Displaying One Session

Plenary
Session Type
Plenary
Room
Hall A
Date
07.11.2020, Saturday
Session Time
04:45 PM - 06:15 PM

WSO Award

Session Type
Plenary
Date
07.11.2020, Saturday
Session Time
04:45 PM - 06:15 PM
Room
Hall A
Lecture Time
04:45 PM - 05:05 PM

WSO Award

Session Type
Plenary
Date
07.11.2020, Saturday
Session Time
04:45 PM - 06:15 PM
Room
Hall A
Lecture Time
05:05 PM - 05:25 PM

DETERMINANTS OF PROGNOSIS OF CRYPTOGENIC STROKE IN PATIENTS WITH PATENT FORAMEN OVALE ON MEDICAL TREATMENT ALONE: POPULATION-BASED STUDY AND SYSTEMATIC REVIEW

Session Type
Plenary
Date
07.11.2020, Saturday
Session Time
04:45 PM - 06:15 PM
Room
Hall A
Lecture Time
05:35 PM - 05:45 PM

Abstract

Background And Aims

Knowledge of determinants of prognosis after cryptogenic TIA/stroke in patients with patent foramen ovale (PFO) on medical treatment alone is essential to inform further trials on PFO-closure at older ages.

Methods

We determined the risk of recurrence in a large population-based (Oxford Vascular Study, OXVASC) cohort after cryptogenic TIA/non-disabling stroke in patients with PFO stratified by age and by RLS size. We also did a systematic review of cohort studies reporting ischaemic stroke recurrence after cryptogenic TIA/stroke in patients with PFO on medical therapy alone, or with PFO vs no-PFO. Absolute risk of ischaemic stroke was regressed against mean study cohort age. Meta-analysis was used to determine risk of recurrent stroke in patients with PFO versus no PFO (stratified by age <65 vs ≥ 65 years), and with “small/medium” versus “large” PFO.

Results

Recurrent ischaemic stroke risk in OXVASC was 2.0/100 patient-years. However, absolute risk increased with mean cohort age on meta-regression (24-studies; R2=0.46; p=0.00034). In the pooled analysis of patients with PFO vs no PFO, risk of stroke recurrence was only increased in patients with PFO at age ≥65 years (4-studies; OR=2.26, 95%CI=1.36-3.75, p=0.02, phet= 0.46). Large RLS increased risk of recurrent stroke in OXVASC (OR=2.87; 1.05-7.87), and on pooled analysis with two other inclusive cohorts (OR=2.32; 1.22-4.43), but not on pooled analysis of 4 highly-selected cohorts (OR= 1.12; 0.64-1.97).

Conclusions

Age and RLS-size are two determinants of stroke recurrence after PFO-associated cryptogenic TIA/stroke. Trials of closure of large PFOs at older ages are justified.

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GENOME-WIDE ASSOCIATION STUDY OF INTRACRANIAL ANEURYSMS REVEALS 17 RISK LOCI, POLYGENIC ARCHITECTURE, GENETIC OVERLAP WITH CLINICAL RISK FACTORS, AND OPPORTUNITIES FOR TREATMENT

Session Type
Plenary
Date
07.11.2020, Saturday
Session Time
04:45 PM - 06:15 PM
Room
Hall A
Lecture Time
05:45 PM - 05:55 PM

Abstract

Group Name

The Intracranial Aneurysm Working Group of the International Stroke Genetics Consortium

Background And Aims

The genetic basis of intracranial aneurysms (IA) is largely unknown. Previous genetic association studies have identified six risk loci, explaining only a minor part of disease heritability.

Methods

We performed a genome-wide association study (GWAS) in over 10,000 ruptured and unruptured IA cases and 300,000 controls of European and East-Asian descent. To dissect the genetic architecture we used recent techniques, including LD-score regression, genetic correlation analysis, mendelian randomization, and drug target enrichment analysis.

Results

Eleven novel risk loci were discovered. More than half of the heritability of IA can be explained by genetic variants tagged in this study, and the heritability is polygenic. The risk loci between ruptured and unruptured IA were highly similar, and the genetic correlation between these traits was nearly 100%. Heritability enrichment was found in endothelial cells. Blood pressure and smoking play independent, causal roles in IA development. Genetic correlation with other cerebrovascular traits, and other aneurysms types was found, and was driven mainly by blood pressure and smoking. Finally, an enrichment of genetic association was found in genes targeted by anti-epileptic drugs.

figure1_miami-50.jpg

Conclusions

This study identified 17 risk loci for IA, including 11 novel ones and showed strong evidence for a polygenic architecture. The main genetic drivers of IA development and the genetic overlap with stroke-related traits are the clinical risk factors blood-pressure and smoking. This study provides a major advance in the pathogenesis of IA, and provides novel insights in the pathophysiology as well as potential treatment options.

