A protective effect of inflammatory bowel disease on the severity of sclerosing cholangitis.

Background: Primary sclerosing cholangitis (PSC) is a chronic liver disease marked by inflammation of the bile ducts and results in the development of strictures and fibrosis. A robust clinical correlation exists between PSC and inflammatory bowel disease (IBD). At present, published data are controversial, and it is yet unclear whether IBD drives or attenuates PSC. Methods: Mdr2-deficient mice or DDC-fed mice were used as experimental models for sclerosing cholangitis. Additionally, colitis was induced in mice with experimental sclerosing cholangitis, either through infection with Citrobacter rodentium or by feeding with DSS. Lastly, fibrosis levels were determined through FibroScan analysis in people with PSC and PSC-IBD. Results: Using two distinct experimental models of colitis and two models of sclerosing cholangitis, we found that colitis does not aggravate liver pathology, but rather reduces liver inflammation and liver fibrosis. Likewise, people with PSC-IBD have decreased liver fibrosis compared to those with PSC alone. Conclusions: We found evidence that intestinal inflammation attenuates liver pathology. This study serves as a basis for further research on the pathogenesis of PSC and PSC-IBD, as well as the molecular mechanism responsible for the protective effect of IBD on PSC development. This study could lead to the discovery of novel therapeutic targets for PSC.

Dopamine Transporter SPECT with 12-Minute Scan Duration Using Multiple-Pinhole Collimators.

This study evaluated the potential to reduce the scan duration in dopamine transporter (DAT) SPECT when using a second-generation multiple-pinhole (MPH) collimator designed for brain SPECT with improved count sensitivity and improved spatial resolution compared with parallel-hole and fanbeam collimators. Methods: The retrospective study included 640 consecutive clinical DAT SPECT studies that had been acquired in list mode with a triple-head SPECT system with MPH collimators and a 30-min net scan duration after injection of 181 ± 10 MBq of [123I]FP-CIT. Raw data corresponding to scan durations of 20, 15, 12, 8, 6, and 4 min were obtained by restricting the events to a proportionally reduced time interval of the list-mode data for each projection angle. SPECT images were reconstructed iteratively with the same parameter settings irrespective of scan duration. The resulting 5,120 SPECT images were assessed for a neurodegeneration-typical reduction in striatal signal by visual assessment, conventional specific binding ratio analysis, and a deep convolutional neural network trained on 30-min scans. Results: Regarding visual interpretation, image quality was considered diagnostic for all 640 patients down to a 12-min scan duration. The proportion of discrepant visual interpretations between 30 and 12 min (1.2%) was not larger than the proportion of discrepant visual interpretations between 2 reading sessions of the same reader at a 30-min scan duration (1.5%). Agreement with the putamen specific binding ratio from the 30-min images was better than expected for 5% test-retest variability down to a 10-min scan duration. A relevant change in convolutional neural network-based automatic classification was observed at a 6-min scan duration or less. Conclusion: The triple-head SPECT system with MPH collimators allows reliable DAT SPECT after administration of about 180 MBq of [123I]FP-CIT with a 12-min scan duration.

Individualized Summary Assessment of Detailed Neuropsychological Testing for the Etiological Diagnosis of Newly Detected Cognitive Impairment in Hospitalized Geriatric Patients.

BACKGROUND: Neuropsychological testing (NPT) of geriatric inpatients can be affected by the acute illness and/or the hospitalization. OBJECTIVE: To test individualized interpretation of detailed NPT for the differentiation between primary 'neurodegenerative' etiologies (predominantly Alzheimer's disease) and 'other' etiologies (including cerebrovascular disease) of newly detected cognitive impairment in geriatric inpatients without and with delirium in remission. METHODS: 96 geriatric inpatients (81.9±5.6 years, 64.6% females) with clinically uncertain cognitive impairment were included. 31.3% had delirium in remission that was not considered the primary cause of the cognitive impairment. Categorization of the most likely etiology as 'neurodegenerative' or 'other' was established retrospectively by a study neuropsychologist based on individualized summary assessment of detailed NPT compiled in a standardized vignette. The etiological diagnosis based on FDG-PET served as gold standard (54.2% 'neurodegenerative', 45.8% 'other'). RESULTS: Individualized summary assessment by the study neuropsychologist was correct in 80 patients (83.3%, 8 false positive, 8 false negative). The impact of delirium in remission was not significant (p = 0.237). Individualized summary assessment by an independent neuropsychologist resulted in more false positive cases (n = 22) at the same rate of false negative cases (n = 8). Automatic categorization with a decision tree model based on the most discriminative NPT scores was correct in 68 patients (70.8%, 14 false positive, 14 false negative). CONCLUSION: Individualized summary assessment of detailed NPT in the context of relevant clinical information might be useful for the etiological diagnosis of newly detected cognitive impairment in hospitalized geriatric patients, also in patients with delirium in remission, but requires task-specific expertise.

