Interplay of tau and functional network connectivity in progressive supranuclear palsy: a [18F]PI-2620 PET/MRI study.

PURPOSE: Progressive supranuclear palsy (PSP) is primary 4-repeat tauopathy. Evidence spanning from imaging studies indicate aberrant connectivity in PSPs. Our goal was to assess functional connectivity network alterations in PSP patients and the potential link between regional tau-burden and network-level functional connectivity using the next-generation tau PET tracer [18F]PI-2620 and resting-state functional MRI (fMRI). MATERIAL AND METHODS: Twenty-four probable PSP patients (70.9 ± 6.9 years, 13 female), including 14 Richardson syndrome (RS) and 10 non-RS phenotypes, underwent [18F]PI-2620 PET/MRI imaging. Distribution volume ratios (DVRs) were estimated using non-invasive pharmacokinetic modeling. Resting-state fMRI was also acquired in these patients as well as in thirteen older non-AD MCI reference group (64 ± 9 years, 4 female). The functional network was constructed using 141 by 141 region-to-region functional connectivity metrics (RRC) and network-based statistic was carried out (connection threshold p < 0.001, cluster threshold pFDR < 0.05). RESULTS: In total, 9870 functional connections were analyzed. PSPs compared to aged non-AD MCI reference group expressed aberrant connectivity evidenced by the significant NBS network consisting of 89 ROIs and 118 connections among them (NBS mass 4226, pFDR < 0.05). Tau load in the right globus pallidus externus (GPe) and left dentate nucleus (DN) showed significant effects on functional network connectivity. The network linked with increased tau load in the right GPe was associated with hyperconnectivity of low-range intra-opercular connections (NBS mass 356, pFDR < 0.05), while the network linked with increased tau load in the left cerebellar DN was associated with cerebellar hyperconnectivity and cortico-cerebellar hypoconnectivity (NBS mass 517, pFDR < 0.05). CONCLUSIONS: PSP patients show altered functional connectivity. Network incorporating deep gray matter structures demonstrate hypoconnectivity, cerebellum hyperconnectivity, while cortico-cortical connections show variable changes. Tau load in the right GPe and left DN is associated with functional networks which strengthen low-scale intra-opercular and intra-cerebellar connections and weaken opercular-cerebellar connections. These findings support the concept of tau load-dependent functional network changes in PSP, by that providing evidence for downstream effects of neuropathology on brain functionality in this primary tauopathy.

Emotional eating and in vivo norepinephrine transporter availability in obesity: A [11 C]MRB PET pilot study.

OBJECTIVE: Emotional eating (EE) has been linked to norepinephrine dysfunction. Therefore, we aimed to investigate the relationship between EE and norepinephrine transporter (NET) availability. METHOD: Ten severely obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2 ) and ten non-obese, healthy controls (BMI 23.9 ± 2.5 kg/m2 ) matched for age and sex were studied using (S,S)-[11 C]-O-methylreboxetine ([11 C]MRB) positron emission tomography (PET). Kinetic modeling of regional tissue time activity curves was performed using multilinear reference tissue model 2 (MRTM2, with the occipital cortex as a reference region) to estimate binding potential based on individual PET-MR coregistration. To test for associations of EE and NET availability, participants completed the EE subscale of the Dutch Eating Behavior Questionnaire before scanning. RESULTS: Obese individuals and non-obese, healthy controls did not significantly differ regarding EE scores and regional NET availability. For obese individuals only, correlative data analyses pointed to a sinoidal distribution pattern as a higher degree of EE related to lower NET availability in the locus coeruleus and to higher NET availability in the left thalamus. DISCUSSION: These results indicate that central in vivo NET availability is altered in EE of individuals with obesity. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2017; 50:152-156).

Hunger and disinhibition but not cognitive restraint are associated with central norepinephrine transporter availability.

