bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 38: New Mutations Linked to Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Africa and North America
Authors: Olowu Adeola , Septien Spence , Khera Alka , Warnack Worthy , Shang Ty
Published: June 2021

Introduction:
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary disease. It is linked to mutations in the high-temperature requirement A serine peptidase 1 gene (
HTRA1
). The clinical presentation is characterized by cerebral small vessel disease, alopecia, and spondylosis. CARASIL was initially thought to be a recessive disorder and exclusively exist in Asian populations. The paradigm of CARASIL has recently expanded. Genetically confirmed heterozygous mutations and manifestation in other ethnicities were reported. A few cases were reported in Hispanic and Caucasian populations but none in the African population. Here we report a new homozygous mutation in a Hispanic male and a known heterozygous mutation in an African female.

Methods:
Patients underwent routine ischemic stroke work up and risk factor management. MRI brain results were consistent with severe small vessel disease out of proportion to age. Genetic testing for vascular dementia for
NOTCH-3
and
HTRA1
in Patient 1 and only
HTRA1
in Patient 2 were performed through Mayo Clinic.

Results: Table 1. Patient Characteristics and
HTRA1
Mutations

Discussion:
The prevalence of CARASIL is unknown but probably underestimated. Since the recognition of heterozygous
HTRA1
mutation in CARASIL, more cases of heterozygous
HTRA1
mutations have been reported. One of the clinical CARASIL triad -alopecia was not reported or observed in our cases. Cases of CARASIL without alopecia have been reported. Thus, CARASIL should still be suspected in the appropriate clinical presentation even if there is no classic triad or in non-Asian populations. Our cases expanded CARASIL mutations and affected populations. Being more aware of the broad clinical presentation of CARASIL can lead to early diagnosis.
Abstract 4: RESILIENT Collaterals and 24-Hour Infarct Growth: Revascularization is Essential
Authors: Liebeskind David S , Rebello Leticia C , Silva Gisele S , Abud Daniel G , MontAlverne Francisco Jose , Pontes-Neto Octavio , Faria Mario B , Lima Fabricio O , Frudit Michel , Cardoso Fabricio B , Carbonera Leonardo , Oliveira-Filho Jamary , Haussen Diogo C , Wagner Mario , Saver Jeffrey L , Martins Sheila O , Nogueira Raul G ,   for the RESILIENT Investigators
Published: June 2021

Background:
The RESILIENT randomized trial of endovascular therapy for anterior circulation stroke within 8 hours of symptom onset excluded subjects with poor collaterals. We analyzed the relationship of CTA collateral grade with respect to subsequent infarct growth over 24 hours, with and without revascularization.

Methods:
The independent RESILIENT imaging and angiography core lab scored baseline CTA Tan collateral grade (0-3) and CT ASPECTS scores at baseline and 24 hours in both arms. ASITN collateral grade (0-4) was adjudicated prior to revascularization in the interventional arm. Descriptive statistics, univariate, multivariate and ANOVA related CTA collateral grade with 24-hour infarct growth.

Results:
210/221 (95%) subjects (median age 67 (53-76) years; 48% women) in RESILIENT had baseline single-phase CTA available to the core lab evaluation. CTA collateral grade was complete (grade 3) in 106 (50.5%), grade 2 (50-99%) in 68 (32.4%), grade 1 (1-49%) in 36 (17.1%), with no collaterals in 0. The extent of collaterals was more robust in the medical arm (55.0% grade 3, 31.4% grade 2, 13.3% grade 1) compared to the interventional arm (45.7% grade 3, 33.3% grade 2, 21.0% grade 1), although this finding was not statistically significant (p=0.11). In the interventional arm, the extent of CTA collaterals had a strong correlation with ASITN grade (ρ=0.59, p<0.001). Overall, the median baseline ASPECTS (n=210) was 8 (range 6-10) with CTA grade 3 collaterals, 8 (5-9) with grade 2 and 7 (2-10) with grade 1. For 24-hour ASPECTS (n=202) the median was 6 (range 0-10) with CTA grade 3 collaterals, 4 (0-8) with grade 2 and 3 (0-7) with grade 1. 24-hour infarct growth (n=200) was greater in those with worse collateral grade, p<0.001. 24-hour infarct growth was more pronounced in the medical arm compared with subjects treated with revascularization in the interventional arm, p<0.01. Multivariate analysis showed that 24-hour infarct growth was worse in the medical arm, despite more extensive collaterals at baseline p=0.001.

Conclusions:
In RESILIENT, CTA collateral grade was linked with higher ASPECTS and less infarct growth over 24 hours. Despite more robust collaterals in the medical arm, greater infarct growth occurred without revascularization or endovascular therapy.
Abstract 40: Time Course of Cerebral Small Vessel Disease Lesions and Sensory Motor Changes in Spontaneously Hypertensive Stroke Prone Rats
Authors: Caceres Eder , Rink Cameron , Zweier Jay L , Hannawi Yousef
Published: June 2021

Introduction:
Animal models of human cerebral small vessel disease (CSVD) are important for the study of the disease underlying mechanisms and testing therapeutic interventions. Spontaneusly Hypertensive Rats - Stroke Prone (SHRSP) are used as an animal model of human CSVD. However, there is a lack of data regarding the time course of cognitive and motor impairment.

Methods:
Male age-matched SHRSP and Wistar Kyoto rats (WKY) were studied. Sensorimotor testing (open field test) and tail-cuff systolic blood pressure (SBP) measurements (Visitech Systems, Inc.) were performed weekly starting from 6 until 24 weeks of age. Brain MRI at 7 and 24 weeks was acquired using a 9.4T MRI system. Brain histology was completed at the same time points. Statistical analysis was performed using a linear mixed model with repeated measurements. P< 0.05 was considered significant.

