Cerebral microglia activation in hepatitis C virus infection correlates to cognitive dysfunction.

Hepatitis C virus (HCV) infection may induce chronic fatigue and cognitive dysfunction. Virus replication was proven within the brain and HCV-positive cells were identified as microglia and astrocytes. We hypothesized that cerebral dysfunction in HCV-afflicted patients is associated with microglia activation. Microglia activation was assessed in vivo in 22 patients with chronic HCV infection compared to six healthy controls using [(11) C]-PK11195 Positron Emission Tomography (PET) combined with magnetic resonance tomography for anatomical localization. Patients were subdivided with regard to their PCR status, Fatigue Impact Scale score (FIS) and attention test sum score (ATS). A total of 12 patients (54.5%) were HCV PCR positive [of which 7 (58.3%) had an abnormal FIS and 7 (58.3%) an abnormal ATS], 10 patients (45.5%) were HCV PCR negative (5 (50%) each with an abnormal FIS or ATS). Patients without attention deficits showed a significantly higher accumulation of [(11) C]-PK11195 in the putamen (P = 0.05), caudate nucleus (P = 0.03) and thalamus (P = 0.04) compared to controls. Patients with and without fatigue did not differ significantly with regard to their specific tracer binding in positron emission tomography. Preserved cognitive function was associated with significantly increased microglia activation with predominance in the basal ganglia. This indicates a probably neuroprotective effect of microglia activation in HCV-infected patients.

(211)At-antiCD33 in NMRI nu/nu mice. Biodistribution, in vivo stability and radiotoxicity.

UNLABELLED: The aim of this study is to verify the in vivo stability, to determine the biodistribution and to estimate the unspecific radiotoxicity of an (211)At-labelled CD33-antibody ((211)At-antiCD33) in mice with a view to therapeutic application in treating leukaemia. ANIMALS, METHODS: (211)At was produced via the (209)Bi(a,2n)(211)At reaction and was linked via 3-(211)At-succinimidyl-benzoate to the antiCD33-antibody. The biodistribution and the in vivo stability in serum were determined after i.v.-injection in NMRI nu/nu-mice. For toxicity experiments, mice received either three times 315-650 kBq (211)At-antiCD33 or unlabelled antibody and NaCl-solution respectively. RESULTS: (211)At-antiCD33 showed a characteristic biodistribution complying with the unspecific antibody retention in the reticular endothelial system. The largest proportion of radioactivity remained in blood and blood-rich tissues with a minor accumulation in the thyroid and stomach. After 21 h, >85% of activity in serum still represented intact antibody. Mice showed no difference in unspecific toxicity of (211)At-labelled antibodies over six months compared to those treated with unlabelled antibody and NaCl-solution respectively, with regard to histopathologic lesions, survival time, behaviour and haemograms. CONCLUSION: The radiolabelling method yielded adequate in vivo stability of (211)At-antiCD33. Biodistribution with rapid elimination of free (211)At via kidneys and urine complies with requirements for targeted therapy. Activity doses potentially required for treatment do not elicit radiotoxicity to normal organs in mice. Further development is required to enhance the apparent specific activity and to verify the efficacy in an adequate animal model before phase I clinical studies in leukaemia can be envisaged.

Insulin resistance in liver cirrhosis. Positron-emission tomography scan analysis of skeletal muscle glucose metabolism.

BACKGROUND: Insulin resistance and glucose intolerance are a major feature of patients with liver cirrhosis. However, site and mechanism of insulin resistance in cirrhosis are unknown. We investigated insulin-induced glucose metabolism of skeletal muscle by positron-emission tomography to identify possible defects of muscle glucose metabolism in these patients. METHODS: Whole body glucose disposal and oxidation were determined by the combined use of the euglycemic-hyperinsulinemic clamp technique (insulin infusion rate: 1 mU/kg body wt per min) and indirect calorimetry in seven patients with biopsy-proven liver cirrhosis (Child: 1A, 5B, and 1C) and five healthy volunteers. Muscle glucose uptake of the thighs was measured simultaneously by dynamic [18F]fluorodeoxyglucose positron-emission tomography scan. RESULTS: Both whole body and nonoxidative glucose disposal were significantly reduced in patients with liver cirrhosis (by 48%, P < 0.001, and 79%, P < 0.0001, respectively), whereas glucose oxidation and the increase in plasma lactate were normal. Concomitantly, skeletal muscle glucose uptake was reduced by 69% in liver cirrhosis (P < 0.003) and explained 55 or 92% of whole body glucose disposal in cirrhotics and controls, respectively. Analysis of kinetic constants using a three-compartment model further indicated reduced glucose transport (P < 0.05) but unchanged phosphorylation of glucose in patients with liver cirrhosis. CONCLUSIONS: Patients with liver cirrhosis show significant insulin resistance that is characterized by both decreased glucose transport and decreased nonoxidative glucose metabolism in skeletal muscle.

