Reduced microglia activity in patients with long-term immunosuppressive therapy after liver transplantation.

PURPOSE: Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand 18F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression. METHODS: PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (VT) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance. RESULTS: In controls, VT was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean VT corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect. CONCLUSION: Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.

Combined Brain-Perfusion SPECT and EEG Measurements Suggest Distinct Strategies for Speech Comprehension in CI Users With Higher and Lower Performance.

Cochlear implantation constitutes a successful therapy of inner ear deafness, with the majority of patients showing good outcomes. There is, however, still some unexplained variability in outcomes with a number of cochlear-implant (CI) users, showing major limitations in speech comprehension. The current study used a multimodal diagnostic approach combining single-photon emission computed tomography (SPECT) and electroencephalography (EEG) to examine the mechanisms underlying speech processing in postlingually deafened CI users (N = 21). In one session, the participants performed a speech discrimination task, during which a 96-channel EEG was recorded and the perfusions marker 99mTc-HMPAO was injected intravenously. The SPECT scan was acquired 1.5 h after injection to measure the cortical activity during the speech task. The second session included a SPECT scan after injection without stimulation at rest. Analysis of EEG and SPECT data showed N400 and P600 event-related potentials (ERPs) particularly evoked by semantic violations in the sentences, and enhanced perfusion in a temporo-frontal network during task compared to rest, involving the auditory cortex bilaterally and Broca's area. Moreover, higher performance in testing for word recognition and verbal intelligence strongly correlated to the activation in this network during the speech task. However, comparing CI users with lower and higher speech intelligibility [median split with cutoff + 7.6 dB signal-to-noise ratio (SNR) in the Göttinger sentence test] revealed for CI users with higher performance additional activations of parietal and occipital regions and for those with lower performance stronger activation of superior frontal areas. Furthermore, SPECT activity was tightly coupled with EEG and cognitive abilities, as indicated by correlations between (1) cortical activation and the amplitudes in EEG, N400 (temporal and occipital areas)/P600 (parietal and occipital areas) and (2) between cortical activation in left-sided temporal and bilateral occipital/parietal areas and working memory capacity. These results suggest the recruitment of a temporo-frontal network in CI users during speech processing and a close connection between ERP effects and cortical activation in CI users. The observed differences in speech-evoked cortical activation patterns for CI users with higher and lower speech intelligibility suggest distinct processing strategies during speech rehabilitation with CI.

Reliable quantification of 18F-GE-180 PET neuroinflammation studies using an individually scaled population-based input function or late tissue-to-blood ratio.

PURPOSE: Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18F-GE-180. This study tested simplified methods for quantification of 18F-GE-180 PET. METHODS: Dynamic 18F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18F-GE-180 distribution volume (VT) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed. RESULTS: Correlation with the reference VT (with individually measured input function) was very high for VT with the population-based input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for VT with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference VT, population-based VT with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based VT with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect. CONCLUSION: These results support the use of a population-based input function scaled with a single blood sample or the ROI-to-whole-blood ratio at a late time point for simplified quantitative analysis of 18F-GE-180 PET.

Visualization of the auditory pathway in rats with 18F-FDG PET activation studies based on different auditory stimuli and reference conditions including cochlea ablation.

Activation studies with positron emission tomography (PET) in auditory implant users explained some of the mechanisms underlying the variability of achieved speech comprehension. Since future developments of auditory implants will include studies in rodents, we aimed to inversely translate functional PET imaging to rats. In normal hearing rats, activity in auditory and non-auditory regions was studied using 18F-fluorodeoxyglucose (18F-FDG) PET with 3 different acoustic conditions: sound attenuated laboratory background, continuous white noise and rippled noise. Additionally, bilateral cochlea ablated animals were scanned. 3D image data were transferred into a stereotaxic standard space and evaluated using volume of interest (VOI) analyses and statistical parametric mapping (SPM). In normal hearing rats alongside the auditory pathway consistent activations of the nucleus cochlearis (NC), olivary complex (OC) and inferior colliculus (IC) were seen comparing stimuli with background. In this respect, no increased activation could be detected in the auditory cortex (AC), which even showed deactivation with white noise stimulation. Nevertheless, higher activity in the AC in normal hearing rats was observed for all 3 auditory conditions against the cochlea ablated status. Vice versa, in ablated status activity in the olfactory nucleus (ON) was higher compared to all auditory conditions in normal hearing rats. Our results indicate that activations can be demonstrated in normal hearing animals based on 18F-FDG PET in nuclei along the central auditory pathway with different types of noise stimuli. However, in the AC missing activation with respect to the background advises the need for more rigorous background noise attenuation for non-invasive reference conditions. Finally, our data suggest cross-modal activation of the olfactory system following cochlea ablation-underlining, that 18F-FDG PET appears to be well suited to study plasticity in rat models for cochlear implantation.

