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An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau–positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast+ individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Pfizer Global Medical Grant Background Amyloid transthyretin cardiomyopathy (ATTR-CM) is a progressive infiltrative cardiomyopathy caused by extracellular deposition of amyloid fibrils. The disease is characterized by congestive heart failure, conduction abnormalities and arrhythmias. Due to the limited overall prognosis, ICDs were rarely indicated in ATTR-CM. However, with the development of new targeted therapies, the role of ICD therapy for ATTR-CM should be reevaluated. Hence, there is an urgent and unmet need to identify patients at high risk for ventricular tachycardias who might possibly benefit from ICD therapy. Methods Between 2020 and 2022, 120 patients were diagnosed with ATTR-CM in a tertiary referral center. Of those, 63 were prospectively evaluated for the presence of ventricular arrhythmias using 24 hours Holter-ECG. Ventricular arrhythmias were further characterized as sustained (sVT) and non-sustained ventricular tachycardias (nsVT). Results In our cohort of unselected ATTR-CMP patients the prevalence of ventricular tachycardias was high with 47.6 % (n= 30/63). Of those, the majority were non-sustained VTs (84%) and the minority sustained VT (16%). Patients with ventricular tachycardias showed significantly more severe left ventricular (LV) hypertrophy, reduced LV ejection fraction (LV-EF) and larger left atrial volumes as well as a trend towards smaller LV cavities (table 1). Interestingly, no significant differences in prevalence of coronary artery disease or cardiac markers such as NTproBNP and troponin were seen between patients with and without ventricular tachycardias (table 1). Furthermore, we evaluated the multivariable predictive performance for discriminating between patients with and without ventricular tachycardias using two backward variable selection procedures (model 1 p-value based and model 2 Akaike information criterion (AIC) based). In the first model, LVEF (OR = 0.865 [0.776;0.963], p=0.008), LVEED (0.837 [0.708;0.991], p=0.039), and LV mass indexed by BSA (1.028[1.003;1.055], p=0.031) remained independent predictors of occurrence of ventricular arrhythmias, while in the second model sodium concentration (1.287 [0.929;1.783], p=0.129) and betablocker medication (5.078, [0.819;31.477], p=0.081) also were retained. Comparing the area under the Receiver Operating-Characteristic (AUROC) we observed no significant difference between both models (AUROC: 0.846 [0.711;0.937] vs. 0.870 [0.737;0.951], p=0.57, figure 1). Conclusion The prevalence of ventricular tachycardia in ATTR-CM is high. Patients with ventricular tachycardia show advanced stage of left ventricular disease, with LVEDD, LV-EF and LV mass indexed by BSA being predictors of ventricular tachycardias in two multivariable predictive models. Further studies validating the predictive value of those variables are needed, including the assessment of nsVT and sVT in predicting sudden cardiac death, possibly allowing the use as a risk score for ventricular arrhythmias.

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Deutsche Stiftung für Herzforschung research grant Background Electromagnetic interference (EMI) poses a risk to patients with cardiac implantable devices (CIEDs) and can result in device malfunction including pacing inhibition or inappropriate shock therapy. Such EMI sources are ubiquitous in the modern world. Battery electric vehicles (BEVs) represent such a potential EMI source. We have previously investigated the EMI risk of driving eCars and found that the largest electromagnetic field is located along the charging cable. New high power chargers deliver higher currents (facilitating rapid recharging), potentially associated with greater electromagnetic fields and higher risk for clinically relevant EMI. This present study aims to evaluate this EMI-risk to address this clinically important question. Methods A consecutive group of 130 patients with a range of CIEDs were recruited to participate. After a complete device interrogation each had their device programmed to optimise EMI detection with ensured ventricular pacing and ICD therapies were disabled. Under continuous 6-lead ECG monitoring each patient then plugged in and charged four different BEVs (Porsche Taycan Turbo, VW ID3 pro, Tesla Model 3 and Audi e-tron 55 Quattro) in addition to a ‘dummy’ eCar (which permitted the maximal charging power flow of 350kW) with the charging cable placed directly over the device. During charging both the magnetic field and electric field was measured. A further complete device interrogation was then performed to evaluate for spontaneous reprogramming and tachycardia detection. Results In total 561 separate charging events were performed by 130 patients with the four eCars and one dummy car. The maximal magnetic field along the charging cable was 38.65µT and at the charging column was 77.9µT. There were no incidences of EMI, specifically there was no pacing inhibition due to oversensing, no spontaneous reprogramming and no tachycardia over-detection. This results in a patient-based risk of 0% (95% CI; 0% - 2.8%) and a charging event-based risk of 0% (95% CI; 0% - 0.6%). Conclusions and Discussion We found that there was no EMI induced during the use of high power charger technology for BEV despite device programming and charging cable placement being optimised for a worst-case scenario and maximising the chance of clinical EMI. Our study suggests that there is a very low risk, if any, posed by BEVs and the new high power chargers. CIED patients should reassured that their use is safe. We would still recommend not to place the charging cable directly above the CIED during use to maximise safety of high power charging.

