bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract WP524: Outcomes With Rivaroxaban in Patients With Nonvalvular Atrial Fibrillation and Worsening Renal Function
Authors: Nakagawara Jyoji , Ikeda Takanori , Ogawa Satoshi , Kitazono Takanari , Minematsu Kazuo , Miyamoto Susumu , Murakawa Yuji , Kidani Yoko , Okayama Yutaka , Sunaya Toshiyuki , Ohashi Yohei , Sakaguchi Toshiaki , Yamamoto Noriyuki , Yamanaka Satoshi
Published: January 2019

Introduction:
Direct oral anticoagulants are widely used in patients with nonvalvular atrial fibrillation (AF) to reduce the risk of stroke and systemic embolism, however, there is not enough real-world data of their effectiveness and safety in patients with worsening renal function (WRF). Xarelto post-authorization safety and effectiveness study in Japanese patients with atrial fibrillation (XAPASS) is a prospective observational post-marketing surveillance study mandated by the Japanese authority. It aims to examine safety and effectiveness of rivaroxaban in everyday clinical practice. This analysis investigated one year outcomes among patients with WRF and stable renal function (SRF) in XAPASS.

Methods:
One year follow-up data of 9578 patients enrolled in XAPASS were analyzed to evaluate baseline characteristics and safety/effectiveness profile among patients with WRF and SRF. WRF was defined as a decrease of more than 20% from enrollment creatinine clearance measurement at any time point during the study. SRF was defined as the absence of WRF at any time.

Results:
We identified 1229 patients (12.8%) with WRF and 6280 patients (65.6%) with SRF among 9578 patients. WRF patients were significantly older, and had significantly higher mean CHA
2
DS
2
-VASc score and modified HAS-BLED score compared to SRF patients. Prevalence of hypertension, congestive heart failure, ischemic stroke/transient ischemic attack, and myocardial infarction was higher in WRF patients. There was no difference in rates of major bleeding (hazard ratio (HR) 1.20; 95% confidence interval (CI) 0.75-1.90; p=0.45) or the composite endpoint of stroke, systemic embolism or myocardial infarction (HR 1.06; 95% CI 0.65-1.71; p=0.82) between patients with WRF and SRF. WRF patients experienced a higher incidence of transfusion of 2 units or more (0.46 versus 0.14 events per 100 patient-years; HR 3.19; 95% CI 1.04-9.74; p=0.03) versus SRF patients. Rates of other major bleeding subgroups defined according to ISTH criteria were similar between patients with WRF and SRF.

Conclusions:
WRF during rivaroxaban treatment did not significantly increase the rates of major bleeding or thromboembolic events, although it was associated with a higher incidence of transfusion of 2 units or more.
Abstract WP525: Adherence and Adherence Recovery in a Stroke Trial
Authors: Kernan Walter N , Viscoli Catherine , Young Lawrence , Gorman Mark
Published: January 2019

Objective:
Standards for reporting and analyzing adherence to medical therapy have recently improved due to international consensus efforts. We report adherence in a stroke trial using the EMERGE guidelines and demonstrate how support of patients can lead to adherence recovery during therapy implementation.

Methods:
We analyzed 3 phases of adherence according to current taxonomy in the Insulin Resistance Intervention after Stroke (IRIS) trial: initiation (did patient start drug), implementation (did patient take a drug holiday, defined as temporary cessation lasting ≥14 days), and persistence (did patient permanently and prematurely discontinue drug). IRIS was a randomized, placebo controlled trial testing pioglitazone to prevent stroke or MI in patients with ischemic stroke/TIA and insulin resistance. Adherence was classified by self-report. Researchers used coaching algorithms to seek adherence recovery if participants went off drug.

Results:
During 2005-2013, 3876 participants were enrolled from 179 sites in 7 countries. Mean age was 63.5 years; 65% were male, 11% Black race, and 4% Hispanic ethnicity. A total of 26 patients (<1%) did not start study drug. During implementation, 706 (18%) patients took a drug holiday: 587 took 1 holiday, 97 took 2, and 22 took ≥3. Study drug was discontinued early in 1275 (33%). Major reasons for holidays and discontinuations are shown below by treatment.

Conclusion:
For the first time in a stroke trial, we report adherence according to internationally recommended guidelines. Results show that holidays are common, but participants will resume drug with coaching. Among reasons for drug cessation, only those secondary to study protocol were unavoidable and misattributions of AEs to study drug were common as seen in the placebo group. Our findings have implications for trials that require high drug adherence to successfully answer scientific hypotheses.
Abstract WP528: Safety and Effectiveness of Rivaroxaban Among Japanese Elderly Patients With Nonvalvular Atrial Fibrillation in Everyday Clinical Practice
Authors: Kitazono Takanari , Ikeda Takanori , Ogawa Satoshi , Nakagawara Jyoji , Minematsu Kazuo , Miyamoto Susumu , Murakawa Yuji , Kidani Yoko , Okayama Yutaka , Sunaya Toshiyuki , Ohashi Yohei , Sakaguchi Toshiaki , Yamamoto Noriyuki , Yamanaka Satoshi
Published: January 2019

Introduction:
Nonvalvular atrial fibrillation (AF) is common in elderly patients, who face increased risk of thromboembolism and bleeding during antithrombotic therapy. Xarelto post-authorization safety & effectiveness study in Japanese patients with atrial fibrillation (XAPASS) is a prospective observational post-marketing surveillance study mandated by the Japanese authority. It aims to examine safety and effectiveness of rivaroxaban in everyday clinical practice. This analysis evaluated one-year outcomes and patient characteristics associated with major bleeding or thromboembolic events among elderly patients enrolled in XAPASS.