Feasibility of 15O-water PET studies of auditory system activation during general anesthesia in children.

BACKGROUND: 15O-Water positron emission tomography (PET) enables functional imaging of the auditory system during stimulation via a promontory electrode or cochlear implant, which is not possible using functional magnetic resonance imaging (fMRI). Although PET has been introduced in this context decades ago, its feasibility when performed during general anesthesia has not yet been explored. However, due to a shift to earlier (and bilateral) auditory implantation, the need to study children during general anesthesia appeared, since they are not able to cooperate during scanning. Therefore, we evaluated retrospectively results of individual SPM (statistical parametric mapping) analysis of 15O-water PET in 17 children studied during general anesthesia and compared them to those in 9 adults studied while awake. Specifically, the influence of scan duration, smoothing filter kernel employed during preprocessing, and cut-off value used for statistical inferences were evaluated. Frequencies, peak heights, and extents of activations in auditory and extra-auditory brain regions (AR and eAR) were registered. RESULTS: It was possible to demonstrate activations in auditory brain regions during general anesthesia; however, the frequency and markedness of positive findings were dependent on some of the abovementioned influence factors. Scan duration (60 vs. 90 s) had no significant influence on peak height of auditory cortex activations. To achieve a similar frequency and extent of AR activations during general anesthesia compared to waking state, a lower cut-off for statistical inferences (p < 0.05 or p < 0.01 vs. p < 0.001) had to be applied. However, this lower cut-off was frequently associated with unexpected, "artificial" activations in eAR. These activations in eAR could be slightly reduced by the use of a stronger smoothing filter kernel during preprocessing of the data (e.g., [30 mm]3). CONCLUSIONS: Our data indicate that it is feasible to detect auditory cortex activations in 15O-water PET during general anesthesia. Combined with the improved signal to noise ratios of modern PET scanners, this suggests reasonable prospects for further evaluation of the method for clinical use in auditory implant users. Adapted parameters for data analysis seem to be helpful to improve the proportion of signals in AR versus eAR.

Expert System for Bone Scan Interpretation Improves Progression Assessment in Bone Metastatic Prostate Cancer.

INTRODUCTION: The bone scan index (BSI) was introduced as a quantitative tool for tumor involvement in bone of patients with metastatic prostate cancer (mPCa). The computer-aided diagnosis device for BSI analysis EXINIboneBSI seems to represent technical progress for the quantitative assessment of bone involvement. But it is not yet clear if the automated BSI (aBSI) could contribute to improved evaluation of progression in patients under antiandrogens or chemotherapy in contrast to the visual interpretation and/or conventional biomarkers such as the prostate-specific antigen (PSA). METHODS: In 49 mPCa patients, bone scans were performed initially and during different therapy courses. Scans were evaluated visually and by the artificial-neural-network-based expert system EXINIboneBSI. Progression of metastatic bone involvement was defined according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria in the visual interpretation. The computer-assisted interpretation was based on different cutoff values in relative changes of the aBSI. Additionally, assessments according to bone scanning were compared to changes in the PSA value as a potential surrogate for treatment response. RESULTS: Using a sensitive cutoff value (5% or 10%) for the relative aBSI increase led to significantly increased progression determination compared to the visual interpretation of bone scans (49% and 43% vs. 27%, p < 0.001). In 63% of the cases PSA and BSI changes matched, whereas in 18% progression was only indicated by the aBSI. A relative cutoff of 5% for the aBSI decrease could reclassify 47 serial scan pairs which were visually interpreted as stable into 22 progressive and 25 remissive scans. CONCLUSION: Distinct thresholds of the relative aBSI could help to better assess disease progression in mPCa patients. Manual corrections of the BSI values are not required in most cases. The aBSI could serve as a useful additional parameter for therapy monitoring in mPCa patients in the future.

