bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 150: Trans-ethnic GWAS of Mri-defined Brain Infarcts: Charge Consortium
Authors: Chauhan Ganesh , Adams Hieab H , Bis Joshua C , Smith Albert V , Beecham Ashley H , Xue Flora , Trompet Stella , Luciano Michelle , Liao Jiemin , Lee Sven v , Guðnason Vilmundur , Wright Clinton B , Schmidt Helena , Grabe Hans , Sacco Ralph L , Craen Ton d , Wardlaw Joanna , Mosley Thomas H , Rajan Kumar B , DeCarli Charlie , Ikram M K , Duijn Cornelia M , Schmidt Reinhold , Fornage Myriam , Launer Lenore J , Tzourio Christophe , Ikram M A , Seshadri Sudha , Longstreth W T , Debette Stephanie
Published: March 2022

Introduction:
MRI-defined brain infarcts (BI), most of which are small sub-cortical brain infarcts (SSBI), are highly prevalent in older persons. Most BI are covert, which is not associated with clinically overt stroke. Nonetheless, they are powerful predictors of future risk for stroke, cognitive decline, and dementia. Little is known about the genetic determinants of BI.

Methods:
We performed a trans-ethnic meta-analysis of GWAS of MRI-defined BI and SSBI in 20,949 participants belonging to 5 ethnic groups: Europeans, African-Americans, Hispanic-Americans, Malays, and Chinese. A total of 23 population-based studies from the CHARGE consortium participated in this effort, comprising of 3,726 cases and 17,223 controls for BI, 2,112 cases and 15,432 controls for SSBI. GWAS based on imputed genotypes using the 1000 Genomes phase 1, version 3 panel was performed in each study [using logistic regression]. Meta-analysis of association statistics was performed using a Bayesian partition model (MANTRA); secondary analyses used fixed effect (FE) inverse variance weighting. Loci with log
10
[Bayesian factor (BF)]>5 were considered genome-wide significant and loci with log
10
[BF]>4.5 and mean imputation accuracy score >0.80 were chosen for replication.

Results:
33 variants (3 loci) reached genome-wide significance, in association with BI, on chromosome: 13q12 (Index SNP: log
10
[BF]=7, P
FE
=5.8х10
-9
, OR
FE
=1.2, minor allele frequency [MAF]=0.34), 5q23 (Index SNP: log
10
[BF]=6.5, P
FE
=1.8х10
-8
, OR
FE
=1.2, MAF=0.21) and 15q26 (Index SNP: log
10
[BF]=5.3, P
FE
=3.4х10
-7
, OR
FE
=1.8, MAF=0.03). These loci comprise genes involved in response to anti-hypertensive drugs, glucose transport, connective tissue assembly and synaptic transmission. Three additional loci showed suggestive associations (log
10
[BF] 4.5 to 5). Five of these six loci were associated with both BI and SSBI (Index SNP log
10
[BF]>2), but none reached genome-wide significance for SSBI.

Conclusion:
This large scale trans-ethnic GWAS meta-analysis identified three novel risk loci for MRI-defined BI. Replication analysis and functional validation are ongoing. These findings may provide novel insight into biological mechanisms underlying covert vascular brain injury
Abstract 152: Vascular Risk Factor Profiles Differ Between Subtypes of MRI Defined Younger Onset Lacunar Stroke
Authors: Rutten-Jacobs Loes C , Markus Hugh S ,   UK YOUNG LACUNAR STROKE DNA STUDY
Published: March 2022

Introduction:
The pathogenesis of lacunar infarct is poorly understood. Two pathological and radiological subtypes have been suggested: isolated infarcts due to microatheroma and multiple smaller lacunar infarcts due to lipohyalinosis. The latter subtype has been associated with leukoaraiosis (LA) on MRI. Differing associations of vascular risk factors with lacunar infarct have been reported, which is likely due to heterogeneity in the classification of lacunar infarcts. Therefore we aimed to investigate the risk factor profile of lacunar infarction and subtypes in a MRI verified cohort of lacunar infarct patients.

Methods:
1029 Caucasian patients with lacunar infarction, aged <=70 years (mean age 56.7 (SD8.5), range 20-70), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Risk factor profiles were compared with 1962 stroke-free population controls. Lacunar infarct was subdivided on MRI into isolated lacunar infarction without confluent LA (ILI) and multiple lacunar infarcts and/or confluent LA (MLI/LA). All MRI’s and clinical histories were reviewed centrally.

Results:
Lacunar infarct was associated with hypertension (OR 2.26 (95% CI 1.89-2.70)), diabetes (OR 2.13 (95% CI 1.63-2.79)), hyperlipidaemia (OR 1.79 (95% CI 1.50-2.12)) and smoking (OR 1.73 (95% CI 1.46-2.05)). The association with hypertension was stronger in women than in men (OR 3.65 (95% CI 2.63-5.07 and 1.83 (95% CI 1.48-2.26) respectively). Compared to ILI, the MLI/LA variant was associated with age (OR 1.04 (95% CI 1.02-1.05)), hypertension (OR 2.16 (95% CI 1.60-2.91)), smoking OR 1.48 (95%CI 1.11-1.96)) and lower estimated glomerular filtration rate (per 10 ml/min, OR 0.94 (95% CI 0.90-0.98)).

Conclusion:
In this younger onset lacunar stroke population we identified a distinct risk factor profile in patients compared to controls. This risk factor profile differed between lacunar infarct subtypes. The association of the MLI/IL subtype with more severe hypertension and renal impairment might reflect a diffuse small vessel arteriopathy.
Abstract 153: Synergistic Effects of Air Pollution Exposure and Neighborhood Socioeconomic Disadvantage on Initial Stroke Severity
Authors: Wing Jeffrey J , Sanchez Brisa N , Adar Sara D , Meurer William J , Morgenstern Lewis B , Smith Melinda A , Lisabeth Lynda D
Published: March 2022

Background:
Stroke risk and severity are patterned by neighborhood socioeconomic disadvantage (ND). Air pollution may also influence stroke severity through biologic mechanisms. We sought to identify potential synergistic effects of ND and air pollution on initial stroke severity in a large population-based stroke study.