Long-lifetime Ru(II) complexes for the measurement of high molecular weight protein hydrodynamics.

We describe the synthesis and characterization of two asymmetrical ruthenium(II) complexes, [Ru(dpp)2(dcbpy)]2+ and [Ru(dpp)2(mcbpy)]2+, as well as the water soluble sulfonated derivatives [Ru(dpp(SO3Na)2)2(dcbpy)]2+ and [Ru(dpp(SO3Na)2)2(mcbpy)]2+ (dpp is 4,7-diphenyl-1,10-phenanthroline, dcbpy is 4,4'-dicarboxylic acid-2,2'-bipyridine, mcbpy is 4-methyl,4'-carboxylic acid-2,2'-bipyridine, and dpp(SO3Na)2 is the disulfonated derivative of dpp) as probes for the measurement of the rotational motions of proteins. The spectral (absorption, emission, and anisotropy) and photophysical (time-resolved intensity and anisotropy decays) properties of these metal-ligand complexes were determined in solution, in both the presence and absence of human serum albumin (HSA). These complexes display lifetimes ranging from 345 ns to 3.8 microseconds in deoxygenated aqueous solutions under a variety of conditions. The carboxylic acid groups on these complexes were activated to form N-hydroxysuccinimide (NHS) esters which were used to covalently lable HSA, and were characterized spectroscopically in the same manner as above. Time-resolved anisotropy measurements were performed to demonstrate the utility of these complexes in measuring long rotational correlation times of bioconjugates between HSA and antibody to HSA. The potential usefulness of these probes in fluorescence polarization immunoassays was demonstrated by an association assay of the Ru(II)-labeled HSA with polyclonal antibody.

Positron emission tomography in neuropsychiatric lupus erythematosus.

We performed positron emission tomography (PET) using 18F-labeled 2-F-2-deoxyglucose in 13 patients with systemic lupus erythematosus (SLE). Ten of them had clinical signs of central nervous system involvement (NP-SLE). All patients with neurologic symptoms showed pathologic changes on PET, always in accordance with the clinical state. Three patients without neuropsychiatric manifestations had normal PETs. Computed tomography of the brain and magnetic resonance imaging proved to be less sensitive to both presence and localization of CNS lesions. We conclude that the combination of PET and MRI constitutes the most useful diagnostic procedure for NP-SLE.

Noninvasive measurement of lung carbon-11-serotonin extraction in man.

The fraction of serotonin extracted on a single passage through the lungs is being used as an early indicator of lung endothelial damage but the existing techniques require multiple arterial blood samples. We have developed a noninvasive technique to measure lung serotonin uptake in man. We utilized the double indicator diffusion principle, a positron camera, 11C-serotonin as the substrate, and 11CO-erythrocytes as the vascular marker. From regions of interest around each lung, we recorded time-activity curves in 0.5-sec frames for 30 sec after a bolus injection of first the vascular marker 11CO-erythrocytes and 10 min later 11C-serotonin. A second uptake measurement was made after imipramine 25-35 mg was infused intravenously. In three normal volunteers, the single-pass uptake of 11C-serotonin was 63.9% +/- 3.6%. This decreased in all subjects to a mean of 53.6% +/- 1.4% after imipramine. The rate of lung washout of 11C was also significantly prolonged after imipramine. This noninvasive technique can be used to measure lung serotonin uptake to detect early changes in a variety of conditions that alter the integrity of the pulmonary endothelium.

Accurate local blood flow measurements with dynamic PET: fast determination of input function delay and dispersion by multilinear minimization.