Multiple Time-Point 68Ga-PSMA I&T PET/CT for Characterization of Primary Prostate Cancer: Value of Early Dynamic and Delayed Imaging.

PURPOSE: The aims of this study were to gain mechanistic insights into prostate cancer biology using dynamic imaging and to evaluate the usefulness of multiple time-point Ga-prostate-specific membrane antigen (PSMA) I&T PET/CT for the assessment of primary prostate cancer before prostatectomy. METHODS: Twenty patients with prostate cancer underwent Ga-PSMA I&T PET/CT before prostatectomy. The PET protocol consisted of early dynamic pelvic imaging, followed by static scans at 60 and 180 minutes postinjection (p.i.). SUVs, time-activity curves, quantitative analysis based on a 2-tissue compartment model, Patlak analysis, histopathology, and Gleason grading were compared between prostate cancer and benign prostate gland. RESULTS: Primary tumors were identified on both early dynamic and delayed imaging in 95% of patients. Tracer uptake was significantly higher in prostate cancer compared with benign prostate tissue at any time point (P ≤ 0.0003) and increased over time. Consequently, the tumor-to-nontumor ratio within the prostate gland improved over time (2.8 at 10 minutes vs 17.1 at 180 minutes p.i.). Tracer uptake at both 60 and 180 minutes p.i. was significantly higher in patients with higher Gleason scores (P < 0.01). The influx rate (Ki) was higher in prostate cancer than in reference prostate gland (0.055 [r = 0.998] vs 0.017 [r = 0.996]). CONCLUSIONS: Primary prostate cancer is readily identified on early dynamic and static delayed Ga-PSMA ligand PET images. The tumor-to-nontumor ratio in the prostate gland improves over time, supporting a role of delayed imaging for optimal visualization of prostate cancer.

Effect of Deep Brain Stimulation on Regional Cerebral Blood Flow in Patients with Medically Refractory Tourette Syndrome.

In this study, alterations in brain perfusion have been investigated in patients with Tourette syndrome (TS) compared with control subjects. In addition, we investigated the effects of deep brain stimulation (DBS) in both globus pallidus internus (GPi) and centromedian-parafascicular/ventralis oralis internus nuclei of the thalamus (CM/Voi) and sham (SHAM) stimulation on cerebral blood flow. In a prospective controlled, randomized, double-blind setting, five severely affected adult patients with TS with predominant motor or vocal tics (mean total tic score on the Yale Global Tic Severity Scale: 39) underwent serial brain perfusion single photon emission computed tomography with (99m)Tc-ECD. Results were compared with data from six age-matched control subjects. All patients were investigated at four different time points: once before DBS implantation (preOP) and three times postoperatively. Postoperative scans were performed in a randomized order, each after 3 months of either GPi, CM/Voi, or SHAM stimulation. At each investigation, patients were injected at rest while awake, but scanned during anesthesia. This procedure ensured that neither anesthesia nor movement artifacts influenced our results. Control subjects were investigated only once at baseline (without DBS or anesthesia). At baseline, cerebral blood flow was significantly reduced in patients with TS (preOP) compared with controls in the central region, frontal, and parietal lobe, specifically in Brodmann areas 1, 4-9, 30, 31, and 40. Significantly increased perfusion was found in the cerebellum. When comparing SHAM stimulation to preOP condition, we found significantly decreased perfusion in basal ganglia and thalamus, but increased perfusion in different parts of the frontal cortex. Compared with SHAM condition both GPi and thalamic stimulation resulted in a significant decrease in cerebral blood flow in basal ganglia and cerebellum, while perfusion in the frontal cortex was significantly increased. Our results provide substantial evidence that, in TS, brain perfusion is altered in the frontal cortex and the cerebellum and that these changes can be reversed by both GPi and CM/Voi DBS.

Improving hospital hygiene to reduce the impact of multidrug-resistant organisms in health care--a prospective controlled multicenter study.

