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Background: Latency remains a major obstacle to finding a cure for HIV despite the availability of antiretroviral therapy. Due to virus dormancy, limited biomarkers are available to identify latent HIV-infected cells. Profiling of individual HIV-infected cells is needed to explore potential latency biomarkers and to study the mechanisms of persistence that maintain the HIV reservoir., Methods: Single cell spatial transcriptomic characterization using the CosMx Spatial Molecular Imager platform was conducted to analyze HIV-infected cells in formalin-fixed paraffin-embedded sections of splenic tissue surgically obtained from an HIV-infected humanized mouse model. Regulation of over a thousand human genes was quantified in both viremic and aviremic specimens. In addition, in situ hybridization and immunohistochemistry were performed in parallel to identify HIV viral RNA- and p24-containing cells, respectively. Finally, initial findings from CosMx gene profiling were confirmed by isolating RNA from CD4 + T cells obtained from a person living with HIV on antiretroviral therapy following either PMA/Ionomycin or DMSO treatment. RNA was quantified using qPCR for a panel of targeted human host genes., Results: Supervised cell typing revealed that most of the HIV-infected cells in the mouse spleen sections were differentiated CD4 + T cells. A significantly higher number of infected cells, 2781 (1.61%) in comparison to 112 (0.06%), and total HIV transcripts per infected cell were observed in viremic samples compared to aviremic samples, respectively, which was consistent with the data obtained from ISH and IHC. Notably, the expression of 55 genes was different in infected cells within tissue from aviremic animals compared to viremic. In particular, both spleen tyrosine kinase (SYK) and CXCL17, were expressed approximately 100-fold higher. This data was further evaluated against bulk RNA isolated from HIV-infected human primary CD4 + T cells. A nearly 6-fold higher expression of SYK mRNA was observed in DMSO-treated CD4 + T cells compared to those stimulated with PMA/Ionomycin., Conclusion: This study found that the CosMx SMI platform is valuable for assessing HIV infection and providing insights into host biomarkers associated with HIV reservoirs. Higher relative expression of the SYK gene in aviremic-infected cells from the humanized mouse HIV model was consistent with levels found in CD4 + T cells of aviremic donors., (© 2024. The Author(s).)

A progressive neurological disorder was observed in a male neutered Weimaraner. Clinical signs included fecal incontinence, lethargy, moderate paraparesis, proprioceptive pelvic limb ataxia, falling, cognitive decline, incoordination, decreased interest in food, changes in posture, and episodes of trance-like behavior. Neurologic signs were first observed at approximately 4 years, 10 months of age and progressed slowly. Magnetic resonance imaging showed generalized brain atrophy with areas of white matter pathology. Humane euthanasia was elected at 6 years, 7 months of age due to increasing severity of the neurological signs. Autofluorescent intracellular granules were observed in the cerebral and cerebellar cortexes, optic nerve, and cardiac muscle of the affected dog. These abnormal inclusions in the cerebral cortex and cardiac muscle immunolabeled with antibodies to mitochondrial ATP synthase subunit c protein, like that observed in the neuronal ceroid lipofuscinosis group of lysosomal storage diseases. Immunolabeling also demonstrated pronounced neuroinflammation in brain tissues. The ultrastructural appearances of the disease-related inclusion bodies in the brain and optic nerve were quite variable. The ultrastructure and locations of many of the inclusions in the nervous tissues suggested that they were derived, at least in part, from the myelin surrounding axons. The storage bodies in the cardiac muscle were located in mitochondria-rich regions and consisted of parallel arrays of membrane-like components interspersed with electron-dense flocculent material. The disease was characterized by pronounced abnormalities in the myelin of the brain and optic nerve consisting of distinctive areas of ballooning between the layers of myelin. The whole genome sequence generated from the affected dog contained a homozygous G-to-A missense mutation in CNP , which encodes proteins with CNPase enzyme activity and a structural role in myelin. The mutation predicts a Thr42Met amino acid sequence substitution. Genotyping of archived Weimaraner DNA samples identified an additional G > A variant homozygote with a clinical history and brain lesions similar to those of the proband. Of 304 Weimaraners and over 4000 other dogs of various breeds, the proband and the other Weimaraner that exhibited similar signs were the only two that were homozygous for the CNP missense variant. CNPase immunolabeling was widespread in brain tissues from normal dogs but was undetectable in the same tissues from the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the late-onset Weimaraner disorder likely results from the missense mutation that results in CNPase deficiency, leading to myelin abnormalities, accumulation of lysosomal storage bodies, and brain atrophy. Similar disorders have been associated with different CNP variants in Dalmatians and in human subjects.

An increasing number of studies have shown the key role that RNA polymerase II (RNA Pol II) elongation plays in gene regulation. We systematically examine how various enhancers, promoters, and gene body composition influence the RNA Pol II elongation rate through a single-cell-resolution live imaging assay. By using reporter constructs containing 5' MS2 and 3' PP7 repeating stem loops, we quantify the rate of RNA Pol II elongation in live Drosophila embryos. We find that promoters and exonic gene lengths have no effect on elongation rate, while enhancers and the presence of long introns may significantly change how quickly RNA Pol II moves across a gene. Furthermore, we observe in multiple constructs that the RNA Pol II elongation rate accelerates after the transcriptional onset of nuclear cycle 14 in Drosophila embryos. Our study provides a single-cell view of various mechanisms that affect the dynamic RNA Pol II elongation rate, ultimately affecting the rate of mRNA production., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a [ 11 C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24-38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [ 11 C]UCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs., (© 2023. The Author(s).)

Background: A prominent finding in major depressive disorder (MDD) is distorted stress hormone dynamics, which is regulated by serotonergic brain signaling. An interesting feature of the cerebral serotonin system is the serotonin 4 receptor (5-HT4R), which is lower in depressed relative to healthy individuals and also has been highlighted as a promising novel antidepressant target. Here, we test the novel hypothesis that brain 5-HT4R availability in untreated patients with MDD is correlated with cortisol dynamics, indexed by the cortisol awakening response (CAR). Further, we evaluate if CAR changes with antidepressant treatment, including a selective serotonin reuptake inhibitor, and if pretreatment CAR can predict treatment outcome., Methods: Sixty-six patients (76% women) with a moderate to severe depressive episode underwent positron emission tomography imaging with [11C]SB207145 for quantification of brain 5-HT4R binding using BPND as outcome. Serial home sampling of saliva in the first hour from awakening was performed to assess CAR before and after 8 weeks of antidepressant treatment. Treatment outcome was measured by change in Hamilton Depression Rating Scale 6 items., Results: In the unmedicated depressed state, prefrontal and anterior cingulate cortices 5-HT4R binding was positively associated with CAR. CAR remained unaltered after 8 weeks of antidepressant treatment, and pretreatment CAR did not significantly predict treatment outcome., Conclusions: Our findings highlight a link between serotonergic disturbances in MDD and cortisol dynamics, which likely is involved in disease and treatment mechanisms. Further, our data support 5-HT4R agonism as a promising precision target in patients with MDD and disturbed stress hormone dynamics., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18 F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (- 8.4%, P = 0.032 vs 15.7%, P < 0.0005) and S1P (- 41.0%, P < 0.0005 vs 19.1%, P < 0.005) plasma levels, respectively. Long-term cooling (n = 44) did not affect plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the individual studies. However, short-term studies combined, showed that increased changes in plasma apoM correlated with BAT metabolic activity (β: 0.44, 95% CI [0.06-0.81], P = 0.024) after adjusting for study design but not BAT volume (β: 0.39, 95% CI [- 0.01-0.78], P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism., (© 2022. The Author(s).)

