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PSMA PET/CT is routinely used for the detection of prostate cancer (PC). However, increased PSMA-ligand uptake has been described in a variety of benign and malignant tissues. A 71-year-old man with biochemical recurrence of PC initially treated with radical prostatectomy was referred for PSMA-ligand PET/CT. Apart from 1 lymph node with intense PSMA-ligand uptake, suspicious for metastasis, disseminated PSMA-ligand-avid subcutaneous lesions were seen. Histopathology of 1 of these lesions revealed an epidermoid cyst. Physicians should remain cognizant of non-PC-related causes of increased PSMA-ligand uptake, of which this case represent yet another example.

Purpose To establish the feasibility of shorter acquisition times (and by analogy, applied activity) on tumour detection and lesion contrast in digital PET/CT. Methods Twenty-one randomly selected patients who underwent oncological [18F]-FDG PET/CT on a digital PET/CT were retrospectively evaluated. Scan data were anonymously obtained and reconstructed in list-mode acquisition for a standard 2 min/bed position (bp), 1 min/bp and 30 s/bp (100%, 50% and 25% time or applied activity, respectively). Scans were randomized and read by two nuclear medicine physicians in a consensus read. Readers were blind to clinical details. Scans were evaluated for the number of pathological lesions detected. Measured uptake for lesions was evaluated by maximum and mean standardized uptake value (SUVmax and SUVmean, respectively) and tumour-to-backround ratio (TBR) were compared. Agreement between the three acquisitions was compared by Krippendorf’s alpha. Results Overall n = 100 lesions were identified in the 2 min and 1 min/bp acquisitions and n = 98 lesions in the 30 s/bp acquisitions. Agreement between the three acquisitions with respect to lesion number and tumour-to-background ratio showed almost perfect agreement (K’s α = 0.999). SUVmax, SUVmean and TBR likewise showed > 98% agreement, with longer acquisitions being associated with slightly higher mean TBR (2 min/bp 7.94 ± 4.41 versus 30 s/bp 7.84 ± 4.22, p Conclusion Shorter acquisition times have traditionally been associated with reduced lesion detectability or the requirement for larger amounts of radiotracer activity. These data confirm that this is not the case for new-generation digital PET scanners, where the known higher sensitivity results in clinically adequate images for shorter acquisitions. Only a small variation in the semi-quantitative parameters SUVmax, SUVmean and TBR was seen, confirming that either reduction of acquisition time or (by analogy) applied activity can be reduced as much as 75% in digital PET/CT without apparent clinical detriment.

To investigate the performance of the new long axial field-of-view (LAFOV) Biograph Vision Quadra PET/CT and a standard axial field-of-view (SAFOV) Biograph Vision 600 PET/CT (both: Siemens Healthineers) system using an intra-patient comparison.Forty-four patients undergoing routine oncological PET/CT were prospectively included and underwent a same-day dual-scanning protocol following a single administration of eitherEquivalent target lesion integral activity to the SAFOV acquisitions (16-min duration for a 106 cm FOV) were obtained on the LAFOV in 1.63 ± 0.19 min (mean ± standard error). Equivalent SNR was obtained by 1.82 ± 1.00 min LAFOV acquisitions. No statistically significant differences (p 0.05) in TBR were observed even for 0.5 min LAFOV examinations. Subjective image quality rated by two physicians confirmed the 10 min LAFOV to be of the highest quality, with equivalence between the LAFOV and the SAFOV at 1.8 ± 0.85 min. By analogy, if the LAFOV scans were maintained at 10 min, proportional reductions in applied radiopharmaceutical could obtain equivalent lesion integral activity for activities under 40 MBq and equivalent doses for the PET component of1 mSv.Improved image quality, lesion quantification and SNR resulting from higher sensitivity were demonstrated for an LAFOV system in a head-to-head comparison under clinical conditions. The LAFOV system could deliver images of comparable quality and lesion quantification in under 2 min, compared to routine SAFOV acquisition (16 min for equivalent FOV coverage). Alternatively, the LAFOV system could allow for low-dose examination protocols. Shorter LAFOV acquisitions (0.5 min), while of lower visual quality and SNR, were of adequate quality with respect to target lesion identification, suggesting that ultra-fast or low-dose acquisitions can be acceptable in selected settings.

OBJECTIVE To investigate the influence of colour scales on the interpretation of [68Ga]Ga-PSMA-11 PET/CT for the diagnosis of recurrent prostate cancer. METHODS 50 consecutive patients who underwent [68Ga]Ga-PSMA-11 PET/CT for recurrent prostate cancer were selected for this retrospective study. The scans were randomised, anonymised and read by five different readers first in the visually nonlinear colour scale 'PET-rainbow'. Scans were then rerandomised and read in the visually linear colour scale 'hot-metal new'. For each scan in each colour scale the numbers of pathological, equivocal and benign lesions were noted. Scans where the majority of readers (���3) reported at least one PET-positive lesion were recorded as 'pathological'. Patient-level sensitivity was obtained by composite standard with 14.8��������1.2���months of follow-up. RESULTS Increased numbers of lesions per patient were reported for all readers in PET-rainbow compared to hot-metal new (37.4��������15.2 vs. 33.9��������16.4, respectively, P���=���0.0005). On a per-patient basis, 43 scans were rated pathological in PET-rainbow, compared to 39 in hot-metal new. Follow-up was available for 30 patients confirming 26 pathological scans with positive follow-up in PET-rainbow, and 23 in hot-metal new. Three pathological scans were missed in hot-metal new. Patient-level sensitivity was higher for PET-rainbow (0.96) compared to hot-metal new (0.85). Inter-reader reliability was higher for hot-metal new (Fleiss �����=���0.76) compared to PET-rainbow (Fleiss �����=���0.60). CONCLUSION Use of PET-rainbow was associated with improved lesion detection and sensitivity compared to hot-metal new, although at cost of reduced inter-rater agreement. Consequently, the use of PET-rainbow for clinical routine and future studies involving [68Ga]Ga-PSMA-11 is recommended.

