Comparison of visual criteria for amyloid-PET reading: could criteria merging reduce inter-rater variability?

BACKGROUND: Three different amyloid tracers labeled with 18-flourine have been introduced into clinical use. The leaflets of tracers indicate different visual criteria for PET reporting. In clinical practice, it is not yet ascertained whether these criteria are equivalent in terms of diagnostic accuracy or if anyone is better than another. We aimed to evaluate the inter and intra-rater variability of visual assessment of 18F-Florbetapir PET/CT images among six independent readers with different clinical experience. METHODS: We analyzed 252 PET/CT scans, visually assessed by each reader three times, applying independently the three different reading criteria proposed. Each reader evaluated the regional uptake specifying for each cortical region a numeric value of grading of positivity in order to assign a final score. At the end of each reading a level of confidence was determined by assigning a score from 0 (negative) to 4 (positive). After first reading, those cases in which the evaluations by two experienced readers did not match (discordant cases) were independently reevaluated merging all the three different visual interpretation criteria. RESULTS: Good agreement was observed for visual interpretation among the six readers' confidence-level using independently the three visual reading criteria: ICC=0.83 (0.80-0.86) for 18F-florbetapir, ICC=0.84 (0.81-0.87) for 18F-florbetaben, and ICC=0.86 (0.83-0.88) for 18F-flutemetamol reading. A good inter-rater agreement was observed for final-score too: ICC=0.74 (0.70-0.78) for 18F-florbetapir; ICC=0.82 (0.79-0.85) for 18F-florbetaben; ICC=0.84 (0.81-0.87) for 18F-flutemetamol. Intra-rater agreement was good for final-score (from 0.76 to 0.90; P<0.001) and confidence-level (Spearman's rho from 0.89 to 1.00; P<0.001). Disagreement between the two experienced readers was observed in 22 of 252 cases (9%). The agreement converged over a second round of independent reading in 12 of 22 cases (54%), by merging all the criteria. CONCLUSIONS: All the criteria proposed are useful to determine the grading of positivity or negativity of amyloid deposition and their merging improves the diagnostic confidence and provides a better agreement.

Emerging topics and practical aspects for an appropriate use of amyloid PET in the current Italian context.

In May 2017 some representatives of the Italian nuclear medicine and neurological communities spontaneously met to discuss the issues emerged during the first two years of routine application of amyloid PET with fluorinated radiopharmaceuticals in the real world. The limitations of a binary classification of scans, the possibility to obtain early images as a surrogate marker of regional cerebral bloos flow, the need for (semi-)quantification and, thus, the opportunity of ranking brain amyloidosis, the correlation with Aß42 levels in the cerebrospinal fluid, the occurrence and biological meaning of uncertain/boderline scans, the issue of incidental amyloidosis, the technical pittfalls leading to false negative/positive results, the position of the tool in the diagnostic flow-chart in the national reality, are the main topics that have been discussed. Also, a card to justify the examination to be filled by the dementia specialist and a card for the nuclear medicine physician to report the exam in detail have been approved and are available in the web, which should facilitate the creation of a national register, as previewed by the 2015 intersocietal recommendation on the use of amyloid PET in Italy. The content of this discussion could stimulate both public institutions and companies to support further research on these topics.

Do Beliefs about the Pathogenetic Role of Amyloid Affect the Interpretation of Amyloid PET in the Clinic.

BACKGROUND: Beliefs of dementia experts about the pathogenic role of amyloid in Alzheimer's disease (AD) may affect the use of amyloid positron emission tomography (PET). OBJECTIVE: To assess the role attributed to amyloid in AD pathogenesis by Italian dementia experts, and whether this modulates the impact of amyloid PET results in their diagnostic workup. METHODS: 22 dementia experts rated their beliefs about the pathogenic role of amyloid. Then, we asked them to rate the probability of change in diagnosis based on the result of amyloid PET for 7 case vignettes, depicting patients who initially received a diagnosis based on a comprehensive workup and later received amyloid PET results consistent or inconsistent with the clinical picture. RESULTS: 55% of the experts assigned a dominant role to amyloid, and 32% attributed a similar role to amyloid and tau in AD pathogenesis. The probability of change in diagnosis ranged from 17% (SD = 21.6) for cases with consistent to 51% (SD = 34) for cases with inconsistent PET versus clinical data. Diagnostic change was not biased by the clinicians' beliefs about AD pathogenesis. CONCLUSIONS: This work supports an unbiased interpretation of amyloid PET across different beliefs about the pathogenic role of amyloid, and a belief-independent reluctance to change diagnosis in cases where change is expected and recommended.