Methods:
A total of 11,308 patients with AF newly starting rivaroxaban were enrolled between April 2012 and June 2014. As of September 2017, one year follow-up data were collected from 9578 patients, and 4685 patients (48.9%) were aged ≥75 years.

Results:
Patients aged ≥75 years had higher rates of major bleeding (2.22 versus 1.35 events per 100 patient-years; p=0.004), and the composite endpoint of stroke, systemic embolism or myocardial infarction (2.41 versus 1.21 events per 100 patient-years; p<0.0001) compared with those aged <75 years. Rates of intracranial hemorrhage were less than 1% in both patient groups aged ≥75 years and <75 years (0.85 versus 0.59 events per 100 patient-years). There was no significant difference in major bleeding or thromboembolism among patients in age groups of 75-79, 80-84, and ≥85 years. Multivariate analysis identified hepatic impairment and concomitant use of acetylsalicylic acid as risk factors of major bleeding events in patients aged ≥75 years (p=0.041 and p<0.0001, respectively). History of stroke was identified as a risk factor of thromboembolic events in the same patient group (p<0.0001).

Conclusions:
Although elderly patients had higher rates of bleeding and thromboembolic events than younger patients, no significant difference was found in the outcomes between age groups of 75-79, 80-84, and ≥85 years. Benefit and risk of antithrombotic therapy should be thoroughly assessed in elderly patients. Additionally, elderly patients with risk factors of bleeding or thromboembolic events should be carefully monitored while taking anticoagulants.
Abstract WP531: Nontraumatic Convexal Subarachnoid Hemorrhage Concomitants with Hyperacute Ischemic Stroke
Authors: Sato Takeo , Komatsu Teppei , Sakuta Kenichi , Sakai Kenichiro , Terasawa Yuka , Omoto Shusaku , Mitsumura Hidetaka , Iguchi Yasuyuki
Published: January 2019

Background and Purpose:
Nontraumatic convexal subarachnoid hemorrhage (cSAH) rarely occurs concomitant with acute ischemic stroke. The purpose of this study was to investigate the incidence, imaging findings, clinical backgrounds, and outcomes of hyperacute ischemic stroke with cSAH.

Methods:
Patients were selected from a comprehensive stroke center with ≤4.5 h from onset to door with symptomatic ischemic stroke between October 2012 and May 2018. All patients underwent CT and/or MRI on admission and we reviewed them to identify cSAH. Follow-up CT and/or MRI were also reviewed. cSAH caused by trauma, detected after thrombolysis or endovascular treatment, and accompanied with intracerebral hemorrhage was excluded. Retrospective review of cSAH incidence, imaging findings, clinical backgrounds, and outcomes was performed.

Results:
We screened 1249 consecutive symptomatic ischemic stroke patients, including 466 patients with ≤4.5 h from onset to door (342 (73%) male, median age 68 years). Of 466 hyperacute ischemic stroke patients, cSAH was observed in 5 (1.1%) patients (5 male, median age 49 years): 3 were detected on admission and the other was detected at follow-up. None had any meningeal irritation signs, and all were detected incidentally. Four patients (case 1-4) were diagnosed as arterial infarction, and 1 as venous infarction. Of the 4 arterial infarction patients, arterial stenosis or occlusion was observed ipsilaterally to the cSAH (Figure). In addition, of the 4 arterial infarction patients, hyperintense vessel signs were observed on FLAIR imaging on admission suggesting retrograde flow via collateral vessels, or slow flow (Figure). In all, cSAH disappeared gradually, and outcomes were favorable (modified Rankin Scale 0-1 at 3 months from the onset).

Conclusions:
cSAH was accompanied with approximately 1% of hyperacute ischemic stroke. Patients with arterial infarction and cSAH had arterial stenosis or occlusion ipsilaterally to cSAH.
Abstract WP532: Hypertension Interacts With Alzheimer’S Disease via Autophagy-related Phenotypic Changes in Vascular Endothelial Cells
Authors: Hayashi Shin-ichiro , Sato Naoyuki , Shinohara Mitsuru , Kawano Yuhei
Published: January 2019

Alzheimer's disease (AD) is characterized by a progressive neuronal disorder that causes dementia, and is recognized as the leading cause of death in the elderly population. The typical features of AD are Aβ (β amyloid) -containing plaques in the diseased brain. Recent clinical and epidemiological evidences suggest that hypertension, a major vascular risk factor, is possibly implicated in neurodegenerative AD. However, the mechanistic interaction between hypertension and AD is mostly unclear. Here, we investigate whether the mutual phenotypic changes of brain vascular endothelium are existed in AD and hypertension. In this study, 8 or 24 month old male APP23 mice, which represent cognitive disturbance, were used as an in vivo model of AD. 8 week old male Spontaneous hypertensive rats (SHR) and the Wister Kyoto rats (WKY) were used as hypertensive animal and those genetic controls, respectively. Aortic ring assay was performed as ex vivo model of endothelial function. Human endothelial cells (EC) were cultured with Aβ40, H2O2, or cyclic mechanical stretch. Immunohistological staining and EM analysis were performed on brain and aortic tissues or cultured human EC. We found that the hippocampal vessel densities were significantly lower in APP23 mice as compared to those in wild type. Importantly, autophagy, a self-eating process, was detected in hippocampal capillary endothelium in 8-month old APP23 mice, and the number of autophagic microvessels was significantly increased in 24-month-old APP23 mice. The advanced stages of autophagy fused with lysosome were also detected in neurovascular endothelium in APP23 mice. Notably, consistent with the findings in APP23 mice, autophagy was also detected in hippocampal endothelium of SHR, but not in WKY. Aortic ring assay showed that endothelial potential for regeneration was impaired in SHR as compared with those in WKY. Furthermore, Aβ40, H2O2, or cyclic mechanical stretch not only induced autophagy but also impaired endothelial proliferation and NO production in cultured ECs. In conclusion, present findings indicate that phenotypic changes of endothelium, characterized by autophagy induction and impaired endothelial function might be the reciprocal mechanistic interaction between AD and hypertension.
Abstract WP533: Chronic Cerebral Damage Aggravates Vascular Remodeling in Cuff-Induced Vascular Injury Mouse Model
Authors: Iwanami Jun , Mogi Masaki , Tsukuda Kana , Higaki Akinori , Kukida Masanori , Nakaoka Hirotomo , Bai Hui-Yu , Shan Bao-Shuai , Min Li-Juan , Horiuchi Masatsugu
Published: January 2019