The relationship between food-intake related behaviours measured by the Three-Factor Eating Questionnaire (TFEQ) and in vivo norepinephrine transporter (NET) availability has not been explored yet. We investigated ten obese individuals (body mass index (BMI) 42.4 ± 3.7 kg/m2) and ten normal-weight healthy controls (HC, BMI 23.9 ± 2.5 kg/m2) with (S,S)-[11C]-O-methylreboxetine ([11C]MRB) positron emission tomography (PET). All participants completed the TFEQ, which measures cognitive restraint, disinhibition and hunger. Image analysis required magnetic resonance imaging data sets onto which volumes-of-interests were drawn. Tissue time activity curves (TACs) were obtained from the dynamic PET data followed by kinetic modeling of these regional brain TACs applying the multilinear reference tissue model (2 parameters) with the occipital cortex as reference region. Obese individuals scored significantly higher on the hunger subscale of the TFEQ. Correlative data analysis showed that a higher degree of hunger correlated negatively with the NET availability of the insular cortex in both obese individuals and HC; however, this finding was more pronounced in obesity. Further, for obese individuals, a negative correlation between disinhibition and NET BPND of the locus coeruleus was detected. In conclusion, these initial data provide in vivo imaging support for the involvement of the central NE system in maladaptive eating behaviors such as susceptibility to hunger.

[Amyloid positron-emission-tomography with [18 F]-florbetaben in the diagnostic workup of dementia patients]. / Amyloid-Positronenemissionstomographie mit [18 F]-Florbetaben in der Demenzdiagnostik.

BACKGROUND: To this day the definite diagnosis of Alzheimer's disease still relies on post-mortem histopathological detection of neurofibrillary tangles and beta-amyloid deposits. Amyloid positron emission tomography (PET) is a new diagnostic tool that enables the in vivo quantification of pathological beta-amyloid deposits. The aim of the current study was to evaluate to what extent 18F-florbetaben-PET (FBB-PET) influences the diagnosis of patients with dementia. MATERIAL AND METHODS: Imaging with FBB-PET was performed on 33 patients from our outpatient department for cognitive neurology. Beforehand all patients underwent a comprehensive clinical, neuropsychiatric and laboratory examination as well as imaging by means of magnetic resonance imaging (MRI) and fluorodeoxyglucose-PET. The working diagnoses before and after FBB-PET imaging were compared. RESULTS: 17 out of 33 patients were scored as FBB-PET positive. In four cases the initial diagnosis had to be changed to Alzheimer's disease (three cases) and cerebral amyloid angiopathy (one case) due to the positive FBB-PET scan. 16 patients showed a negative FBB-PET scan. In three patients the initial diagnosis of Alzheimer's disease could be ruled out due to the negative FBB-PET scan. Overall, in 7 out of 33 examined patients the initial diagnosis had to be changed because of the findings of the FBB-PET scan. In 24 patients the initial diagnosis was confirmed by the results of the FBB-PET scan. CONCLUSION: Amyloid-PET is currently no standard procedure in the diagnosis of dementia; however, it can be a helpful additional diagnostic tool when used according to the "Appropriate Use Criteria" and the S3 guidelines on dementia in cases of unclear clinical presentation, atypically early age of onset as well as in patients with persistent or progressive unexplained mild cognitive impairment. By facilitating early diagnosis amyloid-PET imaging allows patient selection for therapeutic drug trials.

The central nervous norepinephrine network links a diminished sense of emotional well-being to an increased body weight.

OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress remain largely undiscovered. METHODS: In this pilot study, we combined positron emission tomography, using the norepinephrine transporter (NET) tracer [(11)C]-O-methylreboxetine, with functional connectivity magnetic resonance imaging, the Beck depression inventory (BDI), and the impact of weight on quality of life-Lite questionnaire (IWQOL-Lite), to investigate the role of norepinephrine in the severity of depression (BDI), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a small group of lean-to-morbidly obese individuals (n=20), we show that an increased body mass index (BMI) is related to a lowered NET availability within the hypothalamus, known as the brain's homeostatic control site. The hypothalamus displayed a strengthened connectivity in relation to the individual hypothalamic NET availability to the anterior insula/frontal operculum, as well as the medial orbitofrontal cortex, assumed to host the primary and secondary gustatory cortex, respectively (n=19). The resting-state activity in these two regions was correlated positively to the BMI and IWQOL-Lite scores, but not to the BDI, suggesting that the higher the resting-state activity in these regions, and hence the higher the BMI, the stronger the negative impact of the body weight on the individual's emotional well-being was. CONCLUSIONS: This pilot study suggests that the loss in emotional well-being with weight is embedded within the central norepinephrine network.

Sex differences in serotonin-hypothalamic connections underpin a diminished sense of emotional well-being with increasing body weight.

