1 g^–1 vs 0.46±0.20 mol min^–1 g^–1, NS), and lowest in stunned myocardium with reduced MRG and transmural scars.Conclusion Chronic stunning is more prevalent than expected. The degree of MRG reduction in stunned myocardium may disclose segments at higher risk of permanent damage.     

Experimental studies on myocardial glucose metabolism of rats with 18F-2-fluoro-2-deoxy-d-glucose

The myocardial uptake of ¹⁸F-FDG was investigated under various conditions, and compared with brain and tumor uptake as a function of blood glucose level. The uptake by the heart of normal feeding rats was rapid and remained essentially unchanged up to 2 h after ¹⁸F-FDG injection, approximately 3%–4% dose/g tissue. On the other hand, the myocardial uptake of fasted rats was significantly lower than that of control rats throughout the course of the study, and it was about 0.3%–0.4% dose/g tissue. Myocardial uptake of ¹⁸F-FDG was relatively constant at glucose levels under about 120 mg/100 ml and increased steeply at higher blood glucose levels. In contrast, brain uptake decreased linearly with increasing levels of blood glucose, revealing a strong negative correlation between brain uptake of ¹⁸F-FDG and blood glucose levels. The tumor uptake pattern remained relatively unchanged, irrespective of blood glucose levels. It was revealed that the glucose demands of brain, heart, and tumor were entirely different. After a glucose load, the myocardial uptake of fasted rats increased only slightly from 0.4% to 0.6% dose/g tissue, in spite of transitional hyperglycemia. In contrast, insulin caused myocardial uptake to increase extraordinarily, although it caused a decrease in blood glucose levels.     

Assessment of insulin resistance in fructose-fed rats with <Superscript>125</Superscript>I-6-deoxy-6-iodo-<Emphasis Type="SmallCaps">D</Emphasis>-glucose,a new tracer of glucose transport

Purpose Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using ¹²⁵I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Methods Two protocols were performed, a hyperinsulinaemic–euglycaemic clamp and a normoinsulinaemic–normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Results Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. Conclusion This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging.     

MRI measurements of the pons and cerebellum in children born preterm; associations with the severity of periventricular leukomalacia and perinatal risk factors

Our purpose was to measure the size of the pons and cerebellum in preterm babies with periventricular leukomalacia (PVL), and to study their relationship with the severity of PVL and with perinatal risk factors. We examined 33 premature children, mean gestational age 31 weeks, range 26–36 weeks with PVL on MRI, and 27 full-term controls. On MRI at 0.4–5.5 years (mean 1.4 years) we measured the area of the corpus callosum and vermis, the anteroposterior diameter of the pons and the volume of the cerebellum. The area of the corpus callosum was used as a marker of white matter loss and PVL severity. All regional brain measurements except that of the vermis were significantly lower in patients than controls: corpus callosum (mm²): 239.6±92.5 vs 434.8±126.8, P <0.01; pons (mm): 14.8±3.0 vs 17.9±1.4, P <0.01]; cerebellum (cm³): 68.2±31.6 vs 100.6±28.3, P <0.01; vermis (mm²): 808.1±292.2 vs 942.2±246.2, NS. Significant reduction in the area of the vermis: 411.3±203.3 vs 935±252.6 mm²; cerebellar volume: 16.3±12.5 vs 96.6±20.2 mm³; and the diameter of the pons: 10.1±2.2 vs 17.5±1.3 mm (P <0.01) were observed in seven children with gestational age 28 weeks, severe hypotension and large patent ductus arteriosus (PDA). There was a significant correlation between the duration of mechanical ventilation and the size of the vermis, pons and cerebellum (R=–0.65, –0.57 and –0.73, respectively, P <0.01).     

