bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract TP62: Computed Tomography Perfusion Infarct Measurement Compared to Diffusion-Weighted Magnetic Resonance Imaging in Patients Without Revascularization of Anterior Circulation, Large Artery Occlusions
Authors: Karamchandani Rahul R , Singh Sam J , Rhoten Jeremy B , Strong Edwin D , Raheem Enayetur , Bodle Jeffery D , Hines Andrew U , Asimos Andrew W
Published: October 2018

Introduction:
The CT Perfusion (CTP) parameter Time-Maximum greater than 6 seconds (Tm > 6s) represents delayed blood flow in critically hypoperfused brain tissue. Though Tm > 6s is expected to accurately represent infarct size in stroke patients who do not undergo revascularization, some brain tissue at risk may not progress to infarction and recover spontaneously (“benign oligemia”). We sought to investigate the relationship between Tm > 6s and the gold standard of final infarct volume on DWI MRI in patients with anterior circulation, large artery occlusion (LAO) acute ischemic stroke (AIS) who do not achieve reperfusion.

Hypothesis:
Critically hypoperfused brain tissue, as represented by CTP Tm > 6s, overestimates final infarct volume on DWI MRI in at least 50% of patients with ICA or proximal MCA occlusions without angiographic revascularization.

Methods:
From a large healthcare system’s stroke network database, we conducted a retrospective analysis comparing delayed perfusion volume (Tm > 6s; RAPID iSchemaView) on CTP and DWI MRI volume (ADC < 620cc; RAPID iSchemaView) in patients with ICA, M1, or M2 occlusions between November 2016 and June 2017 not treated with acute reperfusion therapy, or without angiographic revascularization (TICI 0).

Results:
Over an 8-month period, 19 cases were identified with baseline CTP, follow-up MRI, and no reperfusion of an ICA, M1, or M2 occlusion. Mean age was 65.8 years old and median NIHSS was 8. Mean duration from last known well time to CTP and MRI was 4.4 and 22.8 hours, respectively. Three patients were treated with IV TPA and endovascular therapy, 4 received only endovascular therapy, and 12 did not receive IV TPA nor endovascular intervention. The Tm >6s volume was greater than follow-up DWI MRI volume in 13/19 (68%) cases by an average of 37.4cc.

Conclusions:
Critically hypoperfused brain tissue on CTP, represented by Tm > 6s, may spontaneously recover in patients with proximal, LAO AIS. Establishing CTP parameters that delineate ischemic penumbra from benign oligemia will aid in identifying the volume of ischemic tissue truly at risk for infarction in LAO patients.
Abstract TP65: Patient Characteristics Affecting Rapidity for Thrombolytic Delivery on the Mobile Stroke Unit
Authors: Mullaguri Naresh , Sheikhi Lila , Nocero John , Russman Andrew N , Uchino Ken
Published: October 2018

Introduction:
Mobile stroke unit (MSU) allows for early intravenous thrombolysis (IVT) delivery in the pre-hospital setting and is ideal for investigation into early stroke therapy. We hypothesized that there are patient characteristics which influence the rapidity of IVT delivery and Door-To-Needle (DTN) time.

Methods:
We reviewed 124 patients treated with IVT on MSU from 2014-2017. Patient characteristics including age, initial National Institute of Health stroke scale (NIHSS), presence of aphasia, gaze deviation, focal motor weakness, history of atrial fibrillation, prior history of stroke or transient ischemic attack (TIA) and presence of anticoagulation (AC) were analyzed with Rank-Sum test and multivariate regression.

Results:
Median door-to-needle (DTN) time was 29 minutes (interquartile range (IQR) 25-38). Median age was 63.5 years old and median initial NIHSS was 9 (IQR 6-16). Focal motor weakness was associated with shorter DTN times (29 minutes with weakness compared to 31 minutes without weakness, p = 0.01). Presence of anticoagulation was associated with longer DTN time (43 minutes with AC compared to 29 minutes without AC, p=0.04). Age, presence of aphasia, gaze deviation, total initial NIH stroke scale, history of atrial fibrillation, prior stroke or TIA were not associated with DTN times. In a multivariate regression model, focal motor weakness and history of anticoagulation but not age were associated with DTN times.

Conclusion:
Focal motor weakness is a notable initial patient characteristic which drives early IVT delivery and history of anticoagulation prolonged DTN in patients treated on MSU.
Abstract TP68: Shorter Door-to-Needle Time is the Only Independent Predictor for Initiation of Intravenous Thrombolysis (IVT) Within the Golden Hour
Authors: Goyal Nitin , Tsivgoulis Georgios , Kerro Ali , Zand Ramin , Krishnan Rashi , Malhotra Konark , Pandhi Abhi , Duden Peter , Deep Aman , Shahripour Reza , Bryndziar Tomas , Nearing Katherine , Chulpayev Boris , Elijovich Lucas , Alexandrov Anne , Alexandrov Andrei
Published: October 2018

Introduction:
Administration of tPA in the first 60 min post-onset, the golden hour (GH), is associated with improved functional outcomes but remains unachievable in the vast majority of patients. We sought to identify independent predictors of IVT in the GH in a prospective, multi-center study.

Methods:
AIS patients treated with IVT during a five-year period in two tertiary care stroke centers were evaluated. Demographics, vascular risk factors, onset to treatment time, door-to-needle time (DTN) admission blood pressure and serum glucose levels were documented. Baseline stroke severity and early hypodensity on baseline CT were assessed by NIHSS-score and ASPECTS by certified physicians. The etiopathogenic mechanism of AIS was documented using TOAST criteria. Subjects with in-hospital stroke or treated in the mobile stroke unit were excluded.