Purpose To investigate the performance of the new long axial field-of-view (LAFOV) Biograph Vision Quadra PET/CT and a standard axial field-of-view (SAFOV) Biograph Vision 600 PET/CT (both: Siemens Healthineers) system using an intra-patient comparison. Methods Forty-four patients undergoing routine oncological PET/CT were prospectively included and underwent a same-day dual-scanning protocol following a single administration of either 18F-FDG (n = 20), 18F-PSMA-1007 (n = 16) or 68Ga-DOTA-TOC (n = 8). Half the patients first received a clinically routine examination on the SAFOV (FOVaxial 26.3 cm) in continuous bed motion and then immediately afterwards on the LAFOV system (10-min acquisition in list mode, FOVaxial 106 cm); the second half underwent scanning in the reverse order. Comparisons between the LAFOV at different emulated scan times (by rebinning list mode data) and the SAFOV were made for target lesion integral activity, signal to noise (SNR), target lesion to background ratio (TBR) and visual image quality. Results Equivalent target lesion integral activity to the SAFOV acquisitions (16-min duration for a 106 cm FOV) were obtained on the LAFOV in 1.63 ± 0.19 min (mean ± standard error). Equivalent SNR was obtained by 1.82 ± 1.00 min LAFOV acquisitions. No statistically significant differences (p > 0.05) in TBR were observed even for 0.5 min LAFOV examinations. Subjective image quality rated by two physicians confirmed the 10 min LAFOV to be of the highest quality, with equivalence between the LAFOV and the SAFOV at 1.8 ± 0.85 min. By analogy, if the LAFOV scans were maintained at 10 min, proportional reductions in applied radiopharmaceutical could obtain equivalent lesion integral activity for activities under 40 MBq and equivalent doses for the PET component of Conclusion Improved image quality, lesion quantification and SNR resulting from higher sensitivity were demonstrated for an LAFOV system in a head-to-head comparison under clinical conditions. The LAFOV system could deliver images of comparable quality and lesion quantification in under 2 min, compared to routine SAFOV acquisition (16 min for equivalent FOV coverage). Alternatively, the LAFOV system could allow for low-dose examination protocols. Shorter LAFOV acquisitions (0.5 min), while of lower visual quality and SNR, were of adequate quality with respect to target lesion identification, suggesting that ultra-fast or low-dose acquisitions can be acceptable in selected settings.

Contains fulltext : 235569.pdf (Publisher’s version ) (Open Access) Medical imaging methods are assuming a greater role in the workup of patients with COVID-19, mainly in relation to the primary manifestation of pulmonary disease and the tissue distribution of the angiotensin-converting-enzyme 2 (ACE 2) receptor. However, the field is so new that no consensus view has emerged guiding clinical decisions to employ imaging procedures such as radiography, computer tomography (CT), positron emission tomography (PET), and magnetic resonance imaging, and in what measure the risk of exposure of staff to possible infection could be justified by the knowledge gained. The insensitivity of current RT-PCR methods for positive diagnosis is part of the rationale for resorting to imaging procedures. While CT is more sensitive than genetic testing in hospitalized patients, positive findings of ground glass opacities depend on the disease stage. There is sparse reporting on PET/CT with [(18)F]-FDG in COVID-19, but available results are congruent with the earlier literature on viral pneumonias. There is a high incidence of cerebral findings in COVID-19, and likewise evidence of gastrointestinal involvement. Artificial intelligence, notably machine learning is emerging as an effective method for diagnostic image analysis, with performance in the discriminative diagnosis of diagnosis of COVID-19 pneumonia comparable to that of human practitioners.

Purpose Amongst others, [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 are available for the detection of recurrent prostate cancer (rPC). There are currently limited data comparing the performance of these two radioligands with respect to clinical outcomes or their cost efficacy, which this study aims to address. Methods Two hundred and forty-four patients undergoing PSMA PET/CT for rPC were retrospectively analysed for this study (one hundred and twenty two with each radiopharmaceutical) to generate rates of PET positivity, negativity and unclear findings. Patients underwent follow-up to determine the rate of additional examinations and to confirm PET findings. A Markov chain decision analysis was implemented to model clinical decision-making processes and to analyse clinical performance of the two tracers. We determine their clinical cost efficacies using cost data from several countries where both radiotracers are in routine use. Results The PET positivity rate was non-significantly higher for [18F]PSMA-1007 compared to [68Ga]Ga-PSMA-11 (91.8% vs. 86.9%, p = 0.68), whereas the rate of uncertain findings was significantly greater (17.2% vs. 8.25%, p = 0.02). The probability of a true positive finding was higher for [68Ga]Ga-PSMA-11 (0.90, 95% CI 0.70-0.98) vs. [18F]PSMA-1007 (0.81, 95% CI 0.66–0.91). A significantly (p < 0.0001) higher PPV for [68Ga]Ga-PSMA-11 (0.99, 95% CI 0.99–1.0 vs. 0.86) was found compared to [18F]PSMA-1007 (0.86, 95% CI 0.82–1.00). Intervention efficacy analysis favoured [68Ga]Ga-PSMA-11, where the number needed to image (to achieve a true positive finding) was 10.58 and the number needed to image to harm (to achieve a false positive finding) was − 8.08. A cost efficacy analysis favours [68Ga]Ga-PSMA-11 in three of the four jurisdictions analysed where health economic data was available (Switzerland, Israel, Australia) and [18F]PSMA-1007 in one jurisdiction (Denmark). Conclusion The analysis reveals a non-significantly higher PET positivity rate for [18F]PSMA-1007, but finds significantly greater rates of uncertain findings and false positive findings when compared to [68Ga]Ga-PSMA-11. We find differences in the two tracers in terms of clinical performance and cost efficacy. The method presented herein is generalisable and can be used with clinical or cost data for other countries or tracers.