We investigated the effect of pharmacologically induced weight loss on markers of glucagon resistance in individuals with overweight during treatment with the glucagon-like peptide-1 receptor agonist liraglutide. We performed an open-label study in 14 men with overweight (age 38 ± 11 years, BMI 32 ± 4 kg/m 2 ) without simultaneously diabetes. Subjects were treated with liraglutide, initiated and titrated with 0.6 mg/day/week to reach the final dose of 3.0 mg/day. Subjects were examined at baseline, during titration (Week 4), after 2 weeks of steady state (Week 6) of final dosing of liraglutide and 3 weeks after discontinuation of liraglutide (follow-up). Study participants lost 3.3 ± 1.9 kg (3%) total body weight during the first 4 weeks of treatment with liraglutide. Simultaneously, liver fat content decreased from 12.4 ± 11.6% to 10.2 ± 11.1%, p = 0.025, whereas fat content in the spleen and subcutaneous tissue was unaltered. Markers of glucagon resistance, including plasma glucagon and the glucagon-alanine-index, also decreased significantly during treatment, but total and individual plasma amino acid concentrations did not. Insulin resistance (HOMA-IR) was unchanged during treatment, whereas insulin clearance increased. Treatment with the GLP-1 receptor analogue liraglutide decreased liver fat content, and simultaneously attenuated glucagon concentrations and the glucagon-alanine index in individuals with overweight without diabetes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how the cerebral 5-HT system associates to disturbances in cognition and mood in PD patients with DBS-STN turned on and off. We used psychological tests and questionnaires to evaluate cognitive function and the effects on mood from turning DBS-STN off. We applied a novel PET neuroimaging methodology to evaluate the integrity of the cerebral serotonin system. We measured 5-HT1BR binding in 13 DBS-STN-treated PD patients, at baseline and after turning DBS off. Thirteen age-matched volunteers served as controls. The measures for cognition and mood were correlated to the 5-HT1BR availability in temporal limbic cortex. 5-HT1BR binding was proportional to working memory performance and inverse proportional to affective bias for face recognition. When DBS is turned off, patients feel less vigorous; the higher the limbic and temporal 5-HT1BR binding, the more they are affected by DBS being turned off. Our study suggests that cerebral 5-HTR binding is associated with non-motor symptoms, and that preservation of serotonergic functions may be predictive of DBS-STN effects.

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [ 18 F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [ 18 F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity)., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Head motion is one of the major reasons for artefacts in Magnetic Resonance Imaging (MRI), which is especially challenging for children who are often intimidated by the dimensions of the MR scanner. In order to optimise the MRI acquisition for children in the clinical setting, insights into children's motion patterns are essential. In this work, we analyse motion data from 61 paediatric patients. We compare structural MRI data of children imaged with and without general anaesthesia (GA), all scanned using the same hybrid PET/MR scanner. We analyse several metrics of motion based on the displacement relative to a reference, decompose the transformation matrix into translation and rotation, as well as investigate whether different regions in the brain are affected differently by the children's motion. Head motion for children without GA was significantly higher, with a median of the mean displacements of 2.19 ± 0.93 mm (median ± standard deviation) during 41.7±7.5 min scans; however, even anaesthetised children showed residual head motion (mean displacement of 1.12±0.35 mm). For both patient groups translation along the z-axis (along the scanner bore) was significantly larger in absolute terms (GA / no GA: 0.87±0.29/0.92 ± 0.49 mm) compared to the other directions. Considering directionality, both patient groups were moving in negative z-direction and thus, out of the scanner. The awake children additionally showed significantly more nodding rotation (0.33±0.20°). In future studies as well as in the clinical setting, these predominant types of motion need to be taken into consideration to limit artefacts and reduce re-scans due to poor image quality., Competing Interests: AE and JS, as well as MG's husband are employees at TracInnovations, Ballerup, Denmark. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eichhorn, Vascan, Nørgaard, Ellegaard, Slipsager, Keller, Marner and Ganz.)

Heterochromatin, typically marked by histone H3 trimethylation at lysine 9 (H3K9me3) or lysine 27 (H3K27me3), represses different protein-coding genes in different cells, as well as repetitive elements. The basis for locus specificity is unclear. Previously, we identified 172 proteins that are embedded in sonication-resistant heterochromatin (srHC) harbouring H3K9me3. Here, we investigate in humans how 97 of the H3K9me3-srHC proteins repress heterochromatic genes. We reveal four groups of srHC proteins that each repress many common genes and repeat elements. Two groups repress H3K9me3-embedded genes with different extents of flanking srHC, one group is specific for srHC genes with H3K9me3 and H3K27me3, and one group is specific for genes with srHC as the primary feature. We find that the enhancer of rudimentary homologue (ERH) is conserved from Schizosaccharomyces pombe in repressing meiotic genes and, in humans, now represses other lineage-specific genes and repeat elements. The study greatly expands our understanding of H3K9me3-based gene repression in vertebrates., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Patients with Parkinson's disease (PD) often suffer from non-motor symptoms, which may be caused by serotonergic dysfunction. Apart from alleviating the motor symptoms, Deep Brain Stimulation (DBS) in the subthalamic nucleus (STN) may also influence non-motor symptoms. The aim of this study is to investigate how turning DBS off affects the serotonergic system. We here exploit a novel functional PET neuroimaging methodology to evaluate the preservation of serotonergic neurons and capacity to release serotonin. We measured cerebral 5-HT 1B R binding in 13 DBS-STN treated PD patients, at baseline and after turning DBS off. Ten age-matched volunteers served as controls. Clinical measures of motor symptoms were assessed under the two conditions and correlated to the PET measures of the static and dynamic integrity of the serotonergic system. PD patients exhibited a significant loss of frontal and parietal 5-HT 1B R, and the loss was significantly correlated to motor symptom severity. We saw a corresponding release of serotonin, but only in brain regions with preserved 5-HT 1B R, suggesting the presence of a presynaptic serotonergic deficit. Our study demonstrates that DBS-STN dynamically regulates the serotonin system in PD, and that preservation of serotonergic functions may be predictive of DBS-STN effects.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. For decades, several in vivo and ex vivo techniques have been used to highlight the mechanisms of the GABA system, however, no studies have currently combined the techniques to create a high-resolution multimodal view of the GABA system. Here, we present a quantitative high-resolution in vivo atlas of the human brain benzodiazepine receptor sites (BZR) located on postsynaptic ionotropic GABA A receptors (GABA A Rs), generated on the basis of in vivo [ 11 C]flumazenil Positron Emission Tomography (PET) data. Next, based on ex vivo autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association between BZR protein density and ex vivo mRNA expression for the 19 subunits in the GABA A R, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein. This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABA A R and the BZR density at each location in the brain., Competing Interests: Declaration of Competing Interest GMK has received honoria as an expert advisor for Sage Therapeutics and as a speaker for Jannsen., (Copyright © 2021. Published by Elsevier Inc.)