Trial Registration Number

Not applicable

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GENETIC INFLUENCES ON EARLY NEUROLOGICAL INSTABILITY AFTER ACUTE ISCHEMIC STROKE: GENISIS RESULTS

Session Type
Plenary
Date
07.11.2020, Saturday
Session Time
04:45 PM - 06:15 PM
Room
Hall A
Lecture Time
05:55 PM - 06:05 PM

Abstract

Background And Aims

Following acute ischemic stroke (AIS) onset, neurological deficits can be highly unstable within the first 24 hours. We hypothesized that early change (ΔNIHSS=NIHSSbaseline–NIHSS24hours), could serve as a quantitative phenotype to capture the genetic architecture of ischemic brain injury.

Methods

AIS patients were prospectively enrolled between 2008-2019 at 7 sites (N=4,876). NIHSS scores were obtained within 6 hours and at 24 hours after stroke onset. Genotyping was generated and imputed. ΔNIHSS was used as a quantitative trait in an association model, with baseline NIHSS, age, sex, PCA1, PCA2, TOAST classification and genotyping round as covariates. All samples were analyzed by site. Fixed effect meta-analysis was used to collapse each ethnic group and a trans-ethnic meta-analysis to collapse all ethnicities. GWAs hits were functionally annotated with bioinformatics tools. Finally, the genetic architecture overlap between ΔNIHSS and stroke risk was explored.

Results

Variance analyses revealed that 6.86% of the variance of ΔNIHSS is explained by genetics. We found eight GWAS significant locus–Figure 1. After deep functional annotation and Mendelian randomization analyses, we identified ADAM23, GRIA1 and ABCB5 as the main driving genes; being the first two expressed in neurons according to our single-nuclei RNAseq dataset (70 brains and 100,000 cell nucleus). We did not find any significant genetic overlap between ΔNIHSS and stroke risk.figure1.png

Conclusions

Early neurological outcome after AIS is influenced by genetics, but does not share the same architecture as stroke risk. ADAM23 and GRIA1 appear to play a role in modulating trans-synaptic excitability, suggesting a role in excitotoxicity in the setting of AIS.

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NOVEL MRI-BASED RISK SCORES FOR INTRACRANIAL HAEMORRHAGE AND ISCHAEMIC STROKE IN PATIENTS TAKING ANTITHROMBOTIC THERAPY: A POOLED ANALYSIS FROM THE MICROBLEEDS INTERNATIONAL COLLABORATIVE NETWORK

Session Type
Plenary
Date
07.11.2020, Saturday
Session Time
04:45 PM - 06:15 PM
Room
Hall A
Lecture Time
06:05 PM - 06:15 PM

Abstract

Group Name

on behalf of the Microbleeds International Collaborative Network

Background And Aims

Balancing the risks of recurrent ischaemic stroke (IS) and intracranial haemorrhage (ICH) is an important consideration in patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack; however, existing predictive models offer limited performance, particularly for ICH. We aimed to develop new risk scores incorporating cerebral microbleeds, an MRI biomarker of ICH and IS risk.

Methods

We developed Cox regression models using data from the Microbleeds International Collaborative Network of prospective observational studies, selecting variables for inclusion on biological relevance and availability. We excluded participants not taking antithrombotics, missing necessary variables, or from heterogeneous centres, leaving 14,526 participants from 36 centres and 13,598 participants from 33 centres with follow-up for ICH and IS respectively. Models were simplified using backward elimination at p > 0.2, and regression coefficients scaled and rounded. We validated our models internally using bootstrapping, and compared predicted to observed risk using Kaplan-Meier plots.

Results

Figures 1 and 2 show variables put forward for backward elimination, the resulting models, and the derived risk scores. Optimism-adjusted c-indices were 0.70 (0.66-0.76) and 0.61 (0.59-0.63) for ICH and IS respectively; calibration slopes were 0.92 (0.76-1.08) and 0.95 (0.83-1.08). Predicted and observed risk were similar across population tertiles (figure 3). Eighty-five participants (0.64%) had a predicted risk of ICH greater than that of IS.

figure 1_revised_rescaled.png

figure 2_revised_rescaled.png

figure3_rescaled_resized.png

Conclusions

A score incorporating cerebral microbleeds offers good discrimination and excellent calibration for predicting ICH. Only a few patients had a higher predicted risk of ICH than IS. External validation and direct comparison with existing risk scores is required.

Trial Registration Number

Not applicable

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