Real-world performance of plasma p-tau181 in a heterogeneous memory clinic cohort.

OBJECTIVE: In light of clinical trials and disease-modifying therapies, an early identification of patients at-risk of developing Alzheimer's disease (AD) is crucial. Blood-based biomarkers have shown promising results regarding the in vivo detection of the earliest neuropathological changes in AD. Herein, we investigated the ability of plasma p-tau181 to act as a prescreening marker for amyloid positivity in a heterogeneous memory clinic-based cohort. METHODS: In this retrospective cross-sectional study, we included a total of 115 patients along the clinical AD continuum (mild cognitive impairment [MCI] due to AD, n = 62, probable AD dementia, n = 53). Based on their biomarker status, they were stratified into an amyloid-positive (Aß+, n = 88) or amyloid-negative cohort (Aß-, n = 27). Plasma and CSF p-tau181 concentrations were quantified using an ultrasensitive single-molecule array (SIMOA©). Furthermore, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong's test for correlated AUC curves. RESULTS: The median (interquartile range [IQR]) concentration of plasma p-tau181 was significantly higher in Aß+ patients (3.6 pg/mL [2.5-4.6]), compared with Aß- patients (1.7 pg/mL [1.2-1.9], p < 0.001). Regarding the distinction between Aß+ and Aß- patients and the prediction of amyloid positivity, a high diagnostic accuracy for plasma p-tau181 with an AUC of 0.89 (95% CI = 0.82-0.95) was calculated. Adding the risk factors, age and APOE4, to the model did not significantly improve its performance. INTERPRETATION: Our findings demonstrate that plasma p-tau181 could be a noninvasive and feasible prescreening marker for amyloid positivity in a heterogeneous clinical AD cohort and therefore help in identifying those who would benefit from more invasive assessment of amyloid pathology.

Serum Markers of Neurodegeneration Are Strongly Linked to Heart Failure Severity and Outcome.

BACKGROUND: Cognitive impairment is prevalent in patients with heart failure with reduced ejection fraction (HFrEF), affecting self-care and outcomes. Novel blood-based biomarkers have emerged as potential diagnostic tools for neurodegeneration. OBJECTIVES: This study aimed to assess neurodegeneration in HFrEF by measuring neurofilament light chain (NfL), total tau (t-tau), amyloid beta 40 (Aß40), and amyloid beta 42 (Aß42) in a large, well-characterized cohort. METHODS: The study included 470 patients with HFrEF from a biobank-linked prospective registry at the Medical University of Vienna. High-sensitivity single-molecule assays were used for measurement. Unplanned heart failure (HF) hospitalization and all-cause death were recorded as outcome parameters. RESULTS: All markers, but not the Aß42:Aß40 ratio, correlated with HF severity, ie, N-terminal pro-B-type natriuretic peptide and NYHA functional class, and comorbidity burden and were significantly associated with all-cause death and HF hospitalization (crude HR: all-cause death: NfL: 4.44 [95% CI: 3.02-6.53], t-tau: 5.04 [95% CI: 2.97-8.58], Aß40: 3.90 [95% CI: 2.27-6.72], and Aß42: 5.14 [95% CI: 2.84-9.32]; HF hospitalization: NfL: 2.48 [95% CI: 1.60-3.85], t-tau: 3.44 [95% CI: 1.95-6.04], Aß40: 3.13 [95% CI: 1.84-5.34], and Aß42: 3.48 [95% CI: 1.93-6.27]; P < 0.001 for all). These associations remained statistically significant after multivariate adjustment including N-terminal pro-B-type natriuretic peptide. The discriminatory accuracy of NfL in predicting all-cause mortality was comparable to the well-established risk marker N-terminal pro-B-type natriuretic peptide (C-index: 0.70 vs 0.72; P = 0.225), whereas the C-indices of t-tau, Aß40, Aß42, and the Aß42:Aß40 ratio were significantly lower (P < 0.05 for all). CONCLUSIONS: Neurodegeneration is directly interwoven with the progression of HF. Biomarkers of neurodegeneration, particularly NfL, may help identify patients potentially profiting from a comprehensive neurological work-up. Further research is necessary to test whether early diagnosis or optimized HFrEF treatment can preserve cognitive function.