Funding Acknowledgements Type of funding sources: None. Aims Pulse field ablation (PFA) is a novel catheter ablation technology with safety benefits due to its tissue selectivity. The risk of physical damage or electromagnetic interference (EMI) of PFA with cardiac implantable electronic devices (CIEDs) is unknown. The aim of our study was to assess the risk of PFA for CIEDs. Methods PFA lesions (45 per CIED) were applied to CIEDs ( Results In total, 44 CIEDs were tested (16 pacemaker, 21 ICDs, 7 CRT-P/D) with 1,980 PFA applications. There was no change in device settings, functionality, electrical parameters and there was no visible damage to the CIEDs or leads. The risk on a device-based analysis is 0/44 (95% CI 0%-8%) and on a PFA pulse-based analysis is 0/1,980 (95% CI 0%-0.2%). Clinically relevant EMI appeared with oversensing and pacing inhibition, but not tachycardia detection. Conclusions Bipolar PFA appears safe and does not result in damage to CIEDs or leads. Clinically relevant EMI does occur, but appropriate peri-procedural programming may mitigate this. In-vivo studies are needed to confirm our findings.

Psychanalyse des nevroses de guerre, apres la guerre du Viet-Nam. Une histoire de cas illustre le propos

Neuronal dysfunction and cognitive deterioration in Alzheimer’s disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we develop and validate a personalized brain activity model that incorporates functional MRI, amyloid-β (Aβ) and tau-PET from AD-related participants (N=132). By simulating electrophysiological activity mediated by toxic protein deposition, this integrative approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

ImportanceThe recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.ObjectiveTo determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET).Design, Setting, and ParticipantsThis was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded.ExposuresAmyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay.Main Outcomes and MeasuresAssociations between p-tau biomarkers with amyloid PET and tau PET.ResultsA total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P 235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts.Conclusions and RelevanceResults of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Background Recent advances in disease-modifying treatments highlight the need for accurately identifying individuals in early Alzheimer’s disease (AD) stages and for monitoring of treatment effects. Plasma measurements of phosphorylated tau (p-tau) are a promising biomarker for AD, but different assays show varying diagnostic and prognostic accuracies. The objective of this study was to determine the clinical performance of a novel plasma p-tau217 (p-tau217) assay, p-tau217+Janssen, and perform a head-to-head comparison to an established assay, plasma p-tau217Lilly, within two independent cohorts. Methods The study consisted of two cohorts, cohort 1 (27 controls and 25 individuals with mild-cognitive impairment [MCI]) and cohort 2 including 147 individuals with MCI at baseline who were followed for an average of 4.92 (SD 2.09) years. Receiver operating characteristic analyses were used to assess the performance of both assays to detect amyloid-β status (+/−) in CSF, distinguish MCI from controls, and identify subjects who will convert from MCI to AD dementia. General linear and linear mixed-effects analyses were used to assess the associations between p-tau and baseline, and annual change in Mini-Mental State Examination (MMSE) scores. Spearman correlations were used to assess the associations between the two plasma measures, and Bland-Altmann plots were examined to assess the agreement between the assays. Results Both assays showed similar performance in detecting amyloid-β status in CSF (plasma p-tau217+Janssen AUC = 0.91 vs plasma p-tau217Lilly AUC = 0.89), distinguishing MCI from controls (plasma p-tau217+Janssen AUC = 0.91 vs plasma p-tau217Lilly AUC = 0.91), and predicting future conversion from MCI to AD dementia (plasma p-tau217+Janssen AUC = 0.88 vs p-tau217Lilly AUC = 0.89). Both assays were similarly related to baseline (plasma p-tau217+Janssen rho = −0.39 vs p-tau217Lilly rho = −0.35), and annual change in MMSE scores (plasma p-tau217+Janssenr = −0.45 vs p-tau217Lillyr = −0.41). Correlations between the two plasma measures were rho = 0.69, p < 0.001 in cohort 1 and rho = 0.70, p < 0.001 in cohort 2. Bland-Altmann plots revealed good agreement between plasma p-tau217+Janssen and plasma p-tau217Lilly in both cohorts (cohort 1, 51/52 [98%] within 95%CI; cohort 2, 139/147 [95%] within 95%CI). Conclusions Taken together, our results indicate good diagnostic and prognostic performance of the plasma p-tau217+Janssen assay, similar to the p-tau217Lilly assay.