Accurate determination of local blood flow in tissue using the Kety-Schmidt one-compartment model for freely diffusible tracers requires knowledge of the true arterial input function in tissue. Because measured input functions are usually delayed and dispersed with respect to true influx, a correction of the experimental input function is necessary. We describe a technique that uses a fast multilinear least-squares minimization procedure to determine simultaneously the dispersion, the blood flow and the partition coefficient as a function of delay. In this approach, a few multilinear fits are sufficient to determine the complete set of parameters necessary to describe the data. Because of the high speed of the procedure, dispersion effects may be taken into account on a pixel-by-pixel basis in calculating parametric images of blood flow and partition coefficient. The described procedure has been used at our institute for about 1 yr in more than 160 investigations and has proven well suited for routine use in a clinical environment.

Oxygen-15-water PET assessment of muscular blood flow in peripheral vascular disease.

UNLABELLED: To assess quantitatively regional nutritive muscular blood flow in patients with peripheral vascular disease (PVD), we evaluated the utility of PET with 15O-water. METHODS: Eight healthy volunteers and 16 patients with angiographically proven PVD were studied. Regional blood flow of the calf was measured with 15O-water PET during rest, after intra-arterial infusion of prostaglandin E1 and during ergometry. The studies were quantified using a one tissue compartment model. RESULTS: Normalized mean tracer uptake from 15-60 sec correlated closely (r = 0.98) with absolute blood flow. Scan times longer than 90 sec were required to determine blood flow reliably. The flow values were overestimated by 2% if arterial blood volume was neglected or if the input function delay was corrected globally for parametric imaging. Mean blood flow of calf muscles at rest did not differ significantly between patients (0.017 +/- 0.006 ml/min/ml) and control subjects (0.018 +/- 0.010 ml/min/ml). In PVD patients, blood flow increased by 100% after intra-arterial infusion of PGE1 in the respective leg. In the control subjects, average flow increased by a factor of six during exercise. The increase was more pronounced in the extensor muscles (0.182 +/- 0.031 ml/min/ml) than in flexor muscles (0.121 +/- 0.045 ml/min/ml). Due to the specific type of ergometry, superficial flexors exhibited higher flow values than the profound ones. CONCLUSION: PET with 15O-water enables reliable determination of regional nutritive skeletal muscle blood flow for research and clinical applications in patients with PVD.

A kinetic model for cardiac PET with [1-carbon-11]-acetate.

UNLABELLED: Carbon-11-labeled acetate is a unique tracer for noninvasive assessment of myocardial oxidative metabolism with PET. Because adequate kinetic models have been missing, data evaluation in the past was performed mostly with phenomenological approaches such as mono- or biexponential fitting which cannot account for the influence of finite input duration and blood volume encountered in noninvasive PET investigations. METHODS: To investigate to what extent the current data evaluation schemes are justified, we developed a comprehensive model of [1-11C]-acetate kinetics in the myocardium which incorporates five tissue compartments: free acetate, activated acetate, CO2 precursors, amino acids and CO2. We derived the analytical solution of the model equations which is used for simulations and data fitting. RESULTS: The five-compartment model can reproduce in detail known experimental data. The resulting values of the eight model parameters compare favorably with existing biochemical facts. We have established the relation between parameters of the detailed model and one- and two-compartment models used for the evaluation of PET investigations. CONCLUSION: The kinetics of [1-11C]-acetate are adequately described by a five-compartment model. One- and two-compartment models are sufficient for simultaneous quantitative assessment of myocardial oxidative metabolism and perfusion with [1-11C]-acetate and PET.

[1-(11)C]Acetate as a quantitative perfusion tracer in myocardial PET.