The integrity of myelination is crucial for maintaining brain interstitial fluid (ISF) drainage in adults; however, the mechanism of ISF drainage with immature myelin in the developing brain remains unknown. In the present study, the ISF drainage from the caudate nucleus (Cn) to the ipsilateral cortex was studied at different developmental stages of the rat brain (P 10, 20, 30, 40, 60, 80, 10-80). The results show that the traced ISF drained to the cortex from Cn and to the thalamus in an opposite direction before P30. From P40, we found impeded drainage to the thalamus due to myelin maturation. This altered drainage was accompanied by enhanced cognitive and social functions, which were consistent with those in the adult rats. A significant difference in diffusion parameters was also demonstrated between the extracellular space (ECS) before and after P30. The present study revealed the alteration of ISF drainage regulated by myelin at different stages during development, indicating that a regional ISF homeostasis may be essential for mature psychological and cognitive functions.

Background Gastrin Releasing Peptide receptor (GRPr)-based radioligands have shown great promise for diagnostic imaging of GRPr-positive cancers, such as prostate and breast. The present study aims at developing and evaluating a versatile GRPr-based probe for both PET/SPECT imaging as well as intraoperative and therapeutic applications. The influence of the versatile chelator AAZTA5 on the radiometal labelling properties and the in vitro performance of the generated radiotracers were thoroughly investigated. The GRPr-based antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was functionalized with the chelator 6-[Bis (carboxymethyl)amino]-1,4-bis (carboyxmethyl)-6-methyl-1,4-diazepane (AAZTA5) through the spacer 4-amino-1-carboxymethyl-piperidine (Pip) to obtain AAZTA5-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (LF1). LF1 was radiolabelled with gallium-68 (PET), indium-111 (SPECT, intraoperative applications) and lutetium-177 (therapy, SPECT). In vitro evaluation included stability studies, determination of lipophilicity, protein-binding studies, determination of Kd and Bmax as well as internalization studies using the epithelial human prostate cancer cell line PC3. In vitro monotherapy as well as combination therapy studies were further performed to assess its applicability as a theranostic compound. Results LF1 was labelled with gallium-68, indium-111 and lutetium-177 within 5 min at room temperature (RT). The apparent molar activities (Am) were ranging between 50 and 60 GBq/μmol for the 68Ga-labelled LF1, 10–20 GBq/μmol for the 111In- and 177Lu-labelled LF1. The radiotracers were stable for a period of 4 h post labeling exhibiting a hydrophilic profile with an average of a LogDoctanol/PBS of − 3, while the bound activity to the human serum protein was approximately 10%. 68/natGa-LF1, 177/natLu-LF1 and 111/natIn-LF1 exhibited high affinity for the PC3 cells, with Kd values of 16.3 ± 2.4 nM, 10.3 ± 2.73 nM and 5.2 ± 1.9 nM, respectively, and the required concentration of the radiotracers to saturate the receptors (Bmax) was between 0.5 and 0.8 nM which corresponds to approximately 4 × 105 receptors per cell. Low specific internalization rate was found in cell culture, while the total specific cell surface bound uptake always exceeded the internalized activity. In vitro therapy studies showed that inhibition of PC3 cells growth is somewhat more efficient when combination of 177Lu-labelled LF1 with rapamycin is applied compared to 177Lu-laballed LF1 alone. Conclusion Encouraged by these promising in vitro data, preclinical evaluation of the LF1 precursor are planned in tumour models in vivo.

Renal excretion of some prostate-specific membrane antigen (PSMA) ligands and consequently increased bladder activity can obscure locally relapsing prostate cancer lesions in PSMA PET/CT. Furthermore, additional late imaging in PSMA PET/CT provides a useful method to clarify uncertain findings. The aim of this retrospective study was to investigate a modified imaging protocol combining late additional imaging with hydration and forced diuresis in individuals undergoing additional late scanning for uncertain lesions or low prostate-specific antigen.

The aim of the present study is to evaluate the intra- and inter-observer agreement in assessing the renal function by means of 99mTc-MAG3 diuretic renography. One hundred and twenty adults were enrolled in the study. One experienced and one junior radiographer processed the renograms twice by assigning manual and semi-automated regions of interest. The differential renal function (DRF, %), time to maximum counts for the right and left kidney (TmaxR-TmaxL, min) and time to half-peak counts (T1/2, min) were calculated. The Bland–Altman analysis (bias±95% limits of agreement), Lin’s concordance correlation coefficient and weighted Fleiss’ kappa coefficient were used to assess agreement. Based on the Bland–Altman analysis, the intra-observer repeatability results for the experienced radiographer using the manual and the semi-automated techniques were 0.2 ± 2.6% and 0.3 ± 6.4% (DRF), respectively, −0.01 ± 0.24 and 0.00 ± 0.34 (TmaxR), respectively, and 0.00 ± 0.26 and 0.00 ± 0.33 (TmaxL), respectively. For the junior radiographer, the respective results were 0.5 ± 5.0% and 0.8 ± 9.4% (DRF), 0.00 ± 0.44 and 0.01 ± 0.28 (TmaxR), and 0.01 ± 0.28 and −0.02 ± 0.44 (TmaxL). The inter-observer repeatability for the manual method was 0.6 ± 5.0% (DRF), −0.10 ± 0.42 (TmaxR) and −0.05 ± 0.38 (TmaxL), and for the semi-automated method −0.2 ± 9.1% (DRF), 0.00 ± 0.31 (TmaxR) and −0.05 ± 0.40 (TmaxL). The weighted Fleiss’ kappa coefficient for the T1/2 assessments ranged between 0.85–0.97 for both intra- and inter-observer repeatability with both methods. These findings suggest a very good repeatability in DRF assessment with the manual method—especially for the experienced observer—but a less good repeatability with the semi-automated approach. The calculation of Tmax was also operator-dependent. We conclude that reader experience is important in the calculation of renal parameters. We therefore encourage reader training in renal scintigraphy. Moreover, the manual tool seems to perform better than the semi-automated tool. Thus, we encourage cautious use of automated tools and adjunct validation by manual methods where possible.

