PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease.

Variant Alzheimer's disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1Delta E9). VarAD is neuropathologically characterized by the presence of unusually large, Abeta42 positive, non-cored 'cotton wool' plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [(11)C]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [(11)C]PIB binding to the amount and type of Abeta deposits in another group of deceased VarAD patients' brains. We studied four patients with VarAD and eight healthy controls with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 60-90 min. Group differences in [(11)C]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [(11)C]PIB uptake was compared to the immunohistochemically demonstrated deposition of Abeta in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [(11)C] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [(11)C]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43% greater than the mean of the control group. The increases in the anterior (28%) and posterior (27%) cingulate gyrus, occipital cortex (21%) and thalamus (14%) were smaller. All VarAD patients showed this similar topographical pattern of increased [(11)C]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [(11)C]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to detect amyloid accumulation in vivo in these patients. The pattern of increased [(11)C]PIB uptake is different from that described in sporadic Alzheimer's disease and resembles that seen in Alzheimer's disease patients with certain presenilin-1 mutations or amyloid precursor protein gene duplication showing predominantly striatal increase in [(11)C]PIB uptake.

alpha2A-adrenoceptor antagonism increases insulin secretion and synergistically augments the insulinotropic effect of glibenclamide in mice.

BACKGROUND AND PURPOSE: The imidazoline-type alpha2-adrenoceptor antagonists (+/-)-efaroxan and phentolamine increase insulin secretion and reduce blood glucose levels. It is not known whether they act by antagonizing pancreatic beta-cell alpha2-adrenoceptors or by alpha2-adrenoceptor-independent mechanisms. Many imidazolines inhibit the pancreatic beta-cell KATP channel, which is the molecular target of sulphonylurea drugs used in the treatment of type II diabetes. To investigate the mechanisms of action of (+/-)-efaroxan and phentolamine, alpha2A-adrenoceptor knockout (alpha2A-KO) mice were used. EXPERIMENTAL APPROACH: Effects of (+/-)-efaroxan, 5 mg kg(-1), and phentolamine, 1 mg kg(-1), on blood glucose and insulin levels were compared with those of the non-imidazoline alpha2-adrenoceptor antagonist [8aR,12aS,13aS]-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine (RS79948-197), 1 mg kg(-1), and the sulphonylurea glibenclamide, in alpha2A-KO and control (wild type (WT)) mice. KEY RESULTS: In fed WT mice, (+/-)-efaroxan, phentolamine and RS79948-197 reduced blood glucose and increased insulin levels. Fasting abolished these effects. In fed alpha2A-KO mice, (+/-)-efaroxan, phentolamine and RS79948-197 did not alter blood glucose or insulin levels, and in fasted alpha2A-KO mice, blood glucose levels were increased. Glibenclamide, at a dose only moderately efficacious in WT mice (5 mg kg(-1)), caused severe hyperinsulinaemia and hypoglycaemia in alpha2A-KO mice. This was mimicked in WT mice by co-administration of RS79948-197 with glibenclamide. CONCLUSIONS AND IMPLICATIONS: These results suggest that (+/-)-efaroxan and phentolamine increase insulin secretion by inhibition of beta-cell alpha2A-adrenoceptors, and demonstrate a critical role for alpha2A-adrenoceptors in limiting sulphonylurea-induced hyperinsulinaemia and hypoglycaemia.

Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity.

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus.