No impact of attenuation and scatter correction on the interpretation of dopamine transporter SPECT in patients with clinically uncertain parkinsonian syndrome.

PURPOSE: The benefit from attenuation and scatter correction (ASC) of dopamine transporter (DAT)-SPECT for the detection of nigrostriatal degeneration in clinical routine is still a matter of debate. The current study evaluated the impact of ASC on visual interpretation and semi-quantitative analysis of DAT-SPECT in a large patient sample. METHODS: One thousand seven hundred forty consecutive DAT-SPECT with 123I-FP-CIT from clinical routine were included retrospectively. SPECT images were reconstructed iteratively without and with ASC. Attenuation correction was based on uniform attenuation maps, scatter correction on simulation. All SPECT images were categorized with respect to the presence versus the absence of Parkinson-typical reduction of striatal 123I-FP-CIT uptake by three independent readers. Image reading was performed twice to assess intra-reader variability. The specific 123I-FP-CIT binding ratio (SBR) was used for automatic categorization, separately with and without ASC. RESULTS: The mean proportion of cases with discrepant categorization by the same reader between the two reading sessions was practically the same without and with ASC, about 2.2%. The proportion of DAT-SPECT with discrepant categorization without versus with ASC by the same reader was 1.66% ± 0.50% (1.09-1.95%), not exceeding the benchmark of 2.2% from intra-reader variability. This also applied to automatic categorization of the DAT-SPECT images based on the putamen SBR (1.78% discrepant cases between without versus with ASC). CONCLUSION: Given the large sample size, the current findings provide strong evidence against a relevant impact of ASC with uniform attenuation and simulation-based scatter correction on the clinical utility of DAT-SPECT to detect nigrostriatal degeneration in patients with clinically uncertain parkinsonian syndrome.

Stereotactical normalization with multiple templates representative of normal and Parkinson-typical reduction of striatal uptake improves the discriminative power of automatic semi-quantitative analysis in dopamine transporter SPECT.

BACKGROUND: The specific binding ratio (SBR) of 123I-FP-CIT in the putamen is widely used to support the interpretation of dopamine transporter (DAT) SPECT. Automatic methods for computation of the putamen SBR often include stereotactical normalization of the individual DAT-SPECT image to an anatomical standard space. This study compared using a single 123I-FP-CIT template image as target for stereotactical normalization versus multiple templates representative of normal and different levels of Parkinson-typical reduction of striatal 123I-FP-CIT uptake. METHODS: 1702 clinical 123I-FP-CIT SPECT images were stereotactically normalized (affine) to the anatomical space of the Montreal Neurological Institute (MNI) with SPM12 either using a single custom-made 123I-FP-CIT template representative of normal striatal uptake or using eight different templates representative of normal and different levels of Parkinson-typical reduction of striatal FP-CIT uptake with and without attenuation and scatter correction. In the latter case, SPM finds the linear combination of the multiple templates that best matches the patient's image. The putamen SBR was obtained using hottest voxels analysis in large unilateral regions-of-interest predefined in MNI space. The histogram of the putamen SBR in the whole sample was fitted by the sum of two Gaussians. The power to differentiate between reduced and normal SBR was estimated by the effect size of the distance between the two Gaussians computed as the differences between their mean values scaled to their pooled standard deviation. RESULTS: The effect size of the distance between the two Gaussians was 3.83 with the single template versus 3.96 with multiple templates for stereotactical normalization. CONCLUSIONS: Multiple templates representative of normal and different levels of Parkinson-typical reduction for stereotactical normalization of DAT-SPECT might provide improved separation between normal and reduced putamen SBR that could result in slightly improved power for the detection of nigrostriatal degeneration.

Multiple-pinhole collimators improve intra- and between-rater agreement and the certainty of the visual interpretation in dopamine transporter SPECT.