Results:
Out of total 658 IVT-treated AIS patients (mean age 64±15 years; 50% men; median NIHSS-score 6, IQR: 4-12) we identified 26 (4%) subjects treated in the GH (mean age 62±15 years; 46% men; median NIHSS-score 8, IQR: 4-12). GH patients had shorter median DTN (23 min, IQR: 18-44 vs. 38 min, IQR: 26-49). DTN
2
30 min was more prevalent in the GH group (62% vs. 20%; p<0.001). DTN emerged as the only independent predictor of IVT in the GH in multivariable logistic regression models adjusting for demographics, risk factors, admission blood pressure and serum glucose levels, TOAST subtype, baseline NIHSS and ASPECTS. A 10-min delay in DTN approximately halved the odds of IVT in the GH (OR: 0.54; 95%CI: 0.41-0.71; p<0.001). Alternatively, DTN equal or less than 30min increased exponentially the likelihood of tPA initiation in the GH (OR: 6.29; 95%CI: 2.78-14.25; p<0.001).

Conclusions:
Shorter DTN is the only independent predictor of IVT initiation within the GH. Continued improvements in systems of acute stroke care should aim to further reduce DTN in order to increase the availability of tPA delivery in the GH.
Abstract TP7: Effect of Tissue Plasminogen Activator or Endovascular Thrombectomy for Mortality of Acute Ischemic Stroke in Nationwide Hospital Cohort : J-ASPECT Study
Authors: Kada Akiko , Kurogi Ai , Onozuka Daisuke , Hagihara Akihito , Nishimura Kunihiro , Kamitani Satoru , Ono Junichi , Nakagawara Jyoji , Okuchi Kazuo , Nagata Izumi , Matsuda Shinya , Nakamura Fumiaki , Suzuki Akifumi , Toyoda Kazunori , Yoshimura Shinichi , Miyachi Shigeru , Shiokawa Yoshiaki , Ogasawara Kuniaki , Ido Keisuke , Kurogi Ryota , Nishimura Ataru , Arimura Kouichi , Iihara Koji
Published: October 2018

Introduction:
In recent years, the treatment of the acute phase of cerebral infarction such as tPA and endovascular thrombectomy has been rapidly changing, and development of a medical system for acute cerebral infarction is desired.

Objective:
To examine the effect of tPA and endovascular thrombectomy on mortality in patients with acute ischemic stroke in the nationwide 5 years hospital cohort in Japan.

Methods:
We conducted annual nationwide survey from 2011 to 2015 using data from the Japanese Diagnosis Procedure Combination database on patients hospitalized with ischemic and hemorrhagic stroke in a nationwide hospital cohort in Japan (J-ASPECT Study). The effect of tPA or endovascular thrombectomy on stroke mortality was analyzed by mixed effect model with years (from 2011 to 2015), age, gender, Japan Coma Scale (JCS), and Comprehensive stroke care (CSC) score as a fixed effect, and hospital as a random effect. CSC score was developed by our study group based on the institutional survey conducted in 2011.

Results:
The total numbers of patients were 292,230 in ischemic stroke. In 5 years, the proportion of tPA or endovascular thrombectomy has increased from 7.2% to 8.4%, while the mortality has decreased from 7.6% to 5.5%. The mortality varied by JCS, which was 37.5% for JCS 3 digit, 15.4% for JCS 2 digit, 4.8% for JCS 1 digit and 1.4% for JCS 0 in 2015. In the analysis of subjects with severe JCS 3 digit, years (OR = 0.97, 95% CI = 0.94 - 1.00), CSC score increase (0.98, 95% CI = 0.97 - 0.99), and tPA or endovascular thrombectomy (OR = 0.75, 95% CI = 0.67 - 0.84) were found to reduce the risk of death.

Conclusion:
According to the analysis of patients with acute ischemic stroke for 5 years, tPA or endovascular thrombectomy was related to reduced mortality in subjects with high severity.
Abstract TP81: Intraprocedural Neurological Deficit in Treatment of Unruptured Aneurysm Under Local Anesthesia
Authors: Kawabata Shuhei , Imamura Hirotoshi , Tani Shoichi , Adachi Hidemitsu , Sakai Nobuyuki
Published: October 2018

Background:
It is widely known that the advantage of endovascular treatment (EVT) of unruptured intracranial aneurysms (UIAs) under local anesthesia (LA) is that neurologic evaluation of the patient during procedure can be performed unlike general anesthesia. However, there have been no literature about intraprocedural neurological deficit and their outcomes.

Purpose:
This study was performed to identify the causes and outcomes of intraprocedural neurological deficit in EVT under LA.

Methods:
We retrospectively evaluated the medical and radiologic data of 1068 UIAs (1050 patients) who underwent coil embolization from 2008 to 2016.

Results:
A total of 1015 procedure (1000 patients) were performed under LA. Intraprocedural neurological deficits were observed in 63 patients (6.3%). The causes were intraprocedural rupture in 13 (1.3%), thromboembolism in 16 (1.6%), intolerance against the balloon or guiding catheter in 19 (1.9%) and reduction of blood flow in 15 patients (1.5%) (thrombus formation in 12 and coil protrusion in 3 patients). The managements of coil protrusion were stent placement in 2 (66%) or balloon inflation in 1 procedure (33%) and those of intolerance were aborting procedures in 3 (16%), stent placement in 4 (21%) or simple technique without balloon catheter in 9 procedures (47%). Of the patients with intraprocedural deficits, 58 patients (92%) had good outcomes and 5 patients (8%) had poor outcomes.

Conclusion:
The morbidity rate in EVT of UIAs can be reduced by appropriate management of intraprocedural neurological deficit under LA.
Abstract TP82: Changes in the Distal Vessel Wall After Flow Diverter Treatment
Authors: Kolumam Parameswaran Praveen , Dai Daying , Ding Yong Hong , Asnafi Solmaz , Urban Matthew M , Kallmes David , Kadirvel Ramanathan
Published: October 2018

Background:
Flow diverters (FD) are increasingly used in the treatment of intracranial aneurysms. The risk of distal thromboembolic complications with FD is high, even in patients treated with dual antiplatelet therapy. The aim of the study was to understand the downstream vascular wall changes, by measuring the pulse wave velocity and vascular contractility following flow diverter treatment in a rabbit model.