Comprehensive genetic screening of early-onset dementia patients in an Austrian cohort-suggesting new disease-contributing genes.

Early-onset dementia (EOD), with symptom onset before age 65, has a strong genetic burden. Due to genetic and clinical overlaps between different types of dementia, whole-exome sequencing (WES) has emerged as an appropriate screening method for diagnostic testing and novel gene-finding approaches. We performed WES and C9orf72 repeat testing in 60 well-defined Austrian EOD patients. Seven patients (12%) carried likely disease-causing variants in monogenic genes, PSEN1, MAPT, APP, and GRN. Five patients (8%) were APOE4 homozygote carriers. Definite and possible risk variants were detected in the genes TREM2, SORL1, ABCA7 and TBK1. In an explorative approach, we cross-checked rare gene variants in our cohort with a curated neurodegeneration candidate gene list and identified DCTN1, MAPK8IP3, LRRK2, VPS13C and BACE1 as promising candidate genes. Conclusively, 12 cases (20%) carried variants relevant to patient counseling, comparable to previously reported studies, and can thus be considered genetically resolved. Reduced penetrance, oligogenic inheritance and not yet identified high-risk genes might explain the high number of unresolved cases. To address this issue, we provide complete genetic and phenotypic information (uploaded to the European Genome-phenome Archive), enabling other researchers to cross-check variants. Thereby, we hope to increase the chance of independently finding the same gene/variant-hit in other well-defined EOD patient cohorts, thus confirming new genetic risk variants or variant combinations.

Analysis of co-medication in people with dementia.

BACKGROUND AND PURPOSE: Dementia prevalence is increasing, with numbers projected to double by 2050. Risk factors for its development include age and cardiovascular comorbidities, which are found more often in patients with dementia and should be treated properly to improve outcomes. In this case-control study, we analysed a large population-based prescription database to explore the patterns of co-medication in patients with dementia. METHODS: Prescription claims covering >99% of the Austrian population from 2005 to 2016 were obtained. Patients who were treated with an approved antidementia drug (ADD) were included and co-medication exposure was recorded. A group of people not taking ADDs was matched for age, sex and follow-up duration as a control. RESULTS: We included 70,799 patients on ADDs who were exposed to a mean of 5.3 co-medications while control patients were treated with a total of 5.2 co-medications (p < 0.001). We found that patients on ADDs received less somatic (4.1 vs. 4.5) but more psychiatric medication (1.1 vs. 0.6; p < 0.001 for both). Patients on ADDs were less likely to be treated for pain, cardiovascular conditions or hyperlipidemia. More than 50% of patients on ADDs were treated with antidepressants or antipsychotics. Greater number of co-medications was associated with markers of more intensive antidementia treatment. CONCLUSION: Patients on ADDs received more medications overall but were less frequently treated for somatic conditions known to be more prevalent in this group. Together, our data suggest that management of comorbidities in dementia could be improved to optimize outcome and quality of life.

Does [99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) soft tissue uptake allow the identification of patients with the diagnosis of cardiac transthyretin-related (ATTR) amyloidosis with higher risk for polyneuropathy?