We tested the hypothesis that defects in insulin stimulation of skeletal muscle blood flow, flow dispersion, and coupling between flow and glucose uptake contribute to insulin resistance of glucose uptake in non-insulin-dependent diabetes mellitus (NIDDM). We used positron emission tomography combined with [15O]H2O and [18F]-2-deoxy--glucose and a Bayesian iterative reconstruction algorithm to quantitate mean muscle blood flow, flow heterogeneity, and their relationship to glucose uptake under normoglycemic hyperinsulinemic conditions in 10 men with NIDDM (HbA1c 8.1+/-0.5%, age 43+/-2 yr, BMI 27.3+/-0.7 kg/m2) and in 7 matched normal men. In patients with NIDDM, rates of whole body (35+/-3 vs. 44+/-3 micromol/kg body weight.min, P < 0.05) and femoral muscle (71+/-6 vs. 96+/-7 micromol/kg muscle.min, P < 0.02) glucose uptake were significantly decreased. Insulin increased mean muscle blood flow similarly in both groups, from 1.9+/-0.3 to 2.8+/-0.4 ml/100 g muscle.min in the patients with NIDDM, P < 0.01, and from 2.3+/-0.3 to 3.0+/-0.3 ml/100 g muscle.min in the normal subjects, P < 0.02. Pixel-by-pixel analysis of flow images revealed marked spatial heterogeneity of blood flow. In both groups, insulin increased absolute but not relative dispersion of flow, and insulin-stimulated but not basal blood flow colocalized with glucose uptake. These data provide the first evidence for physiological flow heterogeneity in human skeletal muscle, and demonstrate that insulin increases absolute but not relative dispersion of flow. Furthermore, insulin redirects flow to areas where it stimulates glucose uptake. In patients with NIDDM, these novel actions of insulin are intact, implying that muscle insulin resistance can be attributed to impaired cellular glucose uptake.

Insulin action on heart and skeletal muscle glucose uptake in essential hypertension.

Essential hypertension is characterized by skeletal muscle insulin resistance but it is unknown whether insulin resistance also affects heart glucose uptake. We quantitated whole body (euglycemic insulin clamp) and heart and skeletal muscle (positron emission tomography and 18F-fluoro-2-deoxy-D-glucose) glucose uptake rates in 10 mild essential hypertensive (age 33 +/- 1 yr, body mass index 23.7 +/- 0.8 kg/m2, blood pressure 146 +/- 3/97 +/- 3 mmHg, VO2max 37 +/- 3 ml/kg per min) and 14 normal subjects (29 +/- 2 yr, 22.5 +/- 0.5 kg/m2, 118 +/- 4/69 +/- 3 mmHg, 43 +/- 2 ml/kg per min). Left ventricular mass was similar in the hypertensive (155 +/- 15 g) and the normotensive (164 +/- 13 g) subjects. In the hypertensives, both whole body (28 +/- 3 vs 44 +/- 3 mumol/kg per min, P < 0.01) and femoral (64 +/- 11 vs 94 +/- 8 mumol/kg muscle per min, P < 0.05) glucose uptake rates were decreased compared to the controls. In contrast, heart glucose uptake was 33% increased in the hypertensives (939 +/- 51 vs 707 +/- 46 mumol/kg muscle per min, P < 0.005), and correlated with systolic blood pressure (r = 0.66, P < 0.001) and the minute work index (r = 0.48, P < 0.05). We conclude that insulin-stimulated glucose uptake is decreased in skeletal muscle but increased in proportion to cardiac work in essential hypertension. The increase in heart glucose uptake in mild essential hypertensives with a normal left ventricular mass may reflect increased oxygen consumption and represent an early signal which precedes the development of left ventricular hypertrophy.

Myocardial oxygen consumption is unchanged but efficiency is reduced in patients with essential hypertension and left ventricular hypertrophy.

