Validation of [18F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity.

AIMS/HYPOTHESIS: The role of the intestine in the pathogenesis of metabolic diseases is gaining much attention. We therefore sought to validate, using an animal model, the use of positron emission tomography (PET) in the estimation of intestinal glucose uptake (GU), and thereafter to test whether intestinal insulin-stimulated GU is altered in morbidly obese compared with healthy human participants. METHODS: In the validation study, pigs were imaged using [(18)F]fluorodeoxyglucose ([(18)F]FDG) and the image-derived data were compared with corresponding ex vivo measurements in tissue samples and with arterial-venous differences in glucose and [(18)F]FDG levels. In the clinical study, GU was measured in different regions of the intestine in lean (n = 8) and morbidly obese (n = 8) humans at baseline and during euglycaemic hyperinsulinaemia. RESULTS: PET- and ex vivo-derived intestinal values were strongly correlated and most of the fluorine-18-derived radioactivity was accumulated in the mucosal layer of the gut wall. In the gut wall of pigs, insulin promoted GU as determined by PET, the arterial-venous balance or autoradiography. In lean human participants, insulin increased GU from the circulation in the duodenum (from 1.3 ± 0.6 to 3.1 ± 1.1 µmol [100 g](-1) min(-1), p < 0.05) and in the jejunum (from 1.1 ± 0.7 to 3.0 ± 1.5 µmol [100 g](-1) min(-1), p < 0.05). Obese participants failed to show any increase in insulin-stimulated GU compared with fasting values (NS). CONCLUSIONS/INTERPRETATION: Intestinal GU can be quantified in vivo by [(18)F]FDG PET. Intestinal insulin resistance occurs in obesity before the deterioration of systemic glucose tolerance.

Cholinergic dysfunction after traumatic brain injury: preliminary findings from a PET study.

OBJECTIVE: There is evidence that the cholinergic system is frequently involved in the cognitive consequences of traumatic brain injury (TBI). We studied whether the brain cholinergic function is altered after TBI in vivo using PET. METHODS: Cholinergic function was assessed with [methyl-(11)C]N-methylpiperidyl-4-acetate, which reflects the acetylcholinesterase (AChE) activity, in 17 subjects more than 1 year after a TBI and in 12 healthy controls. All subjects had been without any centrally acting drugs for at least 4 weeks. RESULTS: The AChE activity was significantly lower in subjects with TBI compared to controls in several areas of the neocortex (-5.9% to -10.8%, p=0.053 to 0.004). CONCLUSIONS: Patients with chronic cognitive symptoms after TBI show widely lowered AChE activity across the neocortex.

Assessment of MAO-B occupancy in the brain with PET and [11C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301.

Inhibition of monoamine oxidase type B (MAO-B) activity in the brain is a putative strategy for the treatment of Alzheimer's disease (AD). We performed a dose-selection and validation study of a novel, reversible MAO-B inhibitor, EVT 301. Sixteen healthy volunteers received selegiline (10 mg) or EVT 301 (25, 75, or 150 mg) daily for 7-8 days, and four subjects with AD received 75 mg of EVT 301. MAO-B occupancy in the brain was assessed using positron emission tomography (PET) with [11C]-L-deprenyl-D2. EVT 301 was found to dose-dependently occupy MAO-B in the human brain, with occupancy ranging from 58-78% at a dose of 25 mg to 73-90% at a dose of 150 mg. The corresponding occupancy after selegiline was 77-92%. Determination of MAO-B inhibition in blood platelets underestimated the actual brain occupancy achieved with EVT 301. A daily EVT 301 dose of 75 or 150 mg appears suitable for clinical efficacy studies in patients with AD.

PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment.