Introduction:
Distant organ dysfunction has been highlighted whereby acute or chronic damage in one organ may induce dysfunctions of the other organs such as cardiorenal syndrome. Vascular injury is an important process in various vascular diseases. However, the relationship cerebral ischemic damage and peripheral vascular disorder is still unclear. Therefore, we have investigated the possible pathophysiological interactions between brain ischemia and vascular remodeling.

Methods:
Eight-week-old male C57BL/6 mice underwent permanent cerebral brain ischemia by permanent occlusion of the left middle cerebral artery occlusion (MCAO) by electrocoagulation using a subtemporal approach. Four weeks after MCAO, vascular injury was induced by polyethylene cuff placement on the femoral artery. Neointima formation was determined 14 days after cuff placement by evaluating intima/media ratio. Mice were administrated 0.5% tempol, antioxidant agent, in drinking water from after MCAO. Macrophage fractions in spleen two weeks after MCAO were examined and M1 and M2-polarized macrophages were separated by flow cytometry and analyzed.

Results:
Cerebral ischemia did not influence the intima/media ratio 6 weeks after MCAO compared with sham-operated mice. Neointima formation in the injured artery was significantly increased 2 weeks after cuff placement. Interestingly, the neointima formation 2 weeks after cuff placement was more marked in MCAO-operated mice compared with sham-operated mice. We observed that treatment with tempol did not improve increased neointima formation in MCAO-operated mice. Next, we examined the macrophage fractions in spleen 2 weeks after MCAO. The macrophage fraction in SVF evaluated by F4/80 staining did not differ between sham- and MCAO-operated mice. There was no significant difference in M1 and M2 fraction with/without MCAO.

Conclusion:
These results suggest that cerebral ischemic injury aggravate peripheral vascular disorders, and we are addressing the possible roles of renin-angiotensin system and inflammation etc. involved in these interesting results, which could provide us with the discovery of new pathological mechanisms concerning the distant organ dysfunctions between brain and peripheral vasculature.
Abstract WP535: Differential Immune Activation in Patients With Acute Ischemic Stroke and Admission Blood Pressure Greater Than 185/110 mm Hg
Authors: Batool Yusra , Sykes Gina , Ander Bradley P , Stamova Boryana , Sharp Frank R , Jickling Glen C
Published: January 2019

Background:
A blood pressure > 185/110 mm Hg is associated with increased risk of tPA related hemorrhagic transformation (HT). Stroke guidelines recommend blood pressure >185/110 mm Hg be lowered before tPA treatment. How high blood pressure increases blood-brain barrier disruption and risk of hemorrhagic transformation remains poorly understood. We evaluated peripheral leukocyte activation in stroke patients in relation to elevated blood pressure and their potential contribution to blood-brain barrier disruption.

Methods:
Blood samples from acute ischemic stroke patients were collected within 3 hours of stroke onset, prior to treatment with thrombolytic. Patients were grouped by BP >185/110 mm Hg (n=19) and BP <185/110 mm Hg (n=46). Total blood RNA was assessed by whole genome microarray and differential gene expression analyzed by ANCOVA. Functional analysis of identified genes was performed. Correlation analysis was conducted to identify genes correlated with systolic blood pressure.

Results:
Strokes with admission BP >185/110 mm Hg had 231 genes differentially expressed compared to strokes with BP <185/110 mm Hg (p <0.05, fold change ≥|1.2|). Key genes and pathways associated with BP>185/110 mm Hg included downregulation of
caveolin-1
and upregulation of matrix metalloproteinases (MMPs). Several of these genes, including MMP-21, linearly correlated with increasing systolic blood pressure (r=0.25, p = 0.02).

Conclusions:
A blood pressure >185/110 mm Hg is associated with differential immune activation in patients with acute ischemic stroke, including
caveolin-1
and matrix metalloproteinases. These differences may contribute to blood-brain barrier disruption and risk of hemorrhagic transformation in acute stroke patients with blood pressure >185/110 mm Hg. Whether modulating immune activation could reduce blood-brain barrier disruption and risk of HT requires further study.
Abstract WP536: Elevated High-Sensitivity C-Reactive Protein and Serum Claudin-5 are Associated With Venous Infarction and/or Severity in Acute/Subacute Cerebral Venous Thrombosis
Authors: Duan Jian Gang , Han ZiPing , Cai Yan ning , Wang Chunxiu , Gary B Rajah , Ding Yu chuan , Song HaiQing , Ji Xun ming
Published: January 2019

Background and Purpose:
Acute/subacute cerebral venous thrombosis (CVT) with venous infarction often has poorer outcomes than CVT alone. Exploring biomarkers relevant to venous infarction and CVT severity would contribute to improved therapy and prognosis of CVT patients with venous infarction. It remains unclear whether blood-brain barrier(BBB) related proteins and hs-CRP play a crucial role in the pathogenesis of CVT with venous thrombosis.

