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Aims: More precise characterization of risk factors for occurring ventricular arrhythmia in patients (pts) with primary prevention implantable cardioverter-defibrillator (ICD) therapy is critical. We sought to investigate whether biomarkers of nitric oxide metabolism can predict the occurrence of ventricular tachyarrhythmias and might be used as risk markers in these pts.Methods and Results: Plasma levels of l-arginine (Arg), asymmetric dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), monomethyl l-arginine, and nitrite/nitrate were examined in 106 consecutive pts (mean age 65 years, 97 male, mean LV-EF 24 ± 6%), with ischaemic (n= 82) or non-ischaemic cardiomyopathy (n= 24) who underwent ICD implantation for primary prevention of SCD. Appropriate ICD intervention was assessed during a mean follow-up of 344 days, and occurred in 18 of 106 (17%) pts. Asymmetric dimethylarginine plasma levels were significantly higher in pts with appropriate ICD intervention compared with those without any ICD intervention (0.564 ± 0.083 μmol/L vs. 0.513 ± 0.088 μmol; P= 0.027). The Arg/ADMA ratio was found lower in pts with appropriate ICD intervention than in those without ICD intervention (144.71 ± 32.50 vs. 175.29 ± 41.29; P= 0.002). Univariate Cox regression showed that ADMA (P = 0.028) and the Arg/ADMA ratio (P = 0.003) were associated with a higher incidence of appropriate ICD intervention. In a multivariable Cox regression analysis, an ADMA concentration above the 50th centile was independently associated with appropriate ICD intervention, revealing a hazard ratio (HR) of 4.21 (CI 95 %: 1.14-15.63; P = 0.028, Table 4). An Arg/ADMA ratio below the 25th centile had a HR of 3.83 (1.360-10.87; P = 0.011).Conclusion: Asymmetric dimethylarginine and the Arg/ADMA ratio seem to be new biomarkers for the prediction of ventricular tachycardia/ventricular fibrillation episodes and of appropriate ICD intervention in pts with left ventricular ejection fraction dysfunction (LV-EF ≤ 35%), suggesting a value for risk stratification in these pts. [ABSTRACT FROM AUTHOR]

Aims: Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden cardiac death in patients with the reduced left ventricular function (LVEF ≤30%) not earlier than 40 days after myocardial infarction (MI). The aim of the prospective Prevention of Sudden Cardiac Death II (PreSCD II) registry was to investigate the clinical practice of ICD therapy in post-MI patients and to assess the impact on survival.Methods and Results: 10,612 consecutive patients (61 ± 12 years, 76% male) were enrolled 4 weeks or later after MI in 19 cardiac rehabilitation centres in Germany from December 2002 to May 2005. All patients with left ventricular ejection fraction (LVEF) ≤40% (n = 952) together with a randomly selected group of patients with preserved left ventricular function (n = 1106) were followed for 36 months. Cox proportional hazard models were used to correlate ICD implantation and survival with baseline characteristics. Of all patients studied, 75.9% were enrolled within 4-8 weeks, 10.7% more than 1 year after MI. Pre-specified Group 1 with an LVEF ≤30% consisted of 269 patients (2.5%), Group 2 with LVEF 31-40% of 727 patients (6.9%), and Group 3 with LVEF >40% of 1148 randomly selected patients from the cohort of 9616 patients with preserved LV function. After 36 months, only 142 patients (6.9%) had received an ICD; 82 (31.7%) of Group 1, 49 (7%) of Group 2, and 11 (1%) in Group 3. The ICD was implanted in 47% of all patients within 1 year after their index MI. Implantable cardioverter-defibrillator patients were predominantly characterized by low ejection fraction, but also by several other independent risk factors. Patients who received an ICD had an adjusted 44% lower mortality (hazard ratio 0.56, 95% confidence intervals 0.32-1.01; P = 0.053) than comparable patients without ICD therapy. All cause mortality of ICD recipients was significantly lower if the ICD was implanted later than 11 months after acute MI (P < 0.001).Conclusions: The PreSCD II registry demonstrated that the number of patients who develop a low LVEF (≤30%) after acute MI is small. However, only few patients with guideline-based ICD indication received ICD therapy. All cause mortality was significantly reduced only if the ICD was implanted late (>11 months) after MI. [ABSTRACT FROM AUTHOR]