Aporphine alkaloids containing a C10 nitrogen motif were synthesized and evaluated for affinity at 5-HT(1A)R, 5-HT(2A)R, 5-HT(6)R and 5-HT(7A)R. Three series of racemic aporphines were investigated: 1,2,10-trisubstituted, C10 N-monosubstituted and compounds containing a C10 benzofused aminothiazole moiety. The 1,2,10-trisubstituted series of compounds as a group displayed modest selectivity for 5-HT(7A)R and also had moderate 5-HT(7A)R affinity. Compounds from the C10 N-monosubstituted series generally lacked affinity for 5-HT(2A)R and 5-HT(6)R and showed strong affinity for 5-HT(1A) or 5-HT(7A)R. Compounds in this series that contained an N6-methyl group were up to 27-fold selective for 5-HT(7A)R over 5-HT(1A)R, whereas compounds with an N6-propyl substituent showed a reversal in this selectivity. The C10 benzofused aminothiazole analogues showed a similar binding profile as the C10 N-monosubstituted series i.e. strong affinity for 5-HT(1A)R or 5-HT(7A)R, with selectivity between the two receptors being similarly influenced by N6-methyl or N6-propyl substituents. Compounds 29 and 34a exhibit high 5-HT(7A)R affinity, excellent selectivity versus dopamine receptors and function as antagonists in 5-HT(7A)R cAMP-based assays. Compounds 29 and 34a have been identified as new lead molecules for further tool and pharmaceutical optimization.

Highlights • Imaging biomarkers of the metabolic trajectory from HC, iRBD and PD are identified. • Frontal, limbic and occipital brain regions as imaging biomarkers in PD. • Frontal, limbic and occipital brain regions as imaging biomarkers of the phenoconversion from iRBD to PD., Objective Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies such as Parkinson’s disease (PD). Positron emission tomography (PET) with 18F-FDG reveals metabolic perturbations, which are scored by spatial covariance analysis. However, the resultant pattern scores do not capture the spatially heterogeneous trajectories of metabolic changes between individual brain regions. Assuming metabolic progression occurs as a continuum from the healthy control (HC) condition to iRBD and then PD, we investigated spatial dynamics of progressively perturbed glucose metabolism in a cross-sectional study. Methods 19 iRBD patients, 38 PD patients and 19 HC subjects underwent 18F-FDG PET. The images were spatially normalized, scaled to the global mean uptake, and automatically parcellated. We contrasted regional metabolism by group, and allocated the inferred progression to one of several possible trajectories. We further investigated the correlations between 18F-FDG uptake and the disease duration in the iRBD and PD groups, respectively. We also explored relationships between 18F-FDG uptake and the Unified Parkinson’s Disease Rating Scale motor (UPDRS III) scores in the PD group. Results PD patients exhibited more extensive relative hyper- and hypo-metabolism than iRBD patients. We identified three dynamic metabolic trajectories, cross-sectional hypo- or hypermetabolism, cross-sectionally unchanged hypo- or hypermetabolism, cross-sectionally late hypo- or hypermetabolism, appearing only in the contrast of PD with iRBD. No correlation was found between relative 18F-FDG metabolism and disease duration in the iRBD group. Regional hyper- and hypo-metabolism in the PD patients correlated with disease duration or clinical UPDRS III scores. Conclusion Cerebral metabolism changes heterogeneously in a continuum extending from HC to iRBD and PD groups in this preliminary study. The distinctive metabolic trajectories point towards a potential neuroimaging biomarker for conversion of iRBD to frank PD, which should be amenable to advanced pattern recognition analysis in future longitudinal studies.

Purpose: 68Ga-PSMA-11 PET/CT is commonly performed at 1 h post injection (p.i.). However, various publications have demonstrated that most prostate cancer (PC) lesions exhibit higher contrast at later imaging. The aim of this study was to compare the “common” protocol of 68Ga-PSMA-11 PET/CT with a modified protocol. Methods: In 2017, we used the following scanning protocol for 68Ga-PSMA-11 PET/CT in patients with recurrent PC: acquisition at 1 h p.i. without further preparations. From 2018, all scans were conducted at 1.5 h p.i. In addition, patients were orally hydrated with 1 L of water 0.5 h p.i. and were injected with 20 mg of furosemide 1 h p.i. Both protocols including 112 patients (2017) and 156 (modified protocol in 2018) were retrospectively compared. Rates of pathologic scans, maximum standardized uptake values (SUVmax), and tumor contrast (ratio lesion-SUVmax/background-SUVmean) as well as average standardized uptake values (SUVmean) of urinary bladder were analyzed. Results: Both tumor contrast and tracer uptake were significantly (p < 0.001) higher in the novel protocol. Although statistically not significant, the rates of pathologic scans were also higher in the modified protocol: 76.3% vs. 68.8% for all PSA values including 38.9% vs. 25.0% for PSA < 0.5 ng/ml and 60.0% vs. 56.7% for PSA > 0.5–≤ 2.0 ng/ml. Average SUVmean of the urinary bladder was significantly (p < 0.001) lower with the modified protocol. Conclusions: The modified protocol, which includes a combination of delayed image acquisition at 1.5 h p.i., hydration, and furosemide resulted in higher tumor contrast and seems to have the potential to increase the rates of pathological scans, especially at low PSA levels.

