Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad ...implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.
For a continuous time‐to‐event outcome and an expensive‐to‐measure exposure, we develop a pooling design and propose a likelihood‐based approach to estimate the hazard ratios (HRs) of a Cox ...proportional hazards (PH) model. Our proposed approach fits a PH model based on pooled exposures with individually observed time‐to‐event outcomes. The design and estimation exploits the equivalence of the conditional logistic likelihood functions arising from a matched case‐control study and the partial likelihood function of a riskset‐matched, nested case‐control (NCC) subset of a cohort study. To create the pools, we first focus on an NCC subcohort. Pools are formed at random while keeping the matching intact. Pool‐level exposure and confounders are then evaluated and used in the likelihood to estimate the HR and the standard error of the estimates. The estimators are MLEs, provide consistent estimates of the individual‐level HRs, and are asymptotically normal. Our simulation results indicate that the pooled estimates are comparable to the estimates obtained from the NCC subcohort. The units of analysis for the pooled design are the pools and not the individual participants. Hence the effective sample size is reduced. Therefore, the variance of the HR estimate increases with increasing poolsize. However, this variance inflation in small samples can be offset by including more matched controls per case within the NCC subcohort. An application is demonstrated with the Second Manifestations of ARTerial disease (SMART) study.
This study evaluated trends and outcomes of tricuspid valve surgery (TVS) in North America over the past decade.
Adults undergoing TVS between 2000 and 2010 were identified in The Society of Thoracic ...Surgeons (STS) National Database. Trends were evaluated using linear regression. Multivariable logistic regression analysis was conducted using covariates from the STS valve risk model to identify significant predictors of operative mortality.
A total of 54,375 patients underwent TVS during the study period. The majority of cases were repairs (89%; n = 48,322) and were performed concomitant with another major procedure (86%; n = 46,593). The proportion of TVS that were repairs increased from 84.6% in 2000 to 89.8% in 2010 (p = 0.01). Trend analysis revealed significant changes in patient characteristics with time, including increasing age, a higher comorbidity burden, and a higher proportion of emergency cases. Despite worsening risk factors, unadjusted operative mortality for TVS declined from 10.6% in 2000 to 8.2% in 2010 (p < 0.001), and this trend persisted after risk adjustment. In the multivariable model, concomitant procedures involving multiple valves or coronary artery bypass grafting were associated with an increased risk of mortality compared with isolated TVS, although other factors including renal failure, congestive heart failure, nonelective presentation, reoperation, and tricuspid valve replacement exerted equal or stronger effects.
During the past decade, repair rates for TVS have increased significantly. Although patients undergoing TVS have demonstrated worsening risk factors, unadjusted and adjusted operative mortalities have declined. Finally, the data suggest that tricuspid valve repair when technically feasible, together with early elective surgical intervention, should be emphasized as potential candidates for continued outcome improvement.
APOEε4 is the most well-established genetic risk factor for sporadic Alzheimer's disease and is associated with cerebral amyloid-β. However, the association between APOEε4 and tau pathology, the ...other major proteinopathy of Alzheimer's disease, has been controversial. Here, we sought to determine whether the relationship between APOEε4 and tau pathology is determined by local interactions with amyloid-β. We examined three independent samples of cognitively unimpaired, mild cognitive impairment and Alzheimer's disease subjects: (1) 211 participants who underwent tau-PET with
FMK6240 and amyloid-PET with
FAZD4694, (2) 264 individuals who underwent tau-PET with
FFlortaucipir and amyloid-PET with
FFlorbetapir and (3) 487 individuals who underwent lumbar puncture and amyloid-PET with
FFlorbetapir. Using a novel analytical framework, we applied voxel-wise regression models to assess the interactive effect of APOEε4 and amyloid-β on tau load, independently of age and clinical diagnosis. We found that the interaction effect between APOEε4 and amyloid-β, rather than the sum of their independent effects, was related to increased tau load in Alzheimer's disease-vulnerable regions. The interaction between one APOEε4 allele and amyloid-β was related to increased tau load, while the interaction between amyloid-β and two APOEε4 alleles was related to a more widespread pattern of tau aggregation. Our results contribute to an emerging framework in which the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results may have implications for future disease-modifying therapeutic trials targeting amyloid or tau pathologies.