The implantable cardioverter defibrillator (ICD) is able to reduce sudden arrhythmic death in patients who are considered to be at high risk. However, the arrhythmic risk may be increased only temporarily as long as the proarrhythmic conditions persist, left ventricular ejection fraction remains low, or heart failure prevails. The wearable cardioverter defibrillator (WCD) represents an alternative approach to prevent sudden arrhythmic death until either ICD implantation is clearly indicated or the arrhythmic risk is considered significantly lower or even absent. The WCD is also indicated for interrupted protection by an already implanted ICD, temporary inability to implant an ICD, and lastly refusal of an indicated ICD by the patient. The WCD is not an alternative to the ICD, but a device that may contribute to better selection of patients for ICD therapy. The WCD has the characteristics of an ICD, but does not need to be implanted, and it has similarities with an external defibrillator, but does not require a bystander to apply lifesaving shocks when necessary. The WCD was introduced into clinical practice about 8 years ago, and indications for its use are currently expanding. This article describes the technological aspects of the WCD, discusses current indications for its use, and reviews the clinical studies with the WCD. Additionally, data are reported on the clinical experience with the WCD based on 354 patients from Germany hospitalized between 2000 and 2008 who wore the WCD for a mean of 3 months. (PACE 2010; 33:353-367) [ABSTRACT FROM AUTHOR]

Background: The relation between flecainide's plasma level and its influence on human atrial electrophysiology during acute and maintenance therapy of atrial fibrillation (AF) is unknown. Therefore, this study determined flecainide plasma levels and atrial fibrillatory rate obtained from the surface ECG during initiation and early maintenance of oral flecainide in patients with persistent lone AF and assessed their relationship.Methods and Results: In 10 patients (5 males, mean age 63 +/- 14 years, left atrial diameter 46 +/- 3 mm) with persistent lone AF, flecainide was administered as a single oral bolus (day 1) followed by 200-400 mg/day (days 2-5). The initial 300 mg flecainide bolus resulted in therapeutic plasma levels in all patients (range 288-629 ng/ml) with no side effects. Flecainide plasma levels increased on day 3 and remained stable thereafter. Day 5 plasma levels were lower (508 +/- 135 vs 974 +/- 276 ng/ml, P = 0.009) in patients with daily mean flecainide doses of 200 mg compared to patients with higher maintenance doses. Fibrillatory rate obtained from the surface electrocardiogram measuring 378 +/- 17 fpm at baseline was reduced to 270 +/- 18 fpm (P < 0.001) after the flecainide bolus but remained stable thereafter. Fibrillatory rate reduction was independent of flecainide plasma levels or clinical variables.Conclusion: A 300 mg oral flecainide bolus is associated with electrophysiologic effects that are not increased during early maintenance therapy in persistent human lone AF. In contrast to drug plasma levels, serial analysis of fibrillatory rate allows monitoring of individual drug effects on atrial electrophysiology. [ABSTRACT FROM AUTHOR]

Three-dimensional mapping in RBBB and heart failure. INTRODUCTION: Recently, right bundle branch block (RBBB) was proved to be an important predictor of mortality in heart failure (HF) patients as much as left bundle branch block (LBBB). We characterized endocardial right ventricular (RV) and left ventricular (LV) activation sequence in HF patients with RBBB using a three-dimensional non-fluoroscopic electroanatomic contact mapping system (3D-Map) in order to provide the electrophysiological background to understand whether these patients can benefit from cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Using 3D-Map, RV and LV activation sequences were studied in 100 consecutive HF patients. Six of these patients presented with RBBB QRS morphology. The maps of these patients were analyzed and compared post hoc with those of the other 94 HF patients presenting with LBBB. Clinical and hemodynamic profile was significantly worse in RBBB group compared to LBBB. Patients with RBBB showed significantly longer time to RV breakthrough (P<0.001), longer activation times of RV anterior and lateral regions (P<0.001), and longer total RV endocardial activation time (P<0.02) compared to patients with LBBB. Time to LV breakthrough was significantly shorter in patients with RBBB (P<0.001), while total and regional LV endocardial activation times were not significantly different between the two groups. CONCLUSIONS: Degree of LV activation delay is similar between HF patients with LBBB and RBBB. Moreover, patients with RBBB have larger right-sided conduction delay compared to patients with LBBB. The assessment of these electrical abnormalities is important to understand the rationale for delivering CRT in HF patients with RBBB. [ABSTRACT FROM AUTHOR]

