Welcome to the ESOC 2021 Virtual Conference Calendar

Background And Aims

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on WMH volume, the contribution of rare variants to WMH burden in the general population remains largely unexplored.

Methods

We conducted a comprehensive analysis of WMH burden in the UK Biobank using publicly available whole-exome sequencing data (N=16,511)

Results

Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 to associate with increased WMH volume (p=5.5E-6). Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (p=9.4E-8). The frequency of such variants in the UK Biobank population was 1 in 450. WMH volume was brought forward by approximately 11 years in carriers of a rare protease domain variant. A comparison with established risk factors revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than being in the upper 99.8% percentile of a polygenic risk score based on common genetic variants. In biochemical experiments, most (6/9) of the identified protease domain variants resulted in reduced protease activity. We further found EGFL8 to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries.

Conclusions

Collectively, these findings highlight an important role of rare genetic variation and of the HTRA1 protease in determining WMH burden in the general population.

Group Name

On behalf of the International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group

Background And Aims

There is currently no clinically relevant risk model for intracranial aneurysms (IA), and phenotypic heterogeneity makes assessing risk of rupture of an IA difficult. Recently, we performed the largest genome-wide association study (GWAS) of IA and subarachnoid hemorrhage (SAH) and explained over half of the genetic contribution to IA. How this genetic risk precisely relates to aneurysm characteristics and rupture risk is still unclear.

Methods

We constructed a genetic risk score (GRS) for IA, by using GWAS summary statistics for IA and its risk factors: a metaGRS. The metaGRS was trained using UK Biobank genotype data and IA status.

In the largest cohort of patients with an IA and with detailed phenotypic information (N=5,560), we associated the metaGRS with aneurysm location, multiplicity, family history, rupture, location, age- and size at rupture. Associations were tested by linear regression, using sex and cohort as covariates.

Results

Persons with an IA that ruptured at a younger age had an increased genetic risk (P=1.82e-8), while persons with an aneurysm at the internal carotid artery had a lower genetic risk (P=0.0041). A nominally significantly higher genetic risk was found in persons with multiple aneurysms versus one aneurysm (P=0.010). All of these effects were independent of smoking and hypertension status.

Conclusions

We found a strong link between genetic risk of IA and IA characteristics. Understanding what drives phenotypic heterogeneity, and using genetic risk scores to identify persons at risk, could have a substantial impact on monitoring IA and preventing SAH.

Trial Registration Number

Not applicable

Background And Aims

Unruptured intracranial aneurysms (UIAs) not undergoing preventive treatment are often followed radiologically to detect aneurysm growth, which is associated with an increased risk of rupture. We aimed to determine the absolute risk of aneurysm rupture after detection of growth.

Methods

In this observational study, we included patients ≥18 years from 15 international cohorts with ≥1 UIA with growth. Growth was defined as ≥1 mm increase in at least one direction. We calculated the absolute risk of rupture at six months, one year, and two years. Hazard ratios (HRs) with 95% CIs were generated. A prediction model was built to estimate an individualized risk of rupture after detection of growth.

Results

We screened 5166 patients who had follow-up imaging for 6928 UIAs, and included 312 patients with 329 aneurysms with growth during follow-up. During 864 aneurysm-years of follow-up after detection of growth, 25 (7.6%) aneurysms ruptured. The absolute risk of rupture after growth was 2.9% [95%CI:0.9-4.9%] at six months, 4.3% [95%CI:1.9-6.7%] at one year, and 6.0% [95%CI:2.9-9.1] at two years. In multivariable analyses, predictors of rupture were size (≥7 mm: HR 4.3 [95%CI:4.1-13.0]), shape (irregular: HR 2.9 [95%CI:1.3-6.4]) and site (middle cerebral artery: HR 3.6 [95%CI:0.7-16.3]; anterior cerebral artery/posterior communicating artery/posterior circulation: HR 2.8 [95%CI:0.6-13.0])). In the triple-S (size, site, shape) prediction model, the one-year risk of rupture ranged from 2.1% to 10.6%.