Results:
20 SHRSP and 20 WKY male rats were studied. 10 per group were euthanized following brain MRI at 7 weeks and the rest were followed until 24 weeks. SHRSP weighed on average 30 grams less than WKY throughout the study (P=0.0003). At 7 weeks SBP was not different (WKY 106.6±5.4 vs SHRSP 120.8±5.4, P=0.06). SHRSP started to develop hypertension at 9-12 weeks and maintained hypertension until 24 weeks (average group difference across time P<0.0001; SBP at 21 weeks WKY 134.8±5.4 vs SHRSP 168.9±5.4, P<0.0001). Sensorimotor testing showed higher total distance travelled (TDT) at 7 weeks in SHRSP that trended down with ageing. Both groups became similar at 21 weeks (TDT: at 7 weeks WKY 3.78±1.3 vs SHRSP 7.8±1.3, P =0.037; at 21 weeks: WKY 4±1.3 vs SHRSP 4.4±1.3, P=0.83; average group difference across time P=0.014). Brain MRI was normal at 7 weeks, but small white matter hyperintensities were seen at 24 weeks. Brain Histology showed normal histology on hematoxylin & eosin staining at 7 weeks in both groups, while at 24 weeks SHRSP showed CSVD histopathological changes including microbleed formation, homeostasis and vascular hyalinosis.

Conclusions:
SHRSP develops hypertension, sensorimotor deficits and CSVD pathology as they age suggesting their utility as human CSVD model. Intervention time points should be selected carefully in future therapeutic drug interventions.
Abstract 43: Readmission for Depression and Suicide Attempt Following Stroke and Myocardial Infarction
Authors: Erdman John H , Kornspun Alana , Stein Laura K , Rossi Kyle C , Tuhrim Stanley S , Dhamoon Mandip S
Published: June 2021

Introduction:
Depression after ischemic stroke (IS) and myocardial infarction (MI) is more common than in the general population and associated with morbidity and mortality. There is a lack of data on the relative risk of depression and suicide attempt (SA) comparing IS to MI, and nationally representative data is needed.

Methods:
The 2013 Nationwide Readmissions Database contains >14 million U.S. admissions. Using validated International Classification of Disease, 9
th
Revision, Clinical Modification Codes in the primary diagnosis position, we identified index admission for IS (weighted n=434,495) and MI (weighted n=539,550) and readmission for depression and SA. To arrive at national estimates, we calculated weighted 30-, 60-, and 90-day readmission rates. We performed Cox Regression to calculate hazard ratios (HR) and 95% confidence intervals (CI) for readmission for depression and SA up to 1 year following IS vs. MI, adjusting for age, depression recorded during the index event, sex, length of stay, income quartile of patient zip code, discharge disposition, alcoholism, estimated severity of illness, and smoking.

Results:
Readmission rates for depression were consistently higher at 30, 60, and 90 days after IS compared to MI (0.04%, 0.09%, 0.12% vs. 0.03%, 0.05%, 0.07%). There was no significant difference in SA readmissions. The HR for readmission due to depression was 1.62 ([1.37-1.92], p=2.49x10
-8
) comparing IS to MI in an unadjusted model and 1.49 [1.25-1.79] in a fully adjusted model. History of depression (3.70 [3.07-4.46], p=2.00x10
-16)
, alcoholism (2.04 [1.34-3.09], p = 8.16x10
-4)
, and smoking (1.38 [1.15-1.64], p = 3.98 x10
-4
) were associated with increased risk of depression readmission. Age >70 years (0.46 [0.37-0.55], p = 7.66 x10
-15
) and discharge home (0.69 [0.57-0.83], p = 1.54 x10
-3
) were associated with reduced risk of depression readmission.

Conclusion:
In conclusion, IS was associated with a greater hazard of readmission for depression compared to MI but there were no differences for SA. Though both are acute ischemic vascular events, the damage to the brain may contribute to depression pathogenesis, and the greater disability from stroke may contribute to higher rates of depression.
Abstract 5: CT Perfusion is Not a Treatment Effect Modifier for Mechanical Thrombectomy in the 0-8-Hour-Window: A Pre-Planned Analysis of the RESILIENT Trial
Authors: Rebello Leticia C , Parente Bruno S , Waihrich Eduardo S , Pontes-Neto Octavio , Abud Daniel G , Montalverne Francisco Jose , Lima Fabricio O , Silva Gisele S , Frudit Michel , Liebeskind David S , Molina Carlos , Freitas Gabriel R , Barbosa Leandro A , Wagner Mario B , Martins Sheila C , Nogueira Raul G
Published: June 2021

Background:
CT perfusion has been increasingly used as a selection tool in acute reperfusion therapies. However, it remains unknown whether its use is associated with a higher treatment benefit in patients undergoing thrombectomy. We sought to evaluate the interaction between imaging selection modalities and treatment effect in the RESILIENT Trial.

Methods:
RESILIENT was a randomized, prospective, multicenter, controlled trial evaluating the safety, efficacy, and cost-effectiveness of thrombectomy versus medical treatment alone in Brazil. A total of 221 patient were enrolled. The trial showed a strong benefit of thrombectomy (90-day mRS ordinal shift, OR 2.28 95%CI [1.41-3.70]; p=0.001). Key imaging selection criteria included ASPECTS ≥6 on non-contrast CT (NCCT) and the exclusion of malignant collateral profile on CT angiography. The use of automated CT perfusion software (RAPID, IschemaView) was optional but was made available in some centers with the pre-specified plan to compare imaging selection modalities. The primary end-point was the common odds ratio (cOR) of mRs at 90 days (shift analysis) and the main secondary endpoint was the rate of functional independence (mRS 0-2) at 90 days. Ordinal logistic and binary regression analyses with imaging selection modality (NCCT versus CTP) as an interaction term were performed with adjustments for potential confounders including age, baseline NIHSS score, occlusion site, IV tPA use and ASPECTS. A p value < 0.05 was considered statistically significant.