Methods:
59 Patients were divided into four groups: acute/subacute CVT patients with venous infarct(ASVI group, n=30), acute/subacute CVT patients without venous infarct(ASOVI group, n=13), chronic CVT group(n=9) and control subjects(n=7). Hs-CRP, claudin-5, occludin, MMP-9, GFAP and S100B were measured on admission in serum and/or cerebrospinal fluid(CSF). Initial CVT severity was assessed by the NIHSS.

Results:
In ASVI group, only serum claudin-5 and hs-CRP were significantly higher than ASOVI group (3.15±1.20 vs. 2.41±0.57, p=0.025; 19.13±15.22 vs. 5.65±6.19, P=0.001, respectively). AUCs for serum claudin-5 and Hs-CRP did not have significant difference (0.70,[95%CI:0.54-0.86]vs.0.795[95%CI:0.66-0.93], P=0.409). AUC for the combination of serum claudin-5 and hs-CRP was greater than that for claudin-5 alone (0.86 [95%CI: 0.75-0.97]vs.0.70[95%CI:0.54-0.86],P=0.0352). After adjustment, serum claudin-5 (adjusted OR, 17.85 [95% CI: 1.23-258.62], P=0.035) and hs-CRP (adjusted OR, 29.22, [95% CI:2.15-397.46], P=0.011) were significantly associated with venous infarction. When serum claudin-5 and hs-CRP were greater than or equal to their cut-off values (2.74 mg/l and 10.97mg/l), 100% of patients had venous infarcts. In ASVI group, hs-CRP was positively associated with NIHSS (
r
=0.640; 95%CI, 0.340- 0.821; P< 0.001).

Conclusions:
For acute/subacute CVT patients,
s
erum claudin-5 and hs-CRP may be clinically valuable biomarkers associated with venous infarction. Hs-CRP was correlated with CVT severity. Anti-inflammation therapy may be useful in the management of severe CVT patients.
Abstract WP539: Treatment With Cilostazol Improves Endothelial Function in Patients With Ischemic Stroke Taking Clopidogrel
Authors: Shirai Yuka , Toi Sono , Kubota Megumi , Higuchi Eiko , Yamazaki Masako , Adachi Utako , Kitagawa Kazuo
Published: January 2019

Background:
Impairment of endothelial function is associated with atherosclerosis. Cilostazol is an antiplatelet drug that inhibits phosphodiesterase III, and has the potential to improve endothelial function. The prospective, open-label, randomized trial to evaluate the safety and efficacy of dual antiplatelet therapy involving cilostazol for secondary ischemic stroke prevention is ongoing (The Cilostazol Stroke Prevention Study for Antiplatelet Combination; CSPS.com) (Int J Stroke Vol 10, Feb 2015, 253).

Objective:
The purpose of this study was to clarify the effect of cilostazol in addition to clopidogrel on endothelial function in patients with ischemic stroke.

Material and Methods:
This study was a sub-study of CSPS.com, and registered in clinical trial (UMIN 000026672). The subjects were enrolled in our hospital from ischemic stroke patients taking clopidogrel after 8-180 days. They were randomly assigned into two groups, one with adding cilostazol on clopidogrel (CIL group), and other without cilostazol (Control group). Endothelial function was evaluated at enrollment and 6 months later, using the Flow Mediated Dilation (FMD) test of the brachial artery under blindness. Endothelial function was expressed as percent increase of brachial vessel diameter (%FMD) after interruption of blood flow with mechanical compression for five minutes. We also measured the plasma levels of inflammatory markers (highly sensitive C-reactive protein, interleukin 6, intercellular adhesion molecule-1, thrombomodulin) at enrollment and 6 months later. The ANOVA was used for statistical analysis.

Results:
Total 29 subjects (Control group 16, CIL group 13) were enrolled. The mean age of subjects was 71.2±8.6 years old, and 81.3% were males. The baseline %FMD was similar between Control group (4.60±0.62%) and CIL group (4.68±0.69%). At 6 months, %FMD did not change in Control group, but %FMD significantly improved in CIL group (p<0.01). There was no significant change in plasma levels of any inflammatory markers in both groups.

Conclusion:
This study showed that the %FMD significantly increased by adding cilostazol to clopidogrel in patients with ischemic stroke. Cilostazol may improve endothelial dysfunction independent of anti-inflammatory action.
Abstract WP541: Profiling of Microrna From Atherosclerotic Tissues and Validation of Their Significance From Peripheral Blood of Ischemic Stroke Patients Having Atherosclerosis
Authors: Jeong Hye Seon , Kim Jee Yeon , Lee Seo Hyun , Hwang Junha , Shin Jong Wook , Lee Sukhoon , Kim Jei
Published: January 2019

Background and Objectives:
To search circulating microRNAs related to atherosclerosis, we first performed a microRNA expression profiling using atherosclerotic plaques. Then, their expression significance was validated using the serum of stroke patients having severe atherosclerosis on cranial vessels.