Methods:
We identified incident ischemic stroke cases from the BASIC project from 2000-2012. NIH Stroke Scale (NIHSS) was determined from the medical record or abstracted. Particulate matter (PM2.5) and ozone (O3) data were obtained from a state website. An ND score was created for census tracts (proxy for neighborhood) of residence using 12 Census variables. The association between pollutants, ND, and NIHSS was modeled continuously (NIHSS score) and dichotomously (upper quartile (≥7) vs. lower quartiles (<7)). Generalized estimating equations accounted for clustering within neighborhoods. Models were adjusted for demographics and stroke risk factors and run as single exposure models of pollution and ND, dual exposure models including both pollution and ND, and by adding interactions between pollution and ND.

Results:
A total of 3,035 ischemic strokes occurred; mean age was 70 (SD=13), 51% female and 53% Mexican American. The difference from the 10th to 90th percentile of the ND score (more disadvantage) was associated with a 24% (95% CI: 0.98 - 1.57) higher odds of severe stroke (Table). Higher previous-day O3 levels were associated with both continuous NIHSS and severe stroke in single and dual exposure models; these associations were not modified by ND. Larger associations between PM2.5 and severe stroke were found for those in higher ND areas than those in lower ND areas (p=0.03). Same-day PM2.5 was not associated with continuous NIHSS nor modified by ND.

Conclusion:
Synergistic effects of air pollution and ND score on stroke severity existed; increases in PM2.5 were associated with greater odds of severe stroke as ND increased.
Abstract 156: Glyceryl Trinitrate for Hyperacute Stroke: Results from the Efficacy of Nitric Oxide in Stroke (ENOS) Trial
Authors: Sprigg Nikola , Woodhouse Lisa , Bath Philip M
Published: March 2022

Background:
High blood pressure (BP) is common during the acute phase of stroke and is associated with a poor outcome. Administration of glyceryl trinitrate (GTN), a nitric oxide donor that lowers BP, improved functional outcome in the small ambulance-based paramedic-delivered RIGHT trial.

Methods:
ENOS was an international prospective randomised single-blind blinded-endpoint trial. Patients with acute (<48 hours) stroke and systolic BP 140-220 mmHg were randomised to GTN (5 mg transdermal) or no GTN. Outcomes included shift in modified Rankin Scale (mRS, primary), Barthel Index (BI) and death at 3 months. Analyses are by regression (binary, ordinal or multiple) with adjustment for baseline covariates; results are odds ratio (OR)/mean difference (MD) with 95% confidence intervals (95% CI).

Results:
Of 4,011 enrolled patients, 273 were randomised (GTN 144, no GTN 129) within 6 hours of onset of stroke: age 70 (SD 13); BP 167 (18)/91 (13) mmHg; Scandinavian Stroke Scale 32 (12); ischaemic 76%, ICH 22%; stroke-randomisation 4.6 hours. Treatment with GTN was associated with improved mRS (OR 0.51, 95% CI 0.32-0.80), BI (MD 13.5, 95% CI 4.6 to 22.5), and reduced death (OR 0.31, 95% CI 0.11-0.91). Significant improvements in mood, quality of life and cognition were also seen.

Summary:
In the subgroup of patients randomised within 6 hours of stroke onset, treatment with GTN was associated with less dependency, disability and death. These positive results mirror those seen in the RIGHT pilot trial.
Abstract 169: IV t-PA May Result in Better Outcomes than Conservative Care in Patients with Mild Acute Ischemic Stroke and Large Vessel Occlusion
Authors: Cerejo Russell , Cheng-Ching Esteban , Hussain Muhammad S , Bullen Jennifer , Uchino Ken , Hui Ferdinand , Toth Gabor
Published: March 2022

Introduction:
Most patients with mild acute ischemic stroke (AIS) symptoms are excluded from acute stroke therapy (AST). Studies have shown that patients presenting with large vessel occlusions (LVO) and low NIH stroke scale (NIHSS) may have poorer outcomes than previously presumed. The optimal treatment strategy in this population is unknown.

Methods:
A retrospective chart review of patients with AIS presenting to our tertiary care center between 2010 and 2013 was carried out. Inclusion criteria included LVO as cause of AIS and initial NIHSS < 8. Patients presenting >24 hours after last known normal were excluded. Patient demographics, administered therapies and short-term clinical outcomes were analyzed. For patients lost to follow up, last known values were imputed. Favorable 30-day outcomes were defined as mRS 2, NIHSS 1 or at least 4 point decrease in NIHSS.

Results:
A total of 121 patients (56.19% males; mean age 63.85±14.08) met inclusion criteria. Anterior circulation was involved in 69.4% cases [MCA (46.28%), ICA (16.52%), ACA (2.47%), ICA-MCA (4.13%)] vs 33.88% posterior circulation cases [PCA (8.26%), Ba (5.7%), V (19%)]. Median admission NIHSS and pre-admission mRS were 4 & 0 respectively, which were statistically significant predictors of favorable outcome. Only 23 patients (19%) received AST [IV t-PA: 13, intrarterial (IA) therapy: 6, IV + IA: 4]. AST patients had shorter time from onset of symptoms to evaluation (mean: 3.7 vs. 9.9 hours, p < 0.001), higher NIHSS on arrival (median: 5 vs. 3, p = 0.024), and were more likely to have a history of stroke (39% vs. 18%, p = 0.049). The odds of a 30-day favorable mRS were 1.7 times higher in the treated group, although not statistically significant (95% CI: 0.58, 5.7; p = 0.333). Numbers in the subgroup analysis remained too small to reach statistical significance, but 85% of patients who received IV t-PA (and 70% with any treatment) had a favorable 30-day outcome versus 62% of patients with conservative care.Conclusion: Our study suggests that qualifying patients with LVO and mild AIS presenting early may have better outcomes if treated with IV t-PA. We propose that rapid evaluation of vessel status may support more aggressive treatment considerations in patients with mild AIS. Further prospective data is needed.
Abstract 173: Current Treatment Status and Predictors of Subsequent Cerebral Ischemic Events in Transient Ischemic Attack Patients with Symptomatic Carotid Stenosis
Authors: Hayakawa Mikito , Uehara Toshiyuki , Ohara Tomoyuki , Sato Shoichiro , Suzuki Rieko , Toyoda Kazunori , Minematsu Kazuo ,   PROMISE TIA Study Investigators
Published: March 2022