PURPOSE Differentiating between prostate cancer (PC) lesions and benign structures which exhibit radiotracer uptake in PSMA-ligand PET/CT can be challenging. Additional late imaging has been shown to be a powerful method for the discrimination between PC and non-PC lesions, owing to the increasing tracer uptake of the former. Nevertheless, there are no pre-existing studies which describe the dynamic tracer uptake for ganglia, which this present study aims to address. METHODS Fifty consecutive patients with PC who received standard and late 68Ga-PSMA-11-PET/CT (by local protocol at 1.5 h "standard" and 2.5 h p.i. "late") underwent retrospective evaluation. All lesions with a tracer uptake above local background indicative for ganglia as well as PC lesions were analysed with regard to their maximum standardised uptake values (SUVmax) and localisation. RESULTS Overall, 86 PSMA-positive ganglia were identified in 70% (n = 35) of the patients. Five ganglia exhibited PSMA avidity at late imaging only, and three at standard imaging only. A total of 66 lesions suggestive for PC were detected in 44 patients (88%), of which 45% (n = 30) were morphologically identified as lymph nodes (LN), the remainder being locally recurrent lesions or bone metastases. No solid organ metastases were present in our cohort. At late scanning, 73% of the LN exhibited an increase in SUVmax, whereas 65% of the ganglia exhibited a decreasing or stable SUVmax. CONCLUSION Whereas the presence of increasing tracer uptake in potential PC lesions can provide additional data about the likelihood of malignancy, increasing SUVmax alone does not reliably differentiate between ganglia and PC lesions and is a potential diagnostic pitfall. We therefore recommend high-resolution CT to enable morphological characterisation of ganglia.

Background: The clinical presentation of early idiopathic Parkinson’s disease (IPD) substantially overlaps with that of atypical parkinsonian syndromes such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has proven useful in assisting in the differential diagnosis of these parkinsonian syndromes. The aim of this study was to develop a metabolic imaging biomarker based on deep learning to support the differential diagnosis of parkinsonism. Methods: In addition to 863 non-parkinsonian subjects, a total of 1275 parkinsonian patients were accessed who underwent FDG PET imaging, clinical evaluation, and follow-up, yielding clinically possible, definite, or confirmative diagnoses of IPD, MSA, and PSP. A 3D deep convolutional neural network was developed to extract a deep metabolic imaging (DMI) biomarker. The accuracy of the DMI biomarker was evaluated with a cross-validation and a blind test. The robustness of the DMI biomarker was assessed on patients with longitudinal follow-up. The functional basis of DMI biomarker was further investigated based on the saliency map of the obtained deep neural network. Findings: The proposed DMI biomarker achieved an area under the receiver operating characteristic curve of 0·986 for the differential diagnosis of IPD, 0·997 for MSA, and 0·982 for PSP in the cross-validation. In the blind test, the DMI biomarker resulted in sensitivities of 98·1%, 88·5%, and 84·5%, as well as specificities of 90·0%, 99·2%, and 97·8% for IPD, MSA, and PSP respectively. The integration of demographic information and clinical assessments to DMI biomarker resulted in slight improvements. Saliencies for the DMI biomarker were found in several parkinsonism-related regions such as midbrain, putamen, and cerebellum. Interpretation: The DMI biomarker based on deep learning shows potential to provide accurate differential diagnosis for parkinsonism on FDG PET. The functional regions behind the DMI biomarker are consistent with known parkinsonian pathology. Funding Statement: The work was supported by grants from the National Natural Science Foundation of China (No. 81771483, 81671239, 81361120393, 81401135, 81971641, 81902282, 91949118, 81771372), from the Ministry of Science and Technology of China (2016YFC1306504), Shanghai Municipal Science and Technology Major Project (No. 2017SHZDZX01, 2018SHZDZX03) and ZJ Lab, Shanghai Sailing Program (No. 18YF1403100). It was also supported by Swiss National Science Foundation (No. 188350) and Siemens Healthineers. Declaration of Interests: W.H.O is Hertie Senior Research Professor, supported by the Charitable Hertie Foundation, Frankfurt/Main, Germany. A.R. and K.S. received research support from Siemens Healthineer. Other authors report no financial interests or potential conflicts of interest regarding the subject matter of the manuscript. Ethics Approval Statement: All procedures performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All the data were from Parkinson's Disease Database and Samples Bank in Huashan Hospital. Ethics permission was obtained from the Institutional Review Board of Huashan Hospital and written consent was obtained from each subject after detailed explanation of the procedures.

The drainage of brain interstitial fluid (ISF) has been observed to slow down following neuronal excitation, although the mechanism underlying this phenomenon is yet to be elucidated. In searching for the changes in the brain extracellular space (ECS) induced by electrical pain stimuli in the rat thalamus, significantly decreased effective diffusion coefficient (DECS) and volume fraction (α) of the brain ECS were shown, accompanied by the slowdown of ISF drainage. The morphological basis for structural changes in the brain ECS was local spatial deformation of astrocyte foot processes following neuronal excitation. We further studied aquaporin-4 gene (APQ4) knockout rats in which the changes of the brain ECS structure were reversed and found that the slowed DECS and ISF drainage persisted, confirming that the down-regulation of ISF drainage following neuronal excitation was mainly attributable to the release of neurotransmitters rather than to structural changes of the brain ECS. Meanwhile, the dynamic changes in the DECS were synchronized with the release and elimination processes of neurotransmitters following neuronal excitation. In conclusion, the downregulation of ISF drainage following neuronal excitation was found to be caused by the restricted diffusion in the brain ECS, and DECS mapping may be used to track the neuronal activity in the deep brain.

BACKGROUND Amyloid-β (Aβ) accumulation in brain of patients with suspected Alzheimer's disease (AD) can be assessed by positron emission tomography (PET) in vivo. While visual classification prevails in the clinical routine, semiquantitative PET analyses may enable more reliable evaluation of cases with a visually uncertain, borderline Aβ accumulation. OBJECTIVE We evaluated different analysis approaches (visual/semiquantitative) to find the most accurate and sensitive interpretation of Aβ-PET for predicting risk of progression from mild cognitive impairment (MCI) to AD. METHODS Based on standard uptake value (SUV) ratios of a cortical-composite volume of interest of 18F-AV45-PET from MCI subjects (n = 396, ADNI database), we compared three different reference region (cerebellar grey matter, CBL; brainstem, BST; white matter, WM) normalizations and the visual read by receiver operator characteristics for calculating a hazard ratio (HR) for progression to Alzheimer's disease dementia (ADD). RESULTS During a mean follow-up time of 45.6±13.0 months, 28% of the MCI cases (110/396) converted to ADD. Among the tested methods, the WM reference showed best discriminatory power and progression-risk stratification (HRWM of 4.4 [2.6-7.6]), but the combined results of the visual and semiquantitative analysis with all three reference regions showed an even higher discriminatory power. CONCLUSION A multi-analytical composite of visual and semiquantitative reference tissue analyses of 18F-AV45-PET gave improved risk stratification for progression from MCI to ADD relative to performance of single read-outs. This optimized approach is of special interest for prospective treatment trials, which demand a high accuracy.