UNLABELLED: Our objective was to investigate the properties of [1-(11)C]acetate as a quantitative perfusion tracer for myocardial PET studies. METHODS: We determined the flow dependence of the effective acetate extraction by a comparison with [(13)N]ammonia in 24 patients at rest (n = 8) and under pharmacologic vasodilation (n = 16). Furthermore, we compared the statistical quality of the perfusion values derived with both tracers. Quantification was based on an irreversible 2-compartment model for [(13)N]ammonia and a reversible 1-compartment model for [1-(11)C]acetate. Area-conserving polar maps were used to determine the correlation between the unidirectional uptake parameters of both tracers on a pixel-by-pixel basis for the whole left ventricular myocardium. RESULTS: A fit of a generalized Renkin-Crone formula to the data yielded the unidirectional acetate extraction fraction E(f) = 1 - 0.64e(-1.20/f). An extraction correction based on this formula led to good quantitative agreement of perfusion values derived with [(13)N]ammonia and [1-(11)C]acetate over the whole observed flow range (average difference of flow values, 3%; correlation coefficient, 0.96). This agreement proved the applicability of acetate as a quantitative perfusion tracer even under stress conditions. An analysis of the statistical properties of the parameter estimates showed, moreover, that statistical errors were reduced by a factor of nearly 2 in comparison with ammonia. CONCLUSION: [1-(11)C]acetate allows accurate quantification of myocardial perfusion with PET at rest as well as under stress conditions. The use of acetate leads to distinctly improved statistical accuracy for the perfusion estimates in comparison with ammonia. This accuracy facilitates the generation of reliable parametric polar maps, which are especially useful for clinical application of myocardial perfusion quantification.

The pharmacokinetics of metoprolol and its metabolites in dialysis patients.

The kinetics of tritiated metoprolol and its metabolites have been determined after intravenous and oral administration in dialysis patients. The kinetic behaviour of metoprolol in these patients does not differ from that in healthy volunteers, since its elimination depends on hepatic metabolism. The pharmacologically less active metabolite alpha-hydroxymetoprolol is formed to an individually varying degree and its half-life is prolonged. The concentration of the total radioactivity, which represents the sum of all metabolites, does not decline in the dialysis interval. During haemodialysis, however, its concentration decreases with a half-life of 5h. It might be assumed, that dialysis of these polar compounds is rather nonspecific and that it depends essentially on the dialysis technique.

Dopamine transporter binding in Gilles de la Tourette syndrome.

Preliminary studies in patients with Gilles de la Tourette syndrome (TS) provided evidence of presynaptic dopaminergic dysfunction, demonstrating increased reuptake sites. Therefore we investigated striatal dopamine transporter binding in 12 TS patients and 9 control subjects using single photon emission computed tomography and 123I-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane. In TS patients we found significantly higher relative striatal activity ratios (mean +/- SD 12.33 +/- 3.58) than in controls (9.36 +/- 1.35, P< 0.05). Only five patients, however, showed striatum/occipital cortex ratios more than 2 SD above the normal means. Seven patients had activity ratios within the average ratio of the control group plus 2 SD. Regarding the relationship between clinical parameters and striatum/occipital cortex ratios, we found an association between binding ratios and "self-injurious behavior" and "lack of impulse control." This study corroborates previous data suggesting an involvement of the dopaminergic system in TS pathology. Our results demonstrate that an increase in dopamine transporter capacity is a possible but not a necessary alteration, and which appears more likely when self-injurious behavior and lack of impulse control are associated.

Psychological testing and psychological assessment. A review of evidence and issues.

This article summarizes evidence and issues associated with psychological assessment. Data from more than 125 meta-analyses on test validity and 800 samples examining multimethod assessment suggest 4 general conclusions: (a) Psychological test validity is strong and compelling, (b) psychological test validity is comparable to medical test validity, (c) distinct assessment methods provide unique sources of information, and (d) clinicians who rely exclusively on interviews are prone to incomplete understandings. Following principles for optimal nomothetic research, the authors suggest that a multimethod assessment battery provides a structured means for skilled clinicians to maximize the validity of individualized assessments. Future investigations should move beyond an examination of test scales to focus more on the role of psychologists who use tests as helpful tools to furnish patients and referral sources with professional consultation.

[11C-methionine PET, IMP-SPECT, CT and MRI in brain tumors]. / 11C-Methionin-PET, IMP-SPECT, CT und MRI bei Hirntumoren.