BACKGROUND: Nosocomial infections are the most common complication during inpatient hospital care. An increasing proportion of these infections are caused by multidrug-resistant organisms (MDROs). This report describes an intervention study which was designed to address the practical problems encountered in trying to avoid and treat infections caused by MDROs. The aim of the HARMONIC (Harmonized Approach to avert Multidrug-resistant Organisms and Nosocomial Infections) study is to provide comprehensive support to hospitals in a defined study area in north-east Germany, to meet statutory requirements. To this end, a multimodal system of hygiene management was implemented in the participating hospitals. METHODS/DESIGN: HARMONIC is a controlled intervention study conducted in eight acute care hospitals in the 'Health Region Baltic Sea Coast' in Germany. The intervention measures include the provision of written recommendations on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and multi-resistant Gram-negative bacteria (MRGN), supplemented by regional recommendations for antibiotic prescriptions. In addition, there is theoretical and practical training of health care workers (HCWs) in the prevention and handling of MDROs, as well as targeted and critically gauged applications of antibiotics. The main outcomes of the implementation and analysis of the HARMONIC study are: (i) screening rates for MRSA, VRE and MRGN in high-risk patients, (ii) the frequency of MRSA decolonization, (iii) the level of knowledge of HCWs concerning MDROs, and (iv) specific types and amounts of antibiotics used. The data are predominantly obtained by paper-based questionnaires and documentation sheets. A computer-assisted workflow-based documentation system was developed in order to provide support to the participating facilities. The investigation includes three nested studies on risk profiles of MDROs, health-related quality of life, and cost analysis. A six-month follow-up study investigates the quality of life after discharge, the long-term costs of the treatment of infections caused by MDROs, and the sustainability of MRSA eradication. DISCUSSION: The aim of this study is to implement and evaluate an area-wide harmonized hygiene program to control the nosocomial spreading of MDROs. Comparability between the intervention and control group is ensured by matching the hospitals according to size (number of discharges per year/number of beds) and level of care (standard or maximum). The results of the study may provide important indications for the implementation of regional MDRO management programs.

Positron Emission Tomography Imaging Reveals Auditory and Frontal Cortical Regions Involved with Speech Perception and Loudness Adaptation.

Considerable progress has been made in the treatment of hearing loss with auditory implants. However, there are still many implanted patients that experience hearing deficiencies, such as limited speech understanding or vanishing perception with continuous stimulation (i.e., abnormal loudness adaptation). The present study aims to identify specific patterns of cerebral cortex activity involved with such deficiencies. We performed O-15-water positron emission tomography (PET) in patients implanted with electrodes within the cochlea, brainstem, or midbrain to investigate the pattern of cortical activation in response to speech or continuous multi-tone stimuli directly inputted into the implant processor that then delivered electrical patterns through those electrodes. Statistical parametric mapping was performed on a single subject basis. Better speech understanding was correlated with a larger extent of bilateral auditory cortex activation. In contrast to speech, the continuous multi-tone stimulus elicited mainly unilateral auditory cortical activity in which greater loudness adaptation corresponded to weaker activation and even deactivation. Interestingly, greater loudness adaptation was correlated with stronger activity within the ventral prefrontal cortex, which could be up-regulated to suppress the irrelevant or aberrant signals into the auditory cortex. The ability to detect these specific cortical patterns and differences across patients and stimuli demonstrates the potential for using PET to diagnose auditory function or dysfunction in implant patients, which in turn could guide the development of appropriate stimulation strategies for improving hearing rehabilitation. Beyond hearing restoration, our study also reveals a potential role of the frontal cortex in suppressing irrelevant or aberrant activity within the auditory cortex, and thus may be relevant for understanding and treating tinnitus.

Mini-review: Epidemiology and zoonotic potential of multiresistant bacteria and Clostridium difficile in livestock and food.