Background and Purpose:
Patients with symptomatic carotid stenosis (SCS) have recently tended to receive aggressive treatments including dual antiplatelet (AP) therapy and early carotid revascularization. The aim of this study was to clarify the current treatment status and predictors of subsequent cerebral ischemic events in TIA patients with SCS.

Methods:
The PROMISE TIA registry prospectively enrolled 1,353 patients with TIA within 7 days of onset from 57 hospitals in Japan between June 2011 and December 2013. All SCS patients were extracted from this registry and divided into 3 stenosis groups; mild (<50%), moderate (50-69%) and severe (≥70%). The endpoint events were ischemic stroke/recurrent TIA within 90 days of index TIA.

Results:
A total of 125 patients (103 men, 73.5±8.8 years old) was included. Thirty-seven patients (29.6%) had mild, 45 (36.0%) had moderate, and 43 (34.4%) had severe SCS. The rates of men and patients with amaurosis fugax (AF) were higher with increasing severity of SCS (men, 70.3% vs 80.0% vs 95.3%, p=0.012; AF, 0% vs 4.4% vs 16.3%, p=0.013). Acute-phase treatments using multiple AP with or without anticoagulant (AC) therapy were performed in 61 patients (48.8%), and 47 patients (37.6%) underwent revascularization within 90 days. The rates of patients receiving multiple AP with AC and those undergoing revascularization were higher with increasing severity of SCS (multiple AP with AC, 8.1% vs 37.8% vs 41.9%, p<0.001; revascularization, 10.8% vs 31.1% vs 67.4%, p<0.001). The endpoint events occurred in 9 patients (7.6%); 2 (5.7%) in mild group, 6 (14.0%) in moderate group and 1 (2.4%) in severe group (p=0.121). On multivariate analysis, dual TIA (HR, 5.9; 95%CI, 1.3-28) predicted the endpoint events.

Conclusion:
In TIA patients with SCS, the rates of treatments with multiple AP and revascularization procedures were approximately 50% and 40%, respectively, being increasingly frequent with increasing severity of SCS. The 90-day risk of cerebral ischemic events was 7.6%, and patients with SCS who experienced dual TIA might need the aggressive treatments, regardless of severity of SCS.
Abstract 178: Reporting of Imaging Time Intervals in patients with Acute Ischemic Stroke undergoing Perfusion Imaging: A Systematic review and Meta-analysis
Authors: Patil Shivanand , d'Esterre Christopher , Cimflova Petra , Singh Dilip , Al-mekhlafi Mohamed , Choi Philip , Dykeman Jonathan , Menon Bijoy , Goyal Mayank
Published: March 2022

BACKGROUND:
Recent STIR guidelines stress the importance of speed and the need to balance the benefits of multi-modal imaging against potential treatment delay. It is essential that studies report on relevant imaging time intervals (ITIs) including image acquisition and interpretation times. We analyzed frequency of various ITIs reported.

METHODS:
The search strategy was conducted by combining the themes of acute ischemic stroke, perfusion imaging, and CT/MRI. Two independent reviewers screened at all levels and disagreements were settled through consensus. The inclusion criteria was CT/MR perfusion within 24 hours of stroke symptom onset and thresholds reporting for core, penumbra, and/or normal/not at risk tissue. We collected data on relevant
a priori
specified ITIs from each study (Table 1) and report these as medians (of either mean or median interval time in each individual study).

RESULTS:
The search resulted in 9184 abstracts from EMBASE, 7249 abstracts from MEDLINE resulting in 11919 abstracts after duplicates. Of 711 studies identified for full-text review, 94 studies reported at least one relevant time interval. Pooled estimates (medians with IQR) are reported for each ITI (Table 1). We noted lack of clarity on whether these ITIs were reporting beginning or end of image (CT or MRI) acquisition. Only 3/94 (3.4%) studies reported admission to imaging time. 54/134 (40%) studies reported image acquisition time; no studies reported on image interpretation times. CT acquisition (30 studies) ranged from 30-120 seconds with a median of 47 (41.25-58.75) seconds. MRI acquisition ranged from 46-144 seconds with a median of 69.50 (60.0-84.25) seconds.

CONCLUSION:
ITIs are significantly under-reported in studies that describe the use of multi-modal imaging (CT/MR perfusion). There exists significant heterogeneity in the definitions of many ITIs. Admission to end of imaging acquisition, an important marker of optimized workflow is minimally reported.
Abstract 183: Use, Safety and Outcomes with Thrombolysis in Ischemic Stroke among Pregnant and Non-Pregnant Women
Authors: Leffert Lisa , Clancy Caitlin , Bateman Brian , Cox Margueritte , Schulte Phillip , Smith Eric , Fonarow Gregg , Kuklina Elena , George Mary , Schwamm Lee
Published: March 2022

Background:
Pregnancy and recent cesarean delivery are thought to pose unacceptable complication risks from IV thrombolysis (tPA), and most pregnant or recently postpartum women with ischemic stroke (IS) do not receive IV tPA. We sought to determine the frequency of IV tPA use and short term outcomes among pregnant vs. non-pregnant women with IS in the Get With the Guidelines Stroke Registry.