Arrays of templated TiO2 nanofibres as improved photoanodes for water splitting under visible light.

Arrays of TiO2 nanofibres (NFs) were successfully prepared by template sol-gel synthesis, using track-etched polycarbonate membranes as structure directing agent. The control of the sol-gel kinetic was crucial in order to homogeneously fill the pores with a continuous framework. For this reason acetylacetone was added to the sol-gel mixture as chelating agent. The band edge positions of TiO2 NFs were determined by a Mott-Schottky plot and diffuse reflectance analysis. The results support the presence of trace dopants which can act favorably with respect to the photoelectrochemical properties. The TiO2 NFs array showed enhanced photoelectrochemical activity both under UV light and visible light when used as photoanodes for the water splitting reaction.

Proposal for an optimized protocol for intravenous administration of insulin in diabetic patients undergoing (18)F-FDG PET/CT.

The objective of this study was to evaluate the usefulness and impact of insulin administration before an F-FDG PET/computed tomography (CT) examination in diabetic patients in order to propose an optimized protocol that can reduce blood glucose levels without increasing muscular F-FDG uptake. A total of 130 patients underwent an F-FDG PET/CT. Twenty patients had glucose levels greater than 180 mg/dl and received endovenous insulin before F-FDG injection (group 1); 10 patients had glucose levels greater than 160 mg/dl and lower than 200 mg/dl and received no insulin (group 2); 100 patients were euglycemic (group 3). Biodistribution was adequate in 19 of 20 patients in group 1. Values of standardized uptake value in the gluteal muscle were 0.50±0.18 for group 1, 0.48±0.10 for group 2, and 0.49±0.08 for group 3; no significant differences in muscular F-FDG uptake could be found among the three groups. No adverse events were recorded. In conclusion, our protocol has been demonstrated to be safe and effective, with only a minor impact on glucose biodistribution and apparently without affecting PET accuracy.

Polycarbonate-based ordered arrays of electrochemical nanoelectrodes obtained by e-beam lithography.

Ordered arrays of nanoelectrodes for electrochemical use are prepared by electron beam lithography (EBL) using polycarbonate as a novel e-beam resist. The nanoelectrodes are fabricated by patterning arrays of holes in a thin film of polycarbonate spin-coated on a gold layer on Si/Si(3)N(4) substrate. Experimental parameters for the successful use of polycarbonate as high resolution EBL resist are optimized. The holes can be filled partially or completely by electrochemical deposition of gold. This enables the preparation of arrays of nanoelectrodes with different recession degree and geometrical characteristics. The polycarbonate is kept on-site and used as the insulator that separates the nanoelectrodes. The obtained nanoelectrode arrays (NEAs) exhibit steady state current controlled by pure radial diffusion in cyclic voltammetry for scan rates up to approximately 50 mV s( - 1). Electrochemical results showed satisfactory agreement between experimental voltammograms and suitable theoretical models. Finally, the peculiarities of NEAs versus ensembles of nanoelectrodes, obtained by membrane template synthesis, are critically evaluated.

SPECT predictors of cognitive decline and Alzheimer's disease in mild cognitive impairment.

Baseline brain single photon emission computed tomography (SPECT) was evaluated in eighty subjects with mild cognitive impairment (MCI) who were followed for a mean of about two years, when twelve patients developed Alzheimer's disease (AD), nineteen showed memory decline (D), and forty-three had normal cognition assessment (stable: S) (six drop-out). Volumetric Regions of Interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures showed significant effects for both the group (S, D, and AD; p < 0.004) and VROI (p < 0.0001) factors, with significant group*region interaction (p < 0.01). At post-hoc comparison, hippocampal VROIs values were lower in AD than in D and S, while parietal VROIs values were lower in D and AD than in S. These four VROI significantly correlated with verbal delayed recall score at follow-up visit. Receiver operating characteristic (ROC) curves for the mean hippocampal VROI value showed 0.81 sensitivity with 0.86 specificity in separation of S+D from AD (p < 0.0001), and 0.69 sensitivity with 0.75 specificity in separation of S from D+AD (p < 0.0002). ROC curves for the mean parietal VROI value showed 0.62 sensitivity with 0.70 specificity in separation of S from D+AD (p < 0.0002). Baseline SPECT can support outcome prediction in subjects with MCI.

Brain SPECT in subtypes of mild cognitive impairment. Findings from the DESCRIPA multicenter study.