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and 18 F-FDG PET/CT is low because of radiation-induced changes. 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) PET has previously demonstrated higher specificity for malignancy than 18 F-FDG PET. We investigated the value of 18 F-FLT PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected of relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy [cRT] or stereotactic body radiotherapy [SBRT]) were included. Sensitivity and specificity were analyzed both within the irradiated high-dose volume (HDV) and on a patient basis. Marginal differences and interobserver agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of 18 F-FLT PET/CT was higher than that of 18 F-FDG PET/CT (HDV, 96% [95% CI, 87-100] vs. 71% [95% CI, 57-83] [ P = 0.0039]; patient-based, 90% [95% CI, 73-98] vs. 55% [95% CI, 36-74] [ P = 0.0020]). The difference in specificity between 18 F-FLT PET/CT and 18 F-FDG PET/CT was higher after cRT than after SBRT. The sensitivity of 18 F-FLT PET/CT was lower than that of 18 F-FDG PET/CT (HDV, 69% [95% CI, 41-89] vs. 94% [95% CI, 70-100] [ P = 0.1250]; patient-based, 70% [95% CI, 51-84] vs. 94% [95% CI, 80-99] [ P = 0.0078]). Adding 18 F-FLT PET/CT when 18 F-FDG PET/CT was positive or inconclusive improved the diagnostic value compared with 18 F-FDG PET/CT alone. In cRT HDVs, the probability of malignancy increased from 67% for 18 F-FDG PET/CT alone to 100% when both tracers were positive. Conclusion: 18 F-FLT PET/CT adds diagnostic value to 18 F-FDG PET/CT in patients with suspected relapse. The diagnostic impact of 18 F-FLT PET/CT was highest after cRT. We suggest adding 18 F-FLT PET/CT when 18 F-FDG PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients for whom histologic confirmation is not easily obtained., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[ 18 F]fluoro-d-glucose (FDG)-uptake. The 3'-deoxy-3'-[ 18 F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUV max and FLT-SUV max were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUV max : 12.8 vs. 4.2; p < 0.001; median FLT-SUV max 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUV peak (median FDG-SUV peak : 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV 50% ): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV 50% ) was prognostic for the overall survival (hazard ratio: 1.07 pr cm 3 [1.01-1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUV max and FLT-SUV max may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

Endogenous serotonin (5-HT) release can be measured noninvasively using positron emission tomography (PET) imaging in combination with certain serotonergic radiotracers. This allows us to investigate effects of pharmacological and nonpharmacological interventions on brain 5-HT levels in living humans. Here, we study the neural responses to a visual stimulus using simultaneous PET/MRI. In a cross-over design, 11 healthy individuals were PET/MRI scanned with the 5-HT 1B receptor radioligand [ 11 C]AZ10419369, which is sensitive to changes in endogenous 5-HT. During the last part of the scan, participants either viewed autobiographical images with positive valence (n = 11) or kept their eyes closed (n = 7). The visual stimuli increased cerebral blood flow (CBF) in the occipital cortex, as measured with pseudo-continuous arterial spin labeling. Simultaneously, we found decreased 5-HT 1B receptor binding in the occipital cortex (-3.6 ± 3.6%), indicating synaptic 5-HT release. Using a linear regression model, we found that the change in 5-HT 1B receptor binding was significantly negatively associated with change in CBF in the occipital cortex (p = .004). For the first time, we here demonstrate how cerebral 5-HT levels change in response to nonpharmacological stimuli in humans, as measured with PET. Our findings more directly support a link between 5-HT signaling and visual processing and/or visual attention., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Aim: To investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans., Materials and Methods: We performed an open-label study in 14 obese men (age 38 ± 11 years, body mass index 32 ± 4 kg/m 2 ) without diabetes. Subjects were examined at baseline, during titration (week 4) of liraglutide towards 3.0 mg/day, and 2 weeks after steady-state treatment (week 6) of a final dose of liraglutide. The primary endpoint was pancreatic volume determined by magnetic resonance imaging. Secondary endpoints included pancreatic oedema and cellularity, positron emission tomography-based [ 18 F]fluorothymidine (FLT) uptake (DNA synthesis) and plasma pancreatic enzymes., Results: Plasma amylase (+7 U/L [95% confidence intervals 3-11], P < .01) and lipase (+19 U/L [7-30], P < .01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm 3 [-8-8], P = .96) and no change in pancreatic cellular infiltration was found (P = .22). During titration of liraglutide, FLT uptake in pancreatic tissue increased numerically (+0.08 [0.00-0.17], P = .0507)., Conclusions: Six weeks of treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes., (© 2020 John Wiley & Sons Ltd.)

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.

The regulatory specificity of a gene is determined by the structure of its enhancers, which contain multiple transcription factor binding sites. A unique combination of transcription factor binding sites in an enhancer determines the boundary of target gene expression, and their disruption often leads to developmental defects. Despite extensive characterization of binding motifs in an enhancer, it is still unclear how each binding site contributes to overall transcriptional activity. Using live imaging, quantitative analysis, and mathematical modeling, we measured the contribution of individual binding sites in transcriptional regulation. We show that binding site arrangement within the Rho-GTPase component t48 enhancer mediates the expression boundary by mainly regulating the timing of transcriptional activation along the dorsoventral axis of Drosophila embryos. By tuning the binding affinity of the Dorsal (Dl) and Zelda (Zld) sites, we show that single site modulations are sufficient to induce significant changes in transcription. Yet, no one site seems to have a dominant role; rather, multiple sites synergistically drive increases in transcriptional activity. Interestingly, Dl and Zld demonstrate distinct roles in transcriptional regulation. Dl site modulations change spatial boundaries of t48 , mostly by affecting the timing of activation and bursting frequency rather than transcriptional amplitude or bursting duration. However, modulating the binding site for the pioneer factor Zld affects both the timing of activation and amplitude, suggesting that Zld may potentiate higher Dl recruitment to target DNAs. We propose that such fine-tuning of dynamic gene control via enhancer structure may play an important role in ensuring normal development., Competing Interests: The authors declare no competing interest.