Results:
CTP was performed in 41% of the thrombectomy group and 45% in the control group. There was no significant difference in the treatment effect size for patients selected on the basis of NCCT and CTA only versus those submitted to CTP in terms of overall functional disability (ordinal mRS shift: aOR: 2.87, 95%CI [1.47-5.61] vs. 2.10, 95%CI [1.01-4.36]; p=0.390) or functional independence (mRS 0-2: aOR: 3.16, 95%CI [1.32-7.57] vs. 2.54 95%CI [0.86-7.49], p=0.40) at 90 days.

Conclusion:
In a randomized clinical trial of thrombectomy within 8 hours of stroke onset, there was no evidence of difference in the treatment effect size across patients selected with NCCT and CTA alone versus automated CT perfusion software.
Abstract 53: Missense Pathogenic Variants in
ANO1
Predispose to Moyamoya Disease
Authors: Pinard Amélie , He Mu , Rosenfeld Jill A , Ye Wenlei , Guey Stéphanie , Hickey Scott , Lewis Andrea M , Cecchi Alana C , Guo Dongchuan , Aloui Chaker ,   Univ of Washington Cntr for Mendelian Genomics, Bamshad Michael J , Nickerson Deborah A , Tournier-Lasserve Elisabeth , Milewicz Dianna M
Published: June 2021

Introduction:
Moyamoya disease (MMD) is a cerebrovascular disease often causing pediatric onset strokes and characterized by progressive bilateral occlusion of the distal internal carotid arteries and formation of a compensatory network of collateral vessels. Several genes harbor variants that increase the risk for MMD, but the majority of cases of European descent does not have an identified genetic cause.

Hypothesis:
MMD is associated with significant genetic heterogeneity, i.e., many genes in the human genome can be altered to predispose to this condition.

Methods:
To identify novel genes for MMD, exome sequencing was performed on DNA from 145 individuals from 80 families with one or more affected members. Bioinformatics filtering included a CADD (GRCh37-v1.4) score > 20 and a minor allele frequency < 0.0001 in gnomAD (v2.1.1 controls). For a subset of
ANO1
mutant alleles, we characterized the channel activities via patch recording and assessed protein localization in heterologous cell cultures.

Results:
We identified 6 rare variants in
ANO1
(
TMEM16A
), which encodes an evolutionarily conserved calcium-activated chloride channel. One rare heterozygous variant, p.Met658Val (CADD: 22.9, absent in gnomAD), was found in two very distantly related MMD families and segregated with disease in multiple affected members; p.Glu459Lys and p.Arg890Gln were identified in two unrelated affected probands. Through Matchmaker Exchange (MyGene2) collaboration, we identified 3 additional rare variants: homozygous p.Glu170Lys in a consanguineous MMD family, heterozygous p.Thr740Ile in a MMD case and p.Ala333Ser in a case with ischemic stroke. Functional analyses determined that p.Glu170Lys affects channel gating and calcium sensitivity, producing much smaller chloride current, but the channel itself is more sensitive to calcium, which means it is more likely to open.
Ano1
knock out (KO) in mice is lethal by 1 week of age with pathology in multiple organ systems. Smooth muscle cells-specific KO is not lethal, and phenotyping of these mice is ongoing.

Conclusions:
ANO1
is a novel gene predisposing to MMD and future studies will focus on defining the role of ANO1 protein to connect the altered gene to the occlusive lesions observed in MMD patients.
Abstract 54: Investigating Correlations Between Infarct Topography and Long-Term Outcomes Following Neonatal Arterial Ischemic Stroke Using Voxel-Based Lesion-Symptom Mapping
Authors: Mackay Mark T , Chen Jian , Yang Joseph , Stojanovski Belinda , Grunt Sebastian , Slavova Nedelina , Pastore-Wapp Manuela , Steinlin Maja
Published: June 2021

Objectives:
To investigate correlations between infarct topography on acute diffusion weighted MRI, using voxel-based lesion-symptom mapping (VLSM), and later development of cerebral palsy (CP) and neurological impairments, in neonatal arterial ischaemic stroke (AIS).

Methods:
Newborns were recruited from prospective Australian and Swiss pediatric stroke registries. CP diagnosis was based on clinical examination. Language or cognitive-behavioural impairments were assessed using the Pediatric Stroke Outcome Measure dichotomized to good (0-0.5) or poor (≥1), at ≥18 months of age. Infarcts were manually segmented using axial DWI images, and coregistered to the
Melbourne Children’s Regional Infant Brain 2.0
atlas. All lesions were projected to the left hemisphere to obtain binary union masks. VLSM was conducted using MATLAB SPM12 toolbox. A generalised linear model was used to correlate the lesion mask with outcomes. Voxel-wise t test statistics were calculated, and corrected for multiple comparisons using family-wise error rate (FWE).

Results:
85 newborns (55 male) met inclusion criteria. Infarct lateralization was left hemisphere in 62%, right in 8% and bilateral in 29%. At median age 2.1 years (IQR1.9-2.6), 34% developed CP and 42% had neurological impairments. 54 ROIs were correlated with CP (t>4.33; FWE <0.05); the 12 highest correlated ROIs were the superior corona radiata, putamen, anterior corona radiata, insula, thalamus, external capsule, pars triangularis, caudate, lateral orbitofrontal cortex, superior temporal cortex, pars opercularis and precentral cortex. (Figure) No significant correlations were found for poor language or cognitive-behavioural outcomes.

Conclusions:
Cerebral palsy following neonatal AIS correlates predominantly with regions of acute infarction directly involved in motor control, or in functionally connected regions. Brain regions associated with language or cognitive-behavioural impairment are less clear.
Abstract 61: Invisible Symptoms Post-Thrombectomy: Evaluating Psychosocial in Addition to Functional Outcomes
Authors: Seagraves Karen B
Published: June 2021

Background and Purpose:
With increased volume of both young adult stroke patients and mechanical thrombectomy for reversal of LVO, young adult stroke survivors (YASS) are increasingly discharged directly home with minimal neurological deficits. No studies have examined the psychosocial experiences of these YASS and whether these experiences are associated with stroke-specific quality of life (SSQOL). The purpose of this study was to describe YASS post-stroke symptoms, their understanding and perception of those symptoms, and to examine relationships among psychosocial variables: anxiety, depression, fatigue, illness threat perceptions and SSQOL.