AIM: Information on the epidemiology of multiresistant bacteria (MRB) with zoonotic potential is growing but still remains quite incomplete. This narrative mini-review provides a general overview of the epidemiology of the most important zoonotic MRB in cattle, swine and poultry in Europe. METHODS: A literature search was conducted mainly on the PubMed website including articles published until April 2012. RESULTS: Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) especially poses a zoonotic risk to people working in close contact with livestock. These people may become carriers themselves and the hazard of transmission into health-care facilities needs surveillance. Extended-spectrum beta-lactamases (ESBL) producing bacteria are widely spread in both humans and livestock, sharing similar genotypes, especially of the CTX-M-group, which makes a zoonotic transfer very likely. Identical strains of vancomycin-resistant enterococci (VRE) were found both in humans and animals, after ingestion of animal strains transient colonization of the human gut may be possible. Only a few data are available on the transmission of methicillin-resistant coagulase-negative staphylococci (MR-CoNS) between humans and animals. Direct contact to colonized animals may be a risk factor as well as the exchange of resistance genes between human and animal staphylococci. Clostridium difficile (C. difficile) ribotype 078 emerges in livestock and humans and a zoonotic transmission seems probable as genotypes and diseases resemble each other. CONCLUSION: All discussed MRB and C. difficile are important nosocomial agents which also occur in livestock and were found in foods of animal origin. Further analysis is needed to reveal the exact transmission routes and to perform a reliable risk assessment.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

BACKGROUND: Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. METHODS: The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. RESULTS: Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. CONCLUSIONS: This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

Repair of segmental long-bone defects by stem cell concentrate augmented scaffolds: a clinical and positron emission tomography--computed tomography analysis.

PURPOSE: Treating segmental long-bone defects remains a major challenge. For defects >3 cm, segmental transport represents the gold standard, even though the method is time consuming and afflicted with several complications. The aim of this study was to evaluate healing of such defects after grafting an osteogenic scaffold previously seeded with stem cell concentrate. METHODS: We evaluated five patients with segmental long-bone defects (3-14 cm) treated with bone marrow aspirate concentrates (BMAC) seeded onto a bovine xenogenous scaffold. The healing process was monitored by X-rays and positron emission tomography-computed tomography (PET-CT) three months after surgery. RESULTS: Centrifugation led to a concentration of leukocytes by factor 8.1 ± 7.5. Full weight bearing was achieved 11.3 ± 5.0 weeks after surgery. PET analysis showed an increased influx of fluoride by factor 8.3 ± 6.4 compared with the contralateral side (p < 0.01). Bone density in the cortical area was 75 ± 16 % of the contralateral side (p < 0.03). The patient with the largest defect sustained an implant failure in the distal femur and finally accomplished therapy by segmental transport. He also had the lowest uptake of fluoride of the patient collective (2.2-fold increase). CONCLUSION: Stem cell concentrates can be an alternative to segmental bone transport. Further studies are needed to compare this method with autologous bone grafting and segmental transport.

Glucose uptake in the placenta, fetal brain, heart and liver related to blood flow redistribution during acute hypoxia.

AIM: We used positron emission tomography (PET) with radioactive glucose (F-18-Fluor-Deoxglucose [FDG]) to investigate whether acute maternal hypoxemia causes alterations of glucose uptake of fetal organs and the placenta. MATERIAL AND METHODS: Investigation was performed under normal conditions and acute hypoxemia in 16 fetal sheep between 108 and 130 days of gestation. Maternal sheep were ventilated with 1.0-1.5% isoflurane/O(2) /N(2) O during whole scanning procedure. Acute hypoxia was induced by reducing O(2) in a ventilated gas mixture to achieve maternal arterial O(2) saturation at a constant level of about 75% baseline. Doppler ultrasound blood flow measurements were performed in the ductus venosus (DV), umbilical artery (UA) and vein (UV). Fetal blood samples were taken by cordocentesis of UV. Dynamic positron emission tomography combined with computed tomography (PET-CT) scans of fetuses were acquired over 60 min after intravenous injection of 300 MBq FDG in the mother. Relative FDG uptake in the fetal brain, heart, and liver was determined on summed images from 40-60 min using manually defined volumes of interest (VOI) normalized to mean FDG uptake in placentomes. RESULTS: Placental blood perfusion reduced significantly from 416.5 ± 116.4 mL/min to 253.5 ± 170.5 mL/min (mean ± SD) during hypoxia. Placental blood supply to the liver decreased from 79.5 ± 14% to 41.1% (P = 0.0001), while DV/UV ratio increased. FDG uptake of the placenta was not changed during hypoxia. Relative FDG uptake in the fetal heart was strongly increased under hypoxia (P = 0.019), whereas it did not differ in the fetal brain and liver. CONCLUSION: Fetal hypoxia is associated with decreased placental perfusion and liver blood supply. However, glucose uptake was not significantly decreased in the placenta and liver.