Background: Small cell lung cancer (SCLC) is an aggressive cancer often presenting in an advanced stage and prognosis is poor. Early response evaluation may have impact on the treatment strategy., Aim: We evaluated 18 F-fluorothymidine-(FLT)-PET/diffusion-weighted-(DW)-MRI early after treatment start to describe biological changes during therapy, the potential of early response evaluation, and the added value of FLT-PET/DW-MRI., Methods: Patients with SCLC referred for standard chemotherapy were eligible. FLT-PET/DW-MRI of the chest and brain was acquired within 14 days after treatment start. FLT-PET/DW-MRI was compared with pretreatment FDG-PET/CT. Standardized uptake value (SUV), apparent diffusion coefficient (ADC), and functional tumor volumes were measured. FDG-SUV peak , FLT-SUV peak , and ADC median ; spatial distribution of aggressive areas; and voxel-by-voxel analyses were evaluated to compare the biological information derived from the three functional imaging modalities. FDG-SUV peak , FLT-SUV peak , and ADC median were also analyzed for ability to predict final treatment response., Results: Twelve patients with SCLC completed FLT-PET/MRI 1-9 days after treatment start. In nine patients, pretreatment FDG-PET/CT was available for comparison. A total of 16 T-sites and 12 N-sites were identified. No brain metastases were detected. FDG-SUV peak was 2.0-22.7 in T-sites and 5.5-17.3 in N-sites. FLT-SUV peak was 0.6-11.5 in T-sites and 1.2-2.4 in N-sites. ADC median was 0.76-1.74 × 10 - 3  mm 2 /s in T-sites and 0.88-2.09 × 10 -3  mm 2 /s in N-sites. FLT-SUV peak correlated with FDG-SUV peak , and voxel-by-voxel correlation was positive, though the hottest regions were dissimilarly distributed in FLT-PET compared to FDG-PET. FLT-SUV peak was not correlated with ADC median , and voxel-by-voxel analyses and spatial distribution of aggressive areas varied with no systematic relation. LT-SUV peak was significantly lower in responding lesions than non-responding lesions (mean FLT-SUV peak in T-sites: 1.5 vs. 5.7; p = 0.007, mean FLT-SUV peak in N-sites: 1.6 vs. 2.2; p = 0.013)., Conclusions: FLT-PET and DW-MRI performed early after treatment start may add biological information in patients with SCLC. Proliferation early after treatment start measured by FLT-PET is a promising predictor for final treatment response that warrants further investigation., Trial Registration: Clinicaltrials.gov, NCT02995902. Registered 11 December 2014 - Retrospectively registered.

Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively capture temporal and spatial information about acute changes in brain neurotransmitter systems. We here evaluate the 5-HT 1B receptor partial agonist PET radioligand, [ 11 C]AZ10419369, for its sensitivity to detect changes in endogenous cerebral serotonin levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain serotonin levels, we compared the [ 11 C]AZ10419369 PET signal in the pig brain to simultaneous measurements of extracellular serotonin levels with microdialysis after various acute interventions (saline, escitalopram, fenfluramine). The interventions increased the cerebral extracellular serotonin levels to two to six times baseline, with fenfluramine being the most potent pharmacological enhancer of serotonin release. The interventions induced a varying degree of decline in [ 11 C]AZ10419369 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular serotonin level in the pig brain and the 5-HT 1B receptor occupancy indicates that [ 11 C]AZ10419369 binding is sensitive to changes in endogenous serotonin levels to a degree equivalent to that reported of [ 11 C]raclopride to dopamine, a much used approach to detect in vivo change in cerebral dopamine.

Quantitative PET/MRI is dependent on reliable and reproducible MR-based attenuation correction (MR-AC). In this study, we evaluated the quality of current vendor-provided thoracic MR-AC maps and further investigated the reproducibility of their impact on 18 F-FDG PET quantification in patients with non-small cell lung cancer. Methods: Eleven patients with inoperable non-small cell lung cancer underwent 2-5 thoracic PET/MRI scan-rescan examinations within 22 d. 18 F-FDG PET data were acquired along with 2 Dixon MR-AC maps for each examination. Two PET images (PET A and PET B ) were reconstructed using identical PET emission data but with MR-AC from these intrasubject repeated attenuation maps. In total, 90 MR-AC maps were evaluated visually for quality and the occurrence of categorized artifacts by 2 PET/MRI-experienced physicians. Each tumor was outlined by a volume of interest (40% isocontour of maximum) on PET A , which was then projected onto the corresponding PET B SUV mean and SUV max were assessed from the PET images. Within-examination coefficients of variation and Bland-Altman analyses were conducted for the assessment of SUV variations between PET A and PET B Results: Image artifacts were observed in 86% of the MR-AC maps, and 30% of the MR-AC maps were subjectively expected to affect the tumor SUV. SUV mean and SUV max resulted in coefficients of variation of 5.6% and 6.6%, respectively, and scan-rescan SUV variations were within ±20% in 95% of the cases. Substantial SUV variations were seen mainly for scan-rescan examinations affected by respiratory motion. Conclusion: Artifacts occur frequently in standard thoracic MR-AC maps, affecting the reproducibility of PET/MRI. These, in combination with other well-known sources of error associated with PET/MRI examinations, lead to inconsistent SUV measurements in serial studies, which may affect the reliability of therapy response assessment. A thorough visual inspection of the thoracic MR-AC map and Dixon images from which it is derived remains crucial for the detection of MR-AC artifacts that may influence the reliability of SUV., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Background The pathophysiology of migraine may involve dysfunction of serotonergic signaling. In particular, the 5-HT 1B receptor is considered a key player due to the efficacy of 5-HT 1B receptor agonists for treatment of migraine attacks. Aim To examine the cerebral 5-HT 1B receptor binding in interictal migraine patients without aura compared to controls. Methods Eighteen migraine patients, who had been migraine free for >48 hours, and 16 controls were scanned after injection of the 5-HT 1B receptor specific radioligand [ 11 C]AZ10419369 for quantification of cerebral 5-HT 1B receptor binding. Patients who reported migraine <48 hours after the PET examination were excluded from the final analysis. We defined seven brain regions involved in pain modulation as regions of interest and applied a latent variable model (LVM) to assess the group effect on binding across these regions. Results Our data support a model wherein group status predicts the latent variable ( p = 0.038), with migraine patients having lower 5-HT 1B receptor binding across regions compared to controls. Further, in a whole-brain voxel-based analysis, time since last migraine attack correlated positively with 5-HT 1B receptor binding in the dorsal raphe and in the midbrain. Conclusion We report here for the first time that migraine patients have low 5-HT 1B receptor binding in pain modulating regions, reflecting decreased receptor density. This is either a primary constitutive trait of the migraine brain or secondary to repeated exposure to migraine attacks. We also provide indirect support for the dorsal raphe 5-HT 1B receptors being temporarily downregulated during the migraine attack, presumably in response to higher cerebral serotonin levels in the ictal phase.