Methods:
We performed miRNA expressions from 10 carotid endarterectomy (CEA) plaques and 2 human umbilical vein endothelial cell (HUVEC) lines using a microRNA microarray kit (TaqMan® Array MicroRNA Cards, Applied Biosystems®, Life Technologies). The expression differences were compared using relative quantitation (RQ=2

-(miRNA expression -reference RNA expression)

) between the CEA plaques and the HUVECs following a criteria including over 4-fold-up or less than 0.25-fold-down regulations after log2 transformation of the expression difference. Among the microRNAs showing significant expression differences, target microRNAs were selected using an internal clustering validation measurement (Xie-Beni index). The expression of the target microRNAs was validated with the serum of 32 patients with severe atherosclerosis and that of 33 patients with no atherosclerosis in intra- and extra-cranial vessels.

Results:
A total of 151 microRNAs were identified after the comparison of the microRNA expressions between CEA and HUVECs. Among them, eight miRNAs (miR199b, miR142-3p, miR145, miR145, miR204, miR9, miR370, miR23b, and miR363) were selected as the final target microRNAs after the clustering validation analysis. As for the validation experiments with the serum of the atherosclerosis and non-atherosclerosis patients, the RQ of miR142-3p (atherosclerosis, 3.79±7.57; no-atherosclerosis patients, 1.10±1.45, p=0.043), among the 8 target miRNAs, showed significant differences in the serum of patients with atherosclerosis.

Conclusion:
The present study profiled miRNAs from CEA plaques and validated their significance within the serum of atherosclerosis patients. These findings suggest that miR142-3P could be a potential marker for atherosclerosis that is detectable from the circulating blood.
Abstract WP542: Basilar Artery Curvature is Associated With Migraine With Aura in the Northern Manhattan Study
Authors: Zhang Cen , Cucchiara Brett , Noam Alperin , Bagci Ahmet , Rundek Tatjana , Santiago Maria , Wright Clinton B , Sacco Ralph L , Elkind Mitchell S , Gutierrez Jose C
Published: January 2019

Introduction:
Genetic and imaging studies demonstrate a link between vascular morphology and migraine with aura (MA). As aura typically originates from the occipital cortex, the vertebrobasilar system that supplies this area is of particular interest. We examined the relationship between basilar artery (BA) curvature and MA in a large, population-based cohort of stroke-free participants.

Methods:
We analyzed Northern Manhattan Study participants who had undergone time of flight MRA at 1.5 Tesla. Migraine, with or without aura, was ascertained through structured interviews. BA curvature was defined as the sum of the total horizontal deviation of the BA at the distal tip, mid-pons, and vertebrobasilar junction, and was used as the primary independent variable in unadjusted and adjusted logistic regression analyses. BA measurements were obtained blinded to migraine status.

Results:
Of 805 participants (mean age 70±9.3 years, 55% women, 66% Hispanic), migraine without aura was present in 13% (N=105) and MA in 3% (N=24). MA was more common among women (P=0.03) and Hispanics (P=0.001). Mean BA curvature was 16 ± 10 mm. In unadjusted analysis, BA curvature was greater in participants with MA than those without MA (19 vs 15 mm, P=0.02). In a model adjusted for demographics, vascular risk factors, head size and height, greater BA curvature was associated with MA (OR 1.06 per mm, 95% CI 1.01-1.11) compared to participants with no migraine. The association between BA curvature and migraine without aura did not reach significance (OR 1.01, 95% CI 0.99-1.04).

Conclusions:
Greater BA curvature was associated with migraine with aura but not migraine without aura. Understanding the physiopathology of this association may provide clues to the underlying mechanisms of migraine and the relationship between migraine and stroke.
Abstract WP545: White Matter Hyperintensity Burden and Quality of Life Following Lacunar Stroke: A Secondary Analysis of SPS3 Study
Authors: Meyer Chelsea , Ruff Jerdan , de Havenon Adam
Published: January 2019

Introduction:
White matter hyperintensity (WMH) burden has been linked to cognitive impairment, but its effect on post-stroke quality of life has not been examined.

Hypothesis:
Larger WMH burden, measured by Fazekas score on MRI, will negatively impact quality of life post lacunar stroke in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.

Methods:
We evaluated patients from SPS3. The primary outcome was the stroke specific quality of life scale (ss-QoL) at baseline and study completion (mean follow-up 3.4 years).

Results:
There were 2804 patients with baseline ss-QoL and 2185 patients with ss-QoL at study completion. Mean age was 62.7 ± 10.7 years, 62% male, and 53.6% white. Higher Fazekas score had a negative impact on ss-QoL (Table 1), which persisted in a multivariate model (Table 2 & 3). On subgroup ss-QoL, Fazekas had a greater impact on self-care, mobility, productivity, upper extremity, family and social roles (Graph 1).

Conclusion:
Larger WMH burden negatively impacts quality of life following lacunar strokes. The negative effect is seen in specific quality of life categories.
Abstract WP546: Changes in Promoter Methylation in AIRE1 and ALOX12: Novel Epigenetic Markers in Atherosclerotic Tissues
Authors: Shin Jong Wook , Kim Jee Yeon Kim , Jelinek Jaroslav , Hwang Junha , Jeong Hye Seon , Kim Dae Hyun , Cho Kwangjo , Rha Seo Hee , Lee Young Ho , Kim Geun-Eun , Kwon Sun U. , Cha Jae Kwan , Issa Jean-Pierre J. , Kim Jei
Published: January 2019

Objective:
The present study aimed to identify and validate specific genes developing changes in promoter methylation in atherosclerotic plaques.