Background: Brugada syndrome is associated with a risk for sudden death, but the arrhythmic risk in an individual Brugada syndrome patient is difficult to predict. Pathologic changes in the early repolarization phase of the ventricular action potential probably constitute part of the arrhythmogenic substrate in Brugada syndrome. Microvolt T wave alternans (TWA) assesses dynamic beat-to-beat changes in repolarization and has been suggested as a marker for repolarization-related sudden death. We therefore tested whether TWA is an indicator for arrhythmias in Brugada syndrome with a focus on right precordial ECG leads.Methods: We assessed TWA in nine symptomatic, inducible patients with established Brugada syndrome and in seven healthy controls. TWA was assessed at rest and during exercise using both standard methods and an algorithm that assesses TWA in the early ST segment and the right precordial leads.Results: None of the Brugada patients developed TWA in this study irrespective of analysis at rest or during exercise, neither using standard methods nor when the early ST segment was included in the analysis. When the early ST segment was included in the analysis, nonsustained TWA was found in three out of seven, and sustained TWA in one control.Conclusion: T wave alternans is not an appropriate test to detect arrhythmic risk in patients with Brugada syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Radiofrequency (RF) catheter ablation currently is used for treatment of cardiac arrhythmias. Although the success rate is high for almost all supraventricular tachycardias (SVT), this technique has some drawbacks, especially when pulmonary veins (PV) are targeted for treatment of atrial fibrillation (AF). Additionally, new techniques for isolation of the PVs have the drawback that they can be used only for PV isolation and not for routine treatment of other SVTs. The aim of this study was to report on the safety and efficacy of a new cryoablation system for treatment of all SVTs. Methods and Results: Forty-nine patients with SVT (38 men; age 48 years, range 23-76) were enrolled in the study. Five patients were withdrawn from the study before they underwent cryoablation. The remaining 44 patients were treated with cryoablation (22 AF, 15 atrial flutter, 3 accessory pathway, 2 AV nodal reentrant tachycardia, 1 AV junction ablation for permanent AF, 1 atrial tachycardia). Cryoablation was performed with the CryoCor[TM] cryoablation system, which uses a precooling system and N2O as a refrigerant. The number of freezes applied varied according to the index arrhythmia treated. Successful isolation of PVs was performed in 20 of (96%) 21 AF patients and 53 of 55 veins. The overall acute success was 98% (43/44). Fifty-three PVs were isolated (2.5/patient). The success rate was 100% (23/23) for right-sided procedures. The average and nadir temperatures reached in right-sided and left-sided procedures were -77°C and -80°C and -75°C and -78°C, respectively. No acute PV stenosis was seen. Conclusion: This novel cryoablation system appears to be safe and can successfully treat different types of SVTs, including AF. Isolation of PVs is possible without producing stenosis. Despite the high blood flow in the right atrial isthmus and PVs, bidirectional conduction block can be achieved. [ABSTRACT FROM AUTHOR]

