Hemoglobin A1c Serum Level Predicts 5-year Mortality in Patients with Cognitive Impairment.

Background: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) may occur as preclinical stages of Alzheimer's disease (AD), ultimately leading to dementia. Glycated hemoglobin A1c (HbA1c) is a diagnostic marker for diabetes mellitus and indicates mortality risk. Objectives: This university-based, exploratory retrospective study examined the impact of HbA1c serum level on 5-year mortality among individuals with cognitive impairment. Methods: Included were 1076 subjects aged at least 50 years who visited the Memory Outpatient Clinic of the Medical University of Vienna due to memory problems. Participants were diagnosed with SCD, MCI, or AD subsequent to neurological examination, standard laboratory blood tests, and neuropsychological testing. Survival was compared between diagnostic subgroups and with respect to HbA1c categories using log-rank tests based on Kaplan-Meier functions. The Neuropsychological Test Battery Vienna (NTBV) was dimensionally reduced, and a principal component analysis (PCA) was performed to further analyze results. Corresponding factor scores, HbA1c values, and baseline characteristics were included in Cox proportional hazards models to assess 5-year mortality risk. Results: During the observation period, 323 patients (30%) died at a mean age comparable between diagnostic subgroups (SCD 84.2 ± 10.1, MCI 81.2 ± 8.3, AD 82.2 ± 7.4 years). Individuals with normal serum HbA1c levels had significant advantages in survival within the MCI (12.9 ± .3 vs. 10.0 ± .8 years) and the AD subgroups (8.2 ± .4 vs. 5.5 ± .6 years), and metric HbA1c predicted 5-year mortality (HR 1.24). Conclusion: This study demonstrates an association between abnormal HbA1c serum levels and increased mortality.

Homocysteine - A predictor for five year-mortality in patients with subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia.

BACKGROUND: Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) are preclinical stages of Alzheimer's Disease (AD), which is the most common entity of dementia. Homocysteine is an amino acid in the methionine cycle, and many studies revealed a significant association between elevated homocysteine serum levels and the progression of dementia. The primary objective of this retrospective study was to investigate whether elevated homocysteine serum levels could be associated with mortality and neuropsychological test results in individuals suffering from SCD, MCI or AD. METHODS: This study is a single-center explorative retrospective data analysis with 976 data protocols from the Memory Outpatient's Clinic of the Medical University of Vienna included. All patients underwent a neurological examination, a laboratory blood test, and neuropsychological testing to establish a diagnosis of either SCD, MCI, or AD. Data was evaluated by Kaplan-Meier functions, factor analysis, and binary logistic regression models. RESULTS: Patients with AD showed significantly higher mean homocysteine levels (SCD 12.15 ± 4.71, MCI 12.80 ± 4.81, AD 15.0 ± 6.44 µmol/L) compared to those with SCD and MCI (p ≤ .001). The mean age of patients with AD (75.2 ± 7.8) was significantly older at the time of testing than of patients with MCI (69.1 ± 9.6) or SCD (66.8 ± 9.3). Since homocysteine levels increase with age, this could be a possible explanation for the higher levels of AD patients. The age at death did not differ significantly between all diagnostic subgroups, resulting in the shortest survival times for AD patients. Homocysteine levels were negatively associated with in Mini-Mental State Examination (MMSE) and Neuropsyhcological Test Battery Vienna (NTBV) factors F1-F4 (F1 = attention, F2 = memory, F3 = executive functions, F4 = naming/verbal comprehension). Moreover, higher homocysteine levels significantly predicted shorter five-year survival in the logistic regression models, even after adjusting for age, diagnostic subgroups, sex, years of education and results of neuropsychological testing. CONCLUSION: The results of this study suggest that homocysteine levels are independently associated with impaired cognitive function and increased five-year mortality.

Arterial stiffness in acute COVID-19 and potential associations with clinical outcome.