The Development of Screening Guidelines and Clinical Criteria of Predementia Alzheimer's Disease (DESCRIPA) multicenter study enrolled patients with MCI or subjective cognitive complaints (SUBJ), a part of whom underwent optional brain perfusion SPECT. These patients were classified as SUBJ (n = 23), nonamnestic MCI (naMCI; n = 17) and amnestic MCI (aMCI; n = 40) based on neuropsychology. Twenty healthy subjects formed the control (CTR) group. Volumetric regions of interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures, corrected for age and center, showed significant differences between groups (p = 0.01) and VROI (p < 0.0001) with a significant group-region interaction (p = 0.029). In the post hoc comparison, SUBJ did not differ from CTR. aMCI disclosed reduced uptake in the left hippocampus and bilateral temporal cortex (compared with CTR) or in the left hippocampus and bilateral parietal cortex (compared with SUBJ). In the naMCI group, reduced VROI values were found in the bilateral temporal cortex and right frontal cortex. In the comparison between aMCI and naMCI, the former had lower values in the left parietal cortex and precuneus. Discriminant analysis between SUBJ/CTR versus all MCI patients allowed correct allocations in 73 % of cases. Mean VROI values were highly correlated (p < 0.0001) with the learning measure of a verbal memory test, especially in the bilateral precunei and parietal cortex and in the left hippocampus. In a subset of 70 patients, mean VROI values showed a significant correlation (p < 0.05) with the white matter hyperintensities score on MRI. In conclusion, MCI subtypes have different perfusion patterns. The aMCI group exhibited a pattern that is typical of early Alzheimer's disease, while the naMCI group showed a more anterior pattern of hypoperfusion. Instead, a homogeneous group effect was lacking in SUBJ.

Nanoelectrode ensembles as recognition platform for electrochemical immunosensors.

In this study we demonstrate the possibility to prepare highly sensitive nanostructured electrochemical immunosensors by immobilizing biorecognition elements on nanoelectrode ensembles (NEEs) prepared in track-etch polycarbonate membranes. The gold nanodisk electrodes act as electrochemical transducers while the surrounding polycarbonate binds the antibody-based biorecognition layer. The interaction between target protein and antibody is detected by suitable secondary antibodies labelled with a redox enzyme. A redox mediator, added to the sample solution, shuttles electrons from the nanoelectrodes to the biorecognition layer, so generating an electrocatalytic signal. This allows one to fully exploit the highly improved signal-to-background current ratio, typical of NEEs. In particular, the receptor protein HER2 was studied as the target analyte. HER2 detection allows the identification of breast cancer that can be treated with the monoclonal antibody trastuzumab. NEEs were functionalized with trastuzumab which interacts specifically with HER2. The biorecognition process was completed by adding a primary antibody and a secondary antibody labelled with horseradish peroxidase. Hydrogen peroxide was added to modulate the label electroactivity; methylene blue was the redox mediator generating voltammetric signals. NEEs functionalized with trastuzumab were tested to detect small amounts of HER2 in diluted cell lysates and tumour lysates.

Brain perfusion correlates of medial temporal lobe atrophy and white matter hyperintensities in mild cognitive impairment.

OBJECTIVE: To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI). METHODS: 56 MCI patients (age = 69.3 +/- 7.0, 32 females) underwent brain MR scan and (99m)Tc ECD SPECT. We evaluated MTA according to Scheltens' fivepoint scale on T1 MR images, and assessed WMHs using the rating scale for age-related white matter changes on T2-weighted and FLAIR MR images. We divided MCI into age-matched subgroups with high and low MTA and high and low WMHs load. We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing high vs. low MTA and high vs. low WMHs, setting p-value at 0.001 uncorrected, thresholding cluster extent at 100 voxels, using proportional scaling and entering age and WMHs or MTA respectively as nuisance covariates. RESULTS: MCI with high compared with low MTA showed hypoperfusion in the left hippocampus and in the left parahippocampal gyrus. MCI with high compared with low WMHs showed a hypoperfusion area in the left insular region and superior temporal gyrus. CONCLUSIONS: MTA in MCI is associated with hippocampal gray matter hypoperfusion while WMHs is associated with gray matter hypoperfusion in areas of the insula and temporal neocortex. These results confirm that MTA is associated with local functional changes and suggest that WMHs may be associated with remote brain cortical dysfunction.

Polycyclic aromatic hydrocarbons degradation by composting in a soot-contaminated alkaline soil.