Background: The increasing use of the pig as a research model in neuroimaging requires standardized processing tools. For example, extraction of regional dynamic time series from brain PET images requires parcellation procedures that benefit from being automated., Comparison With Existing Methods: Manual inter-modality spatial normalization to a MRI atlas is operator-dependent, time-consuming, and can be inaccurate with lack of cortical radiotracer binding or skull uptake., New Method: A parcellated PET template that allows for automatic spatial normalization to PET images of any radiotracer., Results: MRI and [ 11 C]Cimbi-36 PET scans obtained in sixteen pigs made the basis for the atlas. The high resolution MRI scans allowed for creation of an accurately averaged MRI template. By aligning the within-subject PET scans to their MRI counterparts, an averaged PET template was created in the same space. We developed an automatic procedure for spatial normalization of the averaged PET template to new PET images and hereby facilitated transfer of the atlas regional parcellation. Evaluation of the automatic spatial normalization procedure found the median voxel displacement to be 0.22±0.08mm using the MRI template with individual MRI images and 0.92±0.26mm using the PET template with individual [ 11 C]Cimbi-36 PET images. We tested the automatic procedure by assessing eleven PET radiotracers with different kinetics and spatial distributions by using perfusion-weighted images of early PET time frames., Conclusion: We here present an automatic procedure for accurate and reproducible spatial normalization and parcellation of pig PET images of any radiotracer with reasonable blood-brain barrier penetration., (Copyright © 2017 Elsevier B.V. All rights reserved.)

For quantitative tracer distribution in positron emission tomography, attenuation correction is essential. In a hybrid PET/CT system the CT images serve as a basis for generation of the attenuation map, but in PET/MR, the MR images do not have a similarly simple relationship with the attenuation map. Hence attenuation correction in PET/MR systems is more challenging. Typically either of two MR sequences are used: the Dixon or the ultra-short time echo (UTE) techniques. However these sequences have some well-known limitations. In this study, a reconstruction technique based on a modified and optimized non-TOF MLAA is proposed for PET/MR brain imaging. The idea is to tune the parameters of the MLTR applying some information from an attenuation image computed from the UTE sequences and a T1w MR image. In this MLTR algorithm, an [Formula: see text] parameter is introduced and optimized in order to drive the algorithm to a final attenuation map most consistent with the emission data. Because the non-TOF MLAA is used, a technique to reduce the cross-talk effect is proposed. In this study, the proposed algorithm is compared to the common reconstruction methods such as OSEM using a CT attenuation map, considered as the reference, and OSEM using the Dixon and UTE attenuation maps. To show the robustness and the reproducibility of the proposed algorithm, a set of 204 [ 18 F]FDG patients, 35 [ 11 C]PiB patients and 1 [ 18 F]FET patient are used. The results show that by choosing an optimized value of [Formula: see text] in MLTR, the proposed algorithm improves the results compared to the standard MR-based attenuation correction methods (i.e. OSEM using the Dixon or the UTE attenuation maps), and the cross-talk and the scale problem are limited.

Background: We present a quick and easy method to perform quantitatively accurate PET scans of typical water-filled PET plastic shell phantoms on the Siemens Biograph mMR PET/MR system. We perform regular cross-calibrations (Xcal) of our PET systems, including the PET/MR, using a Siemens mCT water phantom., Long-Term Stability: The mMR calibration stability was evaluated over a 3-year period where 54 cross-calibrations were acquired, showing that the mMR on average underestimated the concentration by 16 %, consistently due to the use of MR-based μ-maps. The mMR produced the narrowest calibration ratio range with the lowest standard deviation, implying it is the most stable of the six systems in the study over a 3-year period. MMR ACCURACY WITH PREDEFINED μ-MAPS: With the latest mMR software version, VB20P, it is possible to utilize predefined phantom μ-maps. We evaluated both the system-integrated, predefined μ-map of the long mMR water phantom and our own user-defined CT-based μ-map of the mCT water phantom, which is used for cross-calibration. For seven scans, which were reconstructed with correctly segmented μ-maps, the mMR produced cross-calibration ratios of 1.00-1.02, well within the acceptance range [0.95-1.05], showing high accuracy., Conclusions: The mMR is the most stable PET system in this study, and the mean underestimation is no longer an issue with the easily accessible μ-map, which resulted in correct cross-calibration ratios in all seven tests. We will share the user-defined μ-map of the mCT phantom and the protocol with interested mMR users.

Unlabelled: A spatial bias in brain PET/MR exists compared with PET/CT, because of MR-based attenuation correction. We performed an evaluation among 4 institutions, 3 PET/MR systems, and 4 PET/CT systems using an anthropomorphic brain phantom, hypothesizing that the spatial bias would be minimized with CT-based attenuation correction (CTAC)., Methods: The evaluation protocol was similar to the quantification of changes in neurologic PET studies. Regional analysis was conducted on 8 anatomic volumes of interest (VOIs) in gray matter on count-normalized, resolution-matched, coregistered data. On PET/MR systems, CTAC was applied as the reference method for attenuation correction., Results: With CTAC, visual and quantitative differences between PET/MR and PET/CT systems were minimized. Intersystem variation between institutions was +3.42% to -3.29% in all VOIs for PET/CT and +2.15% to -4.50% in all VOIs for PET/MR. PET/MR systems differed by +2.34% to -2.21%, +2.04% to -2.08%, and -1.77% to -5.37% when compared with a PET/CT system at each institution, and these differences were not significant (P ≥ 0.05)., Conclusion: Visual and quantitative differences between PET/MR and PET/CT systems can be minimized by an accurate and standardized method of attenuation correction. If a method similar to CTAC can be implemented for brain PET/MRI, there is no reason why PET/MR should not perform as well as PET/CT., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: We present a study performing motion correction (MC) of PET using MR navigators sampled between other protocolled MR sequences during simultaneous PET/MR brain scanning with the purpose of evaluating its clinical feasibility and the potential improvement of image quality., Findings: Twenty-nine human subjects had a 30-min [(11)C]-PiB PET scan with simultaneous MR including 3D navigators sampled at six time points, which were used to correct the PET image for rigid head motion. Five subjects with motion greater than 4 mm were reconstructed into six frames (one for each navigator) which were averaged to one image after MC. The average maximum motion magnitude observed was 3.9 ± 2.4 mm (1 to 11 mm). Visual evaluation by a nuclear medicine physician of the five subjects' motion corrected rated three of the five images blurred before motion correction, while no images were rated blurred after. The image quality was scored on a scale of 1-5, 5 being best. The score changed from an average of 3.4 before motion correction to 4.0 after. There was no correlation between maximum motion magnitude and rating. Quantitative SUVr scoring did not change markedly with motion correction., Conclusions: Sparsely sampled navigators can be used for characterization and correction of head motion. A slight, overall decrease in blurring and an increase in image quality with MC was found, but without impact on clinical interpretation. In future studies with noteworthy motion artifacts, our method is an important and simple-to-use tool to have available for motion correction.