BACKGROUND: Coronavirus disease 2019 (COVID-19) interferes with the vascular endothelium. It is not known whether COVID-19 additionally affects arterial stiffness. METHODS: This case-control study compared brachial-ankle pulse wave (baPWV) and carotid-femoral pulse wave velocities (cfPWV) of acutely ill patients with and without COVID-19. RESULTS: Twenty-two COVID-19 patients (50% females, 77 [67-84] years) were compared with 22 age- and sex-matched controls. In COVID-19 patients, baPWV (19.9 [18.4-21.0] vs. 16.0 [14.2-20.4], P = 0.02) and cfPWV (14.3 [13.4-16.0] vs. 11.0 [9.5-14.6], P = 0.01) were higher than in the controls. In multiple regression analysis, COVID-19 was independently associated with higher cfPWV (ß = 3.164, P = 0.004) and baPWV (ß = 3.532, P = 0.003). PWV values were higher in nonsurvivors. In survivors, PWV correlated with length of hospital stay. CONCLUSION: COVID-19 appears to be related to an enhanced PWV reflecting an increase in arterial stiffness. Higher PWV might be related to an increased length of hospital stay and mortality.

Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"

High intensity endurance training is associated with better quality of life, but not with improved cognitive functions in elderly marathon runners.

Impairment of cognitive functions in advanced age leads to a reduced quality of life and impaired ability to perform everyday tasks. The positive impact of physical exercise on the quality of life and well-being, also at a later age, is well established. However, the effect of endurance exercises, including long distance running and cycling, on cognitive function and mental health within the elderly population has still to be elucidated. To this end, elderly active marathoners (N = 50) aged over 60 years and non-athlete controls (N = 49) were followed for four years. Cognitive function was assessed using the CERAD test battery. In addition, the Short Form Health Survey (SF-36) was applied to assess self-reported physical, mental, and emotional health. Except for age, sex and education-corrected z-values of the test "Word list recall", with marathon runners showing a decline compared to an improvement in controls (p < 0.05), there was no statistically significant difference in time trend between groups. In contrast, concerning self-reported health, scores in all eight domains of the SF-36 remained stable over time and, in nearly all of them, marathon runners showed higher self-reported health than controls. The results indicated that extensive endurance exercise is associated with improved subjective health but does not lead to better scores in cognitive performance tests in elderly persons.

A novel PCR-based point-of-care method facilitates rapid, efficient, and sensitive diagnosis of influenza virus infection.

OBJECTIVE: The aim of this single-centre study was the comparative analysis of the GeneXpert (Cepheid Inc.) and the LIAT (Roche) system for the rapid polymerase chain reaction (PCR)-based detection of influenza A (IA) and influenza B (IB) viruses. PATIENTS AND METHODS: During the 2017-2018 flu season, 651 prospectively collected samples (throat and nasal swabs) of patients with symptoms of influenza-like illness or acute respiratory infection were tested for the presence of IA and IB viruses using the GeneXpert and LIAT systems. To evaluate the usefulness for near-patient testing, a LIAT system was installed at the Department of Emergency Medicine, and sample testing was performed on site. Reference testing of all samples was performed with the Xpert Flu assay and for 313 samples in addition with the Xpert Xpress Flu/RSV (respiratory syncytial virus) assay at the central laboratory. Analysis of all samples was carried out within 24 hr after collection. RESULTS: Overall, 267 of the 651 samples analysed were positive for influenza viruses in at least one of the three assays investigated (IA, 88; IB, 179). The overall rates of agreement between the LIAT assay and the Xpert Flu assay was 96.0% for the detection of IA and IB viruses. The sensitivity and specificity of the LIAT assay compared to the Xpert Flu assay for the detection of IA was 98.80% (95% confidence interval (CI) 93.47-99.97%) and 99.12% (95% CI, 97.96% to 99.71%) and for the detection of IB 98.76% (95% CI 95.58-99.85%), and 96.33% (95% CI 94.26-97.81%), respectively. The LIAT assay showed a statistically significant higher detection rate of IB virus than the Xpert Flu assay (p <0.01). No significant difference was found between the detection rate of the LIAT assay and the Xpert Xpress Flu/RSV assay. The mean time to the availability of a definite test result was significantly shorter with the on-site LIAT system than the GeneXpert system (mean 59 min saving time; p <0.01). CONCLUSION: The LIAT system represents a robust and highly sensitive point-of-care device for the rapid PCR-based detection of influenza A and influenza B viruses.

Functional Fc gamma receptor gene polymorphisms and donor-specific antibody-triggered microcirculation inflammation.

