Purpose Tracer kinetic modeling of tissue time activity curves and the individual input function based on arterial blood sampling and metabolite correction is the gold standard for quantitative characterization of microglia activation by PET with the translocator protein (TSPO) ligand 18 F-GE-180. This study tested simplified methods for quantification of 18 F-GE-180 PET. Methods Dynamic 18 F-GE-180 PET with arterial blood sampling and metabolite correction was performed in five healthy volunteers and 20 liver-transplanted patients. Population-based input function templates were generated by averaging individual input functions normalized to the total area under the input function using a leave-one-out approach. Individual population-based input functions were obtained by scaling the input function template with the individual parent activity concentration of 18 F-GE-180 in arterial plasma in a blood sample drawn at 27.5 min or by the individual administered tracer activity, respectively. The total 18 F-GE-180 distribution volume (V T) was estimated in 12 regions-of-interest (ROIs) by the invasive Logan plot using the measured or the population-based input functions. Late ROI-to-whole-blood and ROI-to-cerebellum ratio were also computed. Results Correlation with the reference V T (with individually measured input function) was very high for V T with the populationbased input function scaled with the blood sample and for the ROI-to-whole-blood ratio (Pearson correlation coefficient = 0.989 ± 0.006 and 0.970 ± 0.005). The correlation was only moderate for V T with the population-based input function scaled with tracer activity dose and for the ROI-to-cerebellum ratio (0.653 ± 0.074 and 0.384 ± 0.177). Reference V T , population-based V T with scaling by the blood sample, and ROI-to-whole-blood ratio were sensitive to the TSPO gene polymorphism. Population-based V T with scaling to the administered tracer activity and the ROI-to-cerebellum ratio failed to detect a polymorphism effect. Conclusion These results support the use of a population-based input function scaled with a single blood sample or the ROI-towhole-blood ratio at a late time point for simplified quantitative analysis of 18 F-GE-180 PET.

Purpose Calcineurin inhibitors (CNI) can cause long-term impairment of brain function. Possible pathomechanisms include alterations of the cerebral immune system. This study used positron emission tomography (PET) imaging with the translocator protein (TSPO) ligand 18F-GE-180 to evaluate microglial activation in liver-transplanted patients under different regimens of immunosuppression. Methods PET was performed in 22 liver-transplanted patients (3 CNI free, 9 with low-dose CNI, 10 with standard-dose CNI immunosuppression) and 9 healthy controls. The total distribution volume (VT) estimated in 12 volumes-of-interest was analyzed regarding TSPO genotype, CNI therapy, and cognitive performance. Results In controls, VT was about 80% higher in high affinity binders (n = 5) compared to mixed affinity binders (n = 3). Mean VT corrected for TSPO genotype was significantly lower in patients compared to controls, especially in patients in whom CNI dose had been reduced because of nephrotoxic side effect. Conclusion Our results provide evidence of chronic suppression of microglial activity in liver-transplanted patients under CNI therapy especially in patients with high sensitivity to CNI toxicity.

Background and Aims Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. Methods Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age‐adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N‐acetyl‐aspartate, choline, creatine, myo‐inositol and glutamine + glutamate in frontal‐ (fWM) and parietal white matter (pWM). One‐way analysis of variance and Kruskal‐Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. Results HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N‐acetyl‐aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. Conclusion The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC.

BACKGROUND: Hepatic encephalopathy is a common severe complication of liver cirrhosis that, however, so far is not considered as an indication for organ allocation to patients on the transplant waiting list. Multiple psychometric tests have been developed to detect hepatic encephalopathy. However, there is only rare data about the predictive value of psychometric test results regarding mortality in patients with liver cirrhosis. This retrospective analysis of prospective data determined the predictive value of the Inhibitory Control Test (ICT), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Portosystemic Encephalopathy Syndrome-Test and the Critical Flicker Frequency (CFF) assessment in regard to mortality in patients on the waiting list for liver transplantation. METHODS: 143 patients awaiting liver transplantation were included. They underwent a test battery including the Inhibitory Control Test, the Repeatable Battery for the Assessment of Neuropsychological Status, the Portosystemic Encephalopathy Syndrome-Test which provides the psychometric hepatic encephalopathy score (PHES) and the Critical Flicker Frequency assessment at study inclusion. The PHES was available for all patients (n = 143), the RBANS scores for n = 115, the ICT results for n = 99, and the CFF results for n = 136 patients. Basic characteristics (age, gender, underlying liver disease, accompanying diseases) and Model for End-stage Liver Disease (MELD) -Score at the time of study inclusion were documented. Follow-up was done for 5 years. Patients who either received a liver transplantation or dropped out of the study during the observation period were censored. The five-year survival rate was analyzed with the Kaplan-Meier curve. RESULTS: Patients with abnormal PHES had a significantly higher mortality risk than patients with a normal PHES (P < 0.0001). Also patients with an abnormal RBANS result had a significantly higher risk to die than patients with a normal RBANS result (P = 0.018), but the difference was less significant compared to the PHES. Mortality risk did not significantly differ between patients with normal or abnormal CFF or ICT results. (CFF: P = 0.412; ICT: P = 0.202). In a binary logistic regression analysis the MELD-Score and diabetes were independent prognostic factors for mortality risk (MELD: P = 0.003; diabetes: P = 0.008). The MELD-Score turned out to have significant impact on the test results regarding the PHES (P < 0.0001), but not concerning the other tests (CFF: P = 0.903; RBANS: P = 0.065; ICT: P = 0.139). CONCLUSIONS: An abnormal PHES result is an indicator for an increased mortality risk, though less predictive than the MELD-Score.