Background: In the absence of CT or traditional transmission sources in combined clinical positron emission tomography/magnetic resonance (PET/MR) systems, MR images are used for MR-based attenuation correction (MR-AC). The susceptibility effects due to metal implants challenge MR-AC in the neck region of patients with dental implants. The purpose of this study was to assess the frequency and magnitude of subsequent PET image distortions following MR-AC., Methods: A total of 148 PET/MR patients with clear visual signal voids on the attenuation map in the dental region were included in this study. Patients were injected with [(18)F]-FDG, [(11)C]-PiB, [(18)F]-FET, or [(64)Cu]-DOTATATE. The PET/MR data were acquired over a single-bed position of 25.8 cm covering the head and neck. MR-AC was based on either standard MR-ACDIXON or MR-ACINPAINTED where the susceptibility-induced signal voids were substituted with soft tissue information. Our inpainting algorithm delineates the outer contour of signal voids breaching the anatomical volume using the non-attenuation-corrected PET image and classifies the inner air regions based on an aligned template of likely dental artifact areas. The reconstructed PET images were evaluated visually and quantitatively using regions of interests in reference regions. The volume of the artifacts and the computed relative differences in mean and max standardized uptake value (SUV) between the two PET images are reported., Results: The MR-based volume of the susceptibility-induced signal voids on the MR-AC attenuation maps was between 1.6 and 520.8 mL. The corresponding/resulting bias of the reconstructed tracer distribution was localized mainly in the area of the signal void. The mean and maximum SUVs averaged across all patients increased after inpainting by 52% (± 11%) and 28% (± 11%), respectively, in the corrected region. SUV underestimation decreased with the distance to the signal void and correlated with the volume of the susceptibility artifact on the MR-AC attenuation map., Conclusions: Metallic dental work may cause severe MR signal voids. The resulting PET/MR artifacts may exceed the actual volume of the dental fillings. The subsequent bias in PET is severe in regions in and near the signal voids and may affect the conspicuity of lesions in the mandibular region.

Objective: A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [(64)Cu] [1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid]-d-Phe1,Tyr3-octreotate ((64)Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo., Approach and Results: Ten patients underwent simultaneous PET/MRI to measure (64)Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. (64)Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo (64)Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with (64)Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model., Conclusions: The novel PET tracer (64)Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with (64)Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that (64)Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could potentially improve noninvasive identification and characterization of vulnerable plaques., (© 2015 The Authors.)

A challenge when using current magnetic resonance (MR)-based attenuation correction in positron emission tomography/MR imaging (PET/MRI) is that the MRIs can have a signal void around the dental fillings that is segmented as artificial air-regions in the attenuation map. For artifacts connected to the background, we propose an extension to an existing active contour algorithm to delineate the outer contour using the nonattenuation corrected PET image and the original attenuation map. We propose a combination of two different methods for differentiating the artifacts within the body from the anatomical air-regions by first using a template of artifact regions, and second, representing the artifact regions with a combination of active shape models and k-nearest-neighbors. The accuracy of the combined method has been evaluated using 25 [Formula: see text]-fluorodeoxyglucose PET/MR patients. Results showed that the approach was able to correct an average of [Formula: see text] of the artifact areas.

Background: HIV-infected patients are at increased risk of myocardial infarction and arterial inflammation has been suggested as a pathophysiological explanation. We compared the uptake of (18)F-fluorodeoxyglucose (FDG) by PET in four arterial regions, and factors associated with FDG uptake in well-treated HIV-infected patients without cardiovascular disease (CVD) and healthy controls., Methods and Results: We prospectively scanned 26 HIV-infected patients on stable antiretroviral therapy and 25 healthy volunteers with FDG PET/CT, measuring standardized uptake values (SUV) in the carotid arteries, the ascending, descending, and abdominal aorta. We performed correlation analyses between FDG uptake and intima-media thickness (IMT), and soluble biomarkers of inflammation. We found no difference in arterial FDG uptake between the HIV-infected patients and healthy controls quantified either as mean SUVmax or target-to background ratio in the carotid region, the ascending aorta, the descending aorta, or the abdominal aorta. Correlations between SUV, IMT, and soluble biomarkers were scarce in both groups., Conclusion: In a group of optimally treated HIV-infected patients with full viral suppression, low Framingham risk score and no known CVD, we found no evidence of increased arterial inflammation as assessed by FDG PET/CT compared to healthy volunteers.

Background: The current MR-based attenuation correction (AC) used in combined PET/MR systems computes a Dixon attenuation map (MR-ACDixon) based on fat and water images derived from in- and opposed-phase MRI. We observed an occasional fat/water inversion in MR-ACDixon. The aim of our study was to estimate the prevalence of this phenomenon in a large patient cohort and assess the possible bias on PET data., Methods: PET/MRI was performed on a Siemens Biograph mMR (Siemens AG, Erlangen, Germany). We visually inspected attenuation maps of 283 brain or head/neck (H/N) patients, classified them as non-inverted or inverted, and calculated the fat/water tissue fraction. We selected ten FDG-PET brain patients with non-inverted attenuation maps for further analysis. Tissue inversion was simulated, and PET images were reconstructed using both original and inverted attenuation maps. The FDG-PET images of the ten brain patients were analyzed using 11 concentric annulus regions of 5 mm width placed over a central transaxial image plane traversing PETDixon., Results: Out of the 283 patients, a fat/water inversion in 23 patients (8.1%) was observed. The average fraction of fat in the correct MR-ACDixon was 13% for brain and 17% for H/N patients. In the inverted cases, we found an average fat fraction of 56% for the brain patients and 41% for the H/N patients. The effect of the simulated tissue inversion in the brain studies was clearly seen on AC-PET images. The percent-difference image revealed a radial error where the largest difference was at the ventricles (30% ± 3%) and smallest at the cortical region (10% ± 2%)., Conclusions: Tissue inversion in Dixon MRI is well known and can occur when there is an error in the off-resonance correction method. Tissue inversion needs to be considered if, based on Dixon-AC, the construction of normal PET databases is performed or any quantitative physiological parameters are fitted. Visual inspection is needed if Dixon-AC is to be used in clinical routine.