Purpose Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) reveals altered cerebral metabolism in individuals with mild cognitive impairment (MCI) and Alzheimer’s dementia (AD). Previous metabolic connectome analyses derive from groups of patients but do not support the prediction of an individual’s risk of conversion from present MCI to AD. We now present an individual metabolic connectome method, namely the Kullback-Leibler Divergence Similarity Estimation (KLSE), to characterize brain-wide metabolic networks that predict an individual’s risk of conversion from MCI to AD. Methods FDG-PET data consisting of 50 healthy controls, 332 patients with stable MCI, 178 MCI patients progressing to AD, and 50 AD patients were recruited from ADNI database. Each individual’s metabolic brain network was ascertained using the KLSE method. We compared intra- and intergroup similarity and difference between the KLSE matrix and group-level matrix, and then evaluated the network stability and inter-individual variation of KLSE. The multivariate Cox proportional hazards model and Harrell’s concordance index (C-index) were employed to assess the prediction performance of KLSE and other clinical characteristics. Results The KLSE method captures more pathological connectivity in the parietal and temporal lobes relative to the typical group-level method, and yields detailed individual information, while possessing greater stability of network organization (within-group similarity coefficient, 0.789 for sMCI and 0.731 for pMCI). Metabolic connectome expression was a superior predictor of conversion than were other clinical assessments (hazard ratio (HR) = 3.55; 95% CI, 2.77–4.55; P Conclusion The KLSE indicator identifies abnormal brain networks predicting an individual’s risk of conversion from MCI to AD, thus potentially constituting a clinically applicable imaging biomarker.

Tetrahydroprotoberberine alkaloids have shown interesting polypharmacological actions at dopamine receptors and are a unique template from which to mine novel molecules with dual selective actions at D1 and D3 receptors. Such compounds will be valuable to evaluate as anti-cocaine therapeutics. Towards that eventual goal, we engaged an SAR study in which a series of C9 alkoxy analogues of the D1/D2/D3 ligand (-)-stepholidine that possessed or lacked a C12 bromo functionality, were synthesized and evaluated for affinity at dopamine D1, D2 and D3 receptors. We found that the analogues are generally selective for the D1 receptor. Small n-alkoxy substituents (up to 4 carbons in length) were generally well tolerated for high D1 affinity but such groups reduced D3 affinity. In the case of C12 brominated analogues, C9 alkoxylation also had little effect on D1 affinity for the smaller alkoxy groups, but reduced D2 and D3 affinities significantly. C12 bromination tends to increase D1 receptor selectivity. A number of compounds were identified that retain affinity for D1 and D3 receptors but lack D2 receptor affinity. Among them, compound 22a was found to be a selective D1/D3 dual antagonist (Ki = 5.3 and 106 nM at D1 and D3 receptors). Docking studies performed on the analogues at the D3 receptor revealed a number of interactions that are important for affinity including a critical N - Asp110 salt bridge motif, H-bonds to Ser192 and Cys181 and hydrophobic interactions between the aryl rings and Phe106 and Phe345. The analogues adopt an orientation in which ring A is located in the orthosteric binding site while the C9 alkoxy substituents attached to ring D project into the secondary binding pocket of the D3 receptor.

To illustrate the [18F]FDG-PET/CT findings in patients affected by cancer with clinical diagnosis of Covid-19 METHODS: We retrospectively reviewed the cases of patients who showed pulmonary involvement unrelated to cancer metastases on March 13 and 16 2020. We reviewed the scans, collected medical history, and exposure information.Among the 13 scans, we identified 5 cases with imaging findings suspicious for viral infection. Peripheral lung consolidations and/or ground-glass opacities in two or more lobes were found. Lung abnormalities displayed increased [18F]FDG uptake (SUVmax 4.3-11.3). All the patients on the day of PET/CT acquisition were asymptomatic, and they did not have fever or cough. In view of the PET/CT findings, home isolation, symptom surveillance, and treatment (in 3/5 patients) were indicated. At 1-week follow-up, 2/5 patients experienced the onset of mild respiratory symptoms.The [18F]FDG-PET/CT can identify probable Covid-19 disease in the absence or before symptoms onset and can guide patient management. Nuclear medicine staff needs to be aware of the possibility of contact with patients affected by the SARS-CoV-2 infection even if they do not present any symptom. Therefore, safety measures need to be adopted for other patients and hospital staff in order to block the spread of infection.

Autism spectrum disorder (ASD) comprises a heterogeneous range of neurodevelopmental conditions represented by symptoms including, communication and language deficits, repetitive, and restricted patterns of behavior and inadequate social interactions. Gamma-aminobutyric acid (GABA) is known to mediate I responses in the central nervous system by interacting with GABA signaling receptors. In this context, several recent investigations suggest that imbalances in the GABAergic neurotransmission system may be implicated in the development of ASD as well as several other neurodevelopmental disorders, including Fragile X syndrome (FXS) and Rett syndrome. This review initially expounds the functional role of the GABAergic system in the mature brain and during neurodevelopment. This will be followed by discussions concerning the impact of deficiencies in the system on ASD and the other above-mentioned neurodevelopment disorders. Finally, the connections between these deficiencies and behavioral features observed in the clinic will be considered.

A 76-year-old man with metastatic adenocarcinoma of the prostate presented with increasing dyspnea. After being treated initially with drainage and afterwards with pleurodesis, he was referred for Ga-prostate-specific membrane antigen 11 PET/CT imaging for restaging purposes. PET/CT demonstrated extensive Ga-prostate-specific membrane antigen 11 uptake in the right pleura. Histopathology confirmed the rare case of malignant pleural effusion from metastatic prostate cancer.