Methods:
A cross-sectional, exploratory design was used. YASS 18-55 years of age and 1-18 months post-stroke who received a thrombectomy at a metropolitan CSC and discharged directly home were recruited. Demographic and clinical data (e.g. NIHSS, mRS, TICI scores) were collected from the hospital’s EMR. Participants completed questionnaires to assess psychosocial variables using an online or paper survey. Descriptive statistics and Spearman rho correlations were performed.

Results:
Participants (
N
= 14) had a mean age 45 years (SD = 6.2), were 4-18 months post-stroke, 71% female, 57% Black, and had low discharge NIHSS scores (
M
= 2, SD = 2.6). Five participants had clinically severe fatigue with three borderline cases. There was one case of clinically significant anxiety with one borderline case, and one case of clinically significant depression with three borderline cases. All participants perceived some level of threat of their symptoms, and overall SSQOL was decreased. Higher levels of fatigue, anxiety, depression and illness perception threat were significantly related to lower SSQOL.

Conclusions:
In spite of having minimal to no physical deficits, these YASS described psychosocial symptoms, notably fatigue, that may impact recovery and transition back to the community. Symptom assessments, provision of education, resources and ongoing support before and after discharge home may be beneficial. Standard practice is a 90-day post-procedure patient assessment, however earlier post-procedure follow-up may help providers identify and address these symptoms.
Abstract 63: Infarct Volume and Rate of Edema Growth Predicts Need for Intervention in Patients With Cerebellar Infarction
Authors: Wang Yan , Binkley Michael , Pardon Amanda , Keyrouz Salah , Dhar Rajat , Ford Andria
Published: June 2021

Background:
Predictors of malignant edema in patients with acute cerebellar infarction are understudied. We hypothesized that greater infarct volume and CT-defined edema growth would predict individuals requiring acute intervention.

Methods:
Admissions to a tertiary care neurological ICU with acute cerebellar infarction over three year period were identified. Primary endpoint was defined as needing medical and/or surgical “intervention”: osmotic therapy, extra-ventricular drainage, or surgical decompression. Visible regions of infarct-related hypodensity in the cerebellum were manually outlined on serial CTs to ascertain infarct volumes. Infarct ratio was defined as the ratio of infarct volume to posterior fossa volume on initial CT showing ischemia. Rate in infarct-related edema growth was measured as the change in infarct ratio over time between sequential head CTs.

Results:
Of the 60 patients identified, 27 (45%) received interventions. All except one received osmotic therapy, while 15 patients underwent surgical intervention. Compared with the no-intervention cohort, intervention cohort was more likely to have diabetes (21% vs 48%,
p
= 0.03) and larger initial infarct ratio (0.12 vs 0.22,
p
= 0.001). Diabetes (OR, 6.3 95% CI, 1.6-25.3) and infarct ratio (OR, 3.2; 95% Cl, 1.6-6.3) were independent predictors of intervention. The rate of edema growth was faster in the intervention cohort (time*cohort
p
=0.005) (Fig A). A subgroup analysis of 34 patients with at least 3 CTs showed the intervention cohort had greater edema growth rate (-0.0001/hr vs 0.0044/hr,
p
= 0.02). Multivariate analysis showed edema growth independently predicted intervention (Fig B) and improved the AUC from 0.78 to 0.90 (Fig C), while diabetes was not retained (p=0.056).

Conclusion:
Baseline infarct ratio and rate of edema growth within the first 4 days may provide clinically useful markers to select patients with cerebellar infarction who will benefit from intervention.
Abstract 65: Intrathecal Nicardipine for Cerebral Vasospasm Post Subarachnoid Hemorrhage - A Single Center Experience
Authors: Sadan Ofer , Feng Chen , Pearce David T , Kraft Jacqueline , Pimentel Cederic , Mathew Subin , Akbik Feras , Ameli Pouya A , Taylor Alexis M , Danyluk Lisa , Martin Kathleen S , Garner Krista , Kolenda Jennifer , Pujari Amit , Mei Yajun , Asbury William , Samuels Owen B
Published: June 2021

Introduction:
Cerebral vasospasm leading to delayed cerebral ischemia (DCI) is one of the most significant factors impacting functional outcome in patients diagnosed with non-traumatic subarachnoid hemorrhage (SAH). Effective treatment in this setting is lacking. We now report a single center retrospective cohort experience with intrathecal (IT) Nicardipine for this indication.

Methods:
All patients discharged between 2013-2017 diagnosed with non-traumatic SAH, either aneurysmal or idiopathic, were included in the analysis. Demographics, risk factors, clinical courses, radiological DCI, and functional outcomes were analyzed.

Results:
1,085 patients were admitted with aneurysmal (n=796) or idiopathic (n=289) SAH. The mean age was 54.5±14.1 and 67.7% were women. Low grade hemorrhage (WFNS 1) was found in 42.4%, medium (WFNS 2-3) in 26.9%, and high grade (WFNS 4-5) in 30.7%. Cerebral vasospasm was diagnosed in 36.6% of the patients, and 85.4% of those received IT Nicardipine (n=339). Only 8.4% of all patients required angiography to treat vasospasm. TCD data was available for 159 patients who received IT Nicardipine. Treatment reduced mean velocities in all arteries within one day by 15.4% on average (p<0.01). This reduction was sustained for the duration of treatment. Nineteen patients (1.8%) suffered from bacterial ventriculitis, and no statistically significant correlation was noted between IT treatment and infection (OR 1.06 95%CI[0.42-2.7]). The incidence of radiological DCI, identified by blinded assement of imaging, was 9.4% and clinical DCI was 5.7%. In this cohort, 65.5% had a favorable functional outcome (mRS≤2) at 90 days.