Aim: Combined PET/MR systems have now become available for clinical use. Given the lack of integrated standard transmission (TX) sources in these systems, attenuation and scatter correction (AC) must be performed using the available MR-images. Since bone tissue cannot easily be accounted for during MR-AC, PET quantification can be biased, in particular, in the vicinity of the skull. Here, we assess PET quantification in PET/MR imaging of patients using phantoms and patient data., Materials and Methods: Nineteen patients referred to our clinic for a PET/CT exam as part of the diagnostic evaluation of suspected dementia were included in our study. The patients were injected with 200MBq [(18)F]FDG and imaged with PET/CT and PET/MR in random sequence within 1h. Both, PET/CT and PET/MR were performed as single-bed acquisitions without contrast administration. PET/CT and PET/MR data were reconstructed following CT-based and MR-based AC, respectively. MR-AC was performed based on: (A) standard Dixon-Water-Fat segmentation (DWFS), (B) DWFS with co-registered and segmented CT bone values superimposed, and (C) with co-registered full CT-based attenuation image. All PET images were reconstructed using AW-OSEM, with neither resolution recovery nor time-of-flight option employed. PET/CT (D) or PET/MR (A-C) images were decay-corrected to the start time of the first examination. PET images following AC were evaluated visually and quantitatively using 10 homeomorphic regions of interest drawn on a transaxial T1w-MR image traversing the central basal ganglia. We report the relative difference (%) of the mean ROI values for (A)-(C) in reference to PET/CT (D). In a separate phantom experiment a 2L plastic bottle was layered with approximately 12mm of Gypsum plaster to mimic skull bone. The phantom was imaged on PET/CT only and standard MR-AC was performed by replacing hyperdense CT attenuation values corresponding to bone (plaster) with attenuation values of water. PET image reconstruction was performed with CT-AC (D) and CT-AC using the modified CT images corresponding to MR-AC using DWFS (A)., Results: PET activity values in patients following MR-AC (A) showed a substantial radial dependency when compared to PET/CT. In all patients cortical PET activity was lower than the activity in the central region of the brain (10-15%). When adding bone attenuation values to standard MR-AC (B and C) the radial gradient of PET activity values was removed. Further evaluation of PET/MR activity following MR-AC (A) relative to MR-AC (C) using the full CT for attenuation correction showed an underestimation of 25% in the cortical regions and 5-10% in the central regions of the brain. Observations in patients were replicated by observations from the phantom study., Conclusion: Our phantom and patient data demonstrate a spatially varying bias of the PET activity in PET/MR images of the brain when bone tissue is not accounted for during attenuation correction. This has immediate implications for PET/MR imaging of the brain. Therefore, refinements to existing MR-AC methods or alternative strategies need to be found prior to adopting PET/MR imaging of the brain in clinical routine and research., (© 2013 Elsevier Inc. All rights reserved.)

Unlabelled: In the standard software for the Siemens high-resolution research tomograph (HRRT) positron emission tomography (PET) scanner the most commonly used segmentation in the μ -map reconstruction for human brain scans is maximum a posteriori for transmission (MAP-TR). Bias in the lower cerebellum and pons in HRRT brain images have been reported. The two main sources of the problem with MAP-TR are poor bone/soft tissue segmentation below the brain and overestimation of bone mass in the skull., Method: We developed the new transmission processing with total variation (TXTV) method that introduces scatter correction in the μ-map reconstruction and total variation filtering to the transmission processing., Results: Comparing MAP-TR and the new TXTV with gold standard CT-based attenuation correction, we found that TXTV has less bias as compared to MAP-TR. We also compared images acquired at the HRRT scanner using TXTV to the GE Advance scanner images and found high quantitative correspondence. TXTV has been used to reconstruct more than 4000 HRRT scans at seven different sites with no reports of biases., Conclusion: TXTV-based reconstruction is recommended for human brain scans on the HRRT.

The study aimed at comparing PET/MR to PET/CT for imaging the carotid arteries in patients with known increased risk of atherosclerosis. Six HIV-positive men underwent sequential PET/MR and PET/CT of the carotid arteries after injection of 400 MBq of (18)F-FDG. PET/MR was performed a median of 131 min after injection. Subsequently,PET/CT was performed. Regions of interest (ROI) were drawn slice by slice to include the carotid arteries and standardized uptake values (SUV) were calculated from both datasets independently. Quantitative comparison of (18)F-FDG uptake revealed a high congruence between PET data acquired using the PET/MR system compared to the PET/CT system. The mean difference for SUVmean was -0.18 (p < 0.001) and -0.14 for SUVmax (p < 0.001) indicating a small but significant bias towards lower values using the PET/MR system. The 95% limits of agreement were -0.55 to 0.20 for SUVmean and -0.93 to 0.65 for SUVmax. The image quality of the PET/MR allowed for delineation of the carotid vessel wall. The correlations between (18)F-FDG uptake from ROI including both vessel wall and vessel lumen to ROI including only the wall were strong (r = 0.98 for SUVmean and r = 1.00 for SUVmax) indicating that the luminal (18)F-FDG content had minimal influence on the values. The study shows for the first time that simultaneous PET/MR of the carotid arteries is feasible in patients with increased risk of atherosclerosis. Quantification of (18)F-FDG uptake correlated well between PET/MR and PET/CT despite difference in method of PET attenuation correction, reconstruction algorithm, and detector technology.

Purpose: In combined whole-body PET/MR, attenuation correction (AC) is performed indirectly using the available MR image information and subsequent segmentation. Implant-induced susceptibility artifacts and subsequent signal voids may challenge MR-based AC (MR-AC). We evaluated the accuracy of MR-AC in PET/MR in patients with metallic endoprostheses, and propose a clinically feasible correction method., Methods: We selected patients with uni- or bilateral endoprostheses from 61 consecutive referrals for whole-body PET/MR imaging (mMR; Siemens Healthcare). Simultaneous whole-body PET/MR imaging was performed at 120 min after injection of about 300 MBq [(18)F]FDG. MR-AC was performed using (1) original MR images and subsequent Dixon water-fat segmentation, (2) as method 1 with implant-induced signal voids filled with soft tissue, (3) as method 2 with superimposed coregistered endoprostheses from the CT scan, and (4) as method 1 with implant-induced signal voids filled with metal. Following MR-AC (methods 1-4) PET emission images were reconstructed on 344 × 344 matrices using attenuation-weighted OSEM (three iterations, 21 subsets, 4 mm gaussian). Maximum body-weight normalized standardized uptake values (SUVmax) were obtained for both hips. Mean SUV (SUVmean) in homogeneous reference regions in the gluteal muscle and bladder following MR-AC (methods 1-4) are also reported., Results: In total, four patients presented with endoprostheses, unilateral in two and bilateral in two. The fraction of voxels in MR images affected by the implant was at least twice that of the voxels representing the actual implants. MR-AC using methods 2 and 3 recovered the FDG distribution pattern compared to uncorrected PET images and method 1, while method 4 resulted in severe overestimation of FDG uptake (>460 % SUVmax). When compared to method 1, relative changes in SUVmean in the reference regions from method 2 and 3 were generally small albeit not correlated with the fraction of the attenuation image affected by implant-induced artifacts., Conclusions: Endoprostheses cause PET/MR artifacts that exceed the volume occupied by the implants, and bias PET quantification. Artifacts and bias can be corrected by semiautomated inpainting with soft tissue with a single composition prior to MR-AC, thus restoring quantitative activity distribution.