Methods:
FD (Pipeline Embolic Device, Medtronic) were implanted in normal rabbits and sham-operated aorta were used as controls (n=5 for each group). Pulse wave imaging with ultra-fast ultrasound at 1600 frames per second (Vantage, Verasonics, Inc.) was performed in the vessel wall distal to FD, prior to device implantation and at 8 weeks follow up to measure the pulse wave propagation. Force contraction studies were conducted in the aortic rings using organ bath to assess the vascular functions.

Results:
The difference in pulse wave velocity (PWV) in the follow-up compared to pre-implantation was significantly higher (p=0.03,Fig 1A) in the distal vessels compared to sham controls (mean difference of PWV was 1.18 m/s and -0.37m/s, respectively as shown in Fig 1B). Conversely, the distal aortic segments to FD exhibited 55% increase in the level of vascular contractility compared to that of proximal segments (p=0.002). There is a significant positive correlation between mean PWV and mean vascular contractility.

Conclusion:
Our study found changes in the PWV after implantation of the FD, which correlated with vascular contractility. These results could explain vascular wall changes downstream following FD implantation.
Abstract TP86: Post Hoc Subgroup Analysis of Unruptured Cerebral Aneurysm in Japan Special Reference to Small Sized Aneurysm
Authors: Ikawa Fusao , Morita Akio
Published: October 2018

Introduction:
In Japan, asymptomatic unruptured cerebral aneurysms (UCA) are frequently discovered at brain check-ups. The overall annual rupture rate of these aneurysms has been reported as 0.95% according to UCAS Japan. Japanese people have a 2.8-times increased risk of rupture in UCA according to PHASES score. According to the recent reports, the rate of the small sized ruptured cerebral aneurysm ≤ 5mm (RCA) was over 35%. In this paper, we discuss the post hoc subgroup analysis of UCA in Japan special reference to small aneurysms.

Subjects and Methods:
From January 2001 to March 2004, a total of 6697 UCAs among 5720 patients were prospectively registered from any one of 283 institutions in Japan. In a subgroup of small UCAs ≤ 4mm (sUCA), aneurysms which developed a subarachnoid hemorrhage were extracted for this post hoc analysis. Intrapatient comparisons of each sUCAs were carried out using aneurysm specific factors such as size, location, calcification, thrombosis and shape, and patient specific factors such as age, sex, the reason of discovery for UCA, hypertension, hyperlipidemia, smoking, polycystic kidney and old cerebral infarction. Multivariate logistic regression analysis for rupture by JMP software was performed.

Results:
Eight sUCAs among 3132 sUCAs were ruptured and the annual rupture rate was 0.35% / year. By multivariate logistic regression analysis for rupture, the sCUA discovered by brain check-ups (OR: 3.69, CI: 1.02 – 15.5) and non-hyperlipidemia (OR: 5.65, CI: 1.11 – 103.9) were significant risk factors. The annual rupture rate of sUCA discovered by brain check-ups and with non-hyperlipidemia were 0.62 % and 0.42 %, respectively.

Conclusions:
SUCA has not indicated the category for radical treatment of UCA, however, the countermeasure for sUCA should be required to reduce the incidence of subarachnoid hemorrhage. Using of statin and any psychogenic stress might be related to rupture of sUCAs. Further precise research should be needed about the treatment for sUCA.
Abstract TP89: Angiotensin Receptor (AT2R) Agonist C21 Accelerates Cognitive Functional Recovery After Permanent Stroke in Aged Animals
Authors: Ahmad Heba A , Ishrat Tauheed , Pillai Bindu , Bunting Kristopher , Vazdarjanova Almira , Waller Jennifer L , Ergul Adviye , Fagan Susan C
Published: October 2018

Background and objectives:
Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. Compound 21 (C21), a novel selective non-peptide angiotensin receptor (AT2R) agonist, has also shown therapeutic efficacy in a variety of experimental stroke models, but C21 effect on PSCI model is lacking. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals.

Methods:
Distal docal cerebral ischemia was induced in 14-month-old male Wistar rats by direct electro-coagulation of middle cerebral artery for permanent occlusion (pMCAO). Animals were randomly assigned to receive either C21 or vehicle which was initiated the following day, and continued for a total of 30 days (0.12 mg/kg/d, orally). Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline as well as at different time points post-pMCAO. Repeated measures ANOVA mixed models were used to examine differences in behavioral outcomes.

Results:
C21 reduced weight loss and enhanced recovery (Table). Treatment with C21 showed significant improvement in non-spatial and short-term working memory compared to vehicle. Moreover, C21 preserved reference memory and facilitated associative learning compared to vehicle treated rats after pMCAO. Further, C21 prevented Aβ
1-42
. C21 did not show any effect on motor deficits score compared to vehicle.

Conclusion:
Our findings demonstrate that the angiotensin receptor (AT2R) agonist C21 effectively preserves cognitive function and prevents the development of PSCI in aged animals.
Abstract TP99: Hypoxia Drives Anti-Inflammatory Polarization of Microglia Through the JMJD3-IRF4 Axis
Authors: Koellhoffer Edward C , d’Aigle John , McCullough Louise D
Published: October 2018

Background:
Microglia, as the innate immune cells of the central nervous system, are poised to be the first responders of the immune system to ischemic stroke. In response to an injury or stimulus, microglia polarize from a resting to a pro- or anti-inflammatory phenotype. We have previously shown that hypoxia, such as that in the setting of ischemic stroke, acts as a stimulus itself to polarize microglia to an anti-inflammatory phenotype. Additionally, we have shown that Jumonji Domain Containing 3 (JMJD3) is a histone demethylase that is important for anti-inflammatory polarization of microglia. JMJD3 functions to demethylate trimethylated histone H3 lysine 27 (H3K27me3) at the
Irf4
promoter to monomethylation marks (H3K27me1), resulting in transcriptional activation of
Irf4
and downstream expression of anti-inflammatory genes.