Methods:
Pregnant or recently postpartum (<6 weeks) (n=15) and non-pregnant patients (n=1913) aged 18-44 with IS who were treated with IV tPA (and without intra-arterial therapy) were identified based on medical history or ICD-9 codes from 2008-2013. Patient and hospital categorical variables were compared by Chi-square and continuous variables by Wilcoxon Rank-Sum.

Results:
Pregnant patients were less likely to receive IV tPA than non-pregnant patients (15/338 (4.4%) vs. 1913/24303 (7.9%), p = 0.03). The primary reasons documented for non-treatment in the 0-3 hour timeframe were pregnancy itself (58% vs. 0%) and recent surgery (47% vs. 12%). Other less commonly noted reasons were stroke symptoms too mild (16% vs. 31%) or rapid improvement (13% vs. 32%). There were no differences in major complications between groups (Table). Discharge outcomes between groups were comparable, with low rates of in-hospital mortality (0-2%) and high rates of home discharge (60-72%). Only the proportion with length of stay > 4 days differed, and was more frequent among pregnant patients (Table).

Conclusions:
Pregnant patients with IS undergo IV thrombolysis infrequently; less often than non-pregnant patients of childbearing age. Despite the rare use, the short term outcomes and complication rates in these pregnant patients generally appear to be favorable and similar to non-pregnant women. As the data are underpowered to show true differences between the groups, larger studies are warranted to study the efficacy and safety of thrombolysis in pregnancy.
Abstract 187: Magnetically-Enhanced Diffusion (MED™) of intravenous tPA in Acute Ischemic Stroke: A Pilot Safety and Feasibility Trial
Authors: Bladin Christopher , Levi Christopher , Parsons Mark , Campbell Bruce , Panagos Peter , Derdeyn Colin , Creighton Francis
Published: March 2022

Background:
The MED device (Pulse Therapeutics, St. Louis, MO) uses an external magnet system and IV-administered magnetic particles to enhance delivery tPA within stagnant-flow vessels. We present the first human data from a safety feasibility study examining the utility of the technology for large-vessel intracranial occlusions.

Methods:
AIS patients (63-91y; median 82y) with acute M1 or M2 occlusions were treated within 4.5hrs of symptom onset. Magnetic particles were concurrently delivered to standard-dose IV-tPA. TICI Grade flow in the target vessel segment was assessed prior and post therapy via CTA and/or MRA.

Results:
Seven patients were enrolled with M1(6) and M2(1) arterial occlusion, with clot length >6mm [2(6-8mm), 4(8-10mm), 1(>25mm)]. Median baseline NIHSS was 16(3-24). All patients receiving post-therapy imaging demonstrated early recanalization (+3pnt median TICI improvement, FIGURE) accompanied with 24hr NIHSS improvement (3-15pnts; median 15pnts), sustained out to 90d. One delayed hemorrhage (9hrs post onset) was identified, however, immediate post-therapy imaging showed complete recanalization without hemorrhage. Reversible transient acute hypotension was observed in 5 patients during particle/tPA infusion. This response is associated with particle surface charge.

Conclusion:
These early data support the safety and efficacy of the MED system for enhancing the efficacy of IV tPA in an Emergency Department environment. Further studies will involve modifications of particle surface charge.
Abstract 202: 2B or Not to Be? Defining Successful Reperfusion In IMS III
Authors: Liebeskind David S , Yoo Albert J , Jovin Tudor G , Scalzo Fabien , Nogueira Raul G , Zaidat Osama O , Carrozzella Janice , von Kummer Rüdiger , Demchuk Andrew M , Foster Lydia D , Palesch Yuko Y , Broderick Joseph P , Tomsick Thomas A ,   for the IMS III Investigators
Published: March 2022

Background:
The modified and original variants of the TICI scale (mTICI and oTICI) define substantial reperfusion in endovascular stroke therapy (EVT) as ≥50% (mTICI) or ≥67% (oTICI) of the downstream territory. Despite recent adoption of the mTICI definition, it remains uncertain which threshold better predicts good clinical outcome after EVT.

Methods:
The angiography core lab of the IMS III trial evaluated use of the oTICI definition compared to the mTICI technical endpoint. Inclusion criteria were presence of an intracranial ICA or MCA M1 occlusion, active EVT and available 90-day mRS. Two expert readers independently reviewed the complete angiography studies to categorize mTICI 2B results into 50-66% vs. 67-99% reperfusion and differences were resolved by consensus. ROC analysis was performed to determine the optimal threshold for predicting good clinical outcome (mRS 0-2). Safety endpoints were mortality and symptomatic intracranial hemorrhage. Inter-rater agreement was assessed using the kappa statistic.

Results:
187 patients met inclusion criteria with mean age 65.7 years and median NIHSS 19 were included, with 56 ICA and 131 M1 occlusions. The mTICI was 0 in 32 patients, 1 in 17, 2A in 69, 2B in 64, and 3 in only 5. Of the 64 mTICI 2B cases, 38 (59%) were adjudicated as oTICI 2B (i.e., 67-99%). There was an increase in good outcomes with greater reperfusion (mTICI 2B, 46%; oTICI 2B, 53%; p<0.0001), although there was no significant pairwise difference between 50-66% vs. 67-99% (p=0.80). For good outcome, the c-statistic was non-significantly higher for mTICI vs. oTICI (0.76 vs. 0.73, p=0.19). Overall, the optimal threshold for predicting good outcome was mTICI 2B-3 (sensitivity 68%, specificity 75% vs. sensitivity 45%, specificity 86% for oTICI 2B-3). Similarly, mTICI 2B-3 was the optimal threshold for predicting decreased mortality and decreased sICH. Inter-rater agreement for discriminating 50-66% vs. 67-99% reperfusion was excellent (kappa=0.84).