Purpose: Integrated whole-body PET/MRI tomographs have become available. PET/MR imaging has the potential to supplement, or even replace combined PET/CT imaging in selected clinical indications. However, this is true only if methodological pitfalls and image artifacts arising from novel MR-based attenuation correction (MR-AC) are fully understood., Results: Here we present PET/MR image artifacts following routine MR-AC, as most frequently observed in clinical operations of an integrated whole-body PET/MRI system., Conclusion: A clinical adoption of integrated PET/MRI should entail the joint image display and interpretation of MR data, MR-based attenuation maps and uncorrected plus attenuation-corrected PET images in order to recognize potential pitfalls from MR-AC and to ensure clinically accurate image interpretation.

Unlabelled: Many authors have reported the importance of motion correction (MC) for PET. Patient motion during scanning disturbs kinetic analysis and degrades resolution. In addition, using misaligned transmission for attenuation and scatter correction may produce regional quantification bias in the reconstructed emission images. The purpose of this work was the development of quality control (QC) methods for MC procedures based on external motion tracking (EMT) for human scanning using an optical motion tracking system., Methods: Two scans with minor motion and 5 with major motion (as reported by the optical motion tracking system) were selected from (18)F-FDG scans acquired on a PET scanner. The motion was measured as the maximum displacement of the markers attached to the subject's head and was considered to be major if larger than 4 mm and minor if less than 2 mm. After allowing a 40- to 60-min uptake time after tracer injection, we acquired a 6-min transmission scan, followed by a 40-min emission list-mode scan. Each emission list-mode dataset was divided into 8 frames of 5 min. The reconstructed time-framed images were aligned to a selected reference frame using either EMT or the AIR (automated image registration) software. The following 3 QC methods were used to evaluate the EMT and AIR MC: a method using the ratio between 2 regions of interest with gray matter voxels (GM) and white matter voxels (WM), called GM/WM; mutual information; and cross correlation., Results: The results of the 3 QC methods were in agreement with one another and with a visual subjective inspection of the image data. Before MC, the QC method measures varied significantly in scans with major motion and displayed limited variations on scans with minor motion. The variation was significantly reduced and measures improved after MC with AIR, whereas EMT MC performed less well., Conclusion: The 3 presented QC methods produced similar results and are useful for evaluating tracer-independent external-tracking motion-correction methods for human brain scans.

In this paper, we propose an energy-based algorithm for motion-compensated video super-resolution (VSR) targeted on upscaling of standard definition (SD) video to high-definition (HD) video. Since the motion (flow field) of the image sequence is generally unknown, we introduce a formulation for the joint estimation of a super-resolution (SR) sequence and its flow field. Via the calculus of variations, this leads to a coupled system of partial differential equations for image sequence and motion estimation. We solve a simplified form of this system and, as a by-product, we indeed provide a motion field for super-resolved sequences. To the best of our knowledge, computing super-resolved flows has not been done before. Most advanced SR methods found in literature cannot be applied to general video with arbitrary scene content and/or arbitrary optical flows, as it is possible with our simultaneous VSR method. A series of experiments shows that our method outperforms other VSR methods when dealing with general video input and that it continues to provide good results even for large scaling factors up to 8 × 8.

Experimental studies indicate that the 5-HT(4) receptor activation influence cognitive function, affective symptoms, and the development of Alzheimer's disease (AD). The prevalence of AD increases with aging, and women have a higher predisposition to both AD and affective disorders than men. This study aimed to investigate sex and age effects on 5-HT(4) receptor-binding potentials in striatum, the limbic system, and neocortex. Positron-emission tomographic scans were conducted using the radioligand [(11)C]SB207145 in a cohort of 30 healthy subjects (mean age 44 years; range 20 to 86 years; 14 men and 16 women). The output parameter, BP(ND), was modeled using the simplified reference tissue model, and partial volume correction was performed with the Muller-Gartner method. A decline with age of 1% per decade was found only in striatum. Women had a 13% lower 5-HT(4) receptor binding in the limbic system. The lower limbic 5-HT(4) receptor binding in women supports a role for 5-HT(4) receptors in the sex-specific differences in emotional control and might contribute to the higher prevalence of affective diseases and AD in women. The relatively stable 5-HT(4) receptor binding with aging contrasts others in subtypes of receptors, which generally decrease with aging.

We present a variational framework for deinterlacing that was originally used for inpainting and subsequently redeveloped for deinterlacing. From the framework, we derive a motion adaptive (MA) deinterlacer and a motion compensated (MC) deinterlacer and test them together with a selection of known deinterlacers. To illustrate the need for MC deinterlacing, the problem of details in motion (DIM) is introduced. It cannot be solved by MA deinterlacers or any simpler deinterlacers but only by MC deinterlacers. The major problem in MC deinterlacing is computing reliable optical flow [motion estimation (ME)] in interlaced video. We discuss a number of strategies for computing optical flows on interlaced video hoping to shed some light on this problem. We produce results on challenging real world video data with our variational MC deinterlacer that in most cases are indistinguishable from the ground truth.

Background Information: Cystic fibrosis results from mutations in the ABC transporter CFTR (cystic fibrosis transmembrane conductance regulator), which functions as a cAMP-regulated anion channel. The most prevalent mutation in CFTR, the Phe(508) deletion, results in the generation of a trafficking and functionally deficient channel. The cellular machineries involved in modulating CFTR trafficking and function have not been fully characterized. In the present study, we identified a role for the COPI (coatomer protein I) cellular trafficking machinery in the development of the CFTR polypeptide into a functional chloride channel. To examine the role of COPI in CFTR biosynthesis, we employed the cell line ldlF, which harbours a temperature-sensitive mutation in epsilon-COP, a COPI subunit, to inhibit COPI function and then determined whether the CFTR polypeptide produced from the transfected gene developed into a cAMP-regulated chloride channel., Results: When COPI was inactivated in the ldlF cells by an elevated temperature pulse (39 degrees C), the CFTR polypeptide was detected on the cell surface by immunofluorescence microscopy and cell-surface biotinylation. Therefore, CFTR proceeded upstream in the secretory pathway in the absence of COPI function, a result demonstrated previously by others. In contrast, electrophysiological measurements indicated an absence of cAMP-stimulated chloride efflux, suggesting that channel function was impaired. In comparison, expression of CFTR at the same elevated temperature (39 degrees C) in an epsilon-COP-rescued cell line [ldlF(ldlF)], which has an introduced wild-type epsilon-COP gene in addition to the mutant epsilon-COP gene, showed restoration of cAMP-stimulated channel activity, confirming the requirement of COPI for channel function., Conclusions: These results therefore suggest that generation of the folded-functional conformation of CFTR requires COPI.