This study deals with the biodegradation of the polycyclic aromatic hydrocarbons (PAH)s present in a soil contaminated by soot waste, characterised by a total PAHs content in the 200 mg kg(-1) range. A challenging characteristic of the waste soil treated was its high alkalinity, with a pH of about 12.8. The waste came from a soot-contaminated area located in the industrial zone of Porto Marghera, Venice (Italy). The biodegradation process employed was the composting of the waste with sewage sludge and yard waste. The process was carried out on a pilot scale using a closed tank with forced aeration for a period of 60 days, followed by 70 days with natural aeration. The time evolution of the process was monitored by following the time change in the concentration of the 16 US-EPA PAHs, as well as temperature, pH, electrical conductivity, C and N contents. Also phytotoxicity parameters, such as the growth and respiration indexes, were monitored. An induction time of about 30 days was observed, which corresponded to the time required before observing a significant self-drop in the waste pH and an increase in mass temperature. Afterward, a progressive drop in the PAHs concentration was observed, up to reaching after 130 days an overall degradation percentage in the order of 68%. The degradation was more effective on rather low molecular weight PAHs (2-4 rings).

Chemical analyses of heavy metal contamination in sediments of the Venice Lagoon and toxicological implications.

Heavy metals are extracted from sediments using 1 M HCl; then, solutions are neutralised with 1 M NaOH, to fit the conditions suitable for the Vibrio Fischeri test. In the neutralised solutions different percentages of initial metal concentration are present, depending on the individual solubilities. The chemical investigation of the metal fraction extracted from the sediment with this procedure and the different metal bioavailability depending on the presence of natural complexing agents are the subject of this work. The results obtained confirm the good agreement between heavy metal fraction extracted using 1 M HCl and the anthropogenic component in the sediment. The use of voltammetric techniques, and the addition of low molecular weight humic acids into extracts show the ability of natural complexing agents in affecting heavy metal bioavailability and toxicity.

Preparations, structures, and electrochemical studies of aryldiazene complexes of rhenium: syntheses of the first heterobinuclear and heterotrinuclear derivatives with bis(diazene) or bis(diazenido) bridging ligands.

The mono- and binuclear aryldiazene complexes [Re(C6H5N=NH)(CO)5-nPn]BY4 (1-5) and [(Re(CO)5-nPn)2-(mu-HN=NAr-ArN=NH)](BY4)2 (6-12) [P = P(OEt)3, PPh(OEt)2, PPh2OEt; n = 1-4; Ar-Ar = 4,4'-C6H4-C6H4, 4,4'-(2-CH3)C6H3-C6H3(2-CH3), 4,4'-C6H4-CH2-C6H4; Y = F, Ph) were prepared by reacting the hydride species ReH(CO)5-nPn with the appropriate mono- and bis(aryldiazonium) cations. These compounds, as well as other prepared compounds, were characterized spectroscopically (IR; 1H, 31P, 13C, and 15N NMR data), and 1a was also characterized by an X-ray crystal structure determination. [Re(C6H5N=NH)(CO)(P(OEt)3)4]BPh4 (1a) crystallizes in space group P1 with a = 15.380(5) A, b = 13.037(5) A, c = 16.649(5) A, alpha = 90.33(5) degrees, beta = 91.2(1) degrees, gamma = 89.71(9) degrees, and Z = 2. The "diazene-diazonium" complexes [M(CO)3P2(HN=NAr-ArN identical to N)](BF4)2 (13-15, 17) [M = Re, Mn; P = PPh2OEt, PPh2OMe, PPh3; Ar-Ar = 4,4'-C6H4-C6H4, 4,4'-C6H4-CH2-C6H4] and [Re(CO)4(PPh2OEt)(4,4'-HN=NC6H4-C6H4N identical to N)](BF4)2 (16b) were synthesized by allowing the hydrides MH(CO)3P2 or ReH(CO)4P to react with equimolar amounts of bis(aryldiazonium) cations under appropriate conditions. Reactions of diazene-diazonium complexes 13-17 with the metal hydrides M2H2P'4 and M2'H(CO)5-nP"n afforded the heterobinuclear bis(aryldiazene) derivatives [M1(CO)3P2(mu-HN=NAr-ArN=NH)M2HP'4](BPh4)2 (ReFe, ReRu, ReOs, MnRu, MnOs) and [M1(CO)3P2(mu-HN=NAr-ArN=NH)M2'(CO)5-nP"n](BPh4)2 (ReMn, MnRe) [M1 = Re, Mn; M2 = Fe, Ru, Os; M2' = Mn, Re; P = PPh2OEt, PPh2OMe; P',P" = P(OEt)3, PPh(OEt)2; Ar-Ar = 4,4'-C6H4-C6H4, 4,4'-C6H4-CH2-C6H4; n = 1, 2]. The heterotrinuclear complexes [Re(CO)3(PPh2OEt)2(mu-4,4'-HN=NC6H4-C6H4N=NH)M(P(OEt)3)4(mu-4,4'-HN=NC6H4- C6H4N=NH)Mn(CO)3(PPh2OEt)2](BPh4)4 (M = Ru, Os) (ReRuMn, ReOsMn) were obtained by reacting the heterobinuclear complexes ReRu and ReOs with the appropriate diazene-diazonium cations. The heterobinuclear complex with a bis(aryldiazenido) bridging ligand [Mn(CO)2(PPh2OEt)2(mu-4,4'-N2C6H4-C6H4N2)Fe(P(OEt)3)4]BPh4 (MnFe) was prepared by deprotonating the bis(aryldiazene) compound [Mn(CO)3(PPh2OEt)2(mu-4,4'-HN=NC6H4-C6H4N=NH)Fe(4- CH3C6H4CN)(P(OEt)3)4](BPh4)3. Finally, the binuclear compound [Re(CO)3(PPh2OEt)2(mu-4,4'-HN=NC6H4-C6H4N2)Fe(CO)2(P(OPh)3)2](BPh4)2 (ReFe) containing a diazene-diazenido bridging ligand was prepared by reacting [Re(CO)3(PPh2OEt)2(4,4'-HN=NC6H4-C6H4N identical to N)]+ with the FeH2(CO)2(P(OPh)3)2 hydride derivative. The electrochemical reduction of mono- and binuclear aryldiazene complexes of both rhenium (1-12) and the manganese, as well as heterobinuclear ReRu and MnRu complexes, was studied by means of cyclic voltammetry and digital simulation techniques. The electrochemical oxidation of the mono- and binuclear aryldiazenido compounds Mn(C6H5N2)(CO)2P2 and (Mn(CO)2P2)2(mu-4,4'-N2C6H4-C6H4N2) (P = PPh2OEt) was also examined. Electrochemical data show that, for binuclear compounds, the diazene bridging unit allows delocalization of electrons between the two different redox centers of the same molecule, whereas the two metal centers behave independently in the presence of the diazenido bridging unit.