BACKGROUND: Patients with mild cognitive impairment (MCI) have increased risk to develop Alzheimer disease (AD). In AD increased brain amyloid burden has been demonstrated in vivo with PET using N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) as a tracer. OBJECTIVE: To investigate whether patients with amnestic MCI would show increased [(11)C]PIB uptake, indicating early AD process. METHODS: We studied 13 patients with amnestic MCI and 14 control subjects with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum ratio in each voxel over 60 to 90 minutes. Group differences in [(11)C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis. RESULTS: The SPM analysis showed that patients with MCI had significantly higher [(11)C]PIB uptake vs control subjects in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate showing the most prominent differences. These results were supported by the automated ROI analysis in which MCI patients showed in comparison with healthy control subjects increased [(11)C]PIB uptake in the frontal cortex (39% increase from the control mean, p < 0.01), the posterior cingulate (39%, p < 0.01), the parietal (31%, p < 0.01) and lateral temporal (28%, p < 0.001) cortices, putamen (17%, p < 0.05), and caudate (25%, p < 0.05). Individually, in the frontal cortex and posterior cingulate, 8 of 13 patients with MCI had [(11)C]PIB uptake values above 2 SD from the control mean. MCI subjects having at least one APOE epsilon4 allele tended to have higher [(11)C]PIB uptake than MCI subjects without APOE epsilon4. CONCLUSIONS: At group level the elevated N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) uptake in patients with mild cognitive impairment (MCI) resembled that seen in Alzheimer disease (AD). At the individual level, about half of the MCI patients had [(11)C]PIB uptake in the AD range, suggestive of early AD process.

Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease.

BACKGROUND: PET studies with N-methyl-[(11)C]2-(4':-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) have revealed an increased tracer uptake in several brain regions in Alzheimer disease (AD). OBJECTIVE: To employ voxel-based analysis method to identify brain regions with significant increases in [(11)C]PIB uptake in AD vs healthy control subjects, indicative of increased amyloid accumulation in these regions. METHODS: We studied 17 patients with AD and 11 control subjects with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating a region-to-cerebellum ratio over 60 to 90 minutes in each voxel. Group differences in [(11)C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis. RESULTS: SPM showed increased uptake (p < 0.001) in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate and the striatum. No significant differences in uptake were found in the primary sensory and motor cortices, primary visual cortex, thalamus, and medial temporal lobe. These results were supported by automated ROI analysis, with most prominent increases in AD subjects in the frontal cortex ([(11)C]PIB uptake 163% of the control mean) and posterior cingulate (146%) followed by the parietal (146%) and temporal (145%) cortices and striatum (133%), as well as small increases in the occipital cortex (117%) and thalamus (115%). CONCLUSIONS: Voxel-based analysis revealed widespread distribution of increased [(11)C]PIB uptake in Alzheimer disease (AD). These findings are in accordance with the distribution and phases of amyloid pathology in AD, previously documented in postmortem studies.

Exercise restores skeletal muscle glucose delivery but not insulin-mediated glucose transport and phosphorylation in obese subjects.

CONTEXT/OBJECTIVE: Insulin resistance in obese subjects results in the impaired disposal of glucose by skeletal muscle. The current study examined the effects of insulin and/or exercise on glucose transport and phosphorylation in skeletal muscle and the influence of obesity on these processes. SUBJECTS/METHODS: Seven obese and 12 lean men underwent positron emission tomography with 2-deoxy-2-[(18)F]fluoro-d-glucose in resting and isometrically exercising skeletal muscle during normoglycemic hyperinsulinemia. Data were analyzed by two-tissue compartmental modeling. Perfusion and oxidative capacity were measured during insulin stimulation by [15O]H2O and [15O]O2. RESULTS: Exercise increased glucose fractional uptake (K), inward transport rate (K(1)), and the k(3) parameter, combining transport and intracellular phosphorylation, in lean and obese subjects. In each group, there was no statistically significant difference between plasma flow and K(1). At rest, a significant defect in K(1) (P = 0.0016), k(3) (P = 0.016), and K (P = 0.022) was found in obese subjects. Exercise restored K(1), improved but did not normalize K (P = 0.03 vs. lean), and did not ameliorate the more than 60% relative impairment in k(3) in obese individuals (P = 0.002 vs. lean). The glucose oxidative potential tended to be reduced by obesity. CONCLUSIONS/INTERPRETATION: The study indicates that exercise restores the impairment in insulin-mediated skeletal muscle perfusion and glucose delivery associated with obesity but does not normalize the defect involving the proximal steps regulating glucose disposal in obese individuals. Our data support the use of 2-deoxy-2-[18F]fluoro-d-glucose-positron emission tomography in the dissection between substrate supply and intrinsic tissue metabolism.

Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver.

AIMS/HYPOTHESIS: We investigated the effect of elevated circulating NEFA on insulin-mediated hepatic glucose uptake (HGU) and whole-body glucose disposal (M) in eight healthy male subjects. METHODS: Studies were performed using positron emission tomography (PET) and [(18)F]-2-fluoro-2-deoxyglucose ([(18)F]FDG) during euglycaemic hyperinsulinaemia (0-120 min) and an Intralipid/heparin infusion (IL/Hep; -90-120 min). On a different day, similar measurements were taken during euglycaemic hyperinsulinaemia and saline infusion (SAL). Graphical and compartmental analyses were used to model liver data. RESULTS: Circulating NEFA increased approximately three-fold during IL/Hep, and declined by 81+/-7% in the SAL study ( p

Measurement of striatal and thalamic dopamine D2 receptor binding with 11C-raclopride.

11C-Raclopride is a widely used positron emission tomography (PET) tracer for measurement of striatal D2 dopamine receptor binding characteristics. Recently, 11C-raclopride has also been used for quantification of thalamic D2 receptor binding. We studied reproducibility and validity issues on the thalamic D2 binding measurements using healthy volunteer test-retest data and simulated data. Eight healthy male volunteers received 11C-raclopride as a bolus injection in a standard test-retest design using 3-dimensional PET. The displacement of thalamic 11C-raclopride binding by the D2 receptor antagonist haloperidol was studied in two female schizophrenic patients. With regards to reproducibility and reliability, thalamic 11C-raclopride binding could be described with a simplified reference tissue model resulting in binding potentials (BPs) between 0.38 and 0.66. In comparison, the model failed to describe 11C-raclopride binding consistently in temporal cortex due to low specific signal. Measurement of thalamic 11C-raclopride BP was reproducible with a test-retest variability of 7.6+/-6.2% and reliable with an intraclass correlation coefficient (ICC) of 0.87. Comparable ICCs were observed in caudate and putamen (0.84-0.96). With regard to validity, subchronic low dose haloperidol treatment reduced specific 11C-raclopride binding equally in putamen and thalamus but a higher dose induced clearly higher D2 receptor occupancy in putamen than in thalamus. Noise simulations indicated that this can partly be explained by an over-estimation of thalamic D2 receptor BP in noisy conditions (low signal, high occupancy). The D2 receptor BP in putamen was clearly more resistant to noise. We conclude that the reproducibility and reliability of thalamic 11C-raclopride BP is good and equal to, or only slightly less than, those observed in caudate or putamen. However, the signal-to-noise ratio for quantification may become too low especially in receptor occupancy-type studies, leading to an artefactual underestimation of measured D2 receptor occupancy.

Brain acetylcholinesterase activity in mild cognitive impairment and early Alzheimer's disease.