Wir berichten über eine 34-jährige Patientin, die im Rahmen eines Arbeitsunfalls mit einer Druckluft-Reinigungspistole einen Pneumocephalus über eine konjunktivale Eintrittspforte erlitt. Durch ein interdisziplinäres Vorgehen konnten schwerwiegende Verletzungen ausgeschlossen und [zum vollständigen Text gelangen Sie über die oben angegebene URL]

The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P 18F]-JNJ-067 significantly correlated (p 18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-beta (A beta) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed A beta plaques in frontal cortical brain biopsy and 13 iNPH patients without A beta pathology. CSF Amyloid-beta(42) (A beta(42)), total tau (T-tau), phosphorylated tau (P-tau(181)), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but A beta(42) increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. A beta(42) instead showed divergent longitudinal decrease between A beta-positive and -negative patients in L-CSF, and thereafter increase in A beta-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (A beta(42) R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (A beta(42) 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only A beta(42) showed higher concentration in non-carriers of allele epsilon 4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy A beta pathology, while NFL normalized toward its pre-shunt levels. A beta(42) as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V-than L-CSF yet showing strong correlations.

Funding Acknowledgements Type of funding sources: None. Introduction The implantation of cardiac implantable electronic devices (CIEDs) such as pacemakers and implantable cardioverter-defibrillators is increasing along with the complexitly of these devices. CIED infection is an uncommon, but severe complication associated with the presence of a device and is associated with a high mortality and morbidity. Lead-related infections and frank endocarditis are associated with a systemic inflammatory response and, in general, are readily identified. Isolated pocket infections do not produce such a systemic response and are thus more complex to diagnose. There is a reliance on clinical accumen and examination of local signs of infection. There is thus a need for a reliable biomaker to help identify cases of pocket infection. Aim Our group have previously shown procalcitonin (PCT) to be a potentially useful biomaker in the clinial situation of possible pocket infection. We aim to prospectively validate the proposed cut-off value of 0.05ng/ml for the procalcitonin (PCT) biomaker in an independent cohort, which we have previously identified as showing promise in this clinical situation. Methods In this prospective case-control validation study the PCT levels of 81 patients with confirmed pocket infections were compared to 81 controls, matched for age and renal function, presenting for elective generator replacement or lead revision unrelated to infection. Exclusion criteria included: concomitant infectious or inflammatory diseases, end-stage renal failure, active malignancy or receiving immunosuppressive therapy. Results A PCT over 0.05 ng/ml was found in 68% (n= 55) of pocket infections and 24% (n= 19) of controls. Using the pre­defined cut-off value of 0.05 ng/ml PCT had a sensitivity of 68% and a specificity of 77% for diagnosing pocket infections. ROC analysis revealed area under the curve of 0.752 (standard error 0.039, p Conclusion PCT is a potentially useful biomarker to aid the diagnosis of a pocket infection when used with the prospecitvely validated cut-off value of 0.05ng/ml. The sensitivity of the PCT positive result remained high even in patients pre-treated with antibiotics or with minimal clinical signs of inflammation.