BACKGROUND: With the introduction of several drugs for the therapy of transthyretin-related amyloidosis (ATTR) which slow down the disease, early detection of polyneuropathy (PNP) is becoming increasingly of interest. [99mTc]-3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD) bone scintigraphy, which is used for the diagnosis of cardiac (c)ATTR, can possibly make an important contribution in the identification of patients at risk for PNP. METHODS: Fifty patients with cATTR, who underwent both planar whole-body DPD scintigraphy and nerve conduction studies (NCS) were retrospectively evaluated. A subgroup of 22 patients also underwent quantitative SPECT/CT of the thorax from which Standardized Uptake Values (SUVpeak) in the subcutaneous fat tissue of the left axillar region were evaluated. RESULTS: The Perugini score was significantly increased in patients with cATTR and additional diagnosis of PNP compared to patients without (2.51 ± 0.51 vs 2.13 ± 0.52; P = 0.03). Quantitative SPECT/CT revealed that DPD uptake in the subcutaneous fat of the left axillar region was significantly increased in cATTR patients with compared to patients without (1.36 ± 0.60 vs 0.74 ± 0.52; P = 0.04). CONCLUSION: This study suggests that DPD bone scintigraphy is a useful tool for identification of patients with cATTR and a risk for PNP due to increased DPD soft tissue uptake.

C9orf72 repeat length might influence clinical sub-phenotypes in dementia patients.

BACKGROUND: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. METHODS: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. RESULTS: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). CONCLUSIONS: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.

Real-world applicability of glial fibrillary acidic protein and neurofilament light chain in Alzheimer's disease.

Background: Blood-based biomarkers may add a great benefit in detecting the earliest neuropathological changes in patients with Alzheimer's disease (AD). We examined the utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) regarding clinical diagnosis and differentiation between amyloid positive and negative patients. To evaluate the practical application of these biomarkers in a routine clinical setting, we conducted this study in a heterogeneous memory-clinic population. Methods: We included 167 patients in this retrospective cross-sectional study, 123 patients with an objective cognitive decline [mild cognitive impairment (MCI) due to AD, n = 63, and AD-dementia, n = 60] and 44 age-matched healthy controls (HC). Cerebrospinal fluid (CSF) and plasma concentrations of NfL and GFAP were measured with single molecule array (SIMOA®) technology using the Neurology 2-Plex B kit from Quanterix. To assess the discriminatory potential of different biomarkers, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared. Results: We constructed a panel combining plasma NfL and GFAP with known AD risk factors (Combination panel: age+sex+APOE4+GFAP+NfL). With an AUC of 91.6% (95%CI = 0.85-0.98) for HC vs. AD and 81.7% (95%CI = 0.73-0.90) for HC vs. MCI as well as an AUC of 87.5% (95%CI = 0.73-0.96) in terms of predicting amyloid positivity, this panel showed a promising discriminatory power to differentiate these populations. Conclusion: The combination of plasma GFAP and NfL with well-established risk factors discerns amyloid positive from negative patients and could potentially be applied to identify patients who would benefit from a more invasive assessment of amyloid pathology. In the future, improved prediction of amyloid positivity with a noninvasive test may decrease the number and costs of a more invasive or expensive diagnostic approach.

Clinical applicability of quantitative atrophy measures on MRI in patients suspected of Alzheimer's disease.

OBJECTIVES: Neurodegeneration in suspected Alzheimer's disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics. MATERIALS AND METHODS: We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's dementia (AD). RESULTS: Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94-98% of ADC, but only 68-85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts. CONCLUSION: In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice. In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales. KEY POINTS: • In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer's disease groups. • Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases. • Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer's disease-specific outcomes.

Reduction of physical activity during the COVID-19 pandemic is related to increased neuropsychiatric symptoms in memory clinic patients.

The COVID-19 pandemic led to unprecedented restrictions on social contacts and mobility. Memory clinic patients were disproportionately affected when care was disrupted and routines were abruptly changed. This trial was designed as a pragmatic, prospective, observational study to evaluate the effects of lockdown on memory clinic patients. Outpatients were included when they returned in May to July 2020 for their first follow-up after the lockdown. Indicators of lockdown intensity and its effect on patients were recorded, patients and caregivers were interviewed, and neuropsychological tests were performed. We included 72 patients, most of them suffering from Alzheimer's dementia or mild cognitive impairment. The median time of isolation was 8 weeks and social contacts were significantly reduced from five to two per week (p<0.001). Light physical activity was significantly reduced (3.8 hours to 3 hours, p=0.016) during the lockdown, and this reduction was significantly correlated with higher scores on the Neuropsychiatric Inventory score (R -0.43, p>0.001). Fears regarding the pandemic were common and mostly related to the patients' health. Lockdown restrictions reduced physical activity in memory clinic patients which was associated with increased neuropsychiatric symptoms. Future restrictions should aim to mitigate the impacts on this vulnerable population.