Conclusions:
Greater degrees of reperfusion are associated with a higher likelihood of good outcomes. The most effective threshold, however, for predicting both good clinical outcome and improved safety is mTICI 2B rather than oTICI 2B.
Abstract 209: Intracranial Wall Irregularity and Recurrent Stroke: the SPS3 Trial
Authors: Ohara Nobuyuki , Nakajima Makoto , Pearce Lesly A , Feldmann Edward , Bazan Carlos , Hart Robert G , Liebeskind David S , Benavente Oscar R ,   the SPS3 investigators
Published: March 2022

Background and Purpose:
Intracranial atherosclerosis is an important cause of ischemic stroke and even mild stenosis or subtle wall changes may be a marker for subsequent stroke risk. We tested whether any arterial wall irregularity was predictive of recurrent stroke in participants of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.

Methods:
SPS3 was a randomized trial investigating optimal blood pressure target and antiplatelet regimen in patients with recent, symptomatic, MRI-confirmed lacunar stroke patients. Magnetic resonance angiography (MRA) proximate to study entry was adequate and available for 2169 of 3020 study patients. Seven intracranial arteries (basilar [BA], vertebral [VA], internal carotid [ICA], and middle cerebral artery [MCA]) were assessed on time-of-flight MRA for wall irregularities including stenosis and changes of arterial diameter. Cox Proportional Hazards models adjusted for assigned treatments and clinical risk factors were used to estimate risk for recurrent stroke associated with any wall irregularity overall and in specific arteries.

Results:
Mean age of the 2169 patients was 63 yr with 63% male; hypertension, diabetes, and prior lacunar stroke were present in 75%, 36%, and 10%, respectively. Wall irregularities in ≥1 artery (325 one artery, 250 > 1 artery) were observed in 575 patients (27%). Recurrent stroke occurred in 195 patients during mean follow-up of 3.5 years (annualized rate 2.5% per patient-year). Patients with at least one wall irregularity had an increased risk of recurrent stroke (adjusted HR 1.4, 95% CI 1.0-1.9). There was no interaction between either randomized treatment arm (antiplatelet therapy or blood pressure control target) and wall irregularities. Irregularity by any individual artery (BA, n = 115, 14 strokes; VA, n = 150, 17 strokes; ICA, n = 268, 31 strokes; or MCA, n = 316, 37 strokes) was not predictive of recurrent stroke (each p >0.1).

Conclusion:
In this large well characterized cohort of lacunar stroke patients, any wall irregularity in at least one artery was associated with recurrent stroke independent of clinical risk factors and assigned treatment groups.
Abstract 219: Activity-Dependent Capillary Hyperemia in The Brain Is Not Regulated by Pericytes
Authors: Wei Helen S , Takano Takahiro , Rasheed Izad-Yar D , Kang Hongyi , Reitz Katherine M , Gershteyn Anna , Pillai Priyanka , Pillai Prishanya , Vates G. Edward , Nedergaard Maiken
Published: March 2022

Activity-dependent increases in blood flow comprise the basis for functional brain imaging and are considered a hallmark of normal brain function. The central dogma of blood flow regulation states that flow changes effected by arteriolar tone drive functional hyperemia and that the capillary bed is a passive conduit for hyperemia resulting from upstream vasodilation. Recent evidence has begun to challenge this convention in cerebral blood flow control and suggests that pericytes may dilate capillaries during functional hyperemia, but whether pericytes can regulate flow of individual red blood cells (RBCs) through capillaries during sensory stimulation is unknown. Using high-speed two-photon microscopy in a live mouse model, we document that increases in RBC flow velocity and RBC flux through capillaries were detected within 1.0 second after sensory stimulation, and that the observed activity-evoked capillary hyperemia did not depend on the presence of a pericyte. We further report that local application of vasorelaxants shown to relax pericytes ex vivo did not alter resting RBC velocity in capillaries in vivo and did not affect sensory stimulation-evoked capillary RBC velocity increases. These findings support the hypothesis that cerebral capillary hyperemia occurs rapidly after sensory input, but fail to provide evidence for dynamic pericyte-dependent regulation of capillary functional hyperemia during brain activation. These results provide novel insight into the fundamental mechanisms underlying brain capillary blood flow regulation and have significant implications for targeting the disruption of cerebral microvascular blood flow characteristic of ischemic and hemorrhagic strokes.
Abstract 26: Prevalence of CADASIL and Fabry Disease in a Large Cohort of MRI defined Younger onset Lacunar Stroke
Authors: Rutten-Jacobs Loes C , Kilarski Laura L , Bevan Steve , Baker Rob , Hughes Derralynn A , Markus Hugh S ,   UK Young Lacunar Stroke DNA Study
Published: March 2022

Background:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the
NOTCH3
gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the
GLA
gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, most likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence of CADASIL and FD in a well-defined, MRI verified cohort of patients with lacunar infarct.

Methods:
Caucasian patients with lacunar infarction, aged <=70 years (mean age 56.7 (SD8.5), range 20-70), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. All MRI’s and clinical histories were reviewed centrally. CADASIL screening was performed using denaturing high performance liquid chromatography (DHPLC) and sequencing in cases with a suspected variant. Exons 3, 4 5, 6, 8, 11, 18, 19 and 22 were screened which has been shown to detect 90% of mutations in a UK population. FD screening was performed using high-resolution melt curve analysis with sequencing confirmation.