Introduction: Identification of suitable candidates for cardioversion currently is not based on individual electrical and mechanical atrial remodeling. Therefore, this study analyzed the meaning of atrial fibrillatory rate obtained from the surface ECG (as a measure of electrical remodeling) and left atrial size (as measure of mechanical remodeling) for prediction of early atrial fibrillation (AF) recurrence following cardioversion.Methods and Results: Forty-four consecutive patients (26 men and 18 women, mean age 62 +/- 11 years, no antiarrhythmic medication at baseline) with persistent AF were studied. Fibrillatory rate was obtained from high-gain, high-resolution surface ECG using digital signal processing (filtering, QRST subtraction, Fourier analysis) before electrical cardioversion. Univariate and multivariate regression analysis revealed larger systolic left atrial area (Beta = 0.176, P = 0.031) obtained by precardioversion echocardiogram from the apical four-chamber view and higher atrial fibrillatory rate (Beta = 0.029, P = 0.021) to be independent predictors for AF recurrence (n = 13). Stratification based on the regression equation (electromechanical index [EMI] = 0.176 systolic left atrial area + 0.029 fibrillatory rate - 17.674) allowed identification of groups at low, intermediate, or high risk. No patient with an EMI < -1.85 had early AF recurrence, as opposed to 78% with an EMI > -0.25. Intermediate results (40% recurrence rate) were obtained when the calculated EMI ranged between -1.85 and -0.25 (P < 0.001).Conclusion: Fibrillatory rate obtained from the surface ECG and systolic left atrial area obtained by echocardiography may predict early AF recurrence in patients with persistent AE These parameters might be useful in identifying candidates with a high likelihood of remaining in sinus rhythm after cardioversion. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the relationship between echocardiographic response to cardiac resynchronization therapy (CRT) and the risk of subsequent ventricular tachyarrhythmias (VTAs). Background: Current data regarding the effect of CRT on the risk of VTA are limited and conflicting. Methods: The risk of a first appropriate implantable cardioverter-defibrillator (ICD) therapy for VTA (including ventricular tachycardia, ventricular fibrillation, and ventricular flutter) was compared between high- and low-echocardiographic responders to CRT defibrillator (CRT-D) therapy (defined as ≥ 25% and <25% reductions, respectively, in left ventricular end-systolic volume [LVESV] at 1 year compared with baseline) and ICD-only patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). Results: The cumulative probability of a first VTA at 2 years after assessment of echocardiographic response was highest among low responders to CRT-D (28%), intermediate among ICD-only patients (21%), and lowest among high responders to CRT-D (12%), with p < 0.001 for the overall difference during follow-up. Multivariate analysis showed that high responders to CRT-D experienced a significant 55% reduction in the risk of VTA compared with ICD-only patients (p < 0.001), whereas the risk of VTA was not significantly different between low responders and ICD-only patients (hazard ratio [HR]: 1.26; p = 0.21). Consistently, assessment of response to CRT-D as a continuous measure showed that incremental 10% reductions in left ventricular end-systolic volume were associated with corresponding reductions in the risk of subsequent VTA (HR: 0.80; p < 0.001), VTA/death (HR: 0.79; p < 0.001), ventricular tachycardia (HR: 0.80; p < 0.001), and ventricular fibrillation/ventricular flutter (HR: 0.75; p = 0.044). Conclusions: In patients with left ventricular dysfunction enrolled in the MADIT-CRT trial, reverse remodeling was associated with a significant reduction in the risk of subsequent life-threatening VTAs. (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271). [ABSTRACT FROM AUTHOR]

Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immune system, playing a major role in orchestrating innate and adaptive immune responses. Both Alzheimer's disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are enriched for genes expressed in myeloid cells, but it is not clear whether these myeloid risk factors are shared between the two diseases. Leveraging results of genome-wide association studies, we investigated the causal effect of IBD (including ulcerative colitis (UC) and Crohn's disease (CD)) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed distinct sets of genes and pathways of AD and IBD susceptibility loci. Specifically, AD loci are enriched for microglial eQTLs, while IBD loci are enriched for monocyte eQTLs. However, we also found that genetically determined IBD is associated with a protective effect against AD (p<0.03). Yet, a genetic propensity for the CD subtype is associated with increased amyloid accumulation (beta=7.14, p-value=0.02) and susceptibility to AD. Susceptibility to UC was associated with increased deposition of TDP-43 (beta=7.58, p-value=6.11×10 -4 ). The relation of these gastrointestinal inflammatory disease to AD is therefore complex; while the different subsets of susceptibility variants preferentially affect different myeloid cell subtypes, there do appear to be certain shared pathways and the possible protective effect of IBD susceptibility on the risk of AD which may provide therapeutic insights., Competing Interests: Competing interests The authors declare no competing interests.