BACKGROUND: Multiple-pinhole (MPH) collimators improve the resolution-sensitivity trade-off compared to parallel-hole collimators. This study evaluated the impact of MPH collimators on intra- and between-rater agreement, and on the certainty of visual interpretation in dopamine transporter (DAT)-SPECT. METHODS: The study included 71 patients (62.1 ± 12.7 y). Two SPECT acquisitions were performed in randomized order after a single injection of 182 ± 9 MBq 123I-FP-CIT, one with MPH and one with low-energy-high-resolution-high-sensitivity (LEHRHS) collimators. MPH projections were reconstructed with an iterative 3d Monte Carlo algorithm. LEHRHS projections were reconstructed with filtered backprojection (FBP) or with ordered-subsets expectation-maximization and resolution recovery (OSEM). Images were visually evaluated twice by three independent raters with respect to presence/absence of Parkinson-typical reduction of striatal 123I-FP-CIT uptake using a Likert 6-score (- 3 = clearly normal, …, 3 = clearly reduced). In case of intra-rater discrepancy, an intra-rater consensus was obtained. Intra- and between-rater agreement with respect to the Likert score (6-score and dichotomized score) was characterized by Cohen's kappa. RESULTS: Intra-rater kappa of visual scoring of MPH/LEHRHS-OSEM/LEHRHS-FBP images was 0.84 ± 0.12/0.73 ± 0.06/0.73 ± 0.08 (6-score, mean of three raters) and 1.00 ± 0.00/0.96 ± 0.04/0.97 ± 0.03 (dichotomized score). Between-rater kappa of visual scoring (intra-rater consensus) of MPH/LEHRHS-OSEM/LEHRHS-FBP images was 0.70 ± 0.06/0.63 ± 0.08/0.48 ± 0.05 (6-score, mean of three pairs of raters) and 1.00 ± 0.00/0.92 ± 0.04/0.90 ± 0.06 (dichotomized score). There was a decrease of (negative) Likert scores in normal DAT-SPECT by 0.87 ± 0.18 points from the LEHRHS-OSEM to the MPH setting. The (positive) Likert scores of reduced DAT-SPECT did not change on average. CONCLUSIONS: MPH collimators improve intra- and between-rater agreement as well as the certainty of the visual interpretation of DAT-SPECT.

Impact of Valve Plane Alignment on the Repeatability of Left Ventricular Ejection Fraction in ECG-gatedMyocard ial SPECT Using Corridor 4DM.

Background: In myocardial gated single-photon emission computed tomography (GSPECT), to differentiate true changes of left ventricular ejection fraction (LVEF) from inherent methodical variability is clinically relevant; however, data about repeatability of GSPECT LVEF in the same patients are rather inconsistent in literature. The aim of this study was therefore to determine repeatability coefficient (RC) of GSPECT LVEF at rest and to investigate the effect of the introduction of processing constraints in left ventricular edge detection. Methods: Thirty-five patients referred for one-day myocardial GSPECT stress-rest scan were included. After the routine stress-rest study, patients were completely repositioned on the imaging table for a second rest acquisition using the same acquisition parameters. LVEF was computed using Corridor 4DM software without and with manual alignment of valve plane. Repeatability was assessed using the Bland-Altman method. Results: RC of LVEF from unaligned datasets was 7.6% with upper and lower limits of agreement of 7.4% to -7.8%. After valve plane and ventricular long-axis length alignment, RC improved to 3.6% with upper and lower limits of agreement of 3.4% to -3.8%. Conclusions: RC using unaligned determination of GSPECT LVEF was comparable to that from previous publications. However, RC using valve plane alignment could be improved to below 4% on 95% confidence level.

Impact of age and sex correction on the diagnostic performance of dopamine transporter SPECT.

PURPOSE: The specific binding ratio (SBR) of 123I-FP-CIT (FP-CIT) in the putamen decreases with age by about 5% per decade and most likely is about 10% higher in females. However, the clinical utility of age and sex correction of the SBR is still a matter of debate. This study tested the impact of age and sex correction on the diagnostic performance of the putamen SBR in three independent patient samples. METHODS: Research sample: 207 healthy controls (HC) and 438 Parkinson's disease (PD) patients. Clinical sample A: 183 patients with neurodegenerative parkinsonian syndrome (PS) and 183 patients with non-neurodegenerative PS from one site. Clinical sample B: 84 patients with neurodegenerative PS and 38 patients with non-neurodegenerative PS from another site. Correction for age and sex of the putamen SBR was based on linear regression in the HC or non-neurodegenerative PS, separately in each sample. The area under the ROC curve (AUC) was used as performance measure. RESULTS: The putamen SBR was higher in females compared to males (PPMI: 14%, p < 0.0005; clinical sample A: 7%, p < 0.0005; clinical sample B: 6%, p = 0.361). Age-related decline of the putamen SBR ranged between 3.3 and 10.4% (p ≤ 0.019). In subjects ≥ 50 years, age and sex explained < 10% of SBR between-subjects variance. Correction of the putamen SBR for age and sex resulted in slightly decreased AUC in the PPMI sample (0.9955 versus 0.9969, p = 0.025) and in clinical sample A (0.9448 versus 0.9519, p = 0.057). There was a small, non-significant AUC increase in clinical sample B (0.9828 versus 0.9743, p = 0.232). CONCLUSION: These findings do not support age and sex correction of the putaminal FP-CIT SBR in the diagnostic workup of parkinsonian syndromes. This most likely is explained by the fact that the proportion of between-subjects variance caused by age and sex is considerably below the symptom threshold of about 50% reduction in neurodegenerative PS.