Hypothesis:
Thus, we hypothesized that hypoxia drives microglial anti-inflammatory polarization through the JMJD3-IRF4 axis.

Methods:
We cultured male and female primary microglia from neonatal P0.5-P3 C57Bl/6 mice, inhibited JMJD3 with GSK-J4 (Cayman Chemical) or DMSO control, and stimulated cultures with oxygen glucose deprivation (OGD). After 8hr OGD, we isolated RNA (RNEasy Micro Plus kit, Qiagen) and performed down-stream real-time PCR array analysis (PrimePCR Arrays, Bio-Rad) or protein (RIPA Buffer, Thermo Fisher) for Western blot analysis (Bio-Rad) for JMJD3, histone H3 (Abcam), H3K27me1, and H3K27me3 (Millipore).

Results:
We found that OGD induced up-regulation anti-inflammatory genes, notably
Csf1
,
Cntf
,
Gdf15
,
Il1rn
,
Irf4
,
Mif
, and
Vegfa
while down-regulating pro-inflammatory genes
Tnfa
,
Il1b
, and
Il6
(n=4, p<0.05). Additionally, we found that
Kdm6b
(the gene encoding JMJD3) was up-regulated following 8hr OGD, suggesting JMJD3 is involved in hypoxia-induced anti-inflammatory microglial phenotype polarization. Pharmacological inhibition of JMJD3 with GSK-J4 prevented demethylation of H3K27me3 at the
Irf4
promoter and blocked hypoxia-induced up-regulation of
Irf4
and abrogated hypoxia-induced anti-inflammatory gene up-regulation.

Conclusion:
In conclusion, our data suggests that hypoxia polarizes microglia to an anti-inflammatory phenotype through the JMJD3-IRF4 axis.
Abstract WMP1: Eligibility for Endovascular Trial Enrollment in the 6-24 Hour Time Window: Analysis of a Single Comprehensive Stroke Center
Authors: Desai Shashvat M , Jadhav Ashutosh P , Jovin Tudor G
Published: October 2018

Background and Purpose:
Recent completion of the DAWN trial supports the benefit of endovascular therapy in patients presenting in the 6-24 hour time window with anterior circulation large vessel occlusions. The scope and impact of these results on clinical practice remain unknown.

Methods:
A retrospective review of ischemic stroke admissions to a single comprehensive stroke center was performed during the enrollment period (November 2015-February 2017) to identify patients meeting criteria for DAWN eligibility. Patients presenting beyond 6 hours were further investigated to clarify reasons for trial exclusion.

Results:
Of the 2667 acute ischemic stroke patients admitted within the study period, 30% (n=792) presented within the 6-24 hour time window and 33% (890) had an NIHSS of 10 or higher. Of the 11% (n=298) patients meeting both criteria, trial exclusion occurred due to: absence of large vessel occlusion (LVO) (48%,n=143), presence of sub-occlusive, distal or posterior circulation LVO (18%, n=54), large core infarct or ASPECT < 7 (25%, n=73) or absence of clinical core mismatch (5%, n=16), mRS >1 (13%, n=38). There were 45 patients who met all DAWN criteria.

Conclusions:
Of all acute ischemic stroke patients presenting to a single CSC,
1.7%
of patients qualified for DAWN clinical trial enrollment. Of patients with proximal anterior circulation occlusion presenting in the 6- 24 hour time window with NIHSS of 10 or higher
, 29%
were eligible for treatment based on DAWN criteria. These data predict an increase in thrombectomy utilization with important implications for Comprehensive Stroke Center resource utilization and stroke systems of care.
Abstract WMP100: Underlying Microangiopathy of Mixed Location Intracerebral Hemorrhage and Microbleeds: a PiB-PET Study
Authors: Pasi Marco , Tsai Hsin-Hsi , Tsai Li-Kai , Chen Ya-Fang , Lee Bo-Ching , Tang Sung-Chun , Yen Ruoh-Fang , Jeng Jiann-Shing , Gurol Edip M
Published: October 2018

Background:
Recent MRI-based work suggested that the predominant type of cerebral small vessel disease (SVD) in patients with a combination of lobar and deep intracerebral hemorrhage (ICH)/microbleed (MB) locations (Mixed-ICH) was hypertensive (HTN) SVD. We sought to use in vivo amyloid imaging to test the hypothesis that mixed-ICH is related to HTN-SVD rather than cerebral amyloid angiopathy (CAA).

Methods:
Eighty Asian primary ICH patients without dementia were included in this study. All patients underwent brain MRI and
11
C-Pittsburgh Compound B (PiB) PET. The global, occipital and frontal standardized uptake value ratio (SUVR) were calculated using cerebellum as reference. Fourty-six (51%) patients had Mixed-ICH. Their demographic and clinical profile as well as amyloid deposition patterns were compared to 13 probable CAA (Boston criteria; CAA-ICH) and 21 strictly deep-MB and ICH (HTN-ICH) patients.

Results:
Mixed-ICH patients were younger (62.8±11.7 vs 71.0±14.5 in CAA) and showed a higher burden of vascular risk factors such as hypertension and diabetes than CAA-ICH (all p<0.05). Patients with Mixed-ICH had lower mean global (1.11±0.2 vs 1.31±0.3), frontal (1.09±0.2 vs 1.31±0.3) and occipital SUVR (1.16±0.1 vs 1.32±0.2) than CAA-ICH (all p<0.05). In multivariable analyses, Mixed-ICH diagnosis was associated with hypertension (β=-1.09, 95% Confidence interval [CI]: - 2.5- -0.1, p=0.02) while diagnosis of probable CAA with global-SUVR (β=3.5, CI: 0.3-7.3 p=0.04) after adjustment for age. Mean frontal and occipital-SUVR measures were both associated with probable CAA diagnosis in similar multivariable models. Compared to HTN-ICH, Mixed-ICH showed a similar mean age (62.8±11.7 vs 60±14.5 in HTN-ICH) and risk factor profile (all p>0.1). Furthermore, mean global, frontal and occipital SUVR did not differ between Mixed ICH (values presented above) and HTN-ICH (1.08±0.1, 1.04±0.2 and 1.14±0.1 respectively, all p>0.1).