Prediction of Neurological Recovery After Cardiac Arrest Using Neurofilament Light Chain is Improved by a Proteomics-Based Multimarker Panel.

BACKGROUND: Continuous advances in resuscitation care have increased survival, but the rate of favorable neurological outcome remains low. We have shown the usefulness of proteomics in identifying novel biomarkers to predict neurological outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was to assess the predictive value of NfL in comparison with and in addition to our established model. METHODS: NfL was measured in plasma samples drawn at 48 h after cardiac arrest using single-molecule assays. Neurological function was recorded on the cerebral performance category (CPC) scale at discharge from the intensive care unit and after 6 months. The ability to predict a dichotomized outcome (CPC 1-2 vs. 3-5) was assessed with receiver operating characteristic (ROC) curves. RESULTS: Seventy patients were included in this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1-2), compared with 49 (70%) with an unfavorable outcome (CPC 3-5) at discharge. NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p < 0.001). The addition of NfL to the existing model improved it significantly (Wald test, p < 0.001), and the combination of NfL with a multimarker model showed high areas under the ROC curve (89.7% [95% confidence interval 81.7-97.7] at discharge and 93.7% [88.2-99.2] at 6 months) that were significantly greater than each model alone. CONCLUSIONS: The combination of NfL with other plasma and clinical markers is superior to that of either model alone and achieves high areas under the ROC curve in this relatively small sample.

Catalase Predicts In-Hospital Mortality after Out-of-Hospital Cardiac Arrest.

The generation of harmful reactive oxygen species (ROS), including hydrogen peroxide, in out-of-hospital cardiac arrest (OHCA) survivors causes systemic ischemia/reperfusion injury that may lead to multiple organ dysfunction and mortality. We hypothesized that the antioxidant enzyme catalase may attenuate these pathophysiological processes after cardiac arrest. Therefore, we aimed to analyze the predictive value of catalase levels for mortality in OHCA survivors. In a prospective, single-center study, catalase levels were determined in OHCA survivors 48 h after the return of spontaneous circulation. Thirty-day mortality was defined as the study end point. A total of 96 OHCA survivors were enrolled, of whom 26% (n = 25) died within the first 30 days after OHCA. The median plasma intensity levels (log2) of catalase were 8.25 (IQR 7.64-8.81). Plasma levels of catalase were found to be associated with mortality, with an adjusted HR of 2.13 (95% CI 1.07-4.23, p = 0.032). A Kaplan-Meier analysis showed a significant increase in 30-day mortality in patients with high catalase plasma levels compared to patients with low catalase levels (p = 0.012). High plasma levels of catalase are a strong and independent predictor for 30-day mortality in OHCA survivors. This indicates that ROS-dependent tissue damage is playing a crucial role in fatal outcomes of post-cardiac syndrome patients.

Myocardial Angiotensin Metabolism in End-Stage Heart Failure.

BACKGROUND: The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy. OBJECTIVES: This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy. METHODS: Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients. RESULTS: AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity. CONCLUSIONS: The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions.

Performance of the recommended ESC/EASD cardiovascular risk stratification model in comparison to SCORE and NT-proBNP as a single biomarker for risk prediction in type 2 diabetes mellitus.

BACKGROUND: Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups. CONCLUSION: The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.

Gastric regurgitation predicts neurological outcome in out-of-hospital cardiac arrest survivors.

