Automated GMP production and long-term experience in radiosynthesis of CB1 tracer [18 F]FMPEP-d2.

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB1 receptor imaging tracer (3R,5R)-5-(3-([18 F]fluoromethoxy-d2 )phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([18 F]FMPEP-d2 ), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic 18 F-fluorination of an alkylating agent and its GC purification, the subsequent 18 F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the 18 F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the 18 F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013-2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/µmol at the end of synthesis.

Automated production of [18 F]FTHA according to GMP.

14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid is a tracer for fatty acid imaging by positron emission tomography. High demand for this tracer required us to replace semiautomatic synthesis with a fully automated procedure. An automated synthesis device was constructed in-house for multistep nucleophilic 18 F-fluorination and a control system was developed. The synthesis device was combined with a sterile filtration unit and both were qualified. 14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid was produced according to good manufacturing practice guidelines set by the European Union. The synthesis includes an initial nucleophilic labelling reaction, deprotection, preparative HPLC separation, purification of the final product, and formulation for injection. The duration and temperature of the reaction and hydrolysis were optimized, and the radiochemical stability of the formulated product was determined. The rotary evaporator used to evaporate the solvent after HPLC purification was replaced with solid phase extraction purification. We also replaced the human serum albumin used in the earlier procedure with a phosphate buffer-ascorbic acid mixture in the final formulation solution. From 2011 to 2016, we performed 219 synthesis procedures, 94% of which were successful. The radiochemical yield of 14-(R,S)-[18 F]fluoro-6-thia-heptadecanoic acid, decay-corrected to the end of bombardment, was 13% ± 6.3%. The total amount of formulated end product was 1.7 ± 0.8 GBq at end of synthesis.

[18F]Fluoride uptake in various bone types and soft tissues in rat.

BACKGROUND: In the development of new 18F-labelled tracers, it is important to assess the amount of released [18F]fluoride taken up in the bones of experimental animals because all 18F-labelled PET-tracers are prone, to lesser or higher degree, to undergo defluorination, with subsequent release of [18F]fluoride during scanning. However, the pharmacokinetics of [18F]fluoride in bones and other organs of healthy rats have not been well documented in a comprehensive manner. We aimed to study pharmacokinetics of [18F]NaF in rats in order to increase our understanding of the biodistribution of [18F]fluoride originating from defluorination of 18F-labelled tracers. We studied [18F]fluoride uptake in Sprague Dawley rat bones, including the epiphyseal parts of the tibia and radius, the mandible, ilium, lumbar vertebrae, costochondral joints, tibia, radius, and ribs, with 60-min in vivo PET/CT imaging. Kinetic parameters, K1, Ki, Ki/K1, and k3 were calculated with a three-compartment model. In addition, separate groups of male and female rats were studied with ex vivo bone and soft tissue harvesting and gamma counting over a 6-h period. RESULTS: [18F]fluoride perfusion and uptake varied among the different bones. [18F]fluoride uptake was higher in trabecular bones, due to high perfusion and osteoblastic activity, compared to cortical bones. In soft tissues, the organ-to-blood uptake ratios increased over time in the eyes, lungs, brain, testes, and ovaries during the 6 h study period. CONCLUSION: Understanding the pharmacokinetics of [18F]fluoride in various bones and soft tissues is highly useful for assessing 18F-labelled radiotracers that release [18F]fluoride.

Novel electrophilic synthesis of 6-[¹8F]fluorodopamine and comprehensive biological evaluation.

PURPOSE: 6-[(18)F]Fluorodopamine (4-(2-aminoethyl)-5-[(18)F]fluorobenzene-1,2-diol, 6-[(18)F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[(18)F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/µmol. We also sought to determine an extensive biodistribution pattern for 6-[(18)F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[(18)F]FDA. In addition, to investigate the safety profile of 6-[(18)F]FDA in larger animals, we performed in vivo studies in pigs. METHODS: 6-[(18)F]FDA was synthesised using high SA electrophilic [(18)F]F(2) as the labelling reagent. Biodistribution and metabolism of 6-[(18)F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs. RESULTS: 6-[(18)F]FDA was synthesised with 2.6 ± 1.1% radiochemical yield. The total amount of purified 6-[(18)F]FDA was 663 ± 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 ± 2.7 GBq/µmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[(18)F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[(18)F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects. CONCLUSION: 6-[(18)F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[(18)F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[(18)F]FDA was specific in various peripheral organs, indicating that 6-[(18)F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.