Conclusions:
In addition to validating previous results in an Asian cohort, our study also brings the unique insight that Mixed-ICH patients have much lower amyloid load than CAA-ICH, while being very similar to HTN-ICH. Overall, Mixed-ICH is probably caused by HTN-SVD, an important conclusion with clinical relevance.
Abstract WMP113: Translational Evaluation of Acid/Base and Electrolyte Alterations in Acute Large Vessel Stroke
Authors: Martha Sarah R , Collier Lisa , Davis Stephanie M , Alhajeri Abdulnasser , Grupke Stephen , Fraser Justin F , Pennypacker Keith
Published: October 2018

Background and Purpose:
Monitoring for hypotension, hyperglycemia, hypoxia, and dehydration is key to reducing early death in stroke patients. Evaluation of physiological predictors of infarct volume and mortality may provide opportunities for effective interventions to improve outcomes. The purpose of this study is: 1) to describe and compare the predictive effects of venous blood gas (VBG) on infarct volume and mortality in acute stroke in rats; 2) and we have begun to collect arterial blood gas (ABG) to compare differences obtained proximal and distal to the occluded intracranial thrombi in acute ischemic stroke patients.

Methods:
3-month old Sprague-Dawey rats (n = 9) underwent permanent or transient middle cerebral artery occlusion (MCAO). Pre- and post-MCAO venous samples provided pH, pCO
2
, pO
2
, and electrolyte values (iCa
2+
, K
+
, and Na
+
). Linear regression determined predictors of infarct volume from these values, and Cox regression analyzed VBG changes between tMCAO (n = 28) and pMCAO (n = 29) to determine predictors of mortality. We compared mean proximal and distal pH, pCO
2
, pO
2
, and electrolytes (iCa
2+
, K
+
, and Na
+
) in stroke patients (n = 7) arterial samples using Wilcoxon Signed Ranks test.

Results:
Animal studies demonstrated pH and iCa
2+
are predictors of infarct volume, but not mortality. After pMCAO (n = 9), change in pH or iCa
2+
significantly predicted infarct volume [F(1,7) = 7.351, β = -0.716, p = 0.03] and [F(1, 7) = 6.782, β = -0.701, p = 0.035]; as pH and calcium decreased, infarct volume increased. These variables explained 44% and 42% of the total variance in these models. In human patients (n = 7), there were significant differences in blood samples proximal and distal to the intracranial thrombus for pCO
2
(p = 0.018), HCO
3-
(p = 0.028), iCa
2+
(p = 0.043), K
+
(p = 0.028), and Na
+
(p = 0.044).

Conclusions:
In conclusion, there are acute changes in acid/base balance and electrolytes during stroke in rodent models and humans. In cross-species comparison ionized calcium changes were significant in both, with iCa
2+
changes predicting stroke volume in the rat model. These preliminary findings are novel, and warrant further exploration in human patients.
Abstract WMP117: Perlecan Regulates Pericyte Dynamics in the Repair Process of the Blood-Brain Barrier Against Ischemic Stroke
Authors: Nakamura Kuniyuki , Ikeuchi Tomoko , Zhang Peipei , Rhodes Craig , Chiba Yuta , Ago Tetsuro , Mukouyama Yoh-suke , Yamada Yoshihiko
Published: October 2018

Introduction:
The blood-brain barrier (BBB) breakdown occurs when the integrity of BBB components is lost as a consequence of ischemic stroke. Perlecan, a major heparan sulfate proteoglycan of basement membranes, is expressed by endothelial cells (ECs) and is adjacent to pericytes (PCs), suggesting supportive functions in the BBB. Recent studies highlight the importance of PCs in the process of repairing BBB functions, which are triggered by the upregulation of platelet-derived growth factor receptor β (PDGFRβ). We hypothesized that perlecan may play a protective role in BBB maintenance through the interaction with PCs during the repair process of the BBB disruption.

Methods:
We induced a 60-minute middle cerebral artery occlusion (MCAO) in adult conditional
perlecan
-deficient (

Perlecan
-/-

-Tg) mice in a C57BL/6 background, which express the perlecan transgene only in cartilage to rescue the perinatal lethality of

Perlecan
-/-

mice. Recombinant perlecan C-terminal domain V (DV) was used for in vitro assays.

Results:

Perlecan
-/-

-Tg mice exhibited larger infarct volumes and more BBB leakage than the control mice on post-surgery day (PSD) 2 after MCAO. While the control mice showed increased numbers of PDGFRβ-positive PCs around the ischemic lesion on PSD 3, such upregulation was not observed in

Perlecan
-/-

-Tg mice, suggesting that perlecan may participate in PC activation against the BBB breakdown. In wild-type mice, the expression of integrin α5, a potential receptor for perlecan, was upregulated both in PCs and in ECs in the ischemic lesion. In culture, PCs showed attachment activity to DV through integrin α5β1. DV induced well-assembled actin stress fibers and focal adhesions in PCs and promoted the PC migration induced by PDGF-BB. At molecular level, DV enhanced the PDGF-BB-induced phosphorylation of PDGFRβ, in addition to that of SHP-2 and FAK, suggesting that DV enhanced both PDGFRβ and integrin signaling.