Conclusions

Our newly developed triple-S prediction model can be used by physicians to estimate absolute risks of rupture for the initial period after detection of aneurysm growth.

Group Name

on behalf GeneStroke Consortium and International Stroke Genetics Consortium.

Background And Aims

The genetic architecture of cardioembolic stroke (CES) is still poorly understood. Atrial fibrillation (AF) is the main cause of CES, with which it shares heritability. We aimed to discover novel loci associated with CES by performing a Multitrait Analysis of the GWAS (MTAG) with atrial fibrillation genetic data.

Methods

For the MTAG analysis we used the MEGASTROKE cohort, which comprises European patients with CES and controls (n=362,661) and an AF cohort composed of 1,030,836 subjects. Regional genetic pleiotropy of the significant results was explored using an alternative Bayesian approach, GWAS-pairwise method. As replication we performed Genome Wide Association Studies (GWAS) for CES and AF in an independent cohort comprising 9,128 subjects.

Results

MTAG analysis revealed 40 novel and significant loci (p-value<5x10^-8) associated with CES, four of which had not previously been associated with AF. Interestingly, 51 AF risk loci were not associated with CES. Gene Ontology (GO) analysis revealed that these exclusive AF genes from the 51 loci participate in processes related mainly to cardiac development, whereas genes associated with AF and CES participate mainly in muscle contraction and the conduction of electrical impulses. A significant replication was assessed for five novel loci showing a p-value<0.05 in the CES vs controls analysis, being one of them a locus not previously described associated to AF.

Conclusions

This study expands the number of loci associated with CES, replicates five of them and provides novel insights into the pathogenesis of CES, highlighting multiple candidate genes for use in future functional experiments.

Trial Registration Number

Not applicable

Group Name

Microbleeds International Collaborative Network (MICON)

Background And Aims

Whether statins increase the risk of intracranial hemorrhage (ICrH) after ischemic stroke (IS) in the presence of cerebral microbleeds (CMB) is uncertain. We investigated whether statins are associated the risk of IS recurrence or ICrH for patients with IS and CMB.

Methods

Pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), including 38 hospital-based prospective cohort studies from 18 countries. All patients had previous IS or transient ischemic attack, had a baseline MRI allowing CMB quantification (0/≥1/≥2/≥5/≥10) and distribution (lobar/non-lobar/mixed), registered statin use after the IS (high/moderate/low-intensity), and follow-up ≥3 months. The primary outcome was the occurrence of recurrent IS or ICrH, and secondary outcomes were IS alone or ICrH alone, during follow-up. We used Cox regression models (adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs) to investigate the association of statins with the outcomes.

Results

Among 16,632 patients, 4,743 had ≥1 CMB, and a median follow-up of 1·03 years (IQR: 0·32-2·16) The adjusted hazard ratio (aHR) comparing patients with CMB and statins with those without statins was 0·68 (95% CI 0·56-0·84) for the composite outcome; 0·65 (95%CI 0·51-0·82) for IS; and 0·73 (0·46-1·15) for ICrH. Results in aHR were similar when considering anatomical distribution, number of CMB, statin intensity, or in patients without CMB.

Conclusions

These observational data suggest that statins were associated with a lower risk of all stroke after IS in patients with CMB, regardless of CMB anatomical distribution or burden, with no increase in the risk of ICrH.

Trial Registration Number

Not applicable

Group Name

on behalf of the PROGRESS Collaborators

Background And Aims

People with stroke and transient ischemic attack (TIA) have greater risk of cognitive decline (CD) and dementia. This study determined the effect of randomized blood pressure (BP) lowering and major predictors for CD/dementia in stroke/TIA in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) randomized controlled trial.

Methods

PROGRESS included 6,105 patients with prior stroke/TIA. Multinomial logistic regressions were used to estimate odds ratios (OR) for predictors of CD/dementia, with death considered as a competing risk, and evaluated the effect modification of sex.