Approach and Results:
We initially comprehensively profiled DNA methylation signatures via Solexa sequencing, using amplicons prepared via methylated-CpG island amplification (MCA) in genomic DNA obtained from 5 plaques acquired through carotid endarterectomy (CEA) to identify genes with altered promoter methylation. The changes in promoter methylation of these genes were validated via bisulfite pyrosequencing from plaques and non-plaque intima of the common carotid artery (CCA) harvested from 20 cadavers as well as from 27 CEA plaques and 5 human umbilical vein endothelial cell (HUVEC) lines. Expression changes based on changes in promoter methylation in these genes were evaluated in 20 CEA plaques and in 2 HUVEC cell lines after demethylation with 5-aza-2'-deoxycytidine. Upon MCA-Solexa sequencing, five genes (
AIRE1
,
ALOX12
,
FANK1
,
NETO1
, and
SERHL2
) displayed changes in promoter methylation. Of these,
AIRE1
and
ALOX12
displayed significantly greater promoter methylation in plaques rather than in the non-plaque intima of the CCA. Furthermore, promoter methylation was greater in
AIRE1
in CEA plaques than in HUVECs, while that in
ALOX12
was greater in HUVEC cells than in CEA plaques. Concurrently, gene expression levels decreased with an increase in promoter methylation in these genes in CEA plaques. After DNA demethylation in HUVEC cells,
AIRE1
and
ALOX12
expression levels increased by 23 and 52 folds.

Conclusions:
Changes in promoter methylation in
AIRE1
and
ALOX12
were identified and validated in atherosclerotic plaques, thereby establishing novel epigenetic markers for atherosclerosis.
Abstract WP547: FTY720 (Fingolimod) Ameliorates Ischemia Reperfusion Injury in Experimental Stroke Model
Authors: Feng Wang Z , Kawabori Masahito , Houkin Kiyohiro , Abumiya Takeo , Higashikawa Kei , Yasui Hironobu , Kuge Yuji , Kihara Akio , Ohno Yusuke
Published: January 2019

Background:
Fingolimod (FTY720), a widely known sphingosine-1-phosphate (S1P) receptor agonist, was approved as a treatment for multiple sclerosis due to its strong anti-inflammatory effect.

Methods:
In-vivo study, FTY720 was injected intraperitoneally just before reperfusion. Neurological score and infarct volume were evaluated at Day0, 1, 3, 5, and 7 after MCAO. Evans Blue analysis and immunohistochemistry were conducted at day1 and day7. [18F]DPA-714 PET was performed 2 and 9 days after MCAO. In vitro study, in order to perform OGD, Bovine Brain Microvascular Endothelial Cells (BBMVECs) were incubated in a glucose-free medium under 1% oxygen condition, and then reperfused for 4 hours. In vitro models of ischemia/reperfusion injury were exposed to FTY720, FTY720-P, S1P and SEW (100 nM) immediately after reperfusion. The effects of FTY720 on the blood brain barrier were examined by real-time PCR analysis and immunofluorescence staining.

Results:
In this study, we observed that FTY720 reduced infarction size and improved neurological score after MCAO. [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 2 days after MCAO. Although SUV was increased further 9 days after MCAO in both treatment groups, the increase was significantly inhibited in 1.5mg/kg group. In addition, FTY720 recovered the integrity of blood brain barrier which has been disrupted by ischemia/reperfusion injury. However, we observed that FTY720 can improve the integrity of blood brain barrier by inducing the translocation of tight junction and adherins junction, but FTY720 cannot ameliorate the expression of tight junction and adherins junction.

Conclusions:
The present results suggest that FTY720 improves neurological score, reduces infarction size, inflammatory activation and neuronal apoptosis. Especially ameliorates the integrity of Blood-Brain Barrier by inducing the translocation of tight junction and adherins junction after transient MCAO.
Abstract WP548: Incidence and Prevalence of Headache in Cranio-Cervical Artery Dissection Patients
Authors: Redd Kolby T , Rosati Lauren M , Lim Mihyun , McMillian Brittiny , Grant Alyson , Sen Souvik
Published: January 2019

Introduction:
Spontaneous craniocervical artery dissection (CeAD) occurs commonly in healthy individuals without known risk factors for stroke, whereas traumatic CeAD varies widely from penetrating trauma to motor vehicle crashes to minor movements of the neck. Headache (HA) and cervical pain occur in up to 75% of patients with CeAD. Yet, there are limited data on the incidence of new HA in CeAD patients after diagnosis.

Methods:
All patients from January 2015 to May 2017 consecutively identified by an electronic medical record-based application were enrolled in this prospective longitudinal registry. CeAD was confirmed by imaging during acute hospital visits. Patients were consented and followed for 12 months for HA status and HA Impact Test-6 (HIT-6) score (little to no impact: 49 or less, some impact: 50-55, substantial impact: 56-59, severe impact 60+).

Results:
The cohort included 111 CeAD patients (age 53 ± 15.9 years, 56% Caucasian, 50% female). Prevalence of reported HA at baseline was 40% (n=44) of enrolled patients; yet, there was no reportable difference between HA and no HA based on dissection location (carotid n=62; vertebral n=41; or basilar n=2; p=0.445). At baseline, 43% of patients categorized their HA as severely impacting their lives based on HIT-6. At the 3-month follow up, there was an incidence of 16% (n=11) who now reported HA but had no HA at baseline. At 3 months, 57% of patients categorized their HA as severely impacting on their life. At the 12-month follow up, there was an incidence of 7% (n=4) who now reported HA but no previous HA at baseline or 3 months. At 12 months, 58% of patients were classified into the severe impact category determined using HIT-6 calculations. HA status was not found to be associated with stroke or traumatic brain injury from CeAD (p = non-significant).