BACKGROUND: Patients with hypertension and left ventricular hypertrophy (LVH) are prone to develop heart failure. We tested the hypothesis that compensatory LVH is associated with normalization of myocardial oxygen consumption and that this occurs at the expense of a decrease in the ratio between cardiac work and oxygen consumption (efficiency). METHODS AND RESULTS: Nine hypertensive men with LVH (LVH+) (age 42+/-2 years), left ventricular mass index (LVMI) 161+/-8 g/m(2), blood pressure (BP) 145+/-16/88+/-10 mm Hg (mean+/-SD); 8 hypertensive men without LVH (LVH-) (age 39+/-5 years, LVMI 107+/-15 g/m(2), BP 140+/-15/90+/-11 mm Hg); and 10 normotensive men (CONT) were studied. Myocardial blood flow, oxygen consumption, and glucose uptake were measured during euglycemic hyperinsulinemia using PET techniques. LV dimensions, volumes, and workload were determined by echocardiography, and efficiency was calculated. Myocardial workload (2.5+/-0.8 versus 3.0+/-0.6 versus 2. 3+/-0.5 mm Hg. mL. min(-1). g(-1) for CONT versus LVH- versus LVH+; P<0.05, LVH- versus LVH+), myocardial blood flow (0.84+/-0.16 versus 1.06+/-0.22 versus 0.81+/-0.09 mL. g(-1). min, respectively; P<0.05, LVH- versus other groups) and oxygen consumption (0.09+/-0.02 versus 0.14+/-0.03 versus 0.11+/-0.01 ml. g(-1). min(-1), respectively; P<0. 05, LVH- versus other groups) were increased in the LVH- group. Myocardial efficiency was reduced in the LVH+ group (18.1+/-4.1% versus 15.1+/-2.3% versus 13.5+/-1.9%, respectively; P<0.05, LVH+ versus CONT). CONCLUSIONS: Myocardial oxygen consumption per unit weight is increased in hypertensive patients without LVH but is normal in those with LVH. The normalization of oxygen consumption via hypertrophy occurs at the expense of efficiency, which may predispose hypertensive patients with LVH to heart failure.

Myocardial glucose uptake in patients with NIDDM and stable coronary artery disease.

Whole body insulin resistance characterizes patients with NIDDM, but it is not known whether insulin also has impaired ability to stimulate myocardial glucose uptake (MGU) in these patients. This study was designed to evaluate MGU as measured by 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) in patients with NIDDM and stable coronary artery disease (CAD) under standardized metabolic conditions. Eight patients with NIDDM, 11 nondiabetic patients with CAD, and 9 healthy control subjects were enrolled in the study. MGU was quantitated in the normal myocardial regions with [18F]FDG and PET and the whole body glucose disposal by glucose-insulin clamp technique (serum insulin, -430 pmol/l). Plasma glucose and serum insulin concentrations were comparable in all groups during PET studies. The whole body glucose uptake was 45% lower in NIDDM patients (22 +/- 9 micromol x min(-1) X kg(-1) body wt [mean +/- SD]), compared with healthy control subjects (40 +/- 17 micromol x min(-1) x kg(-1) body wt, P < 0.05). In CAD patients, whole body glucose uptake was 30 +/- 9 micromol x min(-1) x kg(-1) body wt (NS between the other groups). MGU was similar in the normal segments in all three groups (69 +/- 28 micromol x min(-1) x 100 g(-1) in NIDDM patients, 72 +/- 17 micromol x min(-1) x 100 g(-1) in CAD patients, and 76 +/- 10 micromol x min(-1) x 100 g(-1) in healthy control subjects, NS). No correlation was found between whole body glucose uptake and MGU. As studied by [18F]FDG PET under stable normoglycemic hyperinsulinemic conditions, MGU is not reduced in patients with NIDDM and CAD in spite of peripheral insulin resistance. These findings suggest that there is no significant defect in MGU in patients with NIDDM.

Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid.

Free fatty acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA), a fatty acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.

Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography.