Results:
Of 1,049 subjects four had pathogenic
NOTCH3
mutations (R169C, R207C, R587C and C1222G) all resulting in loss of gain of a cysteine in the NOTCH3 protein. All four patients had confluent leukoaraiosis (Fazekas grade ≥2), and three had multiple infarcts. CADASIL prevalence overall was 0.4 (95% CI 0.1%-0.9%) and among cases with confluent leukoaraiosis 1.2% (95% CI 0.4%-2.8%). One additional patient had a missense mutation in the
GLA
gene (R118C) of uncertain significance; conflicting data exists pathogenicity of this mutation.

Conclusions:
CADASIL cases can be detected in younger onset apparently sporadic lacunar stroke, but are rare. FD screening in this patient group has a minimal pick-up.
Abstract 48: Factors Associated With Motor Performance in Patients With Mild Cognitive Impairment and Cerebral Small Vessel Disease: Data From the VMCI-Tuscany study
Authors: Poggesi Anna , Salvadori Emilia , Pracucci Giovanni , Valenti Raffaella , Pescini Francesca , Pasi Marco , Nannucci Serena , Marini Sandro , Del Bene Alessandra , Ciolli Laura , Inzitari Domenico , Pantoni Leonardo ,   VMCI-Tuscany Study Group
Published: March 2022

Background and purpose:
Neuroimaging correlates of cerebral small vessel disease (SVD) are frequently detected in elderly subjects and are clinically associated with cognitive and gait dysfunction. Our aim was to evaluate clinical and neuroimaging factors associated with motor performance in a cohort of patients with mild cognitive impairment (MCI) and cerebral small vessel disease (SVD).

Methods:
the VMCI Tuscany Study is an ongoing, longitudinal, multicenter, observational study aimed at investigating predictors of transition from vascular MCI to dementia. Inclusion criteria were: 1) MCI (Winblad et al. criteria), and 2) evidence on MRI of moderate to severe degrees of white matter hyperintensities [(WMH), modified Fazekas scale]. Centralized visual assessment also included: number of lacunar infarcts, microbleeds, cortical atrophy, and medial temporal lobe atrophy on MRI. All patients underwent clinical and functional evaluation. Quantitative tests of gait and balance included the Short Physical Performance Battery (SPPB; range: 0 [poor] to 12 [normal]).

Results:
Out of the 145 patients enrolled (mean age 74.6±6.7, 55% males, 52% with severe WMH), mean SPPB score was 8.5±2.5, and Montreal Cognitive Assessment test (MoCA) 20.0±4.9. MoCA significantly correlated with SPPB (Spearman coefficient 0.204, p=0.014). The association also remained significant in the multivariate linear regression model (standardized coefficient 0.111, p=0.009), entering MoCA together with age, and neuroimaging variables. Among these latter, global atrophy retained a significant association (standardized coefficient -0.273, p=0.002).

Conclusion:
in our cohort of MCI patients with moderate to severe WMH, motor performance was associated with cognitive performance. Among MRI features, cortical atrophy seem to have a primary role, in line with the recent view that regards cortical atrophy as one of the neuroimaging correlates of SVD.

Study funded by Tuscany Region.
Abstract 52: Establishing the First Mobile Stroke Unit in the United States
Authors: Parker Stephanie , Persse David , Noser Elizabeth , Richardson Laura , Flanagan Tom , Grotta James
Published: March 2022

Background:
A Mobile Stroke Unit (MSU) delivers Emergency Department (ED) care in the pre-hospital setting. We describe establishing the first MSU in the U.S.

Methods:
A full time Medical Director and Project Manager took ownership of the project. A funding plan was developed to build,staff and supply the unit for 3 years. An ambulance company donated a standard ambulance. MSU build-out began after purchase of the CT scanner. A consortium of stakeholders was formed including leaders of the stroke programs and EDs of the city’s 3 Comprehensive Stroke Centers (CSCs) and Houston Emergency Medical Services (EMS). Policies and procedures were developed to obtain both state and city health department licensing and inspection, and an accountability system to maintain the unit to standards. Radiation safety certification was obtained from the state health department. Radiation safety experts inspected the vehicle,obtained rad. measurements and designed safety procedures,confirming minimal risk. Insurance on the vehicle and all equipment was obtained.

Staffing was hired,and a secure location to park the MSU with electrical hook-up and an office were located. An EMS education program was carried out and communication pathway developed enabling immediate MSU dispatch within a 5 mile radius following a 911 call, as well as for first-responders to activate the MSU. A study protocol was written to evaluate logistics,cost-effectiveness,telemedicine (TM) vs. on-scene decisions and patient outcomes. A HIPPA-compliant technology grid enabled viewing of CT images by the TM team and receiving hospital radiologist.

Results:
The MSU effort began in March 2013 and the MSU received Feb 4, 2014. The Houston MSU is a standard 12’ ambulance staffed by a neurologist and registered nurse with stroke expertise, CT tech, and paramedic, with TM connectivity, responding to acute stroke dispatches daily from 8a-6p. All MSU management is standard of care; patient consent is not required except to include patient data. This includes a non-con head CT, point of care labs, blood pressure management and if necessary advanced life support.

Conclusion:
The Houston MSU treated its first patient on May16,2014, and is carrying out acute stroke treatment within 10-18 minutes of arrival on location.
Abstract 62: GRASPS Score to Predict Risk of Clinically Relevant Symptomatic Intracranial Hemorrhage after Intravenous Tissue Plasminogen Activator
Authors: Saver Jeffrey L , Strbian Daniel , Michel Patrik , Seiffge David J , Numminen Heikki , Meretoja Atte , Murao Kei , Weder Bruno , Forss Nina , Parkkila Anna-Kaisa , Eskandari Ashraf , Cordonnier Charlotte , Davis Stephen M , Engelter Stefan T , Jones Philip G , Spertus John A , Tatlisumak Turgut
Published: March 2022

Background:
The NINDS Study definition of symptomatic hemorrhage (sICH) after intravenous tissue plasminogen activator (tPA), requiring only minimal early worsening and minimal petechial hemorrhage, is now widely recognized as overly inclusive. Clinically relevant sICH is better defined by at least moderate worsening and parenchymal hematoma. The 6-item GRASPS scale for predicting sICH was derived from the national US Get with the Guidelines - Stroke registry based on the NINDS Study definition. For use in clinical practice, it is desirable to recalibrate the GRASPS scale to predict more stringently defined symptomatic hemorrhage.