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and high-dimensional MERFISH. We also leverage our dataset as a classification resource, finding that induced pluripotent stem cell model systems capture substantial in vivo heterogeneity. Finally, we identify and validate compounds that recapitulate certain subtypes in vitro, including camptothecin, which downregulates the signature of disease-enriched subtypes and upregulates a signature previously associated with Alzheimer's disease., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Alzheimer's disease (AD) has recently been associated with diverse cell states 1-11 , yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species and recently demonstrated to occur in rare instances from one human generation to the next. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Psychosocial experiences affect brain health and aging trajectories, but the molecular pathways underlying these associations remain unclear. Normal brain function relies on energy transformation by mitochondria oxidative phosphorylation (OxPhos). Two main lines of evidence position mitochondria both as targets and drivers of psychosocial experiences. On the one hand, chronic stress exposure and mood states may alter multiple aspects of mitochondrial biology; on the other hand, functional variations in mitochondrial OxPhos capacity may alter social behavior, stress reactivity, and mood. But are psychosocial exposures and subjective experiences linked to mitochondrial biology in the human brain? By combining longitudinal antemortem assessments of psychosocial factors with postmortem brain (dorsolateral prefrontal cortex) proteomics in older adults, we find that higher well-being is linked to greater abundance of the mitochondrial OxPhos machinery, whereas higher negative mood is linked to lower OxPhos protein content. Combined, positive and negative psychosocial factors explained 18 to 25% of the variance in the abundance of OxPhos complex I, the primary biochemical entry point that energizes brain mitochondria. Moreover, interrogating mitochondrial psychobiological associations in specific neuronal and nonneuronal brain cells with single-nucleus RNA sequencing (RNA-seq) revealed strong cell-type-specific associations for positive psychosocial experiences and mitochondria in glia but opposite associations in neurons. As a result, these "mind-mitochondria" associations were masked in bulk RNA-seq, highlighting the likely underestimation of true psychobiological effect sizes in bulk brain tissues. Thus, self-reported psychosocial experiences are linked to human brain mitochondrial phenotypes., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Depression, a common psychiatric illness and global public health problem, remains poorly understood across different life stages, which hampers the development of novel treatments., Methods: To identify new candidate genes for therapeutic development, we performed differential gene expression analysis of single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of older adults (n = 424) in relation to antemortem depressive symptoms. Additionally, we integrated genome-wide association study results for depression (n = 500,199) along with genetic tools for inferring the expression of 14,048 unique genes in 7 cell types and 52 cell subtypes to perform a transcriptome-wide association study of depression followed by Mendelian randomization., Results: Our single-nucleus transcriptome-wide association study analysis identified 68 candidate genes for depression and showed the greatest number being in excitatory and inhibitory neurons. Of the 68 genes, 53 were novel compared to previous studies. Notably, gene expression in different neuronal subtypes had varying effects on depression risk. Traits with high genetic correlations with depression, such as neuroticism, shared more transcriptome-wide association study genes than traits that were not highly correlated with depression. Complementing these analyses, differential gene expression analysis across 52 neocortical cell subtypes showed that genes such as KCNN2, SCAI, WASF3, and SOCS6 were associated with late-life depressive symptoms in specific cell subtypes., Conclusions: These 2 sets of analyses illustrate the utility of large single-nucleus RNA sequencing data both to uncover genes whose expression is altered in specific cell subtypes in the context of depressive symptoms and to enhance the interpretation of well-powered genome-wide association studies so that we can prioritize specific susceptibility genes for further analysis and therapeutic development., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Molecular omics studies have identified proteins related to cognitive resilience but unrelated to Alzheimer disease and Alzheimer disease-related dementia (AD/ADRD) pathologies. Posttranslational modifications of proteins with glycans can modify protein function. In this study, we identified glycopeptiforms associated with cognitive resilience., Methods: We studied brains from adults with annual cognitive testing with postmortem indices of 10 AD/ADRD pathologies and proteome-wide data from dorsal lateral prefrontal cortex (DLPFC). We quantified 11, 012 glycopeptiforms from DLPFC using liquid chromatography with tandem mass spectrometry. We used linear mixed-effects models to identify glycopeptiforms associated with cognitive decline correcting for multiple comparisons ( p < 5 × 10 -6 ). Then, we regressed out the effect of AD/ADRD pathologies to identify glycopeptiforms that may provide cognitive resilience., Results: We studied 366 brains, average age at death 89 years, and 70% female with no cognitive impairment = 152, mild cognitive impairment = 93, and AD = 121 cognitive status at death. In models adjusting for age, sex and education, 11 glycopeptiforms were associated with cognitive decline. In further modeling, 8 of these glycopeptiforms remained associated with cognitive decline after adjusting for AD/ADRD pathologies: NPTX2a (Est., 0.030, SE, 0.005, p = 1 × 10 -4 ); NPTX2b (Est.,0.019, SE, 0.005, p = 2 × 10 -4 ) NECTIN1(Est., 0.029, SE, 0.009, p = 9 × 10 -4 ), NPTX2c (Est., 0.015, SE, 0.004, p = 9 × 10 -4 ), HSPB1 (Est., -0.021, SE, 0.006, p = 2 × 10 -4 ), PLTP (Est., -0.027, SE, 0.009, p = 4.2 × 10 -3 ), NAGK (Est., -0.027, SE, 0.008, p = 1.4 × 10 -3 ), and VAT1 (Est., -0.020, SE, 0.006, p = 1.1 × 10 -3 ). Higher levels of 4 resilience glycopeptiforms derived through glycosylation were associated with slower decline and higher levels of 4 derived through glycation were related to faster decline. Together, these 8 glycopeptiforms accounted for an additional 6% of cognitive decline over the 33% accounted for the 10 brain pathologies and demographics. All 8 resilience glycopeptiforms remained associated with cognitive decline after adjustments for the expression level of their corresponding protein. Exploratory gene ontology suggested that molecular mechanisms of glycopeptiforms associated with cognitive decline may involve metabolic pathways including pyruvate and NADH pathways and highlighted the importance of molecular mechanisms involved in glucose metabolism., Discussion: Glycopeptiforms in aging brains may provide cognitive resilience. Targeting these glycopeptiforms may lead to therapies that maintain cognition through resilience.