Reproducibility of cerebral glucose utilization measured by PET and the [18F]-2-fluoro-2-deoxy-d-glucose method in resting,healthy human subjects

The stability of cerebral glucose utilization was examined in nine right-handed, healthy men (age, 24.88±2.93 years) using positron emission tomography (PET) and the [¹⁸F]-fluorodeoxyglucose (FDG) method. Each study was run twice at intervals of 1–12 weeks with the subject at rest. The average cerebral metabolic rate for glucose (CMRGlu) was 5.40±0.71 mg/100 g per min (coefficient of variance, 13.08). The average intraindividual variation of CMRGlu was 7.91%±15.46% (P=0.13). Metabolic indices (MI: regional/mean cortical CMRGlu) were used to determine the regional cerebral metabolic distribution. The interindividual (coefficient of variance, 7.13) and intraindividual variabilities (average variation, –0.12%±8.76%) of MI were smaller than those of metabolic rates. No reproducible significant asymmetry was observed. The FDG method used with subjects at rest thus yields low intraindividual variability of both cerebral glucose consumption and regional metabolic distribution, even at an interval of several weeks. Cerebral glucose utilization measured under such conditions may act as a reliable reference for determination of the influences of physiological (activation), pharmacological or pathological processes on cerebral glucose metabolism.Abbreviations FDG [¹⁸F]-fluorodeoxyglucose - CMRGlu cerebral metabolic rates for glucose - MI metabolic indices - EEG electroencephalogram - FWHM full width at half maximum     

The uptake of 3′-deoxy-3′-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels

Purpose The aim of this study was to investigate the role of thymidine kinase 1 (TK₁) protein in 3-deoxy-3-[¹⁸F]fluorothymidine ([¹⁸F]FLT) positron emission tomography (PET) studies.Methods We investigated the in vivo kinetics of [¹⁸F]FLT in TK₁+/– and TK₁–/– L5178Y mouse lymphoma tumours that express different levels of TK₁ protein.Results [¹⁸F]FLT-derived radioactivity, measured by a dedicated small animal PET scanner, increased within the tumours over 60 min. The area under the normalised tumour time–activity curve were significantly higher for the TK₁+/– compared with the –/– variant (0.89±0.02 vs 0.79±0.03 MBq ml^–1 min, P=0.043; n=5 for each tumour type). Ex vivo gamma counting of tissues excised at 60 min p.i. (n=8) also revealed significantly higher tumour [¹⁸F]FLT uptake for the TK₁+/– variant (6.2±0.6 vs 4.6±0.4%ID g^–1, P=0.018). The observed differences between the cell lines with respect to [¹⁸F]FLT uptake were in keeping with a 48% higher TK₁ protein in the TK₁+/– tumours versus the –/– variant (P=0.043). On average, there were no differences in ATP levels between the two tumour variants (P=1.00). A positive correlation between [¹⁸F]FLT accumulation and TK₁ protein levels (r=0.68, P=0.046) was seen. Normalisation of the data for ATP content further improved the correlation (r=0.86, P=0.003).Conclusion This study shows that in vivo [¹⁸F]FLT kinetics depend on TK₁ protein expression. ATP may be important in realising this effect. Thus, [¹⁸F]FLT-PET has the potential to yield specific information on tumour proliferation in diagnostic imaging and therapy monitoring.     

Effect of scatter correction on the compartmental measurement of striatal and extrastriatal dopamine D<Subscript>2</Subscript> receptors using [<Superscript>123</Superscript>I]epidepride SPET

Prior studies with anthropomorphic phantoms and single, static in vivo brain images have demonstrated that scatter correction significantly improves the accuracy of regional quantitation of single-photon emission tomography (SPET) brain images. Since the regional distribution of activity changes following a bolus injection of a typical neuroreceptor ligand, we examined the effect of scatter correction on the compartmental modeling of serial dynamic images of striatal and extrastriatal dopamine D₂ receptors using [¹²³I]epidepride. Eight healthy human subjects [age 30±8 (range 22–46) years] participated in a study with a bolus injection of 373±12 (354–389) MBq [¹²³I]epidepride and data acquisition over a period of 14 h. A transmission scan was obtained in each study for attenuation and scatter correction. Distribution volumes were calculated by means of compartmental nonlinear least-squares analysis using metabolite-corrected arterial input function and brain data processed with scatter correction using narrow-beam geometry (SC) and without scatter correction using broad-beam (NoSC). Effects of SC were markedly different among brain regions. SC increased activities in the putamen and thalamus after 1–1.5 h while it decreased activity during the entire experiment in the temporal cortex and cerebellum. Compared with NoSC, SC significantly increased specific distribution volume in the putamen (58%, P=0.0001) and thalamus (23%, P=0.0297). Compared with NoSC, SC made regional distribution of the specific distribution volume closer to that of [¹⁸F]fallypride. It is concluded that SC is required for accurate quantification of distribution volumes of receptor ligands in SPET studies.     