Methods:
We merged prospectively collected data of patients with consecutive ischemic stroke who received tPA in 7 stroke centers. We applied the GRASPS (glucose at presentation, race [Asian], age, sex [male], systolic blood pressure at presentation, and severity of stroke at presentation [NIH Stroke Scale]) to predict Safe Implementation of Thrombolysis in Stroke (SITS)-defined sICH. To derive a monotonic predictive model, we used a generalized additive model framework and fit 6 different transformations of the GRASPS score: linear scale, log scale, without and with splines, and without and with local smoothing (“loess”) to identify any non-parametric patterns.

Results:
The final cohort comprised 5274 eligible patients, of whom 143 (2.7%) had symptomatic ICH per SITS criteria. Based on favorable residual deviance scores and Akaike's information criterion scores, the linear transformation of raw GRASPS scores provided the best fit. With this model, the area under the curve for predicting SITS sICH was 0.68 (95% CI 0.63-0.72). Risk score values for cardinal GRASPS scale points included 0.6% for GRASPS 50, 2.4% for GRASPS 70, and 9.5% for GRASPS 90.

Conclusions:
The GRASPS scale showed moderate performance in predicting SITS-defined symptomatic intracerebral hemorrhage after IV tPA. With the predictive values available from this study, the GRASPS score can be used to assess risk of clinically relevant symptomatic hemorrhage following thrombolytic therapy.
Abstract 72: Long Non-coding RNAs Mediate Cerebrovascular Endothelial Pathologies in Ischemic Stroke
Authors: Yuan Liyun , Zhang Jifeng , Chen Y. Eugene , Yin Ke-Jie
Published: March 2022

The structural and functional changes in the cerebral endothelium during cerebral ischemia are well-known to affect the extent of ischemic brain injury and stroke outcome. Therefore, the brain endothelium becomes an important therapeutic target for the inhibition of cerebrovascular dysfunction in ischemic stroke. However, the regulatory mechanisms of cerebral endothelial dysfunction after cerebral ischemia remain largely unexplored. Previously we have documented the important regulatory roles of microRNAs in the cerebral vasculature, in particular the cerebral vascular endothelium. However, the functional significance and molecular mechanisms of other classes of non-coding RNAs in the regulation of cerebrovascular endothelial pathophysiology after stroke are completely unknown.

Using RNA-sequencing technology, we profiled long non-coding RNAs (lncRNAs) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD). After 16h of OGD exposure, the expression levels for 362 of the 10,677 lncRNAs analyzed changed significantly, including a total of 147 lncRNAs increased and 70 lncRNAs decreased by more than 2-fold. Interestingly, metastasis associated lung adenocarcinoma transcript 1 (Malat1) is one of the most highly upregulated OGD-responsive endothelial lncRNAs, which has been initially discovered as a tumor-associated lncRNA involved in epigenetic control of gene expression. Increased Malat1 levels were further confirmed in cultured BMECs after OGD as well as isolated cerebral microvessels in mice after 1h MCAO and 24h reperfusion by qPCR. Of note, Malat1 was not pathologically increased in whole mouse brains in response to the same ischemic insult. The expression and nuclear localization of Malat1 were also shown in BMECs by
in situ
hybridization. Furthermore, loss-of-Malat1 function by LNA-GapmeR significantly increased OGD-induced loss of endothelial markers and endothelial inflammation in BMECs, implying Malat1 a critical role in protecting the cerebral microvasculature from cerebral ischemic insults. These findings suggest that lncRNAs may function as a class of novel master regulators in cerebrovascular endothelial pathologies after ischemic stroke.
Abstract 88: Racial Differences in the Use of Helicopters for Emergent Transfer of Stroke Patients
Authors: Vaughan Sarrazin Mary , Leira Enrique
Published: March 2022

Background:
Emergency inter-hospital transfer by helicopter provides clinical benefit by shortening transport time to tertiary facilities while providing specialized medical care. Racial differences in the use of helicopters for interhospital transfers have not been investigated.

Objective:
Investigate racial differences in the use of helicopters for elderly Medicare patients presenting to emergency departments (ED) for stroke.

Methods:
We used claims from 2010-2011 for Medicare patients with a previous diagnoses of atrial fibrillation to identify inter-hospital transfers, defined by an ED visit on the same day as admission for stroke. Patient demographics, rural residence, and comorbidity were determined from claims incurred during the 12 months prior to the stroke admission. Transfer distance was calculated using ED and admitting hospital zipcodes. Statistical analyses compared rates of helicopter use unadjusted and adjusted for patient demographics, stroke type, comorbidity, and geographic area.

Results:
We identified 37,648 stroke admissions with an emergent inter-hospital transfer, of which 10% were for cerebral hemorrhage and 90% for ischemic stroke. Overall, 79%, 11%, 6%, and 4% were white, black, Hispanic, and other non-white, respectively. Compared to white patients, blacks and Hispanics were more likely to reside in urban areas (87% and 92% vs 81%), and had higher comorbidity scores (3.15 and 3.13 vs. 2.87). Overall, 1.5%, 1.0%, 0.6%, 2.1% of black, Hispanic, other non-white race, and white patients were transported by helicopter. Helicopter use was higher for patients with cerebral hemorrhage versus ischemic stroke (14.1% vs. 2.1%). In risk adjusted analysis, black, Hispanic, and other non-white patients were only 0.56, 0.41, and 0.31 times as likely as whites to be transported by helicopter (p<.01). This pattern was similar in separate analysis of urban areas, but not in rural areas. In analysis stratified by census region, significant racial differences in helicopter use were found in the South and Midwest, but not in the West or Northeast.