Hypoxic-ischemic brain injury can affect and disturb the autonomous nervous system (ANS), which regulates various visceral systems including the gastro-intestinal and emetic system. The present study aimed to analyze the predictive value of gastric regurgitation (GReg) for neurological outcome in out-of-hospital cardiac arrest (OHCA) survivors. In this prospective, single-center study, 79 OHCA survivors treated at a university-affiliated tertiary care centre were included and GReg was measured at the first day after successful cardiopulmonary resuscitation. Neurological outcome was assessed by the Cerebral Performance Categories score at discharge. Seventy-six percent of the study population had a poor neurological outcome. GReg was found to be associated with poor neurological outcome with an adjusted OR of 5.37 (95% CI 1.41-20.46; p = 0.01). The area under the ROC curve for GReg was 0.69 (95% CI, 0.56-0.81) for poor neurological outcome. GReg on the first day after OHCA is an early, strong and independent predictor for poor neurological outcome in comatose OHCA survivors. These results are particularly compelling because measurement of GReg is inexpensive and routinely performed in critical care units.

Serum neurofilament light chain withstands delayed freezing and repeated thawing.

Serum neurofilament light chain (sNfL) and its ability to expose axonal damage in neurologic disorders have solicited a considerable amount of attention in blood biomarker research. Hence, with the proliferation of high-throughput assay technology, there is an imminent need to study the pre-analytical stability of this biomarker. We recruited 20 patients with common neurological diagnoses and 10 controls (i.e. patients without structural neurological disease). We investigated whether a variation in pre-analytical variables (delayed freezing up to 24 h and repeated thawing/freezing for up to three cycles) affects the measured sNfL concentrations using state of the art Simoa technology. Advanced statistical methods were applied to expose any relevant changes in sNfL concentration due to different storing and processing conditions. We found that sNfL concentrations remained stable when samples were frozen within 24 h (mean absolute difference 0.2 pg/ml; intraindividual variation below 0.1%). Repeated thawing and re-freezing up to three times did not change measured sNfL concentration significantly, either (mean absolute difference 0.7 pg/ml; intraindividual variation below 0.2%). We conclude that the soluble sNfL concentration is unaffected at 4-8 °C when samples are frozen within 24 h and single aliquots can be used up to three times. These observations should be considered for planning future studies.

Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots.

BACKGROUND: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. METHODS: Within the period of 2014-2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. RESULTS: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. CONCLUSIONS: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.

Prescription patterns of antidementives in a high income country: A pharmacoepidemiologic study.

INTRODUCTION: Dementia is a leading and growing cause of morbidity and mortality. The aim of this study was to investigate real-world prescription patterns of antidementive medication in one of the largest cohorts published thus far to optimize use in this growing population. METHODS: Prescription claims from 2005 to 2016 were provided by Austrian sickness funds, covering 98% of the population of Austria. Patients treated with at least one of the four approved antidementive drugs (ADDs) were included. Prescription prevalence was calculated for 2014 and 2015, and prescription patterns were traced on an individual level during the entire study period. RESULTS: A total of 127,896 patients were treated with an ADD between 2005 and 2016. The prevalence was 0.93% in 2014 and 1% in 2015. The median age at initiation of treatment was 82.3 years, and 65% were female. Initial therapy was a cholinesterase inhibitor (ChEI) in 80% and memantine in 20%. The median duration of therapy was 13.3 months. Eighteen percent of patients switched medication: two thirds to receive memantine, and one third to a different cholinesterase inhibitor. More than 26% discontinued treatment early. CONCLUSION: We find that discontinuation of ADDs is more frequent than switching; memantine is a common starting drug and age at the start of treatment is rather high in this population. Interpretation should be cautious, but the data may suggest that treatment guidelines are followed inconsistently. Appropriate provision of the available options should be emphasized to optimize cognitive survival, comorbidity, quality of life, and health care expenditures.

Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients-a randomized clinical trial.

BACKGROUND: Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients. METHODS: Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 µg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated. FINDINGS: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 µg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group. INTERPRETATION: The IC43 100 µg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality. TRIAL REGISTRATION: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.