Conclusions:
In a retrospective analysis, off-label IT Nicardipine is a safe and potentially effective treatment for cerebral vasospasm and prevention of the subsequent cerebral ischemia. Being the largest of its kind, this cohort could serve as a baseline for future clinical trial designs assessing IT Nicardipine safety and efficacy in a prospective, controlled fashion.
Abstract 66: Causal Associations Between Genetically-determined Smoking and Risk of Subarachnoid Hemorrhage
Authors: Acosta Julian N , Both Cameron , Brown Stacy , Leasure Audrey , Vanent Kevin N , Noche Rommell B , Kirsch Elayna P , Petersen Nils , Matouk Charles C , Gunel Murat , Gill Thomas M , Sheth Kevin N , Falcone Guido J
Published: June 2021

Introduction:
Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and SAH has not been established. We leveraged the causal properties of mutation-disease associations to test the hypothesis that smoking is causally linked to SAH.

Methods:
We conducted a one-sample Mendelian Randomization (MR) study within the UK Biobank, a prospective, population-based observational study. We restricted the analysis to study participants with genetically-confirmed European ancestry. SAH cases were ascertained using previously validated codes. As the instrument, we built a polygenic risk score (PRS) using independent (R2<0.1) genetic variants known to be associated (p<5x10-8) with smoking. For the primary MR analysis, we implemented the ratio method using the estimates obtained from testing the PRS for association with risk of SAH and smoking. In secondary analyses, we implemented the inverse-variance weighted (IVW) and weighted median (WM) methods. Pleiotropy was assessed via the MR-Egger approach.

Results:
We included a total of 408,622 individuals in this study (mean age 57 [SD 8], female sex 220,944 [54%]). Of these, 132,568 (32%) ever smoked regularly and 904 (0.22%) had an SAH. Each additional standard deviation of the smoking PRS was associated with a 9% increased risk of SAH (OR 1.09, 95%CI 1.03-1.17; p=0.006) and 21% increased risk of smoking (OR 1.21, 95%CI 1.2-1.21; p=1x10-16). In the primary analysis, genetically-determined smoking was associated with a 63% increase in risk of SAH (OR 1.63, 95%CI 1.15-2.30; p=0.006). Secondary analyses using the IVW method (OR 1.57, 95%CI 1.13-2.17; p=0.007) and the WM method (OR 1.74, 95%CI 1.06-2.86; p=0.028) yielded comparable results. There was no significant pleiotropy (MR-Egger intercept p=0.38).

Conclusion:
Genetically-determined smoking is strongly associated with the risk of SAH. These findings provide evidence for a causal link between smoking and the occurrence of this often-debilitating condition. Interventions aimed at reducing smoking behavior could offer significant benefits, especially to those at high risk of SAH.
Abstract 69: Trans-eQTL Analysis of Blood After Ischemic Stroke Reveals X-Linked SNP-Gene Relationships
Authors: Amini Hajar , Shroff Natasha , Sitorus Preston P , Carmona-Mora Paulina , Hull Heather , Ferino Eva , Zhan Xinhua , Stamova Boryana , Jickling Glen C , Sharp Frank R , Ander Bradley P
Published: June 2021

Objective:
Single nucleotide polymorphism (SNP) is one of the most common types of genetic variation and likely has a contributing role in ischemic stroke (IS). The influence of SNPs on changes of gene expression in blood after IS remains largely unknown. Thus, we evaluated the association of genetic variants with changes in mRNA expression levels (i.e. expression quantitative trait loci;eQTL) in blood after IS.

Methods:
RNA and DNA were isolated from blood samples collected from 137 IS patients and 138 vascular risk factor controls (VRFC). Gene expression of protein-coding transcripts was quantified by Affymetrix HTA 2.0 microarrays and SNP variants assessed by Axiom Biobank Genotyping microarrays. A linear model with a genotype (SNP)х diagnosis (IS or VRFC) interaction was fit for each SNP-gene pair to identify novel IS diagnosis-dependent eQTL.

Results:
Our
trans-
eQTL interaction analysis found 70 significant SNP-gene pairs (FDR<0.01). Our observations indicated that 24 mRNAs were associated with significant genotype х diagnosis interaction. Among these genes, two X-linked genes
ANOS1
and
POF1B
were found. Expression of
ANOS1
was significantly associated with SNPs rs148791848 and rs149957475. The SNP, rs950391, was significantly associated with expression of
POF1B,
a gene previously shown as sexually dimorphic in stroke. Interestingly, some of the eQTL SNPs affected multiple genes in
trans
that are known to be altered after IS. For example, X-linked SNP rs950391, altered expression of
ABCA6, CLNK, EML6, POF1B,
and
WNT16.

Conclusions:
To our knowledge, this is the first whole-genome study to examine the effect of genotype х diagnosis on gene expression of blood after IS. Some SNP-gene pairs are X-linked and may account for aspects of sexual dimorphism in stroke. Our findings facilitate better understanding of
trans
effects of genetic variation on gene expression in stroke.
Abstract 7: Cerebral Small Vessel Disease Burden and Association With Post-Surgical Rebleeding and Long-Term Outcome in Intracerebral Hemorrhage Patients From the Mistie III Trial
Authors: Li Yunke , Cho Sung-Min , Avadhani Radhika , Ali Hasan , Hanley Daniel F , Ziai Wendy C ,   MISTIE III Investigators
Published: June 2021

Objectives:
To examine the effect of cerebral small vessel disease (CSVD) markers and CSVD burden on hematoma expansion and long-term functional outcomes in large spontaneous intracerebral hemorrhage (ICH) >30 mL.