Analyses of distributed data networks of rare diseases are constrained by legitimate privacy and ethical concerns. Analytical centers (e.g. research institutions) are thus confronted with the ...challenging task of obtaining data from recruiting sites that are often unable or unwilling to share personal records of participants. For time-to-event data, recently popularized disclosure techniques with privacy guarantees (e.g., Differentially Private Generative Adversarial Networks) are generally computationally expensive or inaccessible to applied researchers. To perform the widely used Cox proportional hazards regression, we propose an easy-to-implement privacy-preserving data analysis technique by pooling (i.e. aggregating) individual records of covariates at recruiting sites under the nested case-control sampling framework before sharing the pooled nested case-control subcohort. We show that the pooled hazard ratio estimators, under the pooled nested case-control subsamples from the contributing sites, are maximum likelihood estimators and provide consistent estimates of the individual level full cohort HRs. Furthermore, a sampling technique for generating pseudo-event times for individual subjects that constitute the pooled nested case-control subsamples is proposed. Our method is demonstrated using extensive simulations and analysis of the National Lung Screening Trial data. The utility of our proposed approach is compared to the gold standard (full cohort) and synthetic data generated using classification and regression trees. The proposed pooling technique performs to near-optimal levels comparable to full cohort analysis or synthetic data; the efficiency improves in rare event settings when more controls are matched on during nested case-control subcohort sampling.
National prosthesis use in active aortic valve infective endocarditis (IE) is unreported. Prosthesis usage and outcomes in patients undergoing an aortic valve operation with active IE was evaluated.
...The Society of Thoracic Surgeons Adult Cardiac Surgery Database was used to identify patients with active IE who underwent an aortic valve operation from January 1, 2005, to June 30, 2011. All patients with active IE were included. Demographics, procedures, outcomes, and trends were analyzed.
Of 11,560 patients who were identified as having active IE, 8,421 (73%) had no prior operations (primary) and 3,139 (27%) had a history of any prior cardiac operation (reoperative). Operations for primary vs reoperative patients included isolated replacement in 88.5% vs 58.7% and root replacement in 7.2% vs 29.9%. Major morbidity was 60.8% vs 68%, and the unadjusted mortality rate was 9.8% vs 21.1%. Over time, for primary operations, biologic valve use increased (57% to 67%), and mechanical and homograft valve use decreased (30% to 24% and 9% to 6%; p < 0.001). For reoperations, biologic valve use increased (38% to 52%), and mechanical and homograft use decreased (20% to 17% and 38% to 28%; p < 0.001). Homografts were used more often in reoperations (32% vs 7%).
Morbidity and mortality rates death are high for operations for active IE. Biologic valves were increasingly used vs mechanical and homograft valves. Homograft valves were used more often in reoperative patients after any prior cardiac operation. The mortality rate varied among prosthesis groups but may be related to the severity of infection and type of procedure performed.
INTRODUCTION
Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual‐level benefit from amyloid beta removal ...therapy.
METHODS
Random forest models were applied to the EMERGE trial to create an individual‐level treatment response (ITR) score which represents individual‐level benefit of high‐dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE).
RESULTS
We found statistical evidence of HTE in the Clinical Dementia Rating–Sum of Boxes (CDR‐SB;P = 0.034). The observed CDR‐SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline.
DISCUSSION
This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development.
Highlights
Emerging trials have shown a population‐level benefit from amyloid beta (Aβ) removal in slowing cognitive decline in early Alzheimer's disease (AD).
This work demonstrates significant heterogeneity of individual‐level treatment effect of aducanumab in early AD.
The greatest clinical responders to Aβ removal therapy have a pattern of more severe neurodegenerative process.
Abstract
Introduction
To date, studies have estimated the phenoconversion rate from sleep clinics, using polysomnography proven RBD. However, no population-based estimates have been reported, testing ...to what degree possible RBD, screened by questionnaire is associated with increased risk of neurodegeneration.
Methods
We included those aged 45–85 years, living in one of 10 Canadian provinces in between 2012–2015 (at the baseline), recruited via three population-based sampling methods. Dream enactment behavior/possible RBD was screened using the RBD1Q single question-questionnaire. De-novo parkinsonism was defined as free of pre-existing diagnosis at the baseline with a ‘new’ diagnosis at the follow-up (205–2019). Relative risk (log-binomial regression), hazard ratio (Cox regression), incidence rate (Poisson regression) between the affected group and the symptom naïve group were assessed, adjusting for age and sex (and total years of education and language).
Results
Overall, 58 participants phenoconverted into parkinsonism and 53 into dementia at the follow-up (mean intervals=3.06±0.37 years). Participants with dream enactment behavior had 2.75 times higher risk to phenoconvert into parkinsonism than the symptom-free. Similarly, those with dream enactment behavior at the baseline possessed higher risk to screening positive of parkinsonism. No difference in time to phenoconversion was found between groups, The results remained robust after excluding non-RBD related symptoms, such as apnea and non-REM sleep parasomnia.
Conclusion
Compared to symptom-free, those with pRBD had higher risk to developing parkinsonism in near future.
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