BACKGROUND/OBJECTIVES: The neurobiological mechanisms linking obesity to emotional distress related to weight remain largely unknown. PARTICIPANTS/METHODS: Here we combined positron emission tomography, using the serotonin transporter (5-HTT) radiotracer [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, with functional connectivity magnetic resonance imaging, the Beck Depression Inventory (BDI-II) and the Impact of Weight on Quality of Life-Lite questionnaire (IWQOL-Lite) to investigate the role of central serotonin in the severity of depression (BDI-II), as well as in the loss of emotional well-being with body weight (IWQOL-Lite). RESULTS: In a group of lean to morbidly obese individuals (n=28), we found sex differences in the 5-HTT availability-related connectivity of the hypothalamus. Males (n=11) presented a strengthened connectivity to the lateral orbitofrontal cortex, whereas in females (n=17) we found strengethened projections to the ventral striatum. Both regions are known as reward regions involved in mediating the emotional response to food. Their resting-state activity correlated positively to the body mass index (BMI) and IWQOL-Lite scores, suggesting that each region in both sexes also underpins a diminished sense of emotional well-being with body weight. Contrarily to males, we found that in females also the BDI-II positively correlated with the BMI and by trend with the activity in ventral striatum, suggesting that in females an increased body weight may convey to other mood dimensions than those weight-related ones included in the IWQOL-Lite. CONCLUSIONS: This study suggests sex differences in serotonin-hypothalamic connections to brain regions of the reward circuitry underpinning a diminished sense of emotional well-being with an increasing body weight.

2D imaging spin-filter for NanoESCA based on Au/Ir(001) or Fe(001)-p(1×1)O.

A two-dimensional imaging spin-filter for photo-emission electron microscopy is described. The spin-filter is capable of imaging the electron spin polarization of either real space or momentum space electron distributions. As a scattering target either Au/Ir(001) comes into use, where spin sensitivity results from using spin-orbit scattering or Fe(001)-p(1×1)O that exploits exchange interaction. Both scattering targets were characterized with respect to their working points and Sherman function in a separate setup. Spin-polarization images of secondary electrons from the magnetic domains of a poly-crystalline iron sample are shown using both scattering targets. Images with a spin-filter using Au/Ir(001) show more than 104 discrete detection channels which increases the effective two-dimensional figure-of-merit (FoM) of this spin-filter by four orders of magnitude compared to single-channel spin detectors. Using the exchange scattering target two spin-components have been imaged for the first time. A method to detect all three spin-components is also outlined.

Electric field-driven coherent spin reorientation of optically generated electron spin packets in InGaAs.

Full electric-field control of spin orientations is one of the key tasks in semiconductor spintronics. We demonstrate that electric-field pulses can be utilized for phase-coherent ±π spin rotation of optically generated electron spin packets in InGaAs epilayers detected by time-resolved Faraday rotation. Through spin-orbit interaction, the electric-field pulses act as local magnetic field pulses. By the temporal control of the local magnetic field pulses, we can turn on and off electron spin precession and thereby rotate the spin direction into arbitrary orientations in a two-dimensional plane. Furthermore, we demonstrate a spin-echo-type spin drift experiment and find an unexpected partial spin rephasing, which is evident by a doubling of the spin dephasing time.

Norchloro-fluoro-homoepibatidine (NCFHEB) - a promising radioligand for neuroimaging nicotinic acetylcholine receptors with PET.

Cholinergic neurotransmission depends on the integrity of nicotinic acetylcholine receptors (nAChRs), and impairment of both is characteristic for various neurodegenerative diseases. Visualization of specific receptor subtypes by positron emission tomography (PET) has potential to assist with diagnosis of such neurodegenerative diseases and with design of suitable therapeutic approaches. The goal of our study was to evaluate in vivo the potential of (18)F-labelled (+)- and (-)-norchloro-fluoro-homoepibatidine ([(18)F]NCFHEB) in comparison to 2-[(18)F]F-A-85380 as PET tracers. In the brains of NMRI mice, highest levels of radioactivity were detected at 20 min post-injection of (+)-[(18)F]NCFHEB, (-)-[(18)F]NCFHEB, and 2-F-[(18)F]-A-85380 (7.45, 5.60, and 3.2% ID/g tissue, respectively). No marked pharmacological adverse effects were observed at 25 mug NCFHEB/kg. Uptake studies in RBE4 cells and in situ perfusion studies suggest an interaction of epibatidine and NCFHEB with the carrier-mediated choline transport at the blood-brain barrier. The data indicate that (+)- and (-)-[(18)F]NCFHEB have potential for further development as PET tracers.

Guidance on validation and qualification of processes and operations involving radiopharmaceuticals.