The clinical value of [18F]fluoro-dihydroxyphenylalanine positron emission tomography in primary diagnosis, staging, and restaging of neuroendocrine tumors.

The study was set up to determine the clinical value of dihydroxyphenylalanine positron emission tomography-computed tomography ([(18)F]DOPA PET-CT) in patients with neuroendocrine tumors (NETs). Eighty-two patients with suspected/known NET were imaged with PET(-CT) using [(18)F]DOPA. Patients were divided into two groups: primary diagnosis/staging and restaging of disease. All patients without previous diagnosis of NET had biochemical proof of disease. The diagnostic accuracy of PET was assessed by comparing the histopathology and clinical follow-up. The overall accuracy of [(18)F]DOPA PET was 90%. In patients having PET for primary diagnosis/staging (n=32), the accuracy of PET was 88%, and for restaging 92% (n=61). The mean s.d. sizes of primary and metastatic lesions detected by PET were 26+/-11 and 16+/-9 mm respectively. In organ-region-specific analysis, the sensitivity and specificity were 100% in the primary diagnosis of pheochromocytoma (n=16) and metastases were found in all cases with recurrent disease (n=5). The accuracy for NET of gastrointestinal tract was 92% in restaging (n=24). For the NETs located in the head-neck-thoracic region (n=19), the overall accuracy of PET was 89% including 12 cases of recurrent medullary thyroid cancer with a sensitivity of 90%. In analysis of patients with biochemical proof of disease combined with negative conventional imaging methods, PET had positive and negative predictive value of 92% and 95% respectively. [(18)F]DOPA PET-CT provided important additional information in the diagnosis of pheochromocytoma and restaging of known NET. Both in primary diagnosis and in patients with formerly known NET and increasing tumor markers, [(18)F]DOPA PET-CT is a sensitive first-line imaging method.

A follow-up study on 6-[18F]fluoro-L-dopa uptake in early Parkinson's disease shows nonlinear progression in the putamen.

Sixteen subjects with de novo Parkinson's disease (PD) underwent three 6-[18F]fluoro-L-dopa (Fdopa) positron emission tomography (PET) scans during a follow-up time of 5 years (mean +/- SD 5.5 +/- 0.4 years) to study the progression of striatal dopaminergic hypofunction. Throughout the study, the smallest Fdopa uptake values were found in the dorso-caudal part of the putamen contralateral to the side with dominant motor symptoms. The rate of decline in Fdopa uptake in the contralateral putamen was faster in the beginning of the disease and slowed down as the disease progressed. The annual decline in Fdopa influx constant (Ki, unit x 10(-3) min(-1)) was on average 0.5 during the first 2 years and 0.2 during the subsequent 3 years (P = 0.002) in the contralateral putamen. In caudate, the rate of decline in Fdopa values was slower than in the putamen and did not change significantly during the follow-up time, annual decline in the contralateral caudate being 0.1 between baseline and 2 years and 0.3 between 2 and 5 years (P = 0.4). These results suggest that progression of putaminal dopaminergic hypofuncion in PD follows a nonlinear pattern at least in the contralateral side being faster in the beginning of the disease.

Comparison of 2D and 3D performance for FDG PET with different acquisition times in oncological patients.

OBJECTIVE: Collecting positron emission tomography data in three-dimensional (3D) mode may potentially allow reduction of the tracer dose and/or the acquisition time without compromising image quality thereby making the procedure more patient-friendly and cost effective. The objective of our study was to compare VUE Point iterative reconstruction algorithm in positron emission tomography data obtained in 3D and two-dimensional (2D) mode in routine clinical diagnostic setting in oncological patients. METHODS: Standard whole-body imaging (33 patients) was followed by rescanning of the target region in 2D and 3D mode. The ListMode data were histogrammed to 4, 3 and 2 min frames. Visual and semiquantitative analyses were performed. Effects of tumour volume and body mass index on tissue visualisation were evaluated. RESULTS: Visual image quality in 3D mode was superior to 2D. Maximum and mean standardised uptake values of tumours did not differ between 2D and 3D. Mean background standardised uptake values were significantly lower in 3D compared with 2D. 3D tumour to background ratios were higher than 2D in small lesions and obese patients (body mass index > or = 30) with all acquisition times. CONCLUSION: The new reconstruction method produces images of similar or better quality with 3D compared with 2D mode. The difference is pronounced in small lesions and in obese patients. According to our study, 3D is the preferred acquisition mode for routine whole-body evaluation of oncological patients.