OBJECTIVE: Brain acetylcholinesterase activity was determined in healthy controls and in patients with mild cognitive impairment and early Alzheimer's disease. METHODS: A specific acetylcholinesterase tracer, [methyl-(11)C]N-methyl-piperidyl-4-acetate ([(11)C]MP4A), and a three dimensional PET system with magnetic resonance coregistration were used for imaging. RESULTS: There was a significant difference in the acetylcholinesterase activity in the hippocampus between the groups (p = 0.03), the mean (SD) acetylcholinesterase activity (k(3) values, min(-1)) being 0.114 (0.036) in controls, 0.098 (0.023) in mild cognitive impairment, and 0.085 (0.022) in Alzheimer's disease. The mini-mental state examination score showed no significant relation with acetylcholinesterase activity in any brain area in the combined mild cognitive impairment/Alzheimer group. CONCLUSIONS: Hippocampal acetylcholinesterase activity is only slightly reduced in mild cognitive impairment and early Alzheimer's disease and so the value of in vivo acetylcholinesterase measurements in detecting the early Alzheimer process is limited.

Evidence for spatial heterogeneity in insulin- and exercise-induced increases in glucose uptake: studies in normal subjects and patients with type 1 diabetes.

It is unknown whether resistance to insulin- or exercise-stimulated glucose uptake reflects a spatially uniform or nonuniform decrease in glucose uptake within skeletal muscle. We compared the distributions of muscle glucose uptake and blood flow in eight patients with type 1 diabetes (age 24 +/- 1 yr, body mass index 22.0 +/- 0.8 kg/m2) and seven age- and weight-matched normal subjects using positron emission tomography, [18F]-fluoro-deoxy-glucose, and [15O]-water. Both groups were studied during euglycemic hyperinsulinemia and one-legged exercise. Heterogeneity was evaluated by calculating relative dispersion (SD divided by mean * 100%) of glucose uptake (RD(g)) and flow (RD(f)) in all pixels within a region of interest in femoral muscle. At rest insulin-stimulated glucose uptake was significantly lower in the type 1 diabetic patients (42 +/- 7 micromol/kg per min) than in the normal subjects (78 +/- 9 micromol/kg per min, P < 0.001), while muscle blood flows were similar (26 +/- 1 vs. 31 +/- 3 ml/kg muscle per min, respectively). The exercise-induced increment in glucose uptake but not in blood flow was also significantly lower in the type 1 diabetic patients than in the normal subjects. Heterogeneity of glucose uptake but not of blood flow was greater in the insulin-resistant type 1 diabetic patients both at rest (RD(g) 31 +/- 1 vs. 25 +/- 2%, patients with type 1 diabetes vs. normal subjects, P < 0.05) and during exercise, compared with normal subjects (27 +/- 1 vs. 21 +/- 2%, respectively, P < 0.05). Exercise increased both glucose uptake and blood flow several-fold and significantly decreased both RD(g) and RD(f). Heterogeneity of RD(g), was inversely associated with total glucose uptake (r = -0.54, P < 0.001, pooled data) and was highest in the most insulin-resistant patients. We concluded that both glucose uptake and blood flow are characterized by heterogeneity in human skeletal muscle, whose magnitude is inversely proportional to respective mean values. This implies that an increase in glucose uptake in human skeletal muscle is not a phenomenon, by which each unit increases its glucose uptake by a fixed amount but rather a spatially heterogeneous process.

Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [(15)O]H(2)O and [(18)F]fluoroerythronitroimidazole PET.