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The history of surgical treatment of ventricular tachycardias (VT) is short, lasting from 1978 until 1993. "Indirect procedures" with infarct scar resection were performed without electrophysiologic studies, whereas "direct procedures" consisted of either complete endocardial incisions ("encircling endocardial ventriculotomy") or large endocardial resections ("endocardial peel-off" technique) after precise epicardial and endocardial mapping procedures. In Germany, the first to report on intra-operative electrophysiologic mapping for VT treatment were Ostermeyer, Breithardt and Seipel in 1979. In 1981, the Hannover group (Frank, Klein) published their first results of surgical treatment of VT. In 1984, Ostermeyer et al. demonstrated that a partial endocardial incision resulted in more beneficial results with less myocardial damage (8% versus 46%) than applying a complete encircling incision. In 1987, the Düsseldorf group reported treatment results of 93 patients. After 5 years, 77% had no VT recurrence, while total mortality after 1 year was 11% and after 5 years 30%. In 1992, the Hannover group reported results of 147 patients after endocardial resection for VT. Total mortality after 3 years was 27%; recurrence of VT events occurred in 18% of the surviving cohort.The history of surgical procedures for supraventricular tachycardia (SVT), in particular Wolff-Parkinson-White (WPW) syndrome, is even shorter than that of surgery for VT. As early as 1969, Sealy, Gallagher and Cox reported the first cases of surgical intervention for WPW syndrome via endocardial access in cardioplegic arrest. In 1984, Guiraudon and Klein reported on a new procedure with epicardial access to the accessory bundle without cardioplegia in laterally localised conduction pathways. In Germany, too, the groups in Düsseldorf (Ostermeyer, Seipel, Breithardt, Borggrefe) from 1980 and the Hannover group (Frank, Klein and Kallfelz) from 1981 performed surgical procedures for WPW syndrome. In 1987, Borggrefe reported on 18 patients with WPW syndrome and atrial fibrillation who had undergone surgery. After 2 years, 14 of 18 patients had no recurrences of tachycardia; in 1989, Frank, Klein and Kallfelz (Hannover) reported on 10 children (2-14 years) operated on using the cryoablation technique. Between 1984 and 1992, a total of 120 patients with SVT, mostly WPW syndrome, were operated on in Hannover; after 42 months, 12 patients had a recurrence of SVT. Two patients died during the reoperation., (© 2024. The Author(s).)