Brain FDG PET for the Etiological Diagnosis of Clinically Uncertain Cognitive Impairment During Delirium in Remission.

BACKGROUND: Positron emission tomography (PET) of the brain with 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) is widely used for the etiological diagnosis of clinically uncertain cognitive impairment (CUCI). Acute full-blown delirium can cause reversible alterations of FDG uptake that mimic neurodegenerative disease. OBJECTIVE: This study tested whether delirium in remission affects the performance of FDG PET for differentiation between neurodegenerative and non-neurodegenerative etiology of CUCI. METHODS: The study included 88 patients (82.0±5.7 y) with newly detected CUCI during hospitalization in a geriatric unit. Twenty-seven (31%) of the patients were diagnosed with delirium during their current hospital stay, which, however, at time of enrollment was in remission so that delirium was not considered the primary cause of the CUCI. Cases were categorized as neurodegenerative or non-neurodegenerative etiology based on visual inspection of FDG PET. The diagnosis at clinical follow-up after ≥12 months served as ground truth to evaluate the diagnostic performance of FDG PET. RESULTS: FDG PET was categorized as neurodegenerative in 51 (58%) of the patients. Follow-up after 16±3 months was obtained in 68 (77%) of the patients. The clinical follow-up diagnosis confirmed the FDG PET-based categorization in 60 patients (88%, 4 false negative and 4 false positive cases with respect to detection of neurodegeneration). The fraction of correct PET-based categorization did not differ between patients with delirium in remission and patients without delirium (86% versus 89%, p = 0.666). CONCLUSION: Brain FDG PET is useful for the etiological diagnosis of CUCI in hospitalized geriatric patients, as well as in patients with delirium in remission.

Interleukin-6 elevation in healthy neonates.

OBJECTIVE: This study aimed to identify peripartum and neonatal factors associated with elevated Interleukin-6 levels in the cord blood of neonates without clinical signs of an infection. STUDY DESIGN: We conducted a prospective single-center study with healthy term and preterm neonates between March and November 2017. We investigated correlations between 21 peripartum factors and neonatal IL-6 concentrations. RESULTS: Four hundred and seventy-one infants (GA: 32.9-42.3 weeks) were included. The risk for elevated neonatal IL-6 levels was 3.1 to 4.5-fold increased in the presence of either peripartum maternal temperature >37.5 °C (p = 0.012), duration of labor >12 h (p < 0.001), vaginal delivery (p < 0.001), or neonatal neutrophils >8 × 109 cells/L (p < 0.001). CONCLUSION: The results indicate that a considerable number of neonates with elevated IL-6 levels can sufficiently cope with an exposition to substantial perinatal stress or intrauterine inflammation and do not require postnatal antibiotic treatment.

Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3+ Regulatory T Cells.

Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3+ regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver. However, whether and how this is linked to the Treg and Th17 cell imbalance is unclear. To address this, we used dextran sodium sulfate (DSS) and T cell transfer colitis mouse models. We analyzed the pathological conditions of the intestine and liver on histological, cellular, and molecular levels. We observed bacterial translocation and an influx of inflammatory cells, in particular Th17 cells, to the liver during colitis. In the DSS colitis model, in which Treg were concomitantly increased in the liver, we did not observe an overt pathological condition of the liver. In contrast, the T cell-mediated colitis model, in which Treg are not abundant, was associated with marked liver inflammation and a pathological condition. Of note, upon depletion of Treg in DEREG mice, DSS colitis promotes accumulation of Th17 cells and a pathological condition of the liver. Finally, we studied immune cell migration using KAEDE mice and found that some of these cells had migrated directly from the inflamed intestine into the liver. Overall, these data indicate that colitis can promote a pathological condition of the liver and highlight an important role of Treg in controlling colitis-associated liver inflammation.