Dual-time point PET/CT scanning with [One hundred consecutive patients with biochemically recurrent PC who received standard and late [Seventy-nine of 100 patients had PSMA-positive scans, in whom a total of 185 individual PSMA-positive lesions were identified. These were morphologically characterised as bone lesions (n = 48), solid organ lesions (n = 3), lymph node (LN) lesions (n = 78) and locally recurrent lesions in the prostatic fossa or seminal vesicles (n = 56). The relative uptake between standard and late imaging was considered; all lesions classified as local recurrence presented with increasing (86%) or stable patterns of tracer uptake (14%). In contrast, only 58% of bone lesions exhibited increasing tracer uptake, with 21% exhibiting a stable pattern and 21% exhibiting a decreasing tracer uptake at late imaging.A heterogeneous pattern of dynamic tracer uptake was observed, with a largely increasing pattern observed for locally recurrent lesions and lymph nodes and a significant proportion of bone lesions exhibiting decreasing tracer uptake. The results are of significance not only in the imaging and identification of PC lesions, but they also have implications for PSMA-directed ligand therapy.

A patient with bone metastases of prostate cancer was referred for 68Ga-PSMA-11 PET/CT. Compared to a 68Ga-PSMA-11 PET/CT four months previously, the CT-component of the current PET/CT showed morphological progress in all lesions despite continuous therapy with docetaxel and denosumab. Contrarily, the PET-component showed a reduction of tracer-uptake, which correlated with PSA decrease between the two PET/CT-scans (16.2 ng/ml vs. 3.1 ng/ml). This case highlights 68Ga-PSMA-11 PET/CT as a promising tool for therapy monitoring of prostate cancer and could serve as a basis for a novel monitoring strategy. Volume progress shown by CT must not be classified as tumor progress, but as bone remodeling following effective therapy.

The human protein kinase X gene (PRKX) and cAMP-dependent protein kinase (PKA) are both c-AMP-dependent serine/threonine protein kinases within the protein kinase AGC subgroup. Of all the protein kinases in this group, PRKX is the least studied. PRKX has been isolated from patients with chondrodysplasia punctate and is involved in numerous processes, including sexual differentiation and fertilization, normal kidney development and autosomal dominant polycystic kidney disease (ADPKD), blood maturation, neural development, and angiogenesis in vitro. Although the role of PRKX in development and disease has been reported recently, the underlying mechanism of PRKX activity is largely unknown. In addition, based on the expression pattern of PRKX and the extensive role of PKA in disease and development, PRKX might have additional crucial functions that have not been addressed in the literature. In this review, we summarize the characteristics and developmental functions of PRKX that have been reported by recent studies. In particular, we elucidate the structural and functional differences between PRKX and PKA, as well as the possible roles of PRKX in development and related diseases. Finally, we propose future studies that could lead to important discoveries of more PRKX functions and the underlying mechanisms involved.

A series of 1-phenyl-benzazepines containing bromine or chlorine substituents at the ortho position of the appended phenyl ring (2’-monosubstituted or 2’,6’- disubstituted patterns) were synthesized and evaluated for affinity towards dopamine D(1)R, D(2)R and D(5)R. As is typical of the 1-phenyl-benzazepine scaffold, the compounds displayed selectivity towards D(1)R and D(5)R; analogs generally lacked affinity for D(2)R. Interestingly, 2’,6’-dichloro substituted analogs showed modest D(5)R versus D(1)R selectivity whereas this selectivity was reversed in compounds with a 2’-halo substitution pattern. Compound 10a was identified as a D(1)R antagonist (K(i) = 14 nM; IC(50) = 9.4 nM).

New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT(1A) and 5-HT(2A) receptors and at human dopamine D(1), D(2) and D(5) receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D(5) receptor, thus attaining D(1) versus D(5) selectivity. Compound 20c was the most potent D(1) ligand identified. Docking studies at D(1) and D(5) receptors indicate that the binding mode of 20c at the D(1) receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D(5) receptor, accounting for its D(1) versus D(5) selectivity. Considering the lack of affinity for the D(5) receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D(1) receptor tools.

Owing to their superior uptake and higher detection rate, PSMA-labelled radioligands have largely replaced choline in routine clinical imaging of recurrent prostate cancer (PCa). Nevertheless, even at high PSA values, a small number of patients can present with PSMA negative prostate cancer (PC) lesions. For such patients choline PET continues to play an important role.

A series of C1 aporphine analogues related to compound 5 and that contain substituted allylic, alkynyl, nitrile, ester and benzyl groups was synthesized and evaluated for affinity at h5HT2A and α1A receptors in functional activity assays that measure calcium release. The presence of branched allylic substituent groups diminished affinity for the h5HT2A receptor. Likewise, the alkynyl, nitrile and ester derivatives evaluated displayed lower 5-HT2A receptor affinity as compared to 5. Hydrophobic, steric and electronic effects impact the affinity of p-substituted benzyl derivatives 8i – 8k but in different ways. High hydrophobicity and size favor 5-HT2A affinity whereas, high electronegativity disfavors 5-HT2A affinity. p-bromobenzyl analogue 8k was identified as a 5-HT2A receptor selective ligand, with the highest 5-HT2A receptor affinity of any aporphine known to date. Most of the other analogues were selective for the 5-HT2A versus the α1A receptor. ChemScore binding energies from docking studies correlated qualitatively with the observed trends in affinity for 8i - 8k, although the binding energies were not well differentiated quantitatively.