UNLABELLED: Hypoxia is a characteristic feature of malignant tumors that should be evaluated before the start of therapy. (18)F-labeled fluoroerythronitroimidazole (FETNIM) is a possible candidate for imaging tumor hypoxia with PET. Quantitative analysis of [(18)F]FETNIM uptake in vivo is necessary before proceeding to assays predicting hypoxia. METHODS: Eight patients with untreated head and neck squamous cell carcinoma were enrolled in the study. All patients underwent dynamic PET imaging with [(18)F]FETNIM, coupled with measurements of blood flow with [(15)O]H(2)O and blood volume with [(15)O]CO. The metabolically active tumor volume was determined from [(18)F]FDG PET performed on a separate day. [(18)F]FETNIM uptake in the tumor was correlated with that in neck muscles and arterial plasma and compared with the findings of other PET studies. RESULTS: Blood flow in tumor was 5- to 30-fold greater than in muscle, in contrast to blood volume, which did not significantly differ in the 2 tissues. With [(18)F]FETNIM PET, muscle activity remained invariably less than plasma activity, whereas activity in whole tumors was always greater than that in muscle. In 4 instances, the maximum tumor uptake of [(18)F]FETNIM was 1.2-2.0 times higher than plasma activity in the late dynamic phase. A kinetic model developed for calculation of distribution volume of reversibly trapping tracers was successfully applied in the [(18)F]FETNIM studies. Tumor distribution volume correlated strongly with the standardized uptake value of [(18)F]FETNIM between 60 and 120 min and with blood flow but not with the standardized uptake value of [(18)F]FDG. The relationship between [(18)F]FETNIM uptake and the blood flow of the tumor was less obvious on a pixel-by-pixel level. CONCLUSION: Uptake of [(18)F]FETNIM in head and neck cancer is highly variable and seems to be governed by blood flow at least in the early phase of tissue accumulation. Maximum tumor-to-muscle tracer uptake ratios > 180 min were in the range of 1-4, comparing favorably with those reported previously for [(18)F]fluoromisonidazole. Assessment of the distribution volume of [(18)F]FETNIM after the initial blood-flow phase is feasible for subsequent evaluation of hypoxia-specific retention.

Kinetic modeling of [(18)F]FDG in skeletal muscle by PET: a four-compartment five-rate-constant model.

Various modeling strategies have been developed to convert regional [(18)F]fluorodeoxyglucose ([(18)F]FDG) concentration measured by positron emission tomography (PET) to a measurement of physiological parameters. However, all the proposed models have been developed and tested mostly for brain studies. The purpose of the present study is to select the most accurate model for describing [(18)F]FDG kinetics in human skeletal muscle. The database consists of basal and hyperinsulinemic-euglycemic studies performed in normal subjects. PET data were first analyzed by an input-output modeling technique (often called spectral analysis). These results provided guidelines for developing a compartmental model. A new model with four compartments and five rate constants (5K model) emerged as the best. By accounting for plasma and extracellular and intracellular kinetics, this model allows, for the first time, PET assessment of the individual steps of [(18)F]FDG kinetics in human skeletal muscle, from plasma to extracellular space to transmembrane transport into the cell to intracellular phosphorylation. Insulin is shown to affect transport and phosphorylation but not extracellular kinetics, with the transport step becoming the main site of control. The 5K model also allows definition of the domain of validity of the classic three-compartment three- or four-rate-constant models. These models are candidates for an investigative tool to quantitatively assess insulin control on individual metabolic steps in human muscle in normal and physiopathological states.

Perfusion heterogeneity in human skeletal muscle: fractal analysis of PET data.

Muscle blood flow has been shown to be heterogeneous at the voxel by voxel level in positron emission tomography (PET) studies using oxygen-15 labelled water. However, the limited spatial resolution of the imaging device does not allow direct measurement of true vascular flow heterogeneity. Fractal dimension (D) obtained by fractal analysis describes the relationship between the relative dispersion and the size of the region studied, and has been used for the assessment of perfusion heterogeneity in microvascular units. This study was undertaken to evaluate fractal characteristics of PET perfusion data and to estimate perfusion heterogeneity in microvascular units. Skeletal muscle blood flow was measured in healthy subjects using [15O]water PET and the fractal characteristics of blood flow in resting and exercising skeletal muscle were analysed. The perfusion heterogeneity in microvascular units was estimated using the measured heterogeneity (relative dispersion, RD = SD/mean) and D values. Heterogeneity due to methodological factors was estimated with phantoms and subtracted from the flow data. The number of aggregated voxels was inversely correlated with RD both in phantoms (Pearson r = -0.96-0.97) and in muscle (Pearson r = -0.94) when both parameters were expressed using a logarithmic scale. Fractal dimension was similar between exercising (1.13) and resting (1.14) muscles and significantly lower than the values in the phantoms with different activity levels (1.27-1.29). Measured flow heterogeneity values were 20% +/- 6% (exercise) and 27% +/- 5% (rest, P < 0.001), whereas estimated flow heterogeneity values in microvascular units (1 mm3) were 35% +/- 14% (exercise) and 49% +/- 14% (rest, P < 0.01). In conclusion, these results show that it is feasible to apply fractal analysis to PET perfusion data. When microvascular flow heterogeneity is estimated using fractals, perfusion appears to be more heterogeneous in microvascular units than when obtained by routine spatial analysis of PET data. Analysis of flow heterogeneity using PET and fractals could provide new insight into physiological conditions and diseases associated with changes in peripheral vascular function.