Funding Acknowledgements Type of funding sources: None. Background About three percent of patients with persistent atrial fibrillation [AF] additionally suffer from a concealed sinus node disease [SND]. We sought to determine the ablation success one year after ablation of persistent AF in patients with postprocedurally unmasked SND. Methods and Results In total 2239 patients with an ablation of persistent AF at our center were screened for a postprocedurally unmasked SND, which made cardiac pacing necessary within one week after ablation. In a propensity score matched case control study, the longterm ablation success of 51 patients (mean age 73±8years, 58% male) with postprocedurally unmasked SND after ablation of persistent AF was compared to that of 102 patients without SND after ablation of persistent AF. Controls were matched to cases based on the propensity score considering age, body mass index, left ventricular ejection fraction, gender, blood pressure, diabetes mellitus, atrial low voltage, previous number of ablations and method of ablation. One year after ablation of persistent AF, 20 (39%) patients with postprocedurally unmasked SND and 61 (60%) patients without postprocedurally unmasked SND were in sinus rhythm (p=0.025). The number of repeat ablation procedures within the follow up year did not differ significantly between cases and controls (0.60±0.68 vs 0.53±0.80, p=0.574). Conclusion In patients with a postprocedurally unmasked SND after ablation of persistent AF, longterm ablation success seems to be worse compared to patients without postprocedurally unmasked SND.

Funding Acknowledgements Type of funding sources: None. Introduction The rate of transvenous lead extraction (TLE) is increasing with an increasing rate of complex devices being implanted. TLE is now a routine part of cardiac device management and up to date data on the safety and efficacy of TLE with modern tools and techniques is essential to management decisions regarding non-infectious indications for lead extraction. Purpose To evaluate the safety and efficacy of TLE in a contemporary cohort using mechanical (non-laser) extraction tools. Methods We present a contemporary, prospective review of TLE at our high-volume cardiac centre. All patients undergoing TLE from June 2016 and June 2019 were enrolled in our local database and baseline clinical data, procedural information and outcome data were collected. Results In total 561 leads were explanted (n=153) or extracted (n=408) from 341 patients over the study period. Patients were predominantly male (71%) with a mean age of 65 ± 17 years. The most common indication for lead removal was lead failure (45.2%, n=154) followed by infection of the pocket or device (29.3%, n=100). The mean dwell time of the 408 extracted leads was 7.2 years; 35% had a dwell time of 5-10 years, 23% had a dwell time >10 years and 4% had a dwell time >20 years (Figure 1). In total, complete success was achieved in 96.4% (n=541) leads, clinical success in a further 2.1% (n=12) and failure only in 1.4% (n=8). Clinical success was high (93%) even in leads with dwell time >20 years (Figure 2). There was an overall complication rate of 0.9% (3/341) for major complications and 1.5% (5/341) for minor complications. There were no deaths. Conclusions Our data would suggest that there are ongoing improvements in the safety profile and success rates of lead extraction undertaken by experienced operators now with a major complication rate of

Background: Early and accurate detection and staging is critical to managing Alzheimer’s disease (AD) and supporting clinical trials. Cerebrospinal fluid (CSF) biomarkers for amyloid-β peptides, tau species, and various neurodegenerative and inflammatory analytes are leading the way in this regard, yet there is room for improved sensitivity and specificity. In particular tau is known to be present in many different fragments, conformations, and post-translationally modified forms. While the exact tau species that might best reflect AD pathology is unknown, a growing body of evidence suggests that forms with high levels of phosphorylation in the mid-region may be especially enriched in AD. Objective: Develop an assay for measuring p217tau in CSF. Methods: Here we describe the development and validation of a novel sELISA for measuring CSF tau species containing phosphorylation at threonines 212 & 217, aka p217 + tau, using the PT3 antibody. Results: While the analyte is present at extremely low levels the assay is sufficiently sensitive and specific to quantitate p217 + tau with excellent precision, accuracy, and dilution linearity, allowing good differentiation between diagnostic subgroups. The p217 + tau measurements appear to track AD pathology better than the commonly used p181tau epitope, suggesting superior diagnostic and staging performance. Finally, the assay can also be configured to differentiate antibody-bound versus antibody-free tau, and therefore can be used to measure target engagement by p217 + tau-targeting immunotherapeutics. Conclusion: The assay for measuring p217 + tau described here is highly sensitive, accurate, precise, dilution linear, and shows good potential for identifying and staging AD.