BTBR mice exhibit several autistic-like behaviors and are currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Ras/Raf/ERK1/2 signaling has been suggested to play an important role in neural development, learning, memory, and cognition. Two studies reported that a deletion of a locus on chromosome 16 containing the mitogen-activated protein kinase 3 (MAPK3) gene, which encodes ERK1, is associated with autism. In the present study, Ras/Raf/ERK1/2 signaling was found to be up-regulated in BTBR mice relative to matched control B6 mice, to further suggest involvement in the pathogenesis of autism. To further characterize the developmental pattern of Ras/Raf/ERK1/2 signaling, varying stages during development were sampled to reveal an up-regulation in newborn and 2-week old BTBR mice relative to age-matched B6 mice. By the age of 3-week, Ras/Raf/ERK1/2 signaling in the brain of BTBR mice was unaltered relative to B6 mice, with this trend maintained in 6-week samples. These results suggest that the alteration of Ras/Raf/ERK signaling in the early developmental stages in mice could contribute to the noted autistic phenotype. Furthermore, these findings support the value of BTBR mice to serve as a human analog for autistic etiological research and aid in a better understanding of the developmental mechanisms of autism.

Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. Emerging evidence suggests that aberrant neuroimmune responses may contribute to phenotypic deficits and could be appropriate targets for pharmacologic intervention. Interleukin (IL)-6, one of the most important neuroimmune factors, has been shown to be involved in physiological brain development and in several neurological disorders. For instance, findings from postmortem and animal studies suggest that brain IL-6 is an important mediator of autism-like behaviors. In this review, a possible pathological mechanism behind autism is proposed, which suggests that IL-6 elevation in the brain, caused by the activated glia and/or maternal immune activation, could be an important inflammatory cytokine response involved in the mediation of autism-like behaviors through impairments of neuroanatomical structures and neuronal plasticity. Further studies to investigate whether IL-6 could be used for therapeutic interventions in autism would be of great significance.

A constant challenge for industrialists in cold cathode technologies is the selection of a cathode material which exhibits suitable properties in order to improve performance. One particularly important aspect of performance is the sputter erosion of the cathode, which can lead to lamp failures. Traditionally, refractory metals have been favored for their high densities and energies of sublimation, which result in low sputter yields according to the theory due to Sigmund, and in experiment. However, this paper presents a simple theory which shows that the primary sputter yield is only one step in the liberation of sputtered material from the electrode. The energy of sublimation in fact plays an important role in the energy distribution of the sputtered material. Also, collisions in the bulk gas and the voltage characteristics of the cathode dark space should be taken into consideration for calculating the flux of liberated material. The paper presents a heuristic model of cold cathode sputtering in glow discharges with a view to elucidating the underlying physics in the process. The theory results in a reappraisal of electrode material properties that differs from the traditional view.

Cultivating interdisciplinary connections between freshman and capstone students epitomizes a novel pedagogical approach to deepen student understanding of the learning process in a Community College environment. Within such a context, this article focuses on the outcomes of a two-semester collaborative effort that aims to establish and strengthen interactions between students at opposite ends of the academic spectrum. The work discussed focuses on an initiative in which capstone students in their culminating college class are supported in using their educational experiences to guide their first-year peers as they make the transition to college life. After discussing the creation and implementation of scaffolded collaborative assignments in which capstone students peer-reviewed freshman students work, the paper analyzes the impact of the research on student understanding of the learning process, the outcomes of self-reflection activities, student integration of knowledge and skills from diverse sources and the quality of their work in the peer-review endeavor.

The objective of this study is to evaluate flexural strength, flexural modulus, compressive strength, curing temperature, curing depth, volumetric shrinkage, water sorption, and hygroscopic expansion of two self-, three dual-, and three light-curing resin-based core materials. Flexural strength and water sorption were measured according to ISO 4049, flexural modulus, compressive strength, curing temperature, and curing depth according to well-proven, literature-known methods, and the volumetric behavior was determined by the Archimedes' principle. ANOVA was calculated to find differences between the materials' properties, and correlation of water sorption and hygroscopic expansion was analysed according to Pearson (p 0.05). Clearfil Photo Core demonstrated the highest flexural strength (125 ± 12 MPa) and curing depth (15.2 ± 0.1 mm) and had the highest flexural modulus (≈12.6 ± 1.2 GPa) concertedly with Multicore HB. The best compressive strength was measured for Voco Rebilda SC and Clearfil DC Core Auto (≈260 ± 10 MPa). Encore SuperCure Contrast had the lowest water sorption (11.8 ± 3.3 µg mm(-3)) and hygroscopic expansion (0.0 ± 0.2 vol.%). Clearfil Photo Core and Encore SuperCure Contrast demonstrated the lowest shrinkage (≈2.1 ± 0.1 vol.%). Water sorption and hygroscopic expansion had a very strong positive correlation. The investigated core materials significantly differed in the tested properties. The performance of the materials depended on their formulation, as well as on the respective curing process.

Various efforts within the cold cathode fluorescent lamp (CCFL) industry are underway to decrease costs and increase electrode performance. In order to understand the impact that the choice of gas mixtures and pressures, cathode shape and material might have on the lamp's operation requires a knowledge of the underlying principles governing the glow discharge. We present a review of the literature on the hollow cathode effect and glow discharges, which has particular relevance to the design of CCFL lamp electrodes used in liquid crystal displays. We show that industry-wide standard gas pressures and electrode designs cannot operate in the hollow cathode regime.

Writing, a critical pedagogical tool, cultivates student learning and fosters deeper understanding of the material. When frequent, low -stakes (informal) writing activities help students write more freely, engage with the material and thus become active learners. Looking at students who are at opposite ends of a community college spectrum, this article compares and contrasts students’ writing skills using low-stakes assignments, including peer-reviewing of each other’s work, in a capstone course and in a First-Year Seminar in terms of organization, clarity in communication and content analysis. The data generated from this study stem from an interdisciplinary collaboration among three instructors from Humanities, Mathematics and Natural Sciences, with the goal of creating a network between students in First-Year Seminars and students in the capstone course. Research methods in this context included assigning common readings to students in different classes on the theme of Women in STEM. It also included a peer review component: students reviewed each other’s assignments and instructors visited each other’s class to lead a discussion on the paucity of women in the fields of sciences or as Nobel Prize winner, with the additional aim of improving women’s interest in STEM courses.