Enhanced oxygen extraction and reduced flow heterogeneity in exercising muscle in endurance-trained men.

The aim of this study was to investigate the effects of endurance training on skeletal muscle hemodynamics and oxygen consumption. Seven healthy endurance-trained and seven untrained subjects were studied. Oxygen uptake, blood flow, and blood volume were measured in the quadriceps femoris muscle group by use of positron emission tomography and [15O]O2, [15O]H2O, and [15O]CO during rest and one-legged submaximal intermittent isometric exercise. The oxygen extraction fraction was higher (0.49 +/- 0.14 vs. 0.29 +/- 0.12; P = 0.017) and blood transit time longer (0.6 +/- 0.1 vs. 0.4 +/- 0.1 min; P = 0.04) in the exercising muscle of the trained compared with the untrained subjects. The flow heterogeneity by means of relative dispersion was lower for the exercising muscle in the trained (50 +/- 9%) compared with the untrained subjects (65 +/- 13%, P = 0.025). In conclusion, oxygen extraction is higher, blood transit time longer, and perfusion more homogeneous in endurance-trained subjects compared with untrained subjects at the same workload. These changes may be associated with improved exercise efficiency in the endurance-trained subjects.

Resistance to exercise-induced increase in glucose uptake during hyperinsulinemia in insulin-resistant skeletal muscle of patients with type 1 diabetes.

Insulin and exercise have been shown to activate glucose transport at least in part via different signaling pathways. However, it is unknown whether insulin resistance is associated with a defect in the ability of an acute bout of exercise to enhance muscle glucose uptake in vivo. We compared the abilities of insulin and isometric exercise to stimulate muscle blood flow and glucose uptake in 12 men with type 1 diabetes (age 24 +/- 1 years, BMI 23.0 +/- 0.4 kg/m(2)) and in 11 age- and weight-matched nondiabetic men (age 25 +/- 1 years, BMI 22.3 +/- 0.6 kg/m(2)) during euglycemic hyperinsulinemia (1 mU. kg(-1). min(-1) insulin infusion for 150 min). One-legged exercise was performed at an intensity of 10% of maximal isometric force for 105 min (range 45-150). Rates of muscle blood flow, oxygen consumption, and glucose uptake were quantitated simultaneously in both legs using [(15)O]water, [(15)O]oxygen, [(18)F]-2-fluoro-2-deoxy-D-glucose, and positron emission tomography. Resting rates of oxygen consumption were similar during hyperinsulinemia between the groups (2.4 +/- 0.3 vs. 2.0 +/- 0.5 ml. kg(-1) muscle. min(-1); normal subjects versus patients with type 1 diabetes, NS), and exercise increased oxygen consumption similarly in both groups (25.3 +/- 4.3 vs. 20.1 +/- 3.0 ml. kg(-1) muscle. min(-1), respectively, NS). Rates of insulin-stimulated muscle blood flow and the increments in muscle blood flow induced by exercise were also similar in normal subjects (129 +/- 14 ml. kg(-1). min(-1)) and in patients with type 1 diabetes (115 +/- 12 ml. kg(-1). min(-1)). The patients with type 1 diabetes exhibited resistance to both insulin stimulation of glucose uptake (34 +/- 6 vs. 76 +/- 9 micromol. kg(-1) muscle. min(-1), P < 0.001) and also to the exercise-induced increment in glucose uptake (82 +/- 15 vs. 162 +/- 29 micromol. kg(-1) muscle. min(-1), P < 0.05). We conclude that the ability of exercise to increase insulin-stimulated glucose uptake in vivo is blunted in patients with insulin-resistant type 1 diabetes compared with normal subjects. This could be caused by either separate or common defects in exercise- and insulin-stimulated pathways.

