Molecular Determinants of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes.

Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within five years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding.

Cross-tissue omics-guided drug repurposing triangulates novel targetable mechanisms for Alzheimer's disease and candidate genetic biomarkers for treatment stratification.

White matter hyperintensities (WMH) are covert magnetic resonance imaging (MRI) - markers of microvascular dysfunction and are primary vascular contributors to dementia, emphasizing its importance in prevention strategies. Here, we integrate gene expression and protein levels measured across plasma, cerebrospinal fluid (CSF), brain and multiple other tissues from population-based and biobank-scale data to triangulate druggable genes influencing WMH-burden and Alzheimer's disease (AD) and to map their spatial localization specifically in brain-cell types. Lowering the expression levels of and shows putative causal associations with reduced WMH-burden, and AD risk.

Unravelling the genetic architecture of cerebral small vessel disease in the context of stroke.

Cerebral small vessel disease (cSVD) is a major contributor to stroke, dementia, and cognitive decline. Despite significant progress through large-scale genome-wide association studies (GWAS) for cSVD and stroke, the genetic architecture underlying these conditions remains poorly understood. This review highlights recent advancements in statistical tools and provides a comprehensive overview of current insights into the genetic underpinnings of cSVD and stroke.

Polygenic Hazard Score for Predicting Age-associated Risk of Alzheimer's Disease in European Populations: Development and Validation.

Objectives: Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer's disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models.

Methods: We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model.

mzQuality: An Open-Source Software Tool for Quality Monitoring and Reporting of Targeted Mass Spectrometry Measurements.

Analyzing metabolites using mass spectrometry provides valuable insight into an individual's health or disease status. However, various sources of experimental variation can be introduced during sample handling, preparation, and measurement, which can negatively affect the data. Quality assurance and quality control practices are essential to ensuring accurate and reproducible metabolomics data.

Machine learning in Alzheimer's disease genetics.

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models.

The Ethnic/Racial Variations of Intracerebral Hemorrhage Genetics (ERICH-GENE) Study Protocol.

Background: Spontaneous, non-traumatic intracranial hemorrhage (ICH) is highly heritable disease. However, the identification of the genetic risk factors driving this high genetic predisposition has been limited by small sample sizes and underrepresentation of non-European populations. The ERICH-GENE study will gather and harmonize clinical, neuroimaging and genomic data on the largest and more diverse collection of ICH cases assembled to date.

Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries.

Associations of the LIBRA index with cognitive resilience to genetic susceptibility to dementia.

The role of lifestyle and health-related factors in dementia risk has been established. However, how a combination of modifiable risk factors, as reflected by the LIfestyle for BRAin health (LIBRA) index, contributes to cognitive resilience to genetic susceptibility to dementia (CRgen) remains unclear. We selected 6774 Three-City study participants without dementia at baseline (mean age = 74 years) and with ≥2 cognitive measures over time.

stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene () ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers, hampering the treatment of those with the highest unmet need.

White matter hyperintensity spatial patterns: Risk factors and clinical correlates.

Introduction: White matter hyperintensities (WMHs), a major cerebral small vessel disease (cSVD) marker, may arise from different pathologies depending on their location. We explored clinical and genetic correlates of agnostically derived spatial WMH patterns in two longitudinal population-based cohorts (Three-City Study [3C]-Dijon, LIFE-Adult).

Methods: We derived seven WMH spatial patterns using Bullseye segmentation in 2878 individuals aged 65+ and explored their associations with vascular and genetic risk factors, cognitive performance, dementia and stroke incidence.

Recurrent Stroke Prediction by Applying a Stroke Polygenic Risk Score in the Japanese Population.

Background: Recently, various polygenic risk score (PRS)-based methods were developed to improve stroke prediction. However, current PRSs (including cross-ancestry PRS) poorly predict recurrent stroke. Here, we aimed to determine whether the best PRS for Japanese individuals can also predict stroke recurrence in this population by extensively comparing the methods and maximizing the predictive performance for stroke onset.

Polygenic score integrating neurodegenerative and vascular risk informs dementia risk stratification.

Introduction: An integrative polygenic risk score (iPRS) capturing the neurodegenerative and vascular contribution to dementia could identify high-risk individuals and improve risk prediction.

Methods: We developed an iPRS for dementia (iPRS-DEM) in Europeans (aged 65+), comprising genetic risk for Alzheimer's disease (AD) and 23 vascular or neurodegenerative traits (excluding apolipoprotein E [APOE]). iPRS-DEM was evaluated across cohorts comprising older community-dwelling people (N = 3702), a multi-ancestry biobank (N = 130,797 Europeans; 105,404 non-Europeans), and dementia-free memory clinic participants (N = 2032).

Direct oral anticoagulants versus no anticoagulation for the prevention of stroke in survivors of intracerebral haemorrhage with atrial fibrillation (PRESTIGE-AF): a multicentre, open-label, randomised, phase 3 trial.

Background: Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage.

Methods: PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries.

Headaches attributed to cranial and cervical artery dissections.

Headache is a common neurological symptom, often leading to the investigation of secondary causes, including cerebrovascular conditions such as cranial and cervical artery dissection (CCAD). CCAD, a significant cause of stroke in younger adults, commonly presents with headache or neck pain, isolated or accompanied by neurological deficits, and may mimic primary headache disorders, complicating timely diagnosis. This review explores the role of headache in CCAD, specifically addressing headache as an initial presentation, its evolution post-dissection, and as a potential risk factor of CCAD.

Prevention of Stroke in Intracerebral Haemorrhage Survivors with Atrial Fibrillation: Rationale and Design for PRESTIGE-AF Trial.

Adequate secondary prevention in survivors of intracerebral hemorrhage (ICH) who also have atrial fibrillation (AF) is a long-standing clinical dilemma because these patients are at increased risk of recurrent ICH as well as of ischemic stroke. The efficacy and safety of oral anticoagulation, the standard preventive medication for ischemic stroke patients with AF, in ICH patients with AF are uncertain. PRESTIGE-AF is an international, phase 3b, multi-center, randomized, open, blinded end-point assessment (PROBE) clinical trial that compared the efficacy and safety of direct oral anticoagulants (DOACs) with no DOAC (either no antithrombotic treatment or any antiplatelet drug).

SHIVA-CMB: a deep-learning-based robust cerebral microbleed segmentation tool trained on multi-source T2*GRE- and susceptibility-weighted MRI.

Cerebral microbleeds (CMB) represent a feature of cerebral small vessel disease (cSVD), a prominent vascular contributor to age-related cognitive decline, dementia, and stroke. They are visible as spherical hypointense signals on T2*- or susceptibility-weighted magnetic resonance imaging (MRI) sequences. An increasing number of automated CMB detection methods being proposed are based on supervised deep learning (DL).

Genomic Landscape of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes.

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding.

Evaluation of clonal hematopoiesis and mosaic loss of Y chromosome in cardiovascular risk: An analysis in prospective studies.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) was initially linked to a twofold increase in atherothrombotic events. However, recent investigations have revealed a more nuanced picture, suggesting that CHIP may confer only a modest rise in myocardial infarction (MI) risk. This observed lower risk might be influenced by yet unidentified factors that modulate the pathological effects of CHIP.

Recurrent stroke prediction by applying a stroke polygenic risk score in the Japanese population.

Background: Recently, various polygenic risk score (PRS)-based methods were developed to improve stroke prediction. However, current PRSs (including cross-ancestry PRS) poorly predict recurrent stroke. Here, we aimed to determine whether the best PRS for Japanese individuals can also predict stroke recurrence in this population by extensively comparing the methods and maximizing the predictive performance for stroke onset.