Method:
Retrospective analysis of 288 patients from the MISTIE III trial with qualified MRI sequences. MISTIE III evaluated minimally invasive surgery plus alteplase (vs medical management). We identified 6 CSVD markers including lacunes, cerebral microbleeds (CMB), enlarged perivascular space (EPVS), white matter hyperintensities (WMH), cortical superficial siderosis (cSS), and acute DWI positive lesions. First 5 components were reviewed on day 1 MRI and DWI lesions on day 7. The primary outcome was death or major disability at one year (modified Rankin score 4-6). Secondary outcome was post-surgical rebleeding, defined as symptomatic or asymptomatic hemorrhage expansion within 72 hours post last dose of alteplase.

Result:
Unfavorable outcome occurred in 65.9% at one year. Post-surgical ICH expansion occurred in 34 (22.9%) of 148 surgical patients. Mean time from symptom onset to first MRI was 0.94 (IQR 0.2-6.3) days. Most individual CSVD markers were more common in patients with unfavorable vs. favorable outcome: CMB≧5 (26.1% vs 15.0%, p=0.03), DWI lesions (65.8%vs 49.6%, p=0.006), cSS (16.8% vs 7.1%, p=0.02) severe WMH (67.7% vs 29.9%, p<0.001) severe EPVS in basal ganglia (19.3% vs 10.2%, p=0.047), and lacunes (11.2% vs 6.3%, p=0.21), In the multivariable adjusted model, cumulative CSVD score (one point for each component: CMB≥5, severe EPVS in basal ganglia, lacunes, severe WMH and cSS) was independently associated with unfavorable outcome (OR 0.56, 95%CI 0.41-0.76, p<0.001; AUC 0.855). We did not find a relationship between either independent CSVD markers or CSVD score with post-surgical ICH expansion. Cumulative CSVD score in multivariable analysis adjusted for predictors of hematoma expansion had OR 0.77 (95% CI 0.50-1.19, p=0.77; AUC 0.659).

Conclusion:
In large volume ICH patients with long-term follow-up, heavy burden of CSVD at ICH onset remains an independent predictor of unfavorable outcome, and particularly severe white matter hyperintensities. CSVD markers did not show association with post-surgical ICH expansion.
Abstract 71: Sex and Genetic Predisposition Synergistically Influence Risk of Stroke and Myocardial Infarction in Middle-Aged Persons Without Risk Factors
Authors: Falcone Guido J , Acosta Julian , Leasure Audrey C , Vanent Kevin N , Noche Rommell B , Kirsch Elayna , Petersen Nils H , Schindler Joseph , Sansing Lauren H , Gill Thomas M , Matouk Charles C , Gunel Murat , Sheth Kevin N
Published: June 2021

Background and Hypothesis:
Driven by aging-related physiological changes, the incidence of stroke and myocardial infarction rises rapidly in persons aged >40 years. A significant proportion of these acute vascular events (AVE) take place in persons without vascular risk factors. We tested the hypothesis that sex and genetic predisposition synergistically increase the risk of AVE in middle-aged persons without vascular risk factors.

Methods:
We analyzed data from the UK Biobank, a prospective longitudinal study that enrolled persons aged 40 to 69 years. Our analysis was restricted to middle-aged participants, defined as those aged 40 to 60 years. Prevalent and incident cases of stroke (ischemic and hemorrhagic) and myocardial infarction were included. To quantify the genetic predisposition to sustain an AVE, we constructed a polygenic risk score using 68 independent (R
2
<0.1) genetic variants known to associate (p<5x10
-8
) with AVE. Participants were classified as having low, intermediate or high genetic risk according to tertiles of the score. We used Cox models for association and interaction testing.

Results:
Of the 502,536 study participants enrolled in the UK Biobank, 303,295 (60%) did not have any vascular risk factors. During the follow-up period, there were 5,746 AVEs, including 1,954 strokes and 3,792 myocardial infarctions. The cumulative risk of AVE was 0.12% (n=352), 0.46% (n = 1,386) and 1.32% (n = 4,008) at ages 40, 50 and 60 years (test-for-trend p<0.001). The risk of AVE was 3 times greater in men than women (HR 3.30, 95%CI 3.08 - 3.53). Compared to persons with low genetic risk, those with intermediate and high genetic risk had a 22% (HR 1.22, 95%CI 1.13 - 1.32) and 52% (HR 1.52, 95%CI 1.41 - 1.65) increase in risk of AVE, respectively. There was significant synergy (interaction) between sex and genetic predisposition: compared to females with low genetic risk, males with high genetic risk had 4 times (HR 3.91, 95%CI 3.58 - 4.26) the risk of AVE (interaction analysis p<0.001).

Conclusion:
Genetic information constitutes a promising tool to risk stratify middle-aged persons without vascular risk factors. The synergistic effect of sex and genetic predisposition points to specific subgroups that could benefit from aggressive preventive interventions.
Abstract 73: Sex Hormone Binding Globulin: A Novel Hormonal Biomarker for Ischemic Stroke Risk?
Authors: Madsen Tracy E , Luo Xi , Huang Mengna , Park Ki , Stefanick Marcia L , Manson JoAnn E , Liu Simin
Published: June 2021

Introduction:
Sex hormone binding globulin (SHBG) is a sex-steroid transporter previously linked to cardiometabolic outcomes such as diabetes (DM) and coronary heart disease and their risk factors. It remains uncertain whether SHBG also affects stroke risk, particularly in women. We investigated whether SHBG affects risk of incident ischemic stroke (IS) among women in the Women’s Health Initiative (WHI).

Methods:
The WHI includes randomized trials and an observational cohort of 161808 postmenopausal women enrolled at 40 sites across the U.S. from 1993 - 1998. We identified 13,192 participants free of prevalent stroke at baseline who were included in one of eleven ancillary studies with serum SHBG. Incident IS events through 2017 were identified via physician adjudication of medical records. We used Cox proportional hazards regression to assess IS risk across quartiles of SHBG levels (Q1 - Q4), first adjusted for demographics, body mass index (BMI), hypertension, alcohol use, and smoking status (Model 1). History of DM was added to remove indirect effects through DM (Model 2), followed by the addition of reproductive risk factors and physical activity (Model 3).