Blood-brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls.

Increased blood-brain barrier (BBB) permeability for ammonia is considered to be an integral part of the pathophysiology of hepatic encephalopathy (HE) in patients with liver cirrhosis. Increased glutamate-/glutamine-signal intensity in magnetic resonance spectroscopic studies of the brain in cirrhotic patients was explained as a consequence of increased cerebral ammonia uptake. As similar spectroscopic alterations are present in patients with liver fibrosis, we hypothesized that BBB permeability for ammonia is already increased in liver fibrosis, and thereby contributing to the development of HE. To test this hypothesis, cerebral perfusion and ammonia metabolism were examined through positron emission tomography with (15)O-water, respectively, (13)N-ammonia in patients with Ishak grades 2 and 4 fibrosis, cirrhosis, and healthy controls. There were neither global nor regional differences of cerebral blood flow, the rate constant of unidirectional transport of ammonia from blood into brain tissue, the permeability surface area product of the BBB for ammonia, the net metabolic clearance rate constant of ammonia from blood into glutamine in brain, or the metabolic rate of ammonia. The hypothesis that increased permeability of the BBB for ammonia in patients with liver fibrosis contributes to the later development of HE could not be supported by this study.

Identification of transport processes in bioirrigated muddy sediments by [18F]fluoride PET (Positron Emission Tomography).

In aquatic environments transport processes across the sediment-water interface are intensified by bioirrigating macrozoobenthos. Transport processes caused by Chironomus plumosus larvae dwelling in U-tubes were investigated by dynamic small animal Positron Emission Tomography (PET) with [18F]fluoride. Significant tracer transport from the burrows into the sediment was detected; penetration was deeper at the outlet branch of the burrow than at the inlet branch. Hence, advection plays a significant role in exchange between water in the burrows and muddy sediment.

B-spline-based stereotactical normalization of brain FDG PET scans in suspected neurodegenerative disease: impact on voxel-based statistical single-subject analysis.

A b-spline-based method 'Lobster', originally designed as a general technique for non-linear image registration, was tailored for stereotactical normalization of brain FDG PET scans. Lobster was compared with the normalization methods of SPM2 and Neurostat with respect to the impact on the accuracy of voxel-based statistical analysis. (i) Computer simulation: Seven representative patterns of cortical hypometabolism served as artificial ground truth. They were inserted into 26 normal control scans with different simulated severity levels. After stereotactical normalization and voxel-based testing, statistical maps were compared voxel-by-voxel with the ground truth. This was done at different levels of statistical significance. There was a highly significant effect of the stereotactical normalization method on the area under the resulting ROC curve. Lobster showed the best average performance and was most stable with respect to variation of the severity level. (ii) Clinical evaluation: Statistical maps were obtained for the normal controls as well as patients with Alzheimer's disease (AD, n=44), Lewy-Body disease (LBD, 9), fronto-temporal dementia (FTD, 13), and cortico-basal dementia (CBD, 4). These maps were classified as normal, AD, LBD, FTD, or CBD by two experienced readers. The stereotactical normalization method had no significant effect on classification by of each of the experts, but it appeared to affect agreement between the experts. In conclusion, Lobster is appropriate for use in single-subject analysis of brain FDG PET scans in suspected dementia, both in early diagnosis (mild hypometabolism) and in differential diagnosis in advanced disease stages (moderate to severe hypometabolism). The computer simulation framework developed in the present study appears appropriate for quantitative evaluation of the impact of the different processing steps and their interaction on the performance of voxel-based single-subject analysis.

Association between FDG uptake, CSF biomarkers and cognitive performance in patients with probable Alzheimer's disease.