[18F]SPA-RQ/PET Study of NK1 receptors in the Whole Body of Guinea Pig and Rat.

There is a substantial interest in the development of NK1 substance P antagonists as potential treatments for various neuropsychiatric and somatic disorders. The aim of this study was to determine whether [18F]SPA-RQ can be utilized as a tool for studying the whole body distribution and function of NK1 receptors in preclinical settings. The compound was injected into guinea pigs with or without premedication with a NK1 receptor antagonist (NK1A-2). For comparison, we included two rats in the study, as the affinity of antagonists for NK1 receptors is known to vary between species. The whole body biodistribution of the tracer was determined at several time points. The tracer showed specific binding in organs compatible with the known location of NK1-receptors. Premedication with a NK1 antagonist led to an inhibited uptake of [18F]SPA-RQ in several organs of guinea pigs, notably intestine, pancreas, urinary bladder, uterus, skin and lung. Specific binding was also seen in both cortex and striatum. In contrast, negligible specific binding was observed in the rat brain with [18F]SPA-RQ, whereas the tracer uptake in peripheral tissues was similar to that seen in guinea pigs. We conclude that [18F]SPA-RQ/PET is a useful tool to study the distribution and function of peripherally located NK1 receptors e.g. in different disease models.

Influence of transport line material on the molar activity of cyclotron produced [18F]fluoride.

INTRODUCTION: Production of fluorine-18-labeled radiopharmaceuticals is always associated with the varying levels of the same compound containing stable fluorine-19. In practice, this affects the molar activity (Am), defined as amount of radioactivity divided by the molar quantity (Bq/mol). We have focused on studying how the material of the transport tubing connecting the cyclotron target chamber to the synthesis device affects the concentration of fluoride in the water arriving to the reaction vessel and subsequently the Am of the fluorine-18 labeled radiopharmaceuticals produced. METHODS: Batches of irradiated and non-irradiated water were analyzed for fluoride content after being transported via non-fluorinated (PEEK, PP) and fluorinated (PTFE, ETFE) tubing or using no tubing at all. Am for the [18F]fluoride was determined and compared with the Am of [18F]fluciclatide, synthesized from the same [18F]fluoride containing batches of water. RESULTS: Significantly higher concentrations of fluoride were seen in irradiated water that was transported in fluorinated tubing compared to non-irradiated water transported in tubing of the same material. This elevation of fluoride concentration is presumably caused by the interaction of ionizing radiation with the fluorinated tubing used between the target chamber and hot cell. Likewise, a significant difference was seen for PEEK tubing (non-fluorinated). This could be due to the fact that fluorine containing compounds are used in the manufacture of PEEK. When using fluorinated tubing for transport of the irradiated water, the resulting fluciclatide concentrations were significantly higher compared to when using non-fluorinated tubing. No significant difference was seen between fluciclatide concentrations when PTFE or ETFE tubing was compared to each other. Using no tubing resulted in lowest fluciclatide concentration. CONCLUSIONS: Fluorinated tubing is a source of stable fluoride, and Am can be increased by using non-fluorinated transport tubing. Of all the tubing materials studied PP is preferred.

Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography as a tool to localize an insulinoma or beta-cell hyperplasia in adult patients.

CONTEXT AND OBJECTIVE: Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) is a promising method in localizing neuroendocrine tumors. Recently, it has been shown to differentiate focal forms of congenital hyperinsulinism of infancy. The current study was set up to determine the potential of 18F-DOPA PET in identifying the insulin-secreting tumors or beta-cell hyperplasia of the pancreas in adults. PATIENTS AND METHODS: We prospectively studied 10 patients with confirmed hyperinsulinemic hypoglycemia and presumed insulin-secreting tumor using 18F-DOPA PET. Anatomical imaging was performed with computed tomography (CT) and magnetic resonance imaging (MRI). All patients were operated on, and histological verification was available in each case. Semiquantitative PET findings in the pancreas using standardized uptake values were compared to standardized uptake values of seven consecutive patients with nonpancreatic neuroendocrine tumors. RESULTS: By visual inspection of 18F-DOPA PET images, it was possible in nine of 10 patients to localize the pancreatic lesion, subsequently confirmed by histological analysis. 18F-DOPA uptake was enhanced in six of seven solid insulinomas and in the malignant insulinoma and its hepatic metastasis. Two patients with beta-cell hyperplasia showed increased focal uptake of 18F-DOPA in the affected areas. As compared to CT or MRI, 18F-DOPA PET was more sensitive in localizing diseased pancreatic tissue. CONCLUSION: 18F-DOPA PET was useful in most patients with insulinoma and negative CT, MRI, and ultrasound results. In agreement with previous findings in infants, preoperative 18F-DOPA imaging seems to be a method of choice for the detection of beta-cell hyperplasia in adults. It should be considered for the detection of insulinoma or beta-cell hyperplasia in patients with confirmed hyperinsulinemic hypoglycemias when other diagnostic work-up is negative.