Slow and unrecognized progression of schwannoma of the sciatic nerve.

Schwannoma of the sciatic nerve is a rare occurrence, responsible for aspecific symptomatology, frequently confused with nerve root deficit caused by discopathy. Diagnosis is usually made several years after onset, also because electromyographic examination is normal. Once tumor swelling has been identified, several instrumental tests and intraoperative macroscopic examination provide sufficient elements for diagnosis: histological examination shows typical aspects.

Ion-exchange voltammetry at polymer film-coated nanoelectrode ensembles.

Ensembles of nanoscopic disk-shaped electrodes have been shown to offer enhancements in electroanalytical detection limits relative to electrodes of macroscopic dimensions (e.g., disk electrodes with diameters of ∼1 mm). Enhancements in electroanalytical detection limits have also been observed at macroscopic electrodes that have been coated with films of ion-exchange polymers. In this paper we combine these two concepts. We demonstrate that a nanoelectrode ensemble (NEE) that has been coated with a thin film of the Kodak ion-exchange polymer AQ 55 shows enhanced electroanalytical detection limits relative to the uncoated NEE and to the coated macroscopic electrode. To our knowledge, this is the first investigation of the electrochemistry, and the electroanalytical advantages, of polymer film-coated NEEs.

Bedside postpyloric placement of weighted feeding tubes.

A pilot study to evaluate a technique for the bedside placement of small-bore, weighted feeding tubes past the pylorus in critically ill patients is described. The technique involves the use of a #8 or #10 French small-bore, tungsten-weighted feeding tube, specific patient positioning, and defined insertion techniques, including gastric distention with air. The tubes were placed at the bedside in the intensive care unit by the nutrition support team nurse. Successful postpyloric placement was achieved in 85 (83%) of 103 patients. Approximate time for successful insertion was 30 minutes. A follow-up study to define factors influencing success or failure of this technique is planned.

Determination of residual aromatic amine hydrochlorides in process samples of di-isocyanate used in the manufacture of polyurethane A comparison of electroanalytical methods.

Aromatic diamine hydrochlorides have been determined in the presence of different amounts of hydrochloric acid by acid-base titration followed potentiometrically, by linear sweep voltammetry, by differential pulse voltammetry and also by direct DPV measurement. Tests on simulated and production samples have shown that the best results are obtained by using DPV at a mercury electrode, because of its good resolution, which makes it possible to achieve good accuracy (error < - 1 %) and good precision (rsd 1.5%) at 0.1M levels. Moreover, it has the advantage that neither preliminary treatment of the sample nor a trial titration is required.