Fc-dependent effector mechanisms may contribute to antibody-mediated rejection (ABMR), and distinct gene polymorphisms modifying the function of Fc gamma receptors (FcγRs) may influence the capability of donor-specific antibodies (DSAs) to trigger inflammation. To evaluate the relevance of functional FcγR variants in late ABMR, 85 DSA-positive kidney allograft recipients, who were recruited upon antibody screening of 741 prevalent patients, were genotyped for polymorphisms in FcγRIIA (FCGR2A-H/R131 ; rs1801274), FcγRIIIA (FCGR3A-V/F158 ; rs396991), and FcγRIIIB (FCGR3B-neutrophil antigen 1 ([NA1]/NA2; rs35139848). Individuals with high-affinity FCGR3A-V158 alleles (V/V158 or V/F158 ) showed a higher rate (and extent) of peritubular capillaritis (ptc) in protocol biopsies than homozygous carriers of the lower-affinity allele (ptc score ≥1: 53.6% vs 25.9%; P = .018). Associations were independent of C1q-binding to DSA or capillary C4d. In parallel, there was a trend toward increased macrophage- and injury-repair response-associated transcript subsets. Kidney function over 24 months, however, was not different. In support of a functional role of FcγRIIIA polymorphism, NK92 cells expressing FCGR3A-V158 produced >2 times as much interferon gamma upon incubation with HLA antibody-coated cells as those expressing FCGR3A-F158 . FcγRIIA and FcγRIIIB polymorphisms were not associated with allograft morphology. Our data suggest that the presence of high-affinity FcγRIIIA variants may favor DSA-triggered microcirculation inflammation.

High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: Results from the Vienna Bleeding Biobank (VIBB).

INTRODUCTION: Data on clinical characteristics and the prevalence of underlying coagulopathies in patients with mild-to-moderate bleeding disorders (MBDs) are scarce. AIM: We established the Vienna Bleeding Biobank (VIBB) to characterize and thoroughly investigate Austrian patients with MBDs. RESULTS: Four hundred eighteen patients (female = 345, 82.5%) were included. A platelet function defect (PFD) was diagnosed in 26 (6.2%) and a possible PFD in 30 (7.2%) patients. Eight patients (1.9%) were diagnosed with von Willebrand disease (VWD) (type 1 n = 6; type 2 n = 2), and 29 patients had low VWF (30-50 IU/dL). Deficiencies in factor VIII, IX, XI or XIII were found in 11 (2.6%), 3 (0.7%), 3 (0.7%) and 1 patient(s), 2 patients had dysfibrinogenaemia, and further 2 had possible PFD and FXI deficiency. Probable causal mutations were detected in 8 of 11 patients with FVIII deficiency, 2 of 3 patients with FIX deficiency and 2 of 8 patients with VWD. Three hundred three patients (72.5%) had normal results in the coagulation assays and were categorized as patients with bleeding of unknown cause (BUC). The bleeding score did not differ between patients with and without established diagnosis. A diagnosis of a bleeding disorder was more frequently made in men than in women (49.3% vs 22.9%). Male sex (OR 3.55, 95% CI: 2.02-6.22; P < .001) and blood group 0 (OR 1.86, 95% CI: 1.17-2.94; P = .008) were independently associated with diagnosis of a bleeding disorder. CONCLUSION: The high rate of patients with BUC despite in-depth haemostatic assessment underlines the incompleteness of available routine laboratory tests. Males with MBDs were more likely to be diagnosed with an established bleeding disorder than females.

Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.

ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

Plasma clot properties in patients with a mild-to-moderate bleeding tendency of unknown cause.

In a large proportion of patients with mild bleeding disorders (MBDs) no diagnosis can be established by routine coagulation tests. We investigated whether alterations in plasma clot properties account for MBDs of unknown cause. Ninety-five patients with MBDs of unknown origin and 98 age- and sex-matched healthy controls were investigated. Furthermore, data of 25 patients with a deficiency of factor VIII were analyzed. Plasma clot characteristics in the absence and presence of recombinant tissue plasminogen activator (rtPA) represented by the lag phase, rate of protofibril formation (Vmax), fibrin structure (ΔAbs), time to peak (TTP), half lysis time (t50 and area under the curve (AUC) were measured in turbidometric clot formation and lysis assays. In the fibrinolysis assay, Vmax was lower in patients than in healthy controls. No differences in the other parameters of clot formation and lysis were detected between the groups. There was no clear association of plasma clot properties with the clinical severity of bleeding in patients with MBDs. Patients with known decreased factor VIII levels also showed a lower Vmax. Fibrinogen levels were positively associated with each of the assessed parameters in both groups, with the strongest association with ΔAbs, indicating altered fibrin structure. Factor VIII activity correlated with altered clot characteristics similar to fibrinogen, especially in patients, with the strongest positive correlation to Vmax. This cohort of patients with MBDs of unknown origin showed a lower rate of fibrin formation in the fibrinolysis assay, but otherwise similar plasma clot properties compared to healthy controls.