BACKGROUND: Validation and qualification activities are nowadays an integral part of the day by day routine work in a radiopharmacy. This document is meant as an Appendix of Part B of the EANM "Guidelines on Good Radiopharmacy Practice (GRPP)" issued by the Radiopharmacy Committee of the EANM, covering the qualification and validation aspects related to the small-scale "in house" preparation of radiopharmaceuticals. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of radiopharmaceuticals which are not intended for commercial purposes or distribution. RESULTS: The present guideline covers the validation and qualification activities following the well-known "validation chain", that begins with editing the general Validation Master Plan document, includes all the required documentation (e.g. User Requirement Specification, Qualification protocols, etc.), and leads to the qualification of the equipment used in the preparation and quality control of radiopharmaceuticals, until the final step of Process Validation. CONCLUSIONS: A specific guidance to the qualification and validation activities specifically addressed to small-scale hospital/academia radiopharmacies is here provided. Additional information, including practical examples, are also available.

Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity.

A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine-phosphate-guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36±10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36±7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.

Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment.

Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer's disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.

Combination antiarrhythmic therapy for management of malignant ventricular arrhythmia.

The efficacy of combination drug therapy in the suppression of ambient ventricular arrhythmia was retrospectively evaluated in a study of 49 patients discharged from the hospital taking 2 membrane-active antiarrhythmic agents. Thirty-one patients (63%) had ischemic heart disease, 15 had miscellaneous cardiac disorders and 3 were free of ostensible heart disease. Therapy in all patients had previously been unsuccessful with an average of 3.7 single membrane-active drugs. Antiarrhythmic agents were discontinued for at least 48 hours to determine baseline arrhythmia levels by Holter monitoring and maximal exercise treadmill testing. Ventricular premature beats were evaluated according to the grading system of Lown and Wolf. Data on ventricular ectopic activity were obtained during Holter monitoring and exercise testing for both a control ("drug-free") period and for a period of combination therapy. During the control period, ventricular tachycardia was recorded during 23% of monitored hours, and the level was nearly twofold greater during stress testing. After institution of combined therapy, the percent of monitored hours of arrhythmia were reduced during Holter monitoring, with a greater reduction in couplets and ventricular tachycardia than in single ventricular premature beats. Ventricular tachycardia was more difficult to provoke by exercise testing in patients taking combination therapy than in control subjects. These data indicate that combination therapy can significantly reduce the density of ventricular ectopic activity in patients refractory to monotherapy. During an average follow-up of 26 months, 23 patients (47%) were able to receive decreased drug dosages, affording diminished adverse effects and improved tolerance to long-term use.

Cor triatriatum with isolated pulmonary venous stenosis in an adult: diagnosis with transesophageal two-dimensional echocardiography.

The diagnosis of cor triatriatum in an adult was made from routine two-dimensional transthoracic echocardiography. The findings of aliasing and turbulence in the roof of the left atrium suggested pulmonary venous stenosis. A transesophageal echocardiogram defined both the hemodynamic features of nonobstructing cor triatriatum and the presence of isolated pulmonary venous stenosis. The clinical use of transesophageal echocardiography with color flow Doppler in the elucidation of complex anatomic substrate is demonstrated.

Bulk sensitive hard x-ray photoemission electron microscopy.

Hard x-ray photoelectron spectroscopy (HAXPES) has now matured into a well-established technique as a bulk sensitive probe of the electronic structure due to the larger escape depth of the highly energetic electrons. In order to enable HAXPES studies with high lateral resolution, we have set up a dedicated energy-filtered hard x-ray photoemission electron microscope (HAXPEEM) working with electron kinetic energies up to 10 keV. It is based on the NanoESCA design and also preserves the performance of the instrument in the low and medium energy range. In this way, spectromicroscopy can be performed from threshold to hard x-ray photoemission. The high potential of the HAXPEEM approach for the investigation of buried layers and structures has been shown already on a layered and structured SrTiO3 sample. Here, we present results of experiments with test structures to elaborate the imaging and spectroscopic performance of the instrument and show the capabilities of the method to image bulk properties. Additionally, we introduce a method to determine the effective attenuation length of photoelectrons in a direct photoemission experiment.

Influence of additives to the formulation of n.c.a. [¹¹C]PiB on sterile filter performance.

The influence of different additives (PEG 300, PEG 400, PG) to the product solution of [(11)C]PiB was investigated with regard to tracer retention for a number of commonly used sterile filters for aseptic manufacturing of PET-tracers. The effect of the amount of additive with regard to tracer retention and the resulting viscosity of the filtration solution was determined. Recommendations for the individual combinations of filters and amounts of additives suitable for the different filtration methods that are implemented in commercially available synthesis modules are given as well.