Purpose The accumulation of misfolded tau is a common feature of several neurodegenerative disorders, with Alzheimer’s disease (AD) being the most common. Earlier we identified JNJ-64326067, a novel isoquinoline derivative with high affinity and selectivity for tau aggregates from human AD brain. We report the dosimetry of [18F] JNJ-64326067 and results of a proof-of-concept study comparing subjects with probable Alzheimer’s disease to age-matched healthy controls. Methods [18F] JNJ-64326067 PET scans were acquired for 90 min and then from 120 to 180 min in 5 participants with [18F]-florbetapir PET amyloid positive probable AD (73 ± 9 years) and 5 [18F]-florbetapir PET amyloid negative healthy controls (71 ± 7 years). Whole-body [18F] JNJ-64326067 PET CT scans were acquired in six healthy subjects for 5.5 h in 3 scanning sessions. Brain PET scans were visually reviewed. Regional quantification included kinetic analysis of distribution volume ration (DVR) estimated by Logan graphical analysis over the entire scan and static analysis of SUVr in late frames. Both methods used ventral cerebellar cortex as a reference region. Results One of the healthy controls had focal areas of PET signal in occipital and parietal cortex underlying the site of a gunshot injury as an adolescent; the other four healthy subjects had no tau brain signal. Four of the 5 AD participants had visually apparent retention of [18F] JNJ-64326067 in relevant cortical regions. One of the AD subjects was visually negative. Cortical signal in visually positive subjects approached steady state by 120 min. Temporal and frontal cortical SUVr/DVR values in visually positive AD subjects ranged from 1.21 to 3.09/1.2 to 2.18 and from 0.92 to 1.28/0.91 to 1.16 in healthy controls. Whole-body effective dose was estimated to be 0.0257 mSv/MBq for females and 0.0254 mSv/MBq for males. Conclusions [18F] JNJ-64326067 could be useful for detection and quantitation of tau aggregates.

BackgroundAt ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR–gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses.MethodsParticipants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery–Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25.ResultsIn the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected.ConclusionsVariation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect.Trial RegistrationNCT02417064 and NCT02418585; www.clinicaltrials.gov

Background: Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implantable cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation to prevent ICD shocks for VT) and deferred ablation after 3 ICD shocks for VT. Methods: The BERLIN VT study (Preventive Ablation of Ventricular Tachycardia in Patients With Myocardial Infarction) was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population. Results: During a mean follow-up of 396±284 days, the primary end point occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09 [95% CI, 0.62–1.92]; P =0.77). On the basis of prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, 6 versus 2 patients died (7.9% versus 2.4%; P =0.18), 8 versus 2 patients were admitted for worsening heart failure (10.4% versus 2.3%; P =0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% versus 25.3%; P =0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% versus 48.2%; P =0.050) and appropriate ICD therapy (34.2% versus 47.0%; P =0.020) were numerically reduced in the preventive ablation group. Conclusions: Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up compared with the deferred ablation strategy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02501005.

This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity.Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype.The age and APOE genotype model predicted amyloid status with an area under the curve (AUC) of 0.75. Three assays improved AUCs to 0.81, 0.81, and 0.84 (P.05, uncorrected for multiple comparisons).Measurement of Aβ in plasma contributes to addressing the amyloid component of the ATN (amyloid/tau/neurodegeneration) framework and could be a first step before or in place of a PET or cerebrospinal fluid screening study.The Foundation of the National Institutes of Health Biomarkers Consortium evaluated six plasma amyloid beta (Aβ) assays using Alzheimer's Disease Neuroimaging Initiative samples. Three assays improved prediction of amyloid status over age and apolipoprotein E (APOE) genotype. Plasma Aβ42/40 predicted amyloid positron emission tomography status better than Aβ42 or Aβ40 alone.

We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau).Plasma p217+tau levels were compared toCompared to Aβ- CU, the plasma levels of p217+tau increased 2-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ- the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloidsPlasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.