Results:
Of 13,192 participants (mean age 62.5 years, 67.4% non-Hispanic white, 18.5% black, 5.0% Asian, 7.6% Hispanic), 877 IS events were confirmed during follow-up. Compared to the highest SHBG quartile (referent), women in the lowest quartile had a higher risk of IS in all three models (Model 1: HR 1.51, 95%CI 1.23 - 1.86, Model 2: HR 1.46, 95%CI 1.18 - 1.80, Model 3: HR: 1.38, 95%CI 1.07 - 1.76, trend tests p <0.05 for all). Women in the middle quartiles (Q2, Q3) also had increased IS risk compared with those in the highest SHBG quartile (Table).

Conclusions:
In this prospective cohort of post-menopausal women, there was a statistically significant inverse association between SHBG levels and IS risk, which supports the notion that SHBG could be used as a risk stratification tool for predicting IS in women.
Abstract 8:
M
edical
A
pplication Based
P
ost
S
troke Care
S
trategy (MAPSS) for Survivors and Their Caregivers: A Pilot Study
Authors: Khurana Dheeraj , Kumar Ashok , Pattnaik Smita , Modi Manish , Kaur Sukhpal , Ghai Sandhya
Published: June 2021

Background:
Post stroke care is a major challenge in resource poor settings due to lack of trained caregivers. Mobile application(m-app) based care strategy may provide low cost solution to counter this burden.MAPSS tested m- app in a pilot randomised control study on bed ridden stroke patients.

Objectives:
To develop smartphone based medical application for delivering post stroke care strategies and to evaluate its efficacy in reducing post stroke complications.

Methods:
Patients within 3 months of stroke were randomised to either routine care (Controls) or App based care (MAPPS). Major inclusions were: Modified Rankin Score(mRS) >3, caregivers/patients with smartphone and internet facility and willing to use an app as health care tool.Major exclusion: Patients with no caregiver or hired /illiterate caregiver. MAPSS group was additionally given routine care with booklet.
"Stoke Home Care"
app was installed in caregiver smartphone and explained its use.Follow up was at 3 months which was blinded. Primary outcomes were a.) composite incidence of bed-sores, aspiration pneumonia, catheter associated UTI (CAUTI), shoulder pain and deep vein thrombosis (DVT) b.) Patient’s Health related Quality of Life(HRQOL) and Caregiver stress index (CSI).

Results:
166 patients were recruited (83 each group and one caregiver per patient).Mean age was 54.98±15.76 yrs and 73.5% males (Controls were matched);.53% were ischemic strokes.65% had mRS 5,Median NIHSS was 13. At 3 months,3.6% MAPSS vs 6% controls lost to follow up ,12% MAPPS vs 24.1% controls were dead.33.8% MAPSS vs 56.4% controls developed at least one post stroke complication (composite) (P=0.004); 5% MAPSS vs 15.4% control had bedsore (P=0.031). Trend of reduced aspiration pneumonia in MAPSS (P=0.055) seen. Median HRQOL score was 68 (IQR: 50-80) in MAPSS vs 50 (IQR: 38-61) in controls (P=0.001); CSI- 9 (IQR: 5-13) in MAPSS vs 15 (IQR: 13-20) controls(P=0.001). Multivariate analysis favored MAPPS- composite post stroke complications (aOR: 0.311, 95% CI: 0.151 - 0.643; P=0.002) and mRS (3-6) (aOR: 0.312, 95% CI: 0.098 - 0.998; P=0.049)

Conclusions:
MAPPS is superior to routine care in preventing major post stroke complications and associated with better QOL in stroke patients and reduced caregiver stress.
Abstract 82: Differences Between Caucasians and Asians in Intracranial Arterial Stenosis Among TIA and Minor Stroke Patients: Comparisons of Two Contemporary Cohorts
Authors: Leng Xinyi , Hurford Robert , Feng Xueyan , Chan Ka Lung , Li Linxin , Mok Vincent CT , Leung Thomas W , Rothwell Peter M
Published: June 2021

Background:
Despite numerous reports indicating ethnic difference in intracranial arterial stenosis (ICAS) between Caucasians and Asians, there has been no direct comparison in disease burden and clinical correlates of ICAS in stroke patients in the two populations with the same criteria to define ICAS.

Methods:
Acute minor stroke or transient ischemic attack patients who received cerebral MR/CT angiography exam in two cohorts were analyzed: Oxford Vascular Study (OXVASC, 2011-2018) with predominantly Caucasians, and the Chinese University of Hong Kong (CUHK) stroke registry (2011-2015) with predominantly Chinese. ICAS was defined as ≥50% stenosis in any major intracranial artery in MR/CT angiography. Interobserver agreement between 2 investigators for presence of ICAS was assessed in 50 cases with Cohen’s kappa. We compared the burden and risk factors of ICAS in the two cohorts.

Results:
Overall, 1,287 patients from OXVASC (mean age 69 years) and 640 from the CUHK cohort (mean age 66 years) were analyzed. Interobserver agreement for presence of ICAS was good (kappa=0.82). Prevalence of ICAS was significantly higher in Chinese than in Caucasians: 43.6% in the CUHK cohort versus 20.0% in OXVASC (crude OR 3.10; age-adjusted OR 3.81, 95% CI 3.06-4.75; p<0.001). Mean ages of patients with ICAS in the two cohorts were 75 and 68 years, respectively. The difference between Caucasians and Chinese in ICAS prevalence was smaller in those aged ≥70 years (28.1% versus 51.9%) than those <70 years (9.8% versus 38.0%) (Figure). ICAS shared similar risk factors in the two cohorts, including older age, and history of hypertension and diabetes.