Comprehensive model for simultaneous MRI determination of perfusion and permeability using a blood-pool agent in rats rhabdomyosarcoma

To present a new compartmental analysis model developed to simultaneously measure tissue perfusion and capillary permeability in a tumor using MRI and a macromolecular contrast medium. Rhadomyosarcomas were implanted subcutaneously in 20 rats and studied by 1.5-T MRI using a fast gradient echo sequence (2D fast SPGR TR/TE/ 13 ms/1.2 ms/60°) after injection of a macromolecular contrast medium. The left ventricle and tumor signal intensities were converted into concentrations and modeled using compartmental analysis, yielding tumor perfusion F, distribution volume V_distribution, volume transfer constant K^trans, rate constant of influx k_pe, and initial extraction (fraction) E. Tumor perfusion was F=43±29 ml·min^–1·100 g^–1. The permeability study allowed the measurement of k_pe=0.37±0.12 min^–1 and K^trans=0.01±0.0031 min^–1. The blood volume could be assimilated to the distribution volume (V_distribution=2.9±1.01%) since the capillary leakage was small. The simultaneous assessment of perfusion and permeability allowed quantification of the initial extraction (fraction) E=2.34±1.05%. Quantification of both tumor perfusion and capillary leakage is feasible using MRI using a macromolecular blood pool agent. The method should improve tumor characterization.     

PET imaging of brain with the β-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease

Purpose The purpose of this study was to evaluate the capacity of [¹¹C]6-OH-BTA-1 and positron emission tomography (PET) to quantify -amyloid (A) plaques in the Tg2576 mouse model of Alzheimers disease (AD).Methods PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0±1.8 months; 23.6±2.6 g) overexpressing a mutated form of human -amyloid precursor protein (APP) known to result in the production of A plaques, and in six elderly wild-type litter mates (age 21.8±1.6 months; 29.5±4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13–46 MBq of [¹¹C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time–activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S.Results TACs for [¹¹C]6-OH-BTA-1 in all ROIs peaked early (at 30–55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12–30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06±0.04 vs 0.98±0.07, p=0.04; 1.06±0.09 vs 0.93±0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread A plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice.Conclusion Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [¹¹C]6-OH-BTA-1 binding to A plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while A plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of A plaque binding sites and/or to lower affinity of the binding sites for [¹¹C]6-OH-BTA-1 as compared with AD patients. [¹¹C]6-OH-BTA-1 shows excellent brain uptake in mice.This work was presented at the 51st Annual Meeting of the Society of Nuclear Medicine in Philadelphia, PA, June 19–23, 2004.     

[18F]3′-deoxy-3′-fluorothymidine PET for the diagnosis and grading of brain tumors

Abstract The aim of this study was to evaluate the feasibility of using [¹⁸F] 3-deoxy-3-fluorothymidine (FLT) positron emission tomography (PET) for the diagnosis and grading of brain tumors.Methods The patient population comprised 26 patients (15 males, 11 females) with brain tumors (n=18) or nontumorous lesions (n=8). 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) and FLT PET images were obtained using a dedicated PET scanner 1 h after the injection of 370 MBq of FDG or FLT. Uptake of FDG and FLT by the lesions was visually and semiquantitatively assessed in comparison with normal brain tissue.Results Of 26 brain lesions, four showed increased FDG uptake compared with normal gray matter (grade 5). These four lesions showed intensely increased FLT uptake and were all high-grade tumors. Twenty-two lesions with similar (grade 4) or decreased (grades 1–3) FDG uptake compared with normal gray matter showed variable pathology. Among the 18 brain tumors, FLT PET showed increased uptake in all 12 high-grade tumors but FDG uptake was variable. In 22 brain lesions with similar or decreased uptake compared with normal gray matter on FDG PET, the sensitivity and specificity of FLT PET for the diagnosis of brain tumor were 79% (11/14) and 63% (5/8), respectively. The uptake ratios of 14 brain tumors on FLT PET were significantly higher than the lesion to gray matter ratios (p=0.012) and lesion to white matter ratios (p=0.036) of FDG uptake and differed significantly between high (5.1±2.6) and low (2.1±1.1) grade tumors (p=0.029). In nine gliomas, FLT uptake was significantly correlated with the Ki-67 proliferation index (rho=0.817, p=0.007).Conclusion These findings indicate that FLT PET is useful for evaluating tumor grade and cellular proliferation in brain tumors. It displayed high sensitivity and good contrast in evaluating brain lesions that showed similar or decreased uptake compared with normal gray matter on FDG PET. FLT PET, however, did not appear to be sufficiently useful for differentiating tumors from nontumorous lesions.     