11C-labelled L-methionine uptake was measured in 7 patients with brain tumours prior to surgery, and in 2 patients with infarction, using PET. The strongest uptake occurred in tumours with a high grade of malignancy (astrocytoma IV: Tumour/Non-Tumour T/NT = 2.6) while low-grade tumours accumulated less activity (astrocytoma II: T/NT = 1.4). Conventional 99mTc DTPA scans revealed a damage of blood brain barrier (BBB) in 4 patients (2 infarctions) with no or only slight 11C-methionine accumulation, while one patient with negative 99mTc-scan and negative CT accumulated methionine in the tumour region (astrocytoma II). PET, MRI, and CT are complementary with regard to extent of tumour tissue, necrotic areas and oedema. None of the brain tumours or infarcted regions took up IMP (123I amphetamine). The investigated regions showed definite uptake defects ranging from 10-50% if compared with the contralateral side. In view of the chemical pathway of methionine it is concluded that the uptake reflects metabolic activity in brain tumour tissue rather than a diffuse uptake due to BBB damage.

[Quantitative measurements of regional extra-vascular lung water in dogs using positron emission tomography]. / Quantitative Messung des regionalen extravaskulären Lungenwassers bei Hunden mit der Positronen-Emissionstomographie.

A new method for quantifying regional variations in extravascular lung water (rELW) has been developed. The positron source 15O (T1/2 = 2.0 min.) was provided as H215O 'on line' by constant intravenous injection. Tomographic images (PET) of the water distribution were obtained during equilibrium. The distribution of blood volume was obtained by marking erythrocytes (carboxyhaemoglobin) using a bolus inhalation [C-11)-CO; T1/2 = 20.4 min). Absorption is calculated from transmission tomography. The rELW is defined as: total lung water minus intravascular space. The method was carried out in five intubated and anaesthetised dogs before and after induction of pulmonary oedema with oleic acid (0.06 ml./kg.). Mean ELW (PET) rose from 0.13 +/- 0.02 g./cm.3 to 0.24 +/- 0.04 g./cm.3. There was good correlation with a simultaneously performed thermo-dye method (7.1 +/- 1.3 ml./kg. KG to 13.3 +/- 1.9 ml./kg. KG; r = 0.94). Gravimetric estimations resulted in 13.7 +/- 2.6 ml./kg. KG. The development and distribution of the pulmonary oedema was non-homogeneous and varied regionally.

[Amino acid uptake in brain tumors using positron emission tomography as an indicator for evaluating metabolic activity and malignancy]. / Die Aufnahme von Aminosäuren in Hirntumoren mit der Positronen-Emissionstomographie als Indikator für die Beurteilung von Stoffwechselaktivität und Malignität.

Diagnosis and post-therapeutic follow-up of tumour patients necessitates morphological and particularly functional imaging methods. For the latter approach positron emission tomography has proven a valid tool for the measurement of perfusion, of energy consumption parameters such as oxygen extraction, glucose metabolism and amino acid uptake. However, neither perfusion nor energy consumption parameters have yielded unambiguous information on the clinical status of various tumours in respect of their malignancy and their growth status. It is shown in this paper that amino acid uptake seems to be a valid measure for the functional activity of tumour tissue for a broad range of neoplasms. The uptake of 11C-L-Methionine was measured in 33 patients having various brain tumours, and was compared with 6 patients who had an infarction, and with 8 patients suffering from arachnoidal cysts. The amino acid uptake correlated well with the histological grading of the tumours and the clinical status of the patient. The uptake was well differentiated against metabolically inactive lesions. Parallel investigations on the uptake mechanisms of amino acids in an animal model have shown that transport phenomena regulate the uptake rather than protein synthesis rates. However, protein synthesis may nevertheless exercise a control function on the transport process.

[Constant infusion of 15-O-labeled water and inhalation of 11C-labeled carbon monoxide for the regional determination of lung water by positron emission tomography]. / Konstante Infusion von 15O-markiertem Wasser und Inhalation von 11C-markiertem Kohlenmonoxid als methodische Grundlage zur regionalen Bestimmung des Lungenwassers mittels Positronen-Emissionstomographie.