Good insulin sensitivity is independently associated with a low risk for coronary heart disease, but it is unclear whether this risk factor differs between men and women. We compared insulin sensitivity of glucose uptake directly in muscle and heart tissues between healthy women (age 29 +/- 2 years, body mass index [BMI] 22 +/- 1 kg/m2, VO2max 39 +/- 4 ml.kg-1.min-1) and men matched for age (31 +/- 2 years), BMI (23 +/- 1 kg/m2), and VO2max (44 +/- 3 ml.kg-1.min-1) using [18F]fluoro-2-deoxy-D-glucose and positron emission tomography under hyperinsulinemic (insulin infusion rate 1 mU.kg-1.min-1) normoglycemic conditions. Whole body insulin sensitivity was 41% greater in women (52 +/- 6 mumol.kg body wt-1.min-1) than in men (37 +/- 3 mumol.kg body wt-1.min-1, P < 0.05). This difference was explained by a 47% greater rate of glucose uptake by femoral muscles (113 +/- 10 vs. 77 +/- 7 mumol.kg muscle-1.min-1, women vs. men, P < 0.01). Insulin-stimulated glucose uptake rates in the heart were similar in women (738 +/- 58) and men (749 +/- 62 mumol.kg muscle-1.min-1). Femoral muscle insulin sensitivity was closely correlated with whole body insulin sensitivity (r = 0.84, P < 0.001). Gender and VO2max together explained 68% of the variation in femoral muscle glucose uptake. We conclude that women are more sensitive to insulin than equally fit men because of enhanced muscle but not heart insulin sensitivity.

Evidence for dissociation of insulin stimulation of blood flow and glucose uptake in human skeletal muscle: studies using [15O]H2O, [18F]fluoro-2-deoxy-D-glucose, and positron emission tomography.

We determined the effect of insulin on muscle blood flow and glucose uptake in humans using [15O]H2O, [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), and positron emission tomography (PET). Femoral muscle blood flow was measured in 14 healthy volunteers (age 34 +/- 8 years, BMI 24.6 +/- 3.4 kg/m2 [means +/- SD]) before and at 75 min during a 140-min high-dose insulin infusion (serum insulin 2,820 +/- 540 pmol/l) under normoglycemic conditions. A dynamic scan of the femoral region was performed using PET for 6 min after injection of [15O]H2O to determine the 15O concentration in tissue. Regional femoral muscle blood flow was calculated using an autoradiographic method from the dynamic data obtained with PET and [15O]H2O. Femoral muscle glucose uptake was measured during hyperinsulinemia immediately after the flow measurement using PET-derived [18F]FDG kinetics and a three-compartment model. Whole-body glucose uptake was quantitated using the euglycemic insulin clamp technique. In the basal state, 84 +/- 8% of blood flow was confined to skeletal muscle. Insulin increased leg blood flow from 29 +/- 14 to 54 +/- 29 ml x kg-1 leg x min-1 (P < 0.001) and muscle flow from 31 +/- 18 to 58 +/- 35 ml x kg-1 muscle x min-1 (P < 0.005). Under insulin-stimulated conditions, 81 +/- 8% of blood flow was in muscle tissue (NS versus basal). Skeletal muscle explained 70 +/- 25% of the increase in leg blood flow. No correlation was observed between blood flow and glucose uptake when analyzed individually in identical regions of interest within femoral muscles. These data demonstrate that skeletal muscle accounts for most of the insulin-induced increase in blood flow. Insulin-stimulated rates of blood flow and glucose uptake do not colocalize in the same regions of muscle tissue, suggesting that insulin's hemodynamic and metabolic effects are differentially regulated.

High levels of dopamine activity in the basal ganglia of cigarette smokers.

OBJECTIVE: The authors' goal was to study presynaptic dopamine activity in smoking and nonsmoking human subjects in vivo. METHOD: [(18)F]Fluorodopa ([(18)F]DOPA) uptake K(i) values in the basal ganglia of nine smoking and 10 nonsmoking healthy men were measured with positron emission tomography. RESULTS: Significantly higher [(18)F]DOPA uptake was observed in both the putamen (average 17.3% higher) and the caudate (average 30.4% higher) of smokers than in those of nonsmokers. CONCLUSIONS: Smoking is related to greater dopamine activity in the human basal ganglia. Nicotine-induced dopamine activity may be a relevant mechanism in dependence on cigarette smoking.

Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography.