Planar chromatographic analysis and quantification of short-lived radioactive metabolites from microdialysis fractions.

A sensitive radiochromatographic method for the quantitative determination of compounds labelled with short-lived beta-emitting radionuclides in microdialysates is described. The method is well suited for microdialysis (MD) samples, which have small volumes and low concentrations of compounds. An 18F-labelled (beta+; T(1/2)=109.8 min) radiopharmaceutical, (1R,2S)-4-[18F]fluorometaraminol (FMR), was injected intravenously into rats, and microdialysis fractions were then collected from the blood at 15 min intervals. Fractions were analyzed for FMR and its radioactive metabolites by planar chromatography combined with digital photostimulated luminescence autoradiography. The lowest detectable 18F-radioactivity was 0.24 Bq/application and the limit of quantification was 0.31 Bq/application with 4-16 h exposure. The method was found to be highly sensitive and linear in the range of 0.1 Bq-2 kBq. This method thus allows the quantification of beta-emitting radiopharmaceuticals in sequential microdialysis fractions with good time-resolution.

(18)F-Labeling of Mannan for Inflammation Research with Positron Emission Tomography.

Recently mannan from Saccharomyces cerevisiae has been shown to be able to induce psoriasis and psoriatic arthritis in mice, and the phenotypes resemble the corresponding human diseases. To investigate the pathological processes, we set out to label mannan with fluorine-18 ((18)F) and study the (18)F-labeled mannan in vitro and in vivo with positron emission tomography (PET). Accordingly, mannan has been transformed into (18)F-fluoromannan with (18)F-bicyclo[6.1.0]nonyne. In mouse aorta, the binding of [(18)F]fluoromannan to the atherosclerotic lesions was clearly visualized and was significantly higher compared to blocking assays (P < 0.001) or healthy mouse aorta (P < 0.001). In healthy rats the [(18)F]fluoromannan radioactivity accumulated largely in the macrophage-rich organs such as liver, spleen, and bone marrow and the excess excreted in urine. Furthermore, the corresponding (19)F-labeled mannan has been used to induce psoriasis and psoriatic arthritis in mice, which indicates that the biological function of mannan is preserved after the chemical modifications.

Cortical 6-[18F]fluoro-L-dopa uptake and frontal cognitive functions in early Parkinson's disease.

Patients with Parkinson's disease (PD) have already at the early stages of the disease impaired performance especially in tests measuring frontal lobe functions such as attention. The pathophysiological basis of these deficits is unclear. In the present study, 21 non-demented, non-medicated patients at the early stage of PD and 24 healthy controls underwent a positron emission tomography (PET) scan with 6-[18F]fluoro-L-dopa (Fdopa) as the tracer. In addition, the PD patients performed a neuropsychological test battery, including a test measuring sustained attention (VIG) and a test requiring suppressed attention (Stroop). Both voxel-based Statistical Parametric Mapping (SPM) and automated region of interest (ROI) analysis were employed. Compared to controls, the PD patients had decreased Fdopa uptake in the striatum and a large cortical area of increased Fdopa uptake. The reaction time in the VIG test correlated positively with the Fdopa uptake of the dorsolateral prefrontal cortex and the performance in the Stroop test correlated negatively with the Fdopa uptake in an area including the medial frontal cortex and the anterior cingulate. The results show that cortical Fdopa uptake is increased in early non-medicated PD and suggest that the changes in frontal Fdopa uptake are related to cognitive impairments found in early PD.

Visualization and quantification of neurokinin-1 (NK1) receptors in the human brain.