One year follow-up of overweight and obese hypertensive adults following intensive lifestyle therapy.

OBJECTIVE: To examine the long-term effect on weight maintenance and dietary habits of participants in a clinical trial for weight loss. SETTING: Community-based residents living in Maryland. PARTICIPANTS: Forty-four hypertensive, overweight adults who participated in a randomized clinical trial of weight loss. Participants were randomized to an intensive 'lifestyle' intervention or a 'monitoring' group. MAIN OUTCOME MEASURES: Weight, self-reported current intake of fat and fruit/fibre and self-reported barriers to maintain weight loss were assessed 1 year after the completion of the Diet, Exercise and Weight-loss Intervention Trial (DEW-IT) trial. ANALYSIS: t-tests were used to compare groups for differences in continuous variables and chi-square tests were used to compare groups for categorical variables. RESULTS: Fourty-two of the 44 DEW-IT subjects participated in the follow-up study. Overall, 55% (12/19) of the lifestyle intervention group remained at or below their baseline weight at 1 year, compared with 48% (11/23) of the monitoring group (P = 0.32). However, during that year, 95% (18/19) of the lifestyle intervention group and 52% (12/23) of the monitoring group gained weight from the end of the study. Both groups reported similar intake of fruits/vegetables (servings day(-1)), dietary fibre (g day(-1)) and fat (g day(-1)). CONCLUSIONS AND IMPLICATIONS: The majority of participants who lost weight during the trial regained weight during the course of 1 year. A successful intensive 2-month programme of lifestyle modification (DEW-IT) was ineffective for long-term maintenance of weight loss.

Introducing fluorine-18 fluoromisonidazole positron emission tomography for the localisation and quantification of pig liver hypoxia.

Fluorine-18 labelled fluoromisonidazole ([18F]FMISO) has been shown to accumulate in hypoxic tissue in inverse proportion to tissue oxygenation. In order to evaluate the potential of [18F]FMISO as a possible positron emission tomography (PET) tracer for imaging of liver tissue hypoxia, we measured the [18F]FMISO uptake in 13 domestic pigs using dynamic PET scanning. Hypoxia was induced by segmental arterial hepatic occlusion. During the experimental procedure the fractional concentration of inspired oxygen (FiO2) was set to 0.67 in group A (n=6) and to 0.21 in group B (n=7) animals. Before and after arterial occlusion, the partial pressure of O2 in tissue (TPO2) and the arterial blood flow were determined in normal flow and flow-impaired liver segments. Standardised uptake values [SUV=kBq tissue (in g) / body weight (in kg) x injected dose (in kBq)] for [18F]FMISO were calculated from PET images obtained 3 hours after injection of about 10 MBq/kg body weight [18F]FMISO. Immediately before PET scanning, the mean arterial blood flow was significantly decreased in arterially occluded segments [group A: 0. 41 (0.32-0.52); group B: 0.24 (0.16-0.33) ml min-1 g-1] compared with normal flow segments [group A: 1.05 (0.76-1.46); group B: 1.14 (0.83-1.57) ml min-1 g-1; geometric mean (95% confidence limits); P<0.001 for both groups]. After PET scanning, the TPO2 of occluded segments (group A: 5.1 (4.1-6.4); group B: 3.5 (2.6-4.9) mmHg] was significantly decreased compared with normal flow segments [group A: 26.4 (21.2-33.0); group B: 18.2 (13.3-25.1) mmHg; P<0.001 for both groups]. During the 3-h PET scan, the mean [18F]FMISO SUV determined in occluded segments increased significantly to 3.84 (3.12-4.72) in group A and 5.7 (4.71-6.9) in group B, while the SUV remained unchanged in corresponding normal liver tissue [group A: 1.4 (1.14-1. 71); group B: 1.31 (1.09-1.57); P<0.001 for both groups]. Regardless of ventilation conditions, a significant inverse exponential relationship was found between the TPO2 and the [18F]FMISO SUV (r2=0. 88, P<0.001). Our results suggest that because tracer delivery to hypoxic tissues was maintained by the portal circulation, the [18F]FMISO accumulation in the liver was found to be directly related to the severity of tissue hypoxia. Thus, [18F]FMISO PET allows in vivo quantification of pig liver hypoxia using simple SUV analysis as long as tracer delivery is not critically reduced.