OBJECTIVE: Recent in vivo imaging studies indicate a dysregulated presynaptic function of the striatal dopaminergic system in patients with schizophrenia. To further explore the basis of this phenomenon, the authors studied brain dopamine transporter binding in vivo in patients with first-episode, never-medicated schizophrenia. METHOD: Nine patients with schizophrenia and nine healthy matched comparison subjects were recruited. Striatal dopamine transporter binding was measured with positron emission tomography and a specific dopamine transporter ligand, [(18)F]CFT, a radiolabeled form of 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane. RESULTS: Average caudate and putamen dopamine transporter binding potentials were almost identical in the patients and comparison subjects, but the patients lacked the right-left asymmetry of the caudate dopamine transporter binding seen in the comparison group. CONCLUSIONS: Average striatal dopamine transporter density is unaltered in neuroleptic-naive patients with schizophrenia. However, patients lack asymmetry in caudate dopamine transporter binding, which conforms with disrupted brain lateralization in this disorder.

Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission tomographic study.

OBJECTIVE: To investigate the role of the brain dopaminergic system in cognitive impairment in patients with Parkinson disease (PD). DESIGN: We studied 28 patients with PD and 16 age-matched healthy control subjects using [18F] fluorodopa (fluorodopa F 18) positron emission tomography. Patients with PD showed a variable degree of cognitive impairment, which was assessed using the Mini-Mental State Examination and detailed neuropsychologic assessment, including tests sensitive for frontal lobe function. RESULTS: [18F] Fluorodopa uptake was reduced in the putamen (to 36% of the control mean; P<.001), the caudate nucleus (to 61% of the control mean; P<.001), and the frontal cortex (to 45% of the control mean; P<.001) in patients with PD compared with controls. There was no significant association between the degree of overall cognitive impairment of patients and [18F] fluorodopa uptake values. The influx constant (Ki(occ)) in the caudate nucleus had a negative association with performance in the attention-demanding Stroop interference task, especially with the interference time. The Ki(occ) in the frontal cortex had a positive correlation with performance in the digit span (backwards), verbal fluency, and verbal immediate recall tests. Thus, the better the patient performed in tasks demanding immediate and working memory and executive strategies, the better the [18F] fluorodopa uptake in the frontal cortex. In the putamen, no significant correlation was seen between the Ki(occ) value and any of the cognitive tests. The severity of the motor symptoms of PD and [18F]fluorodopa uptake showed a negative correlation in the putamen (r = -0.38; P = .04), and in the caudate nucleus a similar trend was seen (r = -0.36; P = .06). CONCLUSIONS: Reduced [18F]fluorodopa uptake in PD in the caudate nucleus (and frontal cortex) is related to impairment in neuropsychologic tests measuring verbal fluency, working memory, and attentional functioning reflecting frontal lobe function. This indicates that dysfunction of the dopamine system has an impact on the cognitive impairment of patients with PD. However, our results do not exclude the possibility of more generalized cognitive impairment in PD, the pathophysiology of which is probably different and more generalized.

[18F]FDG-PET reveals temporal hypometabolism in patients with temporal lobe epilepsy even when quantitative MRI and histopathological analysis show only mild hippocampal damage.

BACKGROUND: The relationship between reduced glucose metabolism in positron emission tomography with fludeoxyglucose F 18 ([(18)F]FDG-PET) and hippocampal damage (HD) in patients with temporal lobe epilepsy is still unclear. OBJECTIVE: To determine whether the presence and severity of HD verified by quantitative magnetic resonance imaging (QMRI) and histopathological analysis affect the degree of hypometabolism. PATIENTS AND METHODS: Sixteen patients with drug-resistant temporal lobe epilepsy underwent [(18)F]FDG-PET and QMRI (hippocampal volumetry and T2 relaxometry) before surgery. Histopathological analysis of the hippocampus included measurements of neuronal loss, proliferation of glial cells, and mossy fiber sprouting. The asymmetry in glucose metabolism described the degree of hypometabolism. RESULTS: Temporal hypometabolism was not related to severity of HD as measured by QMRI or histopathological analysis. The degree of hypometabolism did not differ in patients with mild, moderate, or severe HD. In addition, [(18)F]FDG-PET revealed significant temporal hypometabolism even though hippocampal QMRI findings were normal or showed only mild HD. Thus, glucose consumption was reduced over and above the histopathological changes. CONCLUSIONS: [(18)F]FDG-PET is sensitive for localizing the epileptogenic region in patients with temporal lobe epilepsy. However, it is insensitive to reflect the severity of HD.