PURPOSE: This study was conducted to develop a new positron emission tomography (PET) method to visualize neurokinin-1 (NK(1)) receptor systems in the human brain in vivo in order to examine their neuroanatomical distribution and facilitate investigations of the role of substance P, NK(1) receptors, and NK(1) receptor antagonists in central nervous system (CNS) function and dysfunction. METHODS: PET studies were conducted in 10 healthy male volunteers using a novel selective, high-affinity NK(1) receptor antagonist labeled with fluorine-18 to very high specific radioactivity (up to 2000 GBq/micromol) [F-18]SPA-RQ. Data were collected in 3D mode for greatest sensitivity. Different modeling methods were compared and regional receptor distributions determined for comparison with in vitro autoradiographic studies using postmortem human brain slices with [F-18]SPA-RQ. RESULTS: The studies showed that the highest uptake of [F-18]SPA-RQ was observed in the caudate and putamen. Lower binding was found in globus pallidus and substantia nigra. [F-18]SPA-RQ uptake was also widespread throughout the neocortex and limbic cortex including amygdala and hippocampus. There was very low specific uptake of the tracer in the cerebellar cortex. The distribution pattern was confirmed using in vitro receptor autoradiography with [F-18]SPA-RQ on postmortem human brain slices. Kinetic modeling of the [F-18]SPA-RQ uptake data indicated a binding potential between 4 and 5 in the basal ganglia and between 1.5 and 2.5 in the cortical regions. CONCLUSIONS: [F-18]SPA-RQ is a novel tool for exploration of the functions of NK(1) receptors in man. [F-18]SPA-RQ can be used to define receptor pharmacodynamics and focus dose selection of novel NK(1) receptor antagonists in clinical trials thereby ensuring adequate proof of concept testing particularly in therapeutic applications related to CNS dysfunction.

Effect of training status on regional disposal of circulating free fatty acids in the liver and skeletal muscle during physiological hyperinsulinemia.

OBJECTIVE: Fat metabolism is increasingly implicated in the pathogenesis of type 2 diabetes. Endurance training has been shown to prevent hepatic steatosis and to alter skeletal muscle fat metabolism, and regional free fatty acid (FFA) uptake adaptations were suggested as a mechanism. Thus, we tested whether endurance training modifies the uptake of plasma FFAs occurring in the liver and in skeletal muscle during anabolic, i.e., hyperinsulinemic, conditions. RESEARCH DESIGN AND METHODS: Trained and untrained healthy male subjects underwent positron emission tomography scanning of the liver and thigh regions, with the FFA analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid, during euglycemic hyperinsulinemia. Tracer influx rate constants in skeletal muscle (MK(i)) and liver (LK(i)) were multiplied by plasma FFA levels to obtain FFA uptake for skeletal muscle (MFU) and liver (LFU), respectively. RESULTS: Athletes showed increased Vo(2max) (P < 0.0001), insulin-mediated glucose disposal (M value, 61 +/- 4 vs. 46 +/- 3 micromol. min(-1). kg(-1), P = 0.01), and plasma lactate levels during the clamp and lower percentage of body fat mass (P = 0.002). MK(i) was 25% higher in athletes than in sedentary men (P = 0.03). In all subjects, MK(i) and MFU were positively correlated with the M value (r = 0.56, P = 0.02, and r = 0.51, P = 0.03, respectively) and with plasma lactate levels (r = 0.63, P = 0.006, and r = 0.63, P = 0.005, respectively). LK(i) was significantly reduced by 20% in the athletes (P = 0.04). By multiple regression, LFU was inversely correlated with the two fitness categories (P = 0.008), and it was lower in athletes. Linear fitting of liver data showed time consistency, indicating no release of FFAs as a mechanism for the reduced liver retention in athletes. CONCLUSIONS: We conclude that endurance training promotes insulin-mediated glucose and FFA disposal in skeletal muscle, while lowering hepatic FFA uptake. Such changes may result in a divergent pattern of fat accumulation in the two organs.

Hypermetabolism of Olivary Nuclei in a Patient with Progressive Ataxia and Palatal Tremor.

BACKGROUND: The pathophysiology of the movement disorder progressive ataxia with palatal tremor (PAPT) is unclear. CASE REPORT: A 77-year-old male presented with dysarthria, ataxia, and 1-2 Hz palatal tremor. A diagnosis of probable sporadic PAPT was established. Brain magnetic resonance imaging was normal at the presymptomatic phase but later showed olivary hypertrophy. Brain [(18)F]-fludeoxyglucose (FDG) positron emission tomography (PET) showed bilateral hypermetabolism in the olivary nuclei. DISCUSSION: This second reported patient with PAPT and FDG-PET shows that olivary hypertrophy is paralleled with hypermetabolism. The olivary nuclei pathology also appears to be temporally associated with symptom onset.