Direct current (DC) catheter ablation in 5 patients aiming to interrupt rapid atrioventricular (AV) conduction with atrial fibrillation and subsequent pacemaker implantation was first published by M. M. Scheinman et al. (San Francisco, CA, USA) in 1982. In Germany, L. Seipel, G. Breithardt, and M. Borggrefe reported their first experience with DC catheter ablation in 1984, followed by the group in Bonn (M. Manz and B. Lüderitz) in 1985. The first international DC catheter ablation registry, which also included four German centers, reported DC catheter ablation results of 127 patients in 24 centers in 1984. Complete AV block was achieved in 71% patients. In 1992, the Hannover group (H‑J. Trappe, H. Klein and J. Huang) reported results of DC catheter ablation of AV conduction performed between 1983 and 1990 in 100 patients (86% with rapid atrial fibrillation, 14% with AV-node reentry tachycardias). The first successful DC catheter ablation in a patient with Wolff-Parkinson-White (WPW) syndrome was reported in 1985 by F. Morady et al. (San Francisco, CA, USA). In 1987, M. Borggrefe et al. were the first to report a switch from DC catheter ablation to a high-frequency (HF) catheter ablation procedure in a patient with WPW syndrome. The use of DC catheter ablation to treat ventricular tachycardia (VT) was described by G. O. Hartzler (Kansas City, MO, USA) in 3 patients in 1983. M. Borggrefe et al. (1989) reported on 24 patients who underwent DC catheter ablation for VT. Of those, 17 patients did not have VT recurrence within the following 14 months. In 1994, the Hannover group (H-J Trappe, H. Klein) published their 5‑year long-term results of DC catheter ablation of VT in 51 patients. VT recurrence occurred in 57% patients and overall mortality was also high (16%). A comparison of DC catheter ablation with HF catheter ablation for recurrent VT was reported in 1994 by G. Gonska et al. (Göttingen, Germany). After 2 years follow-up, success rates were not found to be significantly different., (© 2024. The Author(s).)

The implantable cardioverter-defibrillator (ICD) was a breakthrough in the prevention of sudden cardiac death. After years of technical development in the USA, Michel Mirowski succeeded in proving reliable automatic defibrillation of ventricular tachyarrhythmias through initial human implantations in 1980, despite many obstacles. Nearly 4 years later, the first patients received ICDs at multiple centers in Germany. Subsequently, outside the USA, Germany became the country with highest implantation rates. The absolute number of implantations remained small as long as implantations required epicardial defibrillation electrodes and therefore thoracotomy by cardiac surgeons. Pacemaker-like implantation using a transvenous defibrillation electrode with a pectoral ICD became feasible in the early 1990s pushing implantation rates to the next level. Technical advancements were accompanied by clinical research in Germany, and often, the first-in-human studies were conducted in Germany. In 1991, the first guidelines for indications were established in the USA and Germany. Several randomized studies on indications were published between 1996 and 2009, mostly led by American teams with German participation, but also under German leadership (CASH, CAT, DINAMIT, IRIS). The DANISH study in 2016 questioned the results of these long-standing studies. Instead of providing ICDs to patients using a broad indication, future efforts aim to identify patients who, despite optimal medical therapy, cardiac resynchronization therapy (CRT), and/or catheter ablation, need protection against sudden cardiac death. Risk scores incorporating myocardial scars in magnetic resonance imaging (MRI) and genetic information are expected to contribute to more individualized and effective indications., (© 2024. The Author(s).)

ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data from human autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins. ZCCHC17 knockdown results in widespread RNA-splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find a significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17's role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that the maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology., (Copyright © 2024 the authors.)

Background and Objectives: Prior work suggests that cognitive resilience may contribute to the heterogeneity of cognitive decline. This study examined whether distinct cortical proteins provide resilience for different cognitive abilities., Methods: Participants were from the Religious Orders Study or the Rush Memory and Aging Project who had undergone annual assessments of 5 cognitive abilities and postmortem assessment of 9 Alzheimer disease and related dementia (ADRD) pathologies. Proteome-wide examination of the dorsolateral prefrontal cortex using tandem mass tag and liquid chromatography-mass spectrometry yielded 8,425 high-abundance proteins. We applied linear mixed-effect models to quantify residual cognitive change (cognitive resilience) of 5 cognitive abilities by regressing out cognitive decline related to age, sex, education, and indices of ADRD pathologies. Then we added terms for each of the individual proteins to identify cognitive resilience proteins associated with the different cognitive abilities., Results: We included 604 decedents (69% female; mean age at death = 89 years) with proteomic data. A total of 47 cortical proteins that provide cognitive resilience were identified: 22 were associated with specific cognitive abilities, and 25 were common to at least 2 cognitive abilities. NRN1 was the only protein that was associated with more than 2 cognitive abilities (semantic memory: estimate = 0.020, SE = 0.004, p = 2.2 × 10 -6 ; episodic memory: estimate = 0.029, SE = 0.004, p = 5.8 × 10 -1 ; and working memory: estimate = 0.021, SE = 0.004, p = 1.2 × 10 -7 ). Exploratory gene ontology analysis suggested that among top molecular pathways, mitochondrial translation was a molecular mechanism providing resilience in episodic memory, while nuclear-transcribed messenger RNA catabolic processes provided resilience in working memory., Discussion: This study identified cortical proteins associated with various cognitive abilities. Differential associations across abilities may reflect distinct underlying biological pathways. These data provide potential high-value targets for further mechanistic and drug discovery studies to develop targeted treatments to prevent loss of cognition.

Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-β, and microglial ADPRS was associated with amyloid-β and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage., (© 2023. The Author(s).)

Motivation: Droplet-based single-cell RNA sequencing (scRNA-seq) is widely used in biomedical research for interrogating the transcriptomes of single cells on a large scale. Pooling and processing cells from different samples together can reduce costs and batch effects. To pool cells, they are often first labeled with hashtag oligonucleotides (HTOs). These HTOs are sequenced alongside the cells' RNA in the droplets and subsequently used to computationally assign each droplet to its sample of origin, a process referred to as demultiplexing. Accurate demultiplexing is crucial but can be challenging due to background HTOs, low-quality cells/cell debris, and multiplets., Results: A new demultiplexing method based on negative binomial regression mixture models is introduced. The method, called demuxmix, implements two significant improvements. First, demuxmix's probabilistic classification framework provides error probabilities for droplet assignments that can be used to discard uncertain droplets and inform about the quality of the HTO data and the success of the demultiplexing process. Second, demuxmix utilizes the positive association between detected genes in the RNA library and HTO counts to explain parts of the variance in the HTO data resulting in improved droplet assignments. The improved performance of demuxmix compared with existing demultiplexing methods is assessed using real and simulated data. Finally, the feasibility of accurately demultiplexing experimental designs where non-labeled cells are pooled with labeled cells is demonstrated., Availability and Implementation: R/Bioconductor package demuxmix (https://doi.org/doi:10.18129/B9.bioc.demuxmix)., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Motor resilience proteins have not been identified. This proteome-wide discovery study sought to identify proteins that may provide motor resilience., Methods: We studied the brains of older decedents with annual motor testing, postmortem brain pathologies, and proteome-wide data. Parkinsonism was assessed using 26 items of a modified United Parkinson Disease Rating Scale. We used linear mixed-effect models to isolate motor resilience, defined as the person-specific estimate of progressive parkinsonism after controlling for age, sex, and 10 brain pathologies. A total of 8 356 high-abundance proteins were quantified from dorsal lateral prefrontal cortex using tandem mass tag and liquid chromatography-mass spectrometry., Results: There were 391 older adults (70% female), mean age 80 years at baseline and 89 years at death. Five proteins were associated with motor resilience: A higher level of AP1B1 (Estimate -0.504, SE 0.121, p = 3.12 × 10-5) and GNG3 (Estimate -0.276, SE 0.068, p = 4.82 × 10-5) was associated with slower progressive parkinsonism. By contrast, a higher level of TTC38 (Estimate 0.140, SE 0.029, p = 1.87 × 10-6), CARKD (Estimate 0.413, SE 0.100, p = 3.50 × 10-5), and ABHD14B (Estimate 0.175, SE 0.044, p = 6.48 × 10-5) was associated with faster progressive parkinsonism. Together, these 5 proteins accounted for almost 25% of the variance of progressive parkinsonism above the 17% accounted for by 10 indices of brain pathologies., Discussion: Cortical proteins may provide more or less motor resilience in older adults. These proteins are high-value therapeutic targets for drug discovery that may lead to interventions that maintain motor function despite the accumulation of as yet untreatable brain pathologies., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Identifying genes underlying memory function will help characterize cognitively resilient and high-risk declining subpopulations contributing to precision medicine strategies. We estimated episodic memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E (APOE)-stratified genome-wide association study (GWAS) analyses and combined individual cohorts' results via meta-analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10 -8 ) among non-carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression (P = 3.8 x 10 -4 ) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P = .003, and amyloid beta load P = .008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus (P = .007) and inferior frontal gyrus (P = .013). Our work identified DCDC2 gene as a novel predictor of memory maintenance., (© 2021 the Alzheimer's Association.)

Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer's disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)