Conclusions:
Chinese are more susceptible to ICAS, with an earlier onset age than Caucasians, but the ICAS burden in Caucasians was higher than previously estimated, especially in older patients.
Abstract 87: Eighteen-Year Trends in Ischemic Stroke Rates in a Bi-Ethnic Population
Authors: Lisabeth Lynda D , Brown Devin , Zhang Xingyu , Kim Sehee , Case Erin , Zahuranec Darin , Smith Melinda , Morgenstern Lewis
Published: June 2021

Introduction:
Elevated stroke rates in Mexican Americans (MA) compared with non-Hispanic whites (NHW) persisted over the first decade of the 21
st
century. Our objective was to investigate recent trends in ischemic stroke (IS) rates by ethnicity and age using data from a longstanding population-based study.

Methods:
ISs were identified in the Brain Attack Surveillance in Corpus Christi (BASIC) Project (2000-2017) and validated by neurologists using a clinical definition. Race-ethnicity was from medical records. Annual population counts from the US Census estimated the at-risk population. Poisson regression was used to model sex-adjusted rate trends by ethnicity and age. Time was modeled using linear and quadratic terms. Ethnic differences were assessed using interaction terms between ethnicity and time.

Results:
4,883 ISs were identified (median age 70 (IQR:59-80); 56% MA). Trends varied by ethnicity and age (figure). In those 45-59, rates increased substantially in NHWs (104%; p<0.001 for rate difference 2000-2017) but decreased in MAs (-21.4%; p=0.04 for rate difference 2000-2017) such that, for the first time, rates were higher in NHWs. In those 60-74, rates declined in both ethnic groups through 2010-2011 but then increased and more steeply in NHWs thereafter. In those ≥75, rates declined in MAs, declined sharply in NHWs through 2012 and then increased.

Conclusions:
New patterns in stroke have emerged. Ethnic disparities have declined as a result of increasing rates in NHWs most notably in midlife. Reasons for increasing rates in recent years are unclear but suggest renewed attention to prevention.
Abstract 88: Increasing False Positive Diagnoses May Lead to Overestimation of Stroke Incidence, Particularly in the Young
Authors: Appukutty Abhinav J , Skolarus Lesli E , Springer Mellanie V , Meurer William J , Burke James F
Published: June 2021

Introduction:
Stroke incidence is reportedly increasing in younger adults. While increasing vascular risk factor prevalence has been suggested as a cause, the reasons for rising stroke incidence in the young are not clear. We explored several alternate explanations: trends in neurologically-focused emergency department (ED) visits, differential diagnostic classification of stroke and TIA over time, and changes in the use of advanced imaging in young and older adults.

Methods:
We performed a retrospective, serial, cross-sectional study on a nationally representative sample of all ED visits in the United States to quantify changes in patterns of neurologically-focused ED visits, stroke and TIA diagnoses, and rates of MRI utilization for young (18 – 44 years) and older (65+ years) adults over a 17-year period (1995 – 2000; 2005 – 2015) using National Hospital Ambulatory Medical Care Survey (NHAMCS) data.

Results:
In young adults, 0.4% (95% CI 0.3% – 0.5%) of neurologically-focused ED visits resulted in a primary diagnosis of stroke vs. 6.8% (95% CI 6.2% – 7.5%) for older adults. In both populations, the incidence of neurologically-focused ED visits has increased over time (+111/100,000 population/year, 95% CI +94 – +130 in the young vs. +70/100,000 population/year, 95% CI +34 – +108 in older adults). There was no evidence of differential classification of TIA to stroke over time (OR 1.001 per year, 95% CI 0.926 – 1.083 in the young; OR 1.003 per year, 95% CI 0.982 – 1.026 in older adults) and no evidence of disproportionate rise in MRI utilization for neurologically-focused ED visits in the young (OR 1.057 per year, 95% CI 1.028 – 1.086 in the young; OR 1.095 per year, 95% CI 1.066 – 1.125 in older adults).

Conclusions:
If the specificity of stroke diagnosis amongst ED visits is similar amongst young and older populations, then the combination of data observed here, including (1) a lower prior probability of stroke diagnoses in the young and (2) an increasing trend in neurologically-focused ED visits in both age groups, suggests that false positive diagnoses will increase over time, with a faster rise in the young compared to older adults. These data suggest a potential explanation that may contribute to higher stroke incidence in the young and merits further scrutiny.
Abstract 92: Stroke Survivors Experience Greater Decline in Life’s Simple 7 Score for Cardiovascular Health Over 10-Year Follow-Up
Authors: Liu Chelsea , Roth David L , Sheehan Orla C , Blinka Marcela D , Gottesman Rebecca
Published: June 2021

Introduction:
Life’s Simple 7 (LS7) is a measure of cardiovascular health based on seven domains of smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. Due to secondary prevention efforts, stroke survivors may experience improvements in LS7 scores over time compared to those who did not experience a stroke.

Methods:
We included participants over 45 years of age enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who had LS7 data at baseline and 10-year follow-up and did not report a history of stroke at baseline (N=7568). Of these, 361 had an adjudicated ischemic stroke between the LS7 assessments. Scores on each domain of LS7 range from 1-3 for a maximum total score of 21, where a higher score represents better cardiovascular health. A general linear model was used to test the association of having an ischemic stroke on the change in LS7 score. Covariates included the LS7 score at baseline, age, race, gender, cognitive status, and education.

Results:
Findings indicated that those who were younger, African American, and had lower levels of education, experienced significant decline in LS7 scores from baseline to follow-up (Table 1). Those who had a stroke also experienced, on average, 0.25 points more decline in total LS7 scores than those who did not have a stroke (p=0.048).

Conclusions:
Stroke survivors did not experience improvements in cardiovascular health due to secondary prevention after an ischemic stroke. On the contrary, they experienced significantly greater decline, indicating the need for greater efforts in lifestyle modification and secondary prevention after a stroke.