In der vorliegenden Stellungnahme der Deutschen Gesellschaft fur Kardiologie (DGK) in Zusammenarbeit mit der Deutschen Gesellschaft fur Arbeits- und Umweltmedizin (DGAUM) werden elektromagnetische Interferenzen bei elektrisch aktiven kardialen Implantaten diskutiert, die vorhandene Literatur zusammengefasst und, soweit moglich, bewertet. Aufgrund der zunehmenden Technisierung des Alltags und des beruflichen Umfelds mit immer mehr elektrischen oder elektronischen Geraten erlangt das Thema zunehmende Relevanz. Dies wird begleitet von Weiterentwicklungen der bestehenden transvenosen Implantate sowie neuen Aggregattechnologien wie kabellosen Schrittmachern und total subkutanen implantierbaren Kardioverter-Defibrillatoren. Die Konfiguration von elektromagnetischen Feldern (EMF) kann bezogen auf Frequenz und Feldstarke stark variieren und ruft im Korper und somit am Aggregat ganz unterschiedliche Reaktionen hervor. Der physikalische Hintergrund der Wirkung von EMF auf Korper und Implantat wird allgemein verstandlich dargestellt. Verschiedene Storszenarien werden auch in Bezug auf die Grunderkrankung erlautert. Aus interdisziplinarer Perspektive werden Aspekte einer Exposition mit EMF sowohl im Alltag als auch im beruflichen Umfeld beleuchtet. Der primaren Implantatversorgung EMF-exponierter Patienten, der Risikobewertung im arbeitsmedizinischen Kontext und der Gerateprogrammierung mit Troubleshooting kommt hierbei besondere Bedeutung zu. Zudem werden konkrete Vorgehensweisen fur Arbeitsmediziner in Betrieben an die Hand gegeben, um den Wiedereingliederungsprozess zu unterstutzen. Im Rahmen dessen erfolgt auch eine kurze Darstellung der aktuellen Gesetzeslage. Uberdies soll das Dokument motivieren, Studien aufzulegen, die das Thema der elektromagnetischen Interferenz in vivo fur aktuelle Aggregatgenerationen sowie Neuentwicklungen systematisch untersuchen, sodass eine suffiziente Risikobewertung fur verschiedene Frequenzbereiche und damit technische Gerate erfolgen kann.

AIM To investigate the accuracy of ultrasonography in the assessment of hepatic steatosis using magnetic resonance imaging (MRI) as standard of reference and to explore the influence of additional hepatic iron overload. MATERIAL AND METHODS A total of 2,783 volunteers (1,442 women, 1,341 men; mean age, 52.3±13.8 years) underwent confounder-corrected chemical-shift-encoded MRI of the liver at 1.5 T. Proton-density fat fraction (PDFF) and transverse relaxation rate (R2*) were calculated to estimate hepatic steatosis and liver iron overload, respectively. In addition, the presence of hepatic steatosis was assessed by B-mode ultrasonography. The sensitivity, specificity, and accuracy of hepatic ultrasonography were determined for different degrees of hepatic steatosis and different amounts of liver iron. RESULTS MRI revealed hepatic steatosis in 40% of participants (n=1,112), which was mild in 68.9% (n=766), moderate in 26.7% (n=297), and severe in 4.4% (n=49) of patients. Ultrasonography detected hepatic steatosis in 37.8% (n=1,052), corresponding to 74.5% sensitivity and 86.6% specificity. The sensitivity of ultrasound increased with the amount of hepatic fat present and was 65.1%, 95%, and 96% for low, moderate, and high fat content; whereas the specificity was constantly high at 86.6%. The diagnostic accuracy of ultrasound for detection of hepatic steatosis did not vary significantly with the amount of liver iron present. CONCLUSION Ultrasonography is an excellent tool to assess hepatic steatosis in the clinical setting with some limitations in patients with a low liver fat content. The detection of hepatic steatosis by ultrasonography is not influenced by liver iron.

New protocols for coronary computed tomography angiography (CCTA) could lower the radiation dose for patients but influence the image quality. To compare image quality and radiation exposure in step-and-shoot CCTA and high-pitch spiral CCTA. Fifty-nine pairs of patients matched for weight, height, sex and heart rate were included in this study (74 m, 44 f, average age 60 years, age range 29–94 years). Step-and-shoot CCTA and high-pitch spiral CCTA was performed on a third generation dual-source CT in equally sized patient groups. The signal-to-noise ratio (SNR) in the ascending aorta and the coronary arteries were determined for each dataset. Image quality was rated using a five-point scale. We used the t-test for paired samples to compare SNR and effective dose, and the Wilcoxon test to compare image quality scores. Mean effective dose for the step-and-shoot protocol (4.15 ± 3.07 mSv) was significantly higher in comparison to the high-pitch spiral protocol (1.2 ± 0.69 mSv; p

In Alzheimer’s disease, the density and spread of aggregated tau protein track well with neurodegeneration and cognitive decline, making the imaging of aggregated tau a compelling biomarker. A structure–activity relationship exploration around an isoquinoline hit, followed by an exploration of tolerated fluorination positions, allowed us to identify 9 (JNJ-64326067), a potent and selective binder to aggregated tau with a favorable pharmacokinetic profile and no apparent off-target binding. This was confirmed in rat and monkey positron emission tomography studies using [18F]9.