Conclusions:
These results revealed that perlecan regulates the activation of PCs through the cooperative function of PDGFRβ and integrin α5β1, contributing to the repair process of the BBB. Perlecan DV may provide a potential therapeutic effect, based on a new approach from extracellular matrix to the disrupted BBB in ischemic stroke.
Abstract WMP120: Critical Role of RGS5 in Modulating Blood-Brain Barrier Integrity During Focal Cerebral Ischemia
Authors: Sladojevic Nikola , Liao James K
Published: October 2018

Background:
Recent studies suggest that regulator of G-protein signaling 5 (RGS5), a negative modulator of the G-protein coupled receptors (GPCR) signaling pathways, may be an important modulator of glutamate receptor activation and calcium overload in endothelial cells after ischemic stroke. While glutamate may cause neuronal damage, it is unknown how glutamate affects blood-brain barrier (BBB) permeability.

Methods:
To investigate the effects of RGS5 on stroke severity, wild type (WT) and RGS5
-/-
mice were subjected to 30 minutes of middle cerebral artery occlusion (MCAO). Cerebral infarct volume was evaluated by TTC and Nissl staining, while neurological deficit was assessed using a 5-point motor grading scale and adhesive tape removal test. BBB permeability was analyzed by measuring brain edema with the wet/dry method and by injecting 40kDA FITC-Dextran into the femoral vein. The role of RGS5 in regulating ischemia/glutamate-induced Rho/ROCK signaling in human brain microvasculare cells (HBMEC) was investigated using lentiviral transduction of RGS5 shRNA. To mimic brain ischemic conditions
in vitro
, we used a model consisting of 3-hour oxygen-glucose deprivation (OGD) with L-glutamate. RhoA/ROCK activity was determined by the phosphorylation MYPT1. In vitro permeability was assessed by Transwell permeability assays. Formation of actin stress fibers was observed with Phalloidin staining. Redistribution of important tight junction (TJ) proteins was analyzed by immunostaining.

Results:
Following MCAO, RGS5
-/-
mice exhibited larger cerebral infarct volume and greater neurological deficits compared to controls. Brain water content and FITC-Dextran leakage were higher in the ipsilateral hemisphere of RGS5
-/-
mice compared to controls. Furthermore, the Transwell permeability assay demonstrated increased permeability of FITC-Dextran in RGS5-deficient HBMEC, higher Rho/ROCK activation, greater actin-stress fiber formation, and redistribution of TJ proteins.

Conclusion:
These findings indicate that RGS5 plays an important role in actin cytoskeleton remodeling and BBB permeability following focal cerebral ischemia, in part, through the upregulation of RhoA/ROCK pathway.
Abstract WMP19: Stroke Risk in the Territory of Symptomatic Intracranial Arteries
Authors: Qiao Ye , Sam Kevin , Hao Qing , Liu Li , Shahriai Mona , Kang Ningdong , Gottesman Rebecca , Wasserman Bruce
Published: October 2018

Introduction:
Recent advances in vessel wall MRI (VWMRI) have allowed characterization of intracranial atherosclerotic disease (ICAD), and some imaging characteristics, such as plaque enhancement, are associated with downstream stroke. We tested whether these features were also associated with recurrent cerebral infarction in stroke patients.

Methods:
79 stroke patients with clinically established ICAD underwent VWMRI . Plaque number and features (enhancement, stenosis, eccentricity) were recorded. The cerebral infarcts were determined using DWI, and their responsible lesions (culprit) were identified based on previous established criteria. Patients were followed-up by routine clinical visits. Clinically-apparent strokes were reported and cerebral infarcts were characterized by a brain MRI acquired soon after event. Associations of imaging features and new infarcts were analyzed with adjustment for vascular risk factors.

Results:
Of the 79 patients (mean age 56y., 62% male, 56% whites), 13 had new infarcts (median follow-up, 16 months [IQR, 9-22 months] ). Among these 13 patients, 19 new brain infarcts were identified, and 16 were in the same vascular territories corresponding to the culprit plaque at baseline. Culprit plaques and plaque enhancement were strongly associated in univariate models with new infarcts, and in adjusted models, culprit plaques remained significant (OR 3.67, 95% CI 1.20-11.23) but plaque enhancement did not (OR 1.72, 95% CI 0.97-3.13) (Table). Plaque enhancement was associated with culprit plaques (OR 3.06, 95% CI 1.66-5.63).

Conclusions:
Culprit lesions were strongly associated with recurrent cerebral infarction in stroke patients, indicating increased risk for stroke in symptomatic arterial territories, likely caused by recurrent plaque rupture. Although plaque enhancement was not associated with new infarcts, its strong association with culprit lesions highlights its potential importance in future studies.
Abstract WMP21: Texture Analysis of Intracranial Thrombus Using CT and CTA Predicts Early Recanalization With Intravenous Alteplase
Authors: Qiu Wu , Kuang Hulin , Najm Mohamed , McDougall Connor , Nair Jay , McDougall Brooklyn , Chung Kevin , Wilson Alexis T , Goyal Mayank , Hill Michael , Demchuk Andrew , Menon Bijoy K
Published: October 2018

Objective:
In acute ischemic stroke (AIS), thrombus lysis and early restoration of blood flow to ischemic brain is the goal of reperfusion therapy. We hypothesize that image texture analysis of thrombus using non-contrast CT (NCCT) and CTA can predict early recanalization with IV alteplase in AIS patients with ICA/M1 MCA thrombi.

Methods:
We used a case control design for the study using the whole cohort of the clinical trial of Identifying New approaches to optimize Thrombus characterization for predicting Early Recanalization and Reperfusion with iv tPA using Serial CT angiography (INTERRSeCT). Cases were 31 patients with ICA/M1 MCA thrombi treated with IV alteplase, who achieved early recanalization (as assessed on first angio run in patients undergoing additional IA therapy or on repeat CTA at 4 hrs). Cases were matched with controls (37 patients with ICA/M1 MCA thrombi treated with IV alteplase who did not achieve recanalization). All patients had thin slice NCCT (slice thickness < 2.5 mm) and CTA (≤ 0.625mm). Thrombi in ICA/M1 MCA region were manually contoured from NCCT guided by co-registered CTA. We extracted 378 features (including thrombus length and volume, first order statistics, and image texture features) from each thrombus in both NCCT and CTA images. This was followed by feature selection using linear discriminative analysis. The top 5 features from NCCT and CTA images along with the clot texture difference between NCCT and CTA were used to train a linear support vector machine classifier. Five times 6-fold cross validation was used to evaluate the trained classifier.