Conclusions:
We report the incidence and prevalence of HA within the CeAD population over a 12-month period. A high prevalence level was observed (40%) within the baseline history of CeAD diagnosis, with incremental incidence of new HA (16% and 7%) reported at 3 months and 12 months, respectively. There was no association found between HA status and stroke, dissection location or traumatic brain injury.
Abstract WP552: Post-stroke Dementia Incidence and Risk Factors in Korea: Linked Big Data Between the Clinical Research Center for Stroke Data and the Health Insurance Review & Assessment Service Data Analysis
Authors: Kim Tae Jung , Lee Ji Sung , Oh Mi-Sun , Lim Jae-Sung , Nam Ki-Woong , Lee Chan-Hyuk , Mo Heejung , Jeong Han-Yeong , Jung Keun-Hwa , Ko Sang-Bae , Yu Kyung-Ho , Lee Byung-Chul , Yoon Byung-Woo
Published: January 2019

Background:
Post-stroke dementia is an important factor of poor functional outcome following stroke. However, few longitudinal studies on the incidence and risk factors of dementia after stroke have been performed.

Hypothesis:
We aimed to investigate the incidence and clinical factors related to dementia after ischemic stroke.

Methods:
A total of 47,779 patients with acute ischemic stroke (within 7 days after stroke onset) were enrolled, who were registered in the Clinical Research Center for Stroke (CRCS) registry from 2006 to 2014 and successfully linked the Health Insurance Review and Assessment Service (HIRA) big database. All included patients did not have dementia before index stroke. The incidence of post-stroke dementia was identified using International Classification of Diseases, Tenth Revision, dementia diagnosis codes (F00, F01, F02, F03, and G30) with prescription of an anti-dementia medications after index stroke based on linked big data.

Results:
Of the 47,779 patients, 10,357 patients (21.7%) had post-stroke dementia. The cumulative incidence of dementia after stroke was 10.4% after 1 year, 15.6 % after 3 years, 19.5% after 5 years, 22.9% after 7 years, and 27.1% after 10 years. The crude incidence rate of post-stroke dementia was 40.03 cases per 1000 person-years in this stroke registry based linkage big data. Post-stroke dementia groups were older, more frequently female, and were more likely to have severe stroke, history of stroke, lower education level, dependency before stroke.

Conclusions:
Our study demonstrated that about 22% of ischemic stroke patients were demented after stroke, particularly were associated with history of stroke, and stroke severity. These patients with high risk of dementia should be controlled risk factors for preventing cognitive impairment following stroke.
Abstract WP553: Differentiation of Cortical Microinfarctions Due to Cerebral Amyloid Angiopathy From Those Caused by Microembolism on 3T MRI
Authors: Ishikawa Hidehiro , Ii Yuichiro , Shindo Akihiro , Maeda Masayuki , Ito Ai , Umino Maki , Matsuura Keita , Taniguchi Akira , Tomimoto Hidekazu
Published: January 2019

Background:
Cortical microinfarctions (CMI) are often detected in patients with cerebral amyloid angiopathy (CAA) and cerebral microembolism.

Purpose:
To evaluate whether the size, location and distribution of CMIs differ between CAA and microembolism on 3T MRI.

Methods:
We retrospectively screened 657 patients who consulted our memory clinic from Jan 2011 to Mar 2018 and underwent detection protocol for CMIs (3-dimensional double inversion recovery (DIR), 3-dimensional fluid attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) on 3T MRI). There were 120 patients which had DIR-positive and SWI-negative lesion less than 10 mm in diameter. These patients were classified to embolic stroke group and CAA group which fulfilled the modified Boston criteria for possible or probable CAA. We analyzed the size, location and distribution of small cortical lesions on each group.

Result:
We enrolled 44 patients as embolic stroke group and 27 patients as CAA group. A total of 175 small cortical lesions were identified in the embolic stroke group and 63 in the CAA group. Mean number of small cortical lesions in the embolic stroke group was significantly higher than those of the CAA group (4.0 vs 2.3; p = 0.001). In the CAA group, the frequency of cortical lesions less than 5mm and localized in the cortical gray matter; ie. CMI, was higher than in the embolic stroke group (92% vs 69%; p < 0.001). By contrast, the frequency of cortical lesions larger than 5mm was significantly higher in the embolic stroke group than in the CAA group (21% vs 8%; p = 0.004). Furthermore, the frequency of cortical lesions involving subcortical area was significantly higher in the embolic stroke group than in the CAA group (30% vs 8%; p < 0.001). Regarding their distribution, the CAA group showed occipital lobe dominance compared to the embolic stroke group (30% vs 10%; p < 0.01).

Conclusion:
Our results suggest that CMIs caused by CAA tend to be less numerous, localized in the cortical gray matter and smaller than 5mm, and show occipital dominance compared to those by microembolism. These characteristics may be helpful for differentiating CMIs due to CAA from those caused by microembolism.
Abstract WP556: Predicting Modified Rankin Scale Using Prior Cognition Measure: Results From CLEAR III Study
Authors: Avadhani Radhika , Thompson Richard E , Yenokyan Gayane , Lane Karen , McBee Nichol , Ziai Wendy C , Awad Issam A , Hanley Daniel F
Published: January 2019

Introduction:
Intraventricular hemorrhage (IVH) is a subtype of intracerebral hemorrhage (ICH) accounting for 50% mortality and serious survivor disability. We examined whether screening Mini-Mental State Examination (MMSE) scores assessed at days 30 and/or 180 could predict good functional outcome, measured by modified Rankin Scale (mRS) at days 180 and 365 post-stroke.