PURPOSE: Brain imaging of FDG uptake and cerebrospinal fluid (CSF) concentration of amyloid-beta 1-42 (Abeta(1-42)) or tau proteins are promising biomarkers in the diagnosis of Alzheimer's disease (AD). There is still uncertainty regarding any association between decreased FDG uptake and alterations in CSF markers. METHODS: The relationship between FDG uptake, CSF Abeta(1-42) and total tau (T-tau), as well as the Mini-Mental State Examination (MMSE) score was investigated in 34 subjects with probable AD using step-wise linear regression. FDG uptake was scaled to the pons. RESULTS: Scaled FDG uptake was significantly reduced in the probable AD subjects compared to 17 controls bilaterally in the precuneus/posterior cingulate area, angular gyrus/inferior parietal cortex, inferior temporal/midtemporal cortex, midfrontal cortex, and left caudate. Voxel-based single-subject analysis of the probable AD subjects at p < 0.001 (uncorrected) revealed a total volume of significant hypometabolism ranging from 0 to 452 ml (median 70 ml). The total hypometabolic volume was negatively correlated with the MMSE score, but it was not correlated with the CSF measures. VOI-based step-wise linear regression revealed that scaled FDG uptake in the precuneus/posterior cingulate was negatively correlated with CSF Abeta(1-42). Scaled FDG uptake in the caudate was positively correlated with CSF T-tau. CONCLUSION: The extent and local severity of the reduction in FDG uptake in probable AD subjects are associated with cognitive impairment. In addition, there appears to be a relationship between local FDG uptake and CSF biomarkers which differs between different brain regions.

[18F]FDG and [18F]FLT PET-CT and MR imaging of human neuroblastomas in a SCID mouse xenograft model.

BACKGROUND: Finding new therapeutic agents is of great clinical interest in neuroblastoma research because prognosis of children with disseminated stages of disease is still poor. As xenograft mouse models are frequently used for studying anticancer drugs in vivo, small animal imaging is an important method of monitoring in anticancer research. MATERIALS AND METHODS: SCID mice inoculated with human neuroblastoma SK-N-SH cells were examined with positron-emission tomography-computed tomography (PET-CT) using [18F]fluorodeoxyglucose (FDG) or [18F]fluoro-L-thymidine (FLT) and with magnetic resonance imaging (MRI). RESULTS: All neuroblastomas were detected by MRI. In PET-CT imaging, no tumour was visualized with [18F]FDG, but 13 out of 14 (93%) were found with [18F]FLT. Uptake of [18F]FLT was significantly associated with tumour weight. Necrotic areas could not be identified either by MR imaging or on PET-CT scans. CONCLUSION: Both MR and PET-CT imaging with [18F]FLT are highly qualified for the detection of neuroblastomas grown in SCID mice. However, [18F]FDG, which is the standard tracer in clinical PET-CT imaging, is not suited for PET-CT imaging in the neuroblastoma model.

Reduced thalamic 18F-flurodeoxyglucose retention in adults with neurofibromatosis type 1.

OBJECTIVE: Neurofibromatosis type1 (NF1) is associated with cognitive and motor deficits whose pathogenesis is not well understood. 18F-Flurodeoxyglucose positron emission tomography (FDG PET) might be used to investigate putative functional correlates in the brain. METHODS: Whole-body FDG PET including the brain had been performed in 29 NF1 patients suspected for malignant peripheral nerve sheath tumours (20 females, nine males, age 31.2+/-11.8 years). Twenty-nine age-matched and sex-matched subjects without evidence of neurological/psychiatric disease in whom FDG PET had been performed for NF1-unrelated oncological indication served as controls. Individual brain FDG retention images were stereotactically normalized and scaled to a common median retention value within the brain. Scaled FDG retention was compared between the NF1 group and the control group on a voxel-by-voxel base using ANCOVA in SPM2 with the FDG uptake period as covariate. The corrected significance level alpha=0.05 was used. Voxel-based analysis was complemented by volume of interest (VOI)-based analysis using predefined standard VOIs. RESULTS: The voxel-based group comparison revealed a significant reduction of scaled FDG retention in the thalamus of the NF1 subjects within a cluster of 11.6 ml. There were no further significant effects, neither hypo-retention nor hyper-retention. Reduction of relative FDG retention in the thalamus in the NF1 subjects was confirmed by VOI analysis. The magnitude of the reduction was about 8%. CONCLUSIONS: The thalamus appears to be affected in adults with NF1. The observed magnitude of the reduction of scaled thalamic FDG retention in adults is smaller than previously reported in children. This may be consistent with a stabilization of the disease process with age.