The P2X7 receptor is an adenosine triphosphate-gated ion channel, which is abundantly expressed in glial cells within the central nervous system and in the periphery. P2X7 receptor activation leads to the release of the proinflammatory cytokine IL-1β in the brain, and antagonism of the P2X7 receptor is a novel therapeutic strategy to dampen adenosine triphosphate-dependent IL-1β signaling. PET ligands for the P2X7 receptor will not only be valuable to assess central target engagement of drug candidates but also hold promise as surrogate markers of central neuroinflammation. Herein we describe the in vitro and in vivo evaluation of 18F-JNJ-64413739, an 18F-labeled PET ligand for imaging the P2X7 receptor in the brain. Methods: P2X7 receptor affinity and specificity, pharmacokinetics, metabolic stability, blood-brain barrier permeability, and off-target binding of JNJ-64413739 were evaluated in a series of in vitro, ex vivo, and in vivo assays. 18F-JNJ-64413739 was radiolabeled via a one-step nucleophilic aromatic substitution. The tracer was also studied in rhesus macaques, and PET images were analyzed with an arterial plasma input function-based Logan graphical analysis. Results: The potency (half-maximal inhibitory concentration) of the P2X7 receptor antagonist JNJ-64413739 is 1.0 ± 0.2 nM and 2.0 ± 0.6 nM at the recombinant human and rat P2X7 receptor, respectively, and the binding affinity is 2.7 nM (rat cortex binding assay) and 15.9 nM (human P2X7 receptor). In nonhuman primate PET imaging studies, dose-dependent receptor occupancy of JNJ-54175446 was observed in 2 rhesus monkeys. At a 0.1 mg/kg dose (intravenous) of JNJ-54175446, the receptor occupancy was calculated to be 17% by Logan graphical analysis, whereas a dose of 2.5 mg/kg yielded a receptor occupancy of 60%. Conclusion: The preclinical evaluation of 18F-JNJ-64413739 demonstrates that the tracer engages the P2X7 receptor. Reproducible and dose-dependent receptor occupancy studies with the P2X7 receptor antagonist JNJ-54175446 were obtained in rhesus monkeys. This novel PET tracer exhibits in vitro and in vivo characteristics suitable for imaging the P2X7 receptor in the brain and warrants further studies in humans.

The [(18)F]-JNJ-64326067-AAA ([(18)F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [(11)C]-PIB amyloid PET scan, and a tau [(18)F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [(18)F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P

Introduction Diagnosis of Alzheimer's disease (AD) based on amyloid beta (A), pathologic tau (T), and neurodegeneration (N) biomarkers in peripheral fluids promises to accelerate clinical trials and intercept disease earlier. Methods Qualification of a Simoa plasma p217+tau assay was performed, followed by clinical utility evaluation in a cohort of 227 subjects with broad A and T spectrum. Results The p217+tau plasma assay was accurate, precise, dilution linear, and highly sensitive. All measured samples were within linear range of the assay, presented higher concentration in AD versus healthy controls (P