A method was developed for the continuous infusion of 15O-labeled water which allows the tomographic reconstruction of the total lung water (TLW). Subsequent inhalation of 11C-labeled carbon-monoxide permits the reconstruction of the blood volume (BV). After normalization of intravascular activities the difference of TLW minus BV yields a quantitative value of regional extravascular lung water (rELW). 15O-O2 is converted on-line to 15O-H2O and trapped in a 2 ml buffer reservoir which is fed by a pump with 0.9% NaCl. A precision pump is used to withdraw the labeled H2O and infuse it at a rate of 6 ml/min. The radioactivity level of the infusate (ca. 3.7 MBq/sec) is controlled and can be kept constant with a deviation of less than 5% over 40 min. The sterility and apyrogenicity of the system effluent is assured by frequent bacteriological, rabbit and limulus tests. A constant radioactivity level in the lung area is reached after 8-10 min. The infusion is continued for the tomographic reconstruction (Positron Camera System 4200, Cyclotron Corp.) which takes 15 min. A fast change of cyclotron parameters (MC-36, Scanditronix) and automated chemistry procedures allow a single breath administration of 11C-CO (ca. 40 MBq) 15 min after the end of the 15O-H2O infusion. Blood pool equilibrium is reached after 3-4 min, and the blood volume is reconstructed within 15 min also. Intravascular activities as determined from reconstructed slices in the region of the aortic arch correlate linearly with blood sample activities up to 100 kBq/ml.

[Use of fluorodeoxyglucose PET in the diagnosis of central nervous system lupus erythematosus and a comparison with CT and MRI]. / Einsatz der FDG-PET bei der Diagnostik des zentralnervösen Lupus erythematodes und Vergleich mit CT und MRI.

Central nervous system involvement has been found in 30-75% of all cases of systemic lupus erythematosus (SLE). Up to now, clinical diagnosis is difficult and there are no markers for disease activity. We have compared cranial computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) using fluorodesoxyglucose (FDG) in two cases. FDG-PET is shown to be the most sensitive method demonstrating even reversible deficits and a better correlation with other neurological findings. MRI seems to be more sensitive than CT. A survey of the literature concerning imaging methods in neuropsychiatric SLE is given. The special problem of neuronal desactivation by antineuronal activity is discussed.

123I-IBZM SPECT: reconstruction methodology and results in parkinsonism and dystonia.

In 58 patients with Parkinsonism or dystonia striatal dopamine D2 receptors were investigated using 123I-iodobenzamide (123I-IBZM) single-photon emission computed tomography (SPECT). The influence of SPECT reconstruction methodology on semiquantification and the clinical value of 123I-IBZM SPECT were evaluated. Delineation of the striatal uptake and striatum/frontal cortex (ST/FC) ratios were improved by the use of compensation procedures for scatter and attenuation as well as the choice of an adequate filter. Satisfactory results were achieved using a Metz prefilter with a comparatively high order number (i.e. high cut-off and low suppression of higher frequencies via roll-off). Regarding clinical diagnoses it was not possible to differentiate between advanced idiopathic Parkinson's disease (IP) and Parkinsonism of other aetiology (OP) on the basis of 123I-IBZM SPECT. But patients with IP and favourable response to L-Dopa showed significantly higher ST/FC ratios than those with fluctuating response. In patients with dystonia ST/FC ratios were significantly higher compared to patients with IP or OP.

[Bone SPECT of the jaws after fracture, onlay osteoplasty of insertion of implants]. / Knochen-SPECT des Kiefers nach Fraktur, Auflagerungsosteoplastik oder Implantatinsertion.

AIM: The aim of this study was early differentiation between uncomplicated and complicated processes of healing in the jaw using bone SPECT. METHODS: Investigations were performed in 40 mandibular fractures and 26 jaws after onlay osteoplasty as well as secondary insertion of implants. Bone SPECT was carried out within 1-2 months and after approximately 4-5 months. The uptake in the jaw was assessed semi-quantitatively using ROI analysis. RESULTS: Fractures with uncomplicated healing showed a decrease of uptake in follow-up, whereas fractures with an infection in the later course showed an increase, resulting in a significantly higher uptake at the follow-up investigation for the latter group. 1-2 months after onlay osteoplasty significantly lower uptake was found in regions with later occurrence of sequestration. In regions with implants in which osseointegration failed, there was significant reduction of uptake initially and significant elevation at the follow-up investigation. CONCLUSION: These results indicate a prognostic relevance of bone SPECT in the evaluation of processes of healing in the jaw.