Results:
Receiver operator curves show that thrombus texture from NCCT and CTA are predictive of early recanalization with IV alteplase. Combined NCCT & CTA features and texture difference is the best predictor (AUC: 0.82).

Conclusions:
Thrombus texture features from NCCT and CTA are strongly predictive of early recanalization with IV alteplase in AIS patients with proximal occlusions.
Abstract WMP25: Outcome After Clipping and Coiling for Aneurysmal Subarachnoid Haemorrhage in Clinical Practice in Europe, USA and Australia
Authors: Lindgren Antti E , Bragan Turner Elllie , Sillekens Tomas , Meretoja Atte , Lee Jin-Moo , Hemmen Thomas M , Koivisto Timo , Alberts Mark , Lemmens Robin , Jääskeläinen Juha E , Vergouwen Mervyn D , Rinkel Gabriel J ,   Stroke GOAL Group, Dr Foster Global Comparators Project, Dr Foster Ltd
Published: October 2018

Background:
RCTs have demonstrated better outcomes for coiling compared to clipping in patients with aneurysmal subarachnoid haemorrhage (aSAH). After these trials, the proportion of patients with coiled aneurysms has steadily increased, as have the numbers of physicians and hospitals providing the treatment. We studied whether coiling is also associated with a better outcome than clipping after aSAH in daily clinical practice.

Methods:
In Dr Foster Global Comparators, an administrative dataset from 22 tertiary care hospitals from Europe, the USA, and Australia, we retrieved data from 7658 aSAH patients discharged in 2007-2013 in whom the aneurysm had been occluded by clipping (n=3510) or coiling (n=4148). We calculated crude case-fatality rates with 95% confidence intervals (CI) at 14 days, and used multiple logistic regression to adjust for age, sex and differences in comorbidity/disease severity. Because the results from the administrative dataset contradicted those of the RCTs, we further explored our findings in a large clinical dataset (n=1501) consisting of prospectively collected consecutive aSAH patients treated 2006-2015 with clipping or coiling in two large European centres allowing additional adjustment for clinical condition on admission, aneurysm size and location.

Results:
In the administrative dataset the overall crude case-fatality rate at 14 days was 6·4% (95%CI 5·6
-
7·2%) after clipping and 8·2% (95%CI 7·4-9·1%) after coiling. After adjustment for age, sex and comorbidity/severity, the odds ratio (OR) for case-fatality within 14 days after coiling compared to clipping was 1·32 (95%CI 1·10-1·58). In the clinical dataset crude 14-day fatality rate was 5·7% (95%CI 4·2-7·8%) for clipping and 9·0% (95%CI 7·3-11·2%) for coiling. In multivariable logistic regression analysis the OR for case-fatality within 14 days for coiling compared to clipping was 1·7 (95%CI 1·1-2·7), for case-fatality within 90 days 1·28 (95%CI 0·91-1·82) and for poor functional outcome at 90 days 0·78 (95%CI 0·6-1·01).

Conclusion:
In current clinical practice, outside the setting of a clinical trial, coiling after aSAH is associated with higher 14-day case-fatality and not with the substantial benefit on functional outcome as observed within the trials.
Abstract WMP26: Association of Aortic Aneurysm and Dissection With Subarachnoid Hemorrhage
Authors: Al-Kawaz Mais , Merkler Alexander E , Kamel Hooman
Published: October 2018

Introduction:
It is uncertain whether aortic diseases such as aneurysm and dissection are associated with aneurysmal subarachnoid hemorrhage (SAH).

Methods:
We performed a retrospective cohort study using 2008-2015 data from a nationally representative 5% sample of Medicare beneficiaries. Our exposure of interest was hospital discharge diagnosis of an unruptured or ruptured aortic aneurysm or aortic dissection. Our primary outcome was nontraumatic SAH. Predictors and the outcome were ascertained by validated

International Classification of Diseases, 9
th
Revision, Clinical Modification

(
ICD-9-CM
) diagnosis codes
.
Survival statistics were used to calculate incidence rates. Cox proportional hazards analysis was used to examine the association between aortic aneurysm/dissection and SAH while adjusting for demographics, vascular risk factors, and Charlson comorbidities.

Results:
Among 1,781,917 beneficiaries, 32,551 (1.8%) had a documented aortic aneurysm or dissection. During 4.6 (±2.2) years of follow-up, 2,538 patients (0.14%) developed a nontraumatic SAH. The incidence of SAH was 0.09% (95% confidence interval [CI], 0.07-0.11%) per year in patients with aortic aneurysm/dissection as compared to 0.03% (95% CI, 0.03-0.03%) per year in patients without aortic aneurysm/dissection. After adjustment for demographics, stroke risk factors, and Charlson comorbidities, patients with aortic aneurysm/dissection faced an increased risk of SAH (hazard ratio, 1.9; 95% CI, 1.4-2.7).

Conclusion:
In a nationally representative sample of Medicare beneficiaries, aortic aneurysm/dissection was associated with an increased risk of nontraumatic SAH. This association may reflect shared vascular risk factors and/or a common genetic basis or underlying structural deficits within the arterial wall resulting in aneurysm formation.
Abstract WMP39: Clopidogrel Resistance Predicts Early Neurological Worsening In Patients With Acute Large Artery Atherosclerotic Stroke
Authors: Lee Jun , Gwon Jungim , Kim Mingyeong
Published: October 2018

Introduction:
Although platelet reactivity on clopidogrel is related to outcomes in patients with acute coronary syndromes, few studies have investigated its relation to clinical outcomes in acute ischemic stroke.