Detection of response to COMT inhibition in FDOPA PET in advanced Parkinson's disease requires prolonged imaging.

The aim was to investigate whether the improved 6-[(18)F]fluoro-L-dopa (FDOPA) availability induced by catechol-O-methyltransferase (COMT) inhibition can be more clearly seen during late than during standard (early) imaging in FDOPA uptake in Parkinson's disease (PD) patients with severe dopaminergic hypofunction. Six PD patients and six healthy controls were investigated up to 3.5 h after FDOPA injection with and without a single 400-mg dose of a peripheral COMT inhibitor, entacapone. Prolonged (late) imaging showed a significantly higher increase in FDOPA uptake than standard 1.5 h (early) imaging after entacapone both in controls and in PD patients. The increase in the (putamen-occipital):occipital ratios was 37.4% during early and 70.4% during late imaging in controls. In PD patients, there was no significant change in the ratios during early imaging, but the late imaging showed a significant increase in the putamen-to-occipital ratio of 54.2% after COMT inhibition. Late imaging reveals more clearly the prolonged FDOPA availability induced by COMT inhibition leading to higher cumulated striatal activity compared with early imaging. This might be worth considering in FDOPA studies, especially if investigations are planned to do without blood sampling. Late imaging shows the storing potential of FDA better than is seen during early FDOPA PET imaging after entacapone administration. In patients with severe presynaptic dopaminergic hypofunction, its detection requires prolonged imaging.

Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457--a test-retest analysis.

[11C]FLB 457 is a radioligand for positron emission tomography (PET) that possesses high affinity to D2/D3 receptors. It has been suggested to be useful for quantification of low-density dopamine D2 receptor populations, e.g. in cortical and limbic brain areas. We explored the reproducibility of five methods for measuring extrastriatal D2-like receptor binding potential with [11C]FLB 457. Seven healthy male volunteers were examined twice with [11C]FLB 457 (high specific radioactivity) on the same day, at least 3 h apart. Four brain areas, frontal cortex, nucleus thalamus, temporal cortex and cerebellar cortex, were examined. Binding potentials (BPs) were derived from (1) a target to cerebellum distribution volume ratio, (2/3) two reversible reference tissue compartment models and (4) a transient equilibrium approach. For comparison, BP values were also calculated with the standard three-compartment kinetic model that does not assume a receptor-free reference region. The use of the standard three-compartment model did not result in reproducible BP estimates. The distribution volume (DV) ratio, reference tissue compartment models and the transient equilibrium method all had good to excellent intraclass correlation coefficients (ICCs) in the studied brain areas ranging from 0.56 to 0.93. Absolute variability was also relatively low, ranging from 5.3% to 10.4%. There were no marked differences in the ICC or absolute and relative variability between the four methods based on a reference tissue (cerebellum). In addition, we did not observe systematic differences in the BP between the first and the second scan. These data indicate that the reproducibility of the DV ratio, reference tissue models and the transient equilibrium method is good or excellent. However, each of these methods includes assumptions affecting their validity. Thus, the choice of method will be critically dependent on the purpose of the study.

Lumped constant for [(18)F]fluorodeoxyglucose in skeletal muscles of obese and nonobese humans.