Conclusions:
Significant racial differences in the use of helicopter emergent evacuation of stroke patients cannot be explained by geography/distance or stroke severity.
Abstract 93: Do Intracerebral Hemorrhage “Non-Expanders” Actually Expand into the Ventricular Space?
Authors: Deshpande Anirudda , Demchuk Andrew M , Luna David R , Aviv Richard I , Molina Carlos A , Blas Yolanda S , Dzialowski Imanuel , Lum Cheemun , Czlonkowska Anna , Boulanger Jean M , Kase Carlos S , Gubitz Gord , Bhatia Rohit , Padma Vasantha , Roy Jayanta , Hill Michael D , Dowlatshahi Dar
Published: March 2022

Background:
The CT-angiography spot sign as a predictor of hematoma expansion (HE) is limited by its modest sensitivity and PPV. Spot sign studies restrict HE definitions to the parenchymal component of ICH and do not consistently evaluate intraventricular hemorrhage (IVH) expansion. Decompression of ICH into the ventricular space can lead to underestimation of HE and overestimation of false-positive spot signs. We hypothesized that a proportion of ICH “non-expanders” expand into the ventricular space and including IVH expansion in HE definitions will improve the predictive performance of the spot sign. Our objectives were: 1) determine the proportion of ICH “non-expanders” who have IVH expansion, 2) determine the proportion of “false-positive” spot signs that have IVH expansion, 3) compare the known predictive performance of the spot sign to its performance when using an HE definition incorporating IVH expansion, and 4) explore the predictors of IVH expansion.

Methods:
We analyzed patients from the multicenter PREDICT ICH spot sign study. We defined HE as ≥6mL or ≥33% ICH expansion or >2ml IVH expansion, and compared the performance of this new definition with the conventional 6mL/33% parenchymal definition using ROC analysis. We used regression analysis to determine the predictors of IVH expansion.

Results:
Of 315 patients with complete imaging, 215 did not meet the 6mL/33% expansion definition ("non-expanders"). Only 14/215 (6.5%) of “non-expanders” had ≥2mL IVH expansion. Of the “false positive” spot signs, 4/39 (10.3%) had >2mL ventricular expansion. The AUC for spot sign to predict significant ICH expansion was 0.65 [95% CI 0.58-0.72], which was no different then when IVH expansion was added to the HE definition: AUC 0.64 [95% CI 0.58-0.71]. Predictors for IVH expansion included IVH at baseline (aOR 2.5, p=0.013), elevated INR (aOR 2.5, p=0.011), and spot sign (aOR 5.9, p<0.001).

Conclusions:
IVH expansion occurs in a small minority of “non-expanders”, and only 10% of “false positive” post signs actually expended in the ventricular space. Furthermore, revising HE definitions to include IVH expansion did not alter the predictive performance of the spot sign.
Abstract 94: Mortality Review For The First 400 Patients Enrolled In The Clot Lysis: Evaluation Of Accelerated Resolution Of Intraventricular Hemorrhage Trial (CLEAR III)
Authors: McBee Nichol , Kase Carlos , Carhuapoma Juan R , Jallo Jack , Aldrich Charlene , Lane Karen , Tuhrim Stanley , Awad Issam , Hanley Daniel F , Ziai Wendy ,   CLEAR III Investigators
Published: March 2022

Objective:
CLEAR III is a Phase III, 500-subject, multicenter, double-blind, randomized study comparing extraventricular drainage (EVD) plus intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD plus placebo for treatment of intraventricular hemorrhage (IVH) in patients with intracerebral hemorrhage (ICH) volume <30cc. We compared proximate causes of death in the acute and post-hospitalization phase of the first 400 subjects enrolled.

Methods:
We reviewed serious adverse event (SAE) reports for 106 events that resulted in death within 1 year follow-up. We recorded clinical and volumetric data including ICH and IVH volumes on diagnostic, stability, and end-of-treatment (EOT) computed tomography (CT) scans. EOT was defined as the CT at 72 hours post administration of last dose of test article.

Results:
Of the first 400 subjects enrolled, 27% (106) died, 12% (47) within 30 days of symptom onset. Median [iqr] time to death was 41.5 [71] days. Mean age (±SEM) was 64.0(±1.0) years. Proximate cause of death was neurologic in 52.8% (56), followed by respiratory (14.1%; 15), cardiac (10.4%; 11), multi-organ failure (5.7%; 6), infection (3.8%; 4) and unknown (11.3%; 12). Withdrawal of care (WOC) occurred in 46.2% (49); the majority of deaths were neurologic. Median time to death depended on proximate cause (p=0.0005): Neurologic deaths occurred at 25.5 [36] days vs. 67 [102] days for non-neurologic deaths (p=0.0002). WOC led to death 22 [53] days after ICH and cardiac arrest at 27 [25] days. Patients with no WOC and non-neurologic death died at 76 [106.5] days after ICH. After adjusting for diagnostic IVH volume, age and WOC, factors independently associated with early (≤30d) vs. later (>30-365d) death were male gender (p=0.01), lower admission Glasgow coma scale (p=0.02), no pneumonia (p=0.02) and higher EOT IVH volume (trend p=0.06).

Conclusion:
The CLEAR III mortality rate for the first 400 subjects enrolled remains below literature estimates for severe IVH and is below the pre-specified recruitment suspension threshold of 40%. Approximately half of known causes of death are directly due to neurologic events and occur significantly earlier than non-neurologic causes. Reduction in IVH volume may lower early mortality risk.