Hypothesis:
This study evaluated the association between clopidogrel resistance and early neurological outcomes in patients diagnosed with acute large artery atherosclerotic stroke.

Methods:
1067 consecutive patients with onset within 7 days and stroke classification of large artery atherosclerosis were included. Platelet reactivity on clopidogrel was assessed using VeryfyNow P2Y12 assay at least 72 hours after the time of first clopidogrel dosage. Optimal cutoff value of clopidogrel resistance was obtained by using receiver-operating characteristic curve. Early neurological deterioration was defined as an increment of motor NIHSS score ≥1 before P2Y12 assay. We assessed any hemorrhagic transformation on 5-day MRI.

Results:
A total of 235 patients who met inclusion criteria were analyzed. The median initial dose of clopidogrel was 300 mg, and their median P2Y12 % inhibition was 26.3. P2Y12 % inhibition <29 was the significant discriminator of clopidogrel resistance with an AUC of 0.632 (95% CI 0.48-0.67; p=0.048). A multivariate analysis revealed that clopidogrel resistance is an independent risk factor even after adjustment for the variables that may affect the outcome (OR 2.75; 95% CI 1.11 to 6.83; p=0.029). Hemorrhagic transformation was not influenced by clopidogrel resistance (OR 0.60, 95% CI 0.14 to 2.540; P=0.484).

Conclusion:
In conclusion, high platelet reactivity with clopidogrel is an independent risk factor of early neurological worsening in acute large artery atherosclerotic stroke. Evaluation of ischemic stroke patients regarding antiplatelet resistance might be of clinical importance and alternative pharmacological strategies could be investigated in patients with high platelet reactivity.
Abstract WMP42: Hypoperfusion Symptoms Perform Poorly as an Indicator of Hemodynamic Compromise in Vertebrobasilar Disease: Results From the VERiTAS Study
Authors: Amin-Hanjani Sepideh , Du Xinjian , Rose-Finnell Linda , Pandey Dilip K , Elkind Mitchell S , Zipfel Gregory J , Liebeskind David S , Silver Frank L , Kasner Scott E , Caplan Louis R , Derdeyn Colin P , Gorelick Philip B , Charbel Fady T ,   for the VERiTAS Study Group
Published: October 2018

Introduction:
Hypoperfusion symptoms, defined as symptoms related to change in position (i.e. supine to seated), effort or exertion, or recent change in antihypertensive medication have been used in stroke studies as a surrogate for detecting hemodynamic compromise. However, the validity of these symptoms in identifying flow compromise in patients has not been well established. We examined whether hypoperfusion symptoms correlated with quantitative evaluation of flow compromise in the prospective observational Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) study.

Methods:
VERiTAS enrolled patients with recent vertebrobasilar TIA or stroke and ≥50% atherosclerotic stenosis or occlusion in vertebral and/or basilar arteries. Hemodynamic status using large vessel flow in the vertebrobasilar territory was measured using quantitative magnetic resonance angiography (QMRA), and patients were designated as low, borderline or normal flow based on distal territory regional flow, incorporating collateral capacity, as previously reported. The presence of qualifying event hypoperfusion symptoms was assessed relative to the quantitatively determined flow status (normal vs borderline/low), and also examined as a predictor of subsequent stroke risk.

Results:
Of the 72 enrolled subjects, 66 had data on hypoperfusion symptoms available. On initial QMRA designation, 43 subjects were designated as normal flow vs. 23 subjects designated as low flow (n=16) or borderline (n=7). Of these, 5 (11.6%) normal flow and 3 (13.0%) low/borderline flow subjects reported at least one qualifying event hypoperfusion symptom (p=0.99, Fisher’s exact test). Hypoperfusion symptoms had a positive predictive value of 37.5% and negative predictive value of 65.5% for low/borderline flow status. Compared to flow status, which strongly predicted subsequent stroke risk, hypoperfusion symptoms were not associated with stroke outcome (p=0.87, log rank test).

Conclusions:
These results suggest that hypoperfusion symptoms alone correlate poorly with actual hemodynamic compromise, and subsequent stroke risk in vertebrobasilar disease, and are not a reliable surrogate for flow measurement.
Abstract WMP44: Postmortem Study Exploring Distribution and Patterns of Intracranial Arterial Calcification
Authors: Yang Wenjie , Zheng Lu , Wu Xiaohong , Niu Chunbo , Leung Thomas W , Chen Xiangyan
Published: October 2018

Backgrounds:
Intracranial arterial calcification detected by computer tomography (CT) is found to be associated with ischemic stroke as an indicator of intracranial atherosclerosis. However, little is known about the histology of intracranial arterial calcification.

Methods:
Based on a biobank collecting cerebral arteries from 32 adult autopsy cases, we described the distribution and patterns of arterial calcification in middle cerebral artery (MCA), vertebral artery (VA) and basilar artery (BA).

Results:
Among the total 96 segments evaluated, 43 (45%) showed visible calcification, including 27 intimal calcification, 8 internal elastic lamina (IEL) calcification, 2 medial calcification, and 6 adventitial calcification.
(Figure 1)
Intimal calcification occurred more often in the VA compared with BA (41% vs. 16%, P=0.039). IEL calcification was more commonly detected in VA (22%).
(Table 1)
Among the 27 intimal calcification, 12 showed a stippling calcification pattern, 9 displayed a morula pattern and 6 had large calcium deposits. (
Figure 2
) Of the 96 arteries, 30 (31%) had Pre-atherosclerotic intimal lesions whereas 66 (69%) segments showed progressive atherosclerotic lesions. All of the 27 (100%) intimal calcification was present in the progressive atherosclerotic lesions (p<0.001), while only 3/8 IEL calcification, 1/2 medial calcification, and 4/6 adventitial calcification were associated with progressive plaques (all p>0.05). (
Table 2
)

Conclusions:
Intracranial calcification predominantly occur in the intima, but also spread over IEL, media and adventitia, the latter may not being a proxy for the progressive atherosclerotic plaques.