Introduction: Herbal medicinal plants as Hypericum perforatum L., known as St. John’s wort (SJW) have been in use for a long time. SJW that is specifically used for the treatment of depressive disorders. Inflammatory cytokines derived from microglia play an important role in the regulation of the synthesis and reuptake of glutamate and influence synaptic function, morphology and neuronal plasticity. The present study was performed to investigate, whether STW3-VI, a special SJW extract has protective effects on mouse SIM-A9 microglia against cytotoxic and proinflammatory effects of ROS, glutamate, NMDA or cortisol. Additionally, we investigated the effects of SJW on migratory and phagocytic properties of microglia.Results: Pre-treatment (48 h) of microglia with STW3-VI (5 or 10 μg/ml)—in contrast to desipramine—inhibited the H2O2-induced TNF-α release by 20–40%. Pre-treatment (48 h) of microglia with STW3-VI (5 or 10 μg/ml) delayed the 3 or 4 mM H2O2-induced intracellular ROS level by 26.9 and 44.4%, respectively. Furthermore, pre-treatment (48 h) of microglia with STW3-VI (5 μg/ml) - in contrast to desipramine - lowered the glutamate-induced cytotoxicity by 13.2%. Besides, pre-treatment (48 h) of microglia with STW3-VI (5 or 10 μg/ml) or desipramine (5 µM) inhibited the NMDA-induced decrease of the viability by 16.5–28.8% or 12%, respectively. Finally, pre-treatment (48 h) of microglia with STW3-VI (5 or 10 μg/ml)—in contrast to desipramine - reduced the cortisol-induced cytotoxicity by 15.5 and 12.9%. Treatment of microglia with STW3-VI (10 or 100 μg/ml) increased the migratory and the phagocytic capacities by 100 and 40%.Conclusion: Our data provide evidence that STW3-VI—in contrast to desipramine - protects microglia from oxidative stress, NMDA- or glutamate-induced cytotoxicity, and has anti-inflammatory properties that are accompanied by improvement of their migratory and phagocytic capacity. These protective (particularly the anti-inflammatory) properties may be beneficial in the treatment of depressive disorders.

The prevalence of atrial fibrillation (AF) is significantly higher in adults with congenital heart disease (ACHD) compared to patients without congenital heart disease (CHD). As AF in ACHD patients might have significant hemodynamic consequences, rhythm control is particularly desirable but rarely achieved by antiarrhythmic drugs. The aim of this study was to investigate safety and long-term outcome of AF ablation in ACHD patients. All ACHD patients (n = 46) that underwent AF ablation at our centre from 2013 to 2017 were included in the study. CHD was classified as simple (46%), moderate (41%) or complex (13%). The majority of patients (61%) suffered from persistent AF (paroxysmal AF 39%). Persistent AF was present in 57% of patients with simple, in 58% of patients with moderate and 83% of patients with complex CHD. All patients underwent radiofrequency (RF) ablation on uninterrupted oral anticoagulation. Pulmonary vein isolation (PVI) was performed in patients with paroxysmal AF, whereas patients with persistent AF underwent PVI and ablation of complex fractionated atrial electrograms (CFAE). No major complications occurred. Single-procedure success after 18 months off antiarrhythmic drugs was 61% for paroxysmal AF and 29% for persistent AF (p = 0.003). Multiple procedures (mean 2.1 ± 1.4) increased long-term success to 82% for paroxysmal AF and 48% for persistent AF (p = 0.05). Long-term ablation success was 64% for simple, 62% for moderate and 50% for complex CHD patients. AF ablation in ACHD patients is feasible and safe regardless of CHD complexity. Success rates in patients with paroxysmal AF are high and comparable to patients without CHD. In ACHD patients with persistent AF, success rates of ablation are markedly reduced which might be due to a different and/or more extensive (bi-)atrial substrate. In the cohort of complex ACHD patients with persistent AF as the dominant AF type, long-term success of AF ablation is limited.

The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [18F]JNJ-64413739 has been recently disclosed. We evaluated [18F]JNJ-64413739 in a rat model of neuroinflammation induced by an intracerebral injection of lipopolysaccharide (LPS). In vivo brain uptake was determined by PET imaging. Upregulation of neuroinflammatory biomarkers was determined by quantitative polymerase chain reaction (qPCR). Distribution of the tracer in the brain was determined by ex vivo autoradiography (ARG). The specificity of [18F]JNJ-64413739 was confirmed by performing blocking experiments with the P2X7 antagonist JNJ-54175446. Brain regions of rats injected with LPS had a significantly increased uptake (34 % ± 3 % s.e.m., p = 0.036, t test, standardized uptake value measured over the entire scanning period) of [18F]JNJ-64413739 relative to the corresponding brain regions of control animals injected with phosphate-buffered saline (PBS). The uptake in the contralateral regions and cerebellum was not significantly different between the groups of animals. The increase in uptake of [18F]JNJ-64413739 at the LPS-injected site observed by PET imaging was concordant with ex vivo ARG, upregulation of neuroinflammatory biomarkers, and elevated P2X7 expression levels. While further work is needed to study [18F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [18F]JNJ-64413739 as a potential PET tracer of central neuroinflammation.