[18F]-6-fluorodopa PET scanning in Parkinson's disease after selective COMT inhibition with nitecapone (OR-462).

PET studies were performed to investigate the effects of a new cathechol-O-methyltransferase (COMT) inhibitor, nitecapone (OR-462 [3-(3,4-dihydroxy-5-nitrobenzylidene)- 2,4-pentadione]), on the accumulation of dopamine in the striatum and whether it is able to improve [18F]6-fluorodopa imaging of the brain. Altogether, three patients with Parkinson's disease (PD) and three normal volunteers were examined, first without nitecapone and then with an oral dose of 100 mg of nitecapone 1 hour before the IV injection of 3 mCi of [18F]6-fluorodopa. High-pressure liquid chromatography analysis of arterial plasma samples showed a significant reduction in the metabolic conversion rate from [18F]6-fluorodopa to [18F]3-O-methylfluorodopa after the administration of nitecapone. PET studies showed that nitecapone significantly (p less than 0.05) increased the [18F]6-fluorodopa accumulation in the striatum both in PD patients and normal controls; the magnitude of this increase was 20.0 +/- 5.5% (mean +/- SEM). The ratio of radioactivity in the striatum and arterial plasma was increased 39.0 +/- 5.0% (mean +/- SEM) after the administration of nitecapone. Consequently, the quality of PET images after OR-462 was better, which has implications for future [18F]6-fluorodopa studies. In addition, COMT inhibition may have clinical advantages by improving levodopa treatment in PD.

An FDOPA PET study in patients with periodic limb movement disorder and restless legs syndrome.

The authors investigated nine drug-naive patients with periodic limb movement disorder and restless legs syndrome (PLMD-RLS) and 27 healthy controls with PET using 6-[18F]fluoro-L-dopa (FDOPA). In the patients, the FDOPA uptake (Ki(occ)) in the caudate nucleus was 88% and in the putamen 89% of the control mean values. This equal affection of the caudate and the putamen differs, for example, from the dopaminergic dysfunction in Parkinson's disease, which affects the putamen earlier and more severely than the caudate. The current results indicate mild nigrostriatal presynaptic dopaminergic hypofunction in PLMD-RLS.

Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle.

OBJECTIVE: To determine whether insulin-stimulated blood flow in patients with mild essential hypertension is altered. SUBJECTS: Eleven untreated mildly hypertensive patients [aged 35 +/- 2 years, body mass index 25.1 +/- 0.4 kg/m2, mean arterial pressure 110 +/- 2 mmHg (means +/- SEM) and 10 matched normotensive subjects (mean arterial pressure 94 +/- 3 mmHg). METHODS: Blood flow was quantitated directly in skeletal muscle both basally and during supraphysiologic hyperinsulinemia (serum insulin approximately = 450 mU/l) using radiowater ([15O]H2O) and positron emission tomography. Whole-body and femoral muscle glucose uptakes were determined using the euglycemic insulin clamp technique, [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography. RESULTS: Rates of whole-body and femoral muscle glucose uptake were significantly lower in the hypertensive than in the normotensive group. Insulin increased muscle blood flow by 91% in the normotensive group, but only by 33% in the hypertensive group. CONCLUSIONS: The ability of insulin to stimulate blood flow in patients with mild essential hypertension is impaired.

Free fatty acid uptake in the myocardium and skeletal muscle using fluorine-18-fluoro-6-thia-heptadecanoic acid.