Comparative biodistribution of indium- and yttrium-labeled B3 monoclonal antibody conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1 B4M-DTPA) or 2-(p-SCN-Bz)-1,4,7,10-tetraazacyclododecane tetraacetic acid (2B-DOTA)

The biodistribution of indium-111/yttrium-88-labeled B3 monoclonal antibody, a murine IgG1k, was evaluated in non-tumor-bearing mice. B3 was conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M) or 2-(p-SCN-Bz)-1,4,7,10 tetraazacyclododecane tetra-acetic acid (2B-DOTA) and labeled with ¹¹¹In at 1.4–2.4 mCi/mg and ⁸⁸Y at 0.1–0.3 mCi/mg. Non-tumor-bearing nude mice were co-injected i.v. with 5–10 Ci/4–10 g of ¹¹¹In/⁸⁸Y-labeled B3 conjugates and sacrificed at 6 h and daily up to 168 h post-injection. Mice injected with ¹¹¹In/⁸⁸Y (IB4M)-B3 showed a similar biodistribution of the two radiolabels in all tissues except the bones, where significantly higher accretion of ⁸⁸Y than ¹¹¹In was observed, with 2.8% ± 0.2% vs 1.3% ± 0.16% ID/g in the femur at 168 h, respectively (P<0.0001). In contrast, mice receiving the ¹¹¹In/⁸⁸Y-(DOTA)-B3 conjugate showed significantly higher accumulation of ¹¹¹In than ⁸⁸Y in most tissues, including the bones, with 2.0% ± 0.1% vs 1.2% ± 0.09% ID/g in the femur at 168 h, respectively (P<0.0001). Whereas the ratios of the areas underneath the curve (%ID × h/g) in the blood, liver, kidney and bone were 0.96, 1.12, 1.13, and 0.74 for ¹¹¹In/⁸⁸Y-(IB4M)-B3 and 0.84, 1.23, 1.56, and 1.31 for ¹¹¹In/⁸⁸Y (DOTA)-B3, respectively, ratios 1 were observed between ¹¹¹In-(IB4M)-B3 and ⁸⁸Y-(DOTA)-B3. In summary, while neither IB4M nor DOTA was equally stable for ¹¹¹In and ⁸⁸Y, the fate of ⁸⁸Y- (DOTA)-B3 could be closely traced by that of ¹¹¹ In-(IB4M)-B3.     

Quantification of baboon cortical S2 serotonin receptors in vivo with 3-N-(2′-Fl8)fluoroethylspiperone and positron emission tomography

We used the ligand 3-N-(2-F 18)fluoroethylspiperone (FESP) and positron emission tomography (PET) to quantify in vivo serotonin S₂ neuroreceptor density and affinity in the baboon frontal cortex. In the cortex, FESP binds specifically and exclusively to S₂ receptors, and an equilibrium is reached when the rate of ligand-receptor association and dissociation become equal. Using multiple studies in the same baboon, an equilibrium (saturation) analysis approach provided a linear Hill plot with a slope of 1.02 (r ² =0.988,P <0.0001), indicative of ligand binding to a single receptor class. Using serial PET scans, a dynamic approach was also used to quantify S₂ receptors in the frontal cortex of the baboon, which provided an estimate of receptor densityB _max =35.6 ± 10.9 pmol/g. The rate constants corresponding to transport into and out of tissue wereK _* ¹ = 0.2720 ± 0.0299 mol/min g andk _* ² = 0.0786 ± 0.0315 min^–1, respectively. The ligand-receptor dissociation constant wask _* ⁴ = 0.0154 ± 0.0109 min^–1.