Quantitative 2-[(18)F]fluoro-2-deoxy-D-glucose ([(18)F]FDG) positron emission tomography (PET) has been widely used to calculate glucose utilization in skeletal muscle. FDG-PET results depend partly on the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [(18)F]FDG and glucose. In this study, we estimated the LC for [(18)F]FDG directly in normal and in insulin-resistant obese subjects by combining FDG PET with the microdialysis technique. Eight obese [age 29.4 +/- 1.0 yr, body mass index (BMI) 33.6 +/- 1.0 kg/m(2)] and eight nonobese (age 25.0 +/- 1.0 yr, BMI 23.1 +/- 1.0 kg/m(2)) males were studied during euglycemic hyperinsulinemia (1 mU. kg(-1).min(-1) for 150 min). Muscle blood flow was measured using (15)O-labeled water and PET. Muscle [(18)F]FDG uptake (rGU(FDG)) was calculated with Patlak graphic analysis. Interstitial glucose concentration of the quadriceps femoris muscle was measured simultaneously with [(18)F]FDG scanning using microdialysis. Muscle glucose uptake (by microdialysis, rGU(MD)) was calculated by multiplying glucose extraction by regional muscle blood flow. A significant correlation was found between rGU(MD) and rGU(FDG) (r = 0.78, P < 0.01). The LC was determined as the ratio of the rGU(FDG) to the rGU(MD). The LC averaged 1.16 +/- 0.16 and was similar in the obese and nonobese subjects (1.15 +/- 0.11 vs. 1.16 +/- 0.07, respectively, not significant). In conclusion, the microdialysis technique can be reliably combined with FDG PET to measure glucose uptake in skeletal muscle. Direct measurements with these two independent techniques suggest an LC value of 1.2 for [(18)F]FDG in human skeletal muscle during insulin stimulation, and the LC appears not to be sensitive to insulin resistance.

Quantification of [Carbonyl-(11)C]WAY-100635 binding: considerations on the cerebellum.

The specific binding of [carbonyl-(11)C]WAY-100635 to 5-hydroxytryptamine(1A) receptors was quantitated using different kinetic models. Ten healthy subjects were studied using a GE Advance PET scanner. We suggest that tissue heterogeneity explains part of the nonspecific binding seen in cerebellum, which leads to an underestimation of binding potential with reference tissue methods. The nonlinear three-compartmental model with metabolite-corrected plasma input provides accurate estimates of receptor binding because of the favorable kinetics of tracer in the brain and circulation.

[11 C]Flumazenil binding in the medial temporal lobe in patients with temporal lobe epilepsy: correlation with hippocampal MR volumetry, T2 relaxometry, and neuropathology.

OBJECTIVE: To detect reduced [11C]flumazenil in patients with temporal lobe epilepsy (TLE) and to relate binding to histopathology. METHODS: The authors studied 16 patients who underwent epilepsy surgery because of drug-resistant TLE using [11C]flumazenil PET and quantitative MRI. In 12 patients, resected hippocampus was available for histologic analysis. [11C]Flumazenil binding potential (fitted BP) was assessed with the simplified reference tissue model. RESULTS: [11C]Flumazenil fitted BP in the medial temporal lobe was reduced in all patients with abnormal hippocampal volumetry or T2 relaxometry on MRI. Fitted BP was also reduced in 46% of the patients with hippocampal volume within the normal range and in 38% of patients with less than 2 SD T2 prolongation. In all MRI-negative/PET-positive patients, the histologic analysis verified hippocampal damage. Also, [11C]flumazenil fitted BP correlated with the severity of reduced hippocampal volume, T2 prolongation, and histologically assessed neuronal loss and astrogliosis. CONCLUSION: [11C]Flumazenil PET provides a useful tool for investigating the hippocampal damage in vivo even in patients with no remarkable hippocampal abnormalities on quantitative MRI.