UNLABELLED: 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) has been recently introduced as a new tracer for fatty acid metabolism. Myocardial [18F]FTHA uptake is believed to reflect mainly beta-oxidation of the circulating free fatty acids (FFAs), since it is trapped in the mitochondria because subsequent steps of beta-oxidation are inhibited by sulfur heteroatom. We investigated [18F]FTHA kinetics in myocardial and skeletal muscle in vivo. METHODS: Two dynamic PET studies were performed in seven patients with stable coronary artery disease, once in the fasting state and once during euglycemic hyperinsulinemia (serum insulin approximately 60 mU/liter). The fractional [18F] FTHA uptake rates (Ki) were multiplied with serum FFA concentrations and were considered to represent FFA uptake. RESULTS: Serum FFA concentration decreased by 80% during insulin clamp. After tracer injection, rapid myocardial uptake was identified both in the fasting state and during insulin stimulation. The cardiac image quality was excellent in both occasions. In addition, femoral muscles were clearly visualized in both studies. The fractional myocardial [18F]FTHA uptake rates (Ki) in the normal myocardial regions were similar in the fasting state (0.11 +/- 0.04 ml/g/min (mean +/- s.d.) and during insulin clamp (0.12 +/- 0.03 ml/g/min; ns). The calculated myocardial FFA uptake was four times higher in the fasting state than during insulin clamp (5.8 +/- 1.7 versus 1.4 +/- 0.5 micromol/100 g/min, p < 0.005). The femoral muscle fractional [18F]FTHA uptake rates (Ki) were lower (0.0071 +/- 0.0014 ml/g/min) in the fasting state than during insulin clamp (0.0127 +/- 0.0036 ml/g/min; p = 0.03), but the estimated femoral muscle FFA uptake was three times higher in the fasting state (0.38 +/- 0.09 micromol/100 g/min) as compared to that during insulin clamp (0.12 +/- 0.05 micromol/100 g/min, p < 0.005). CONCLUSION: Fluorine-18-FTHA PET appears to be a feasible method to estimate fatty acid kinetics in myocardial and skeletal muscle. Physiologically reasonable rates of FFA uptake in myocardium and skeletal muscle were obtained. Furthermore, the uptake rates were suppressed in response to insulin both in the myocardial and femoral muscle as expected.

Prediction of survival with fluorine-18-fluoro-deoxyglucose and PET in head and neck cancer.

UNLABELLED: The aim of this prospective study was to investigate if high uptake of 18F-fluoro-2-deoxy-D-glucose (FDG) is associated with aggressiveness in head and neck cancer and low probability of survival. METHODS: Thirty-seven patients with squamous-cell carcinoma of the head and neck underwent FDG-PET in the fasting state before cancer treatment. FDG uptake in primary tumor was quantitated as the standardized uptake value of FDG normalized to the predicted lean body mass (SUVlean, n = 37) and as the graphically determined metabolic rate for FDG (rMR[FDG], n = 34). Paraffin-embedded tumor samples were used for histologic evaluation, and expression of cytokeratin and Ki-67 antigen were assessed by immunohistochemistry. RESULTS: Interobserver agreement for the determination of quantitative uptake of FDG in tumors was excellent (r2 = 0.996, p < 0.00001), and all 37 primary tumors were visualized. A high uptake of FDG as assessed by SUVlean was associated with a higher than the median mitotic count (p = 0.01), absence of keratinization (p = 0.03), low or moderate histological grade of differentiation (p = 0.046) and advanced stage (p = 0.03), but not with Ki-67 expression (p = 0.11). The overall survival of patients with a SUVlean lower than or equal to the median value (9.0) was clearly better in univariate analysis than that of patients with a SUVlean higher than the median (3-yr survival 73% versus 22%, relative risk of death (RR) 4.2, 1.6-11.0). However, in a multivariate analysis the only independent predictors of survival were the mitotic count (RR 4.0, 1.4-11.7) and stage (3.8, 1.2-12.2). CONCLUSION: High uptake of FDG in untreated head and neck cancer is associated with advanced disease, and may portend poor survival. Aggressive treatment approaches should be considered for patients presenting with a tumor with high uptake of FDG.