Azithromycin suppresses CD4(+) T-cell activation by direct modulation of mTOR activity.

Advanced macrolides, such as azithromycin (AZM) or clarithromycin (CLM), are antibiotics with immunomodulatory properties. Here we have sought to evaluate their in vitro influence on the activation of CD4(+) T-cells. Isolated CD4(+) T-cells were stimulated with agonistic anti-CD3/anti-CD28 monoclonal antibodies in the presence of 0.6 mg/L, 2.5 mg/L, 10 mg/L or 40 mg/L AZM or CLM. Cell proliferation, cytokine level in supernatants and cell viability was assessed. Intracellular signaling pathways were evaluated using reporter cell lines, FACS analysis, immunoblotting and in vitro kinase assays. AZM inhibited cell proliferation rate and cytokine secretion of CD4(+) T-cells in a dose-dependent manner. Similarly, high concentrations of CLM (40 mg/L) also suppressed these T-cell functions. Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein, a downstream target of mTOR. This effect was also observed at 40 mg/L CLM. In vitro kinase studies using recombinant mTOR showed that AZM inhibited mTOR activity. In contrast to rapamycin, this inhibition was independent of FKBP12. We show for the first time that AZM and to a lesser extent CLM act as immunosuppressive agents on CD4(+) T-cells by inhibiting mTOR activity. Our results might have implications for the clinical use of macrolides.

Myeloperoxidase levels predict executive function.

The main purpose of the study was to investigate whether baseline myeloperoxidase (MPO) levels are associated with executive cognitive function in individuals with high physical activity. Baseline serum MPO levels of 56 elderly marathon runners and 58 controls were assessed by ELISA. Standardized tests were applied to survey domain-specific cognitive functions. Changes in brain morphology were visualized by magnetic resonance imaging (MRI). High baseline serum MPO levels correlated with worse outcome in tests assessing executive cognitive function in athletes but not in the control group (NAI maze test p<0.05, Trail Making Test ratio p<0.01). In control participants, subcortical white matter hyperintensities were associated with higher scores on the Geriatric Depression Scale (p<0.05), whereas athletes seem to be protected from this effect. During strenuous exercising, MPO as well as its educts may be elevated due to increased oxygen intake and excretion of pro-inflammatory mediators inducing host tissue damage via oxidative stress. This outweighs the potential benefits of physical activity on cognitive function.

Sex differences in the association between albumin and all-cause and vascular mortality.

BACKGROUND: Low serum albumin levels are associated with cardiovascular disease and mortality risk. This study evaluated the predictive value of low serum albumin for all-cause-mortality in a large Viennese patient cohort and investigated sex differences in the association between serum albumin and mortality. MATERIALS AND METHODS: Serum albumin concentrations of 285 930 patients, who attended the General Hospital Vienna between 1992 and 2002, were evaluated and linked with the Austrian Death Registry. The median observation period was 7.4 +/- 4.0 years and the death rate was 16.8%. For Cox regression analysis, albumin levels were divided into deciles, the highest category served as reference value. To analyse associations between albumin and mortality independent of liver function, results were adjusted for cholinesterase, which indicates protein synthesis capacity of the liver. RESULTS: Hazard ratios for all-cause-mortality increased linearly with decreasing albumin levels from 1.05 in the 9th to 2.98 in the 1st decile. Adjusted for cholinesterase, the relative risk for mortality was still 1.91 in the lowest category. Compared with women, men had an average 50% increased risk of death in almost every decile, adjusting for cholinesterase reduced the sex difference to a 10-20% higher mortality risk for men. In critically ill patients, hazard ratios for all-cause-mortality ranged from 4.5 in the 9th decile to 9.5 in the lowest albumin category. CONCLUSION: This study demonstrates a strong inverse association between serum albumin and mortality in a large patient cohort. The predictive value of low albumin was remarkably higher in men than in women.