Enabling [(18)F]-bicyclo[6.1.0]nonyne for oligonucleotide conjugation for positron emission tomography applications: [(18)F]-anti-microRNA-21 as an example.

A bicyclononyne-based prosthetic group has been developed for (18)F-labeling of anti-microRNA-21, an oligonucleotide, in a near-stoichiometric manner.

Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients.

BACKGROUND AND PURPOSE: CADASIL causes repeated ischemic strokes leading to subcortical vascular dementia. The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR(gluc)) in CADASIL patients are affected in early adulthood. METHODS: CBF and rCMR(gluc) were examined with positron emission tomography in correlation with magnetic resonance imaging (MRI) in 14 adult (19 to 41 years) CADASIL patients with the Notch3 R133C mutation. Seven patients had experienced transient ischemic attack and 3 had experienced > or =1 strokes. RESULTS: The mean CBF in the CADASIL patients was significantly lower in both frontal (P=0.019) and occipital (P=0.009) white matter (WM) than those in the controls. CBF decreased significantly with increased severity of the disease. The patients had lower mean rCMR(gluc) values than the controls, although differences were not statistically significant. Sum scores of semiquantitative MRI rating scale (Scheltens) correlated significantly with WM CBF but not with rCMR(gluc). CONCLUSIONS: In CADASIL, there is an early and significant decrease in the CBF of WM associated with simultaneous MRI changes. These are obviously caused by the arteriopathy in long penetrating arteries and indicate early tissue damage, also expressed as impaired rCMR(gluc) in the WM.

Defective liver disposal of free fatty acids in patients with impaired glucose tolerance.

The liver exchanges high fluxes of glucose and free fatty acids (FFA) and is one main site of their reciprocal regulation. Acute exposure to hyperglycemia and hyperinsulinemia has been shown to reduce splanchnic beta-oxidation in healthy humans. We investigated whether a spontaneous condition of chronic mild hyperglycemia and hyperinsulinemia affects liver FFA uptake. Hepatic FFA influx rate constant (LKi) was measured after a 12-15-h fast in 10 patients with impaired glucose tolerance (IGT) and eight control subjects using positron emission tomography in combination with the long-chain FFA analog 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Compared with controls, IGT patients had higher serum insulin, glucose, and triglyceride levels (1.71 +/- 0.24 vs. 0.59 +/- 0.06 mmol/liter, P < 0.001), lower high-density lipoprotein (1.04 +/- 0.11 vs. 1.42 +/- 0.13 mmol/liter, P < 0.05), and similar FFA levels (0.59 +/- 0.06 vs. 0.56 +/- 0.05 mmol/liter(-1), P = not significant). LKi was significantly reduced in IGT (0.288 +/- 0.014 min(-1)) compared with control subjects (0.341 +/- 0.014 min(-1), P < 0.02). LKi was negatively correlated with plasma glucose (r = 0.51, P < 0.03), glycosylated hemoglobin (r = 0.55, P < 0.02), and blood lactate levels (r = 0.52, P < 0.03). We conclude that, in IGT patients, the ability of the liver to extract FFA from the circulation appears to be impaired. The reciprocal relationship between hepatic FFA extraction and glucose/lactate flux may derive from intrahepatic substrate competition.

Personality traits and striatal dopamine synthesis capacity in healthy subjects.

OBJECTIVE: Neuroimaging and genetic studies suggest that individual differences in the brain dopaminergic system contribute to the normal variability of human personality (e.g., social detachment and novelty seeking). The authors studied whether presynaptic dopamine function is also associated with personality traits. METHOD: Presynaptic dopamine synthesis capacity in the brain was measured with positron emission tomography and [(18)F]fluorodopa in 33 healthy adults, and personality traits were assessed with the Karolinska Scales of Personality. Associations were studied by using a linear regression model controlling for the effects of age and gender on both variables. RESULTS: High scores on two of the anxiety-related personality scales, somatic anxiety and muscular tension, and on one aggressivity-related scale, irritability, were significantly associated with low [(18)F]fluorodopa uptake in the caudate. No statistically significant associations were observed between [(18)F]fluorodopa uptake and the detachment scale or scales related to novelty-seeking behavior (impulsiveness and monotony avoidance). CONCLUSIONS: The results suggest a role for the dopaminergic system in the regulation of anxiety in healthy subjects. Together with previous studies, they also indicate differential involvement of various components of the dopaminergic system in normal and pathological personality traits.