Results

Over a median 4-year follow-up, 779 CD/dementia (31% women) were recorded. Active treatment was associated with lower odds of CD/dementia (OR:0.85, 95% confidence interval:0.73–0.99), with no evidence of a sex difference. Higher baseline cognitive function (0.84, 0.82–0.86 (per point in Mini-Mental State Examination) and longer years of education (0.96,0.94–0.98 (per year)) were associated with lower odds of CD/dementia. Higher diastolic BP (1.11, 1.03–1.20 (per 10 mmHg)), low estimated glomerular filtration rate (eGFR, <60 ml/min/1.73m²) (1.55,1.20–2.01), and peripheral arterial disease (1.86,1.32–2.61) were associated with greater odds of CD/dementia. Greater dependency and disability, and residual neurological signs were all associated with greater odds of CD/dementia than their comparators. Women had lower odds of CD/dementia than men (0.77,0.63–0.95), low eGFR was more strongly associated with CD/dementia in women than men, and diabetes was more strongly associated in men than women.

Conclusions

Several factors were associated with CD/dementia in people with stroke/TIA. The long-term cognitive sequelae of stroke should be taken into consideration to strengthen the joint prevention strategies for stroke and dementia.

Trial Registration Number

This trial was not registered because patients were enrolled before July 1, 2005.

Background And Aims

Non-valvular atrial fibrillation (NVAF) is associated with an increased risk of dementia. Thus, we assessed whether the use of OACs may decrease the risk of dementia in this population.

Methods

Using the Clinical Practice Research Datalink, a UK primary care database, we formed a cohort of all patients aged 50 years or more, with an incident diagnosis of NVAF (cohort entry) between 1988 and 2017 and no prior OAC use, with follow-up until 2019. Patients were considered unexposed until six months after their first OAC prescription and exposed thereafter until the end of follow-up. We used time-dependent Cox regression to estimate adjusted HRs with 95% CIs for dementia associated with OAC use, compared with non-use.

Results

The cohort included 142,227 NVAF patients, with 8,023 cases of dementia over a mean follow-up of 4.7 years (incidence rate 12.1; 95% CI: 11.9-12.4 per 1,000 person-years). OAC use decreased the risk of dementia (HR: 0.90; 95% CI: 0.85-0.94), compared with non-use. A restricted cubic spline also suggested a decreased risk of dementia, reaching a low at approximately 1.5 years of cumulative OAC use and stabilizing thereafter. Moreover, OAC use decreased the risk in patients aged ≥75 years (HR: 0.84; 95% CI: 0.80-0.89), but not in those younger. The decrease in risk did not vary according to sex.

Conclusions

In patients with incident NVAF, OAC use decreased the risk of dementia, evident after 1-2 years of OAC use.

Trial Registration Number

Not applicable

Group Name

CVST After Immunisation Against COVID-19 (CAIAC) Collaborators

Background And Aims

A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous sinus thrombosis (CVST) is its most common manifestation but has not previously been described in detail. Our objectives were to document the features of post-vaccination CVST with and without VITT and to assess whether VITT is associated with a worse outcome.

Methods

We collected clinical characteristics, laboratory results and radiological features on admission of patients with CVST following vaccination against COVID-19. We compared the VITT and non-VITT groups for the proportion of patients who were dead or dependent at the end of admission.

Results

70 patients with CVST following vaccination against COVID-19 had VITT, and 25 did not. The median age of the VITT group (47 years) was lower than in the non-VITT group (57 years, p=0.0045).

Patients with VITT-associated CVST had more intracranial veins thrombosed (median 3) than non-VITT patients (median 2, p=0.041) and more frequently had extracranial thrombosis (44%) than non-VITT patients (4%, p=0.0003).

Death or dependency (mRS 3-6) occurred more frequently in VITT-associated CVST (47%) than in non-VITT CVST (13%, p=0.0020). This adverse outcome was less frequent in VITT patients who received non-heparin anticoagulation (36%) than in those who did not (75%, p=0.0031) and in those who received intravenous immunoglobulin (40%) than in those who did not (73%, p=0.022).

Conclusions

CVST is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin may improve outcome of VITT-associated CVST.

Trial Registration Number

Not Applicable (Surveillance Study)