Methodology:
CLEAR III was a multicenter, randomized, phase III trial that tested the benefits of accelerated IVH clot removal. Patients were followed for one year with MMSE and mRS collected at days 30 (D30), 180 (D180) and 365 (D365). Good functional outcome was defined as mRS 0-3. Of 500 patients randomized, 354 known survivors were analyzed. Multivariate logistic regression (MLR) was used to estimate the relationship between good D180 and D365 mRS and D30 and/or D180 MMSE adjusting for age and any ICH location.

Results:
The model predicted a 15% increase in the odds of good D180 mRS for each unit increase in D30 MMSE (OR [95% CI] =1.15 [1.11, 1.20], p-value<0.001). Based on this model, a score of MMSE of 14 or higher is associated with good D180 mRS with 77% sensitivity, 75% specificity, and 76% correctly classified cases (AUC=0.84). In MLR model, D30 MMSE (AOR [95% CI]=1.14 [1.10, 1.19], p-value<0.001) and thalamus ICH location (AOR [95% CI]=0.18 [0.09, 0.38], p-value<0.001) were significant predictors of good D180 mRS, with no significant association with age (AOR [95% CI]=0.97 [0.94, 1.00], p-value=0.073). Similarly, we saw a 14% increase (AOR [95% CI]=1.14, [1.09, 1.20], p-value<0.001) in the odds of good D365 mRS for each unit increase in D30 MMSE, and 9% increase (AOR [95% CI]=1.09, [1.03, 1.15], p-value=0.002) in the odds of good D365 mRS for each unit increase in D180 MMSE (p-value <0.001, AUC=0.88). D30 MMSE (AOR [95% CI]=1.12 [1.06, 1.18], p-value<0.001), D180 MMSE (AOR [95% CI]=1.12 [1.05, 1.19], p-value=0.001), age (AOR [95% CI]=0.96 [0.92, 1.00], p-value=0.041), and thalamus ICH location (AOR [95% CI]=0.17 [0.07, 0.44], p-value<0.001) were significantly associated with good D365 mRS.

Conclusion:
Cognition measurements, such as MMSE, may be helpful in predicting good functional outcomes at D180 and D365 post-stroke.
Abstract WP557: Chronic Remote Ischemic Conditioning (C-RIC) Induces Collateral Remodeling and Improves Functional Outcomes Independent of Sex in Aged Mouse Model of Vascular Cognitive Impairment and Dementia (VCID)
Authors: Khan Mohammad B , Siddiqui Shahneela , Vaibhav Kumar , Hafez Sherif , Yashar David , Li Yong , Batori Robert , Braun Molly , Khodadadi Hesam , Dhandapani Krishnan , Baban Babak , Hoda Md. Nasrul , Hess David C
Published: January 2019

Background and Purpose:
There is presently no specific therapy for the treatment of VCID. We reported that daily C-RIC (4mo) is effective in young mice by improving cerebral blood flow (CBF), minimizing white matter (WM) damage and improving functional outcomes in Bilateral Carotid Artery Stenosis model (BCAS.) The purpose of this study was to evaluate whether 4 months (4 MO-C-RIC) is effective in
male and female aged
mouse and if the treatment effects are durable out to 6MOS.

Methods:
Microcoil induced BCAS model was used to induce chronic hypoperfusion. Adult C57BL/6 both male & female mice
(14-months
) were randomly assigned to 3-different groups (N=10), and subjected to Sham, BCAS+sham RIC, BCAS+RIC. C-RIC was started 7d post-surgery daily for 4MOs. Behavioral test and CBF was performed at 1, 4 and 6MO after BCAS and Sham surgery. Functional outcomes were assessed using novel object recognition (NOR) test for non-spatial working memory, and hanging wire and beam walk test for motor/muscular impairment. Histopathology as well as immunohistochemistry for CD31/α-SMA; GFAP, myelin basic protein (MBP) and beta-amyloid were also performed on the brain tissue collected after the neurobehavioral tests.

Results:
C-RIC-therapy for 4MO significantly improved CBF in the male and female BCAS+C-RIC groups at all time points compared to BCAS-Sham RIC groups. Mice from the BCAS group +Sham C-RIC group showed significant loss in the discrimination index as determined by the NOR test, and poor motor function in hanging wire and beam walk test. C-RIC- significantly improved these functional outcomes. Histopathology showed prevention of WM degeneration and myelin basic protein by C-RIC. Immunohistochemical analysis at 6 MOs showed increased CD31 (angiogenesis) and a-SMA staining (arteriogenesis) indicating collateral remodeling in the C-RIC group compared to BCAS-sham RIC.

Conclusions:
Daily 4MO C-RIC-therapy improves long term CBF and vascular architecture at 6 MO and reduces WM damage and improves functional outcomes in aged males and females C-RIC induces durable long term collateral remodeling. C-RIC is a promising therapy for VCID and is ready for future clinical trials in VCID.
Abstract WP558: Benefits of Perlecan Domain V in Diabetic Co-morbid Models of VCID
Authors: Trout Amanda L , Hartz Anika M , Roberts Jill M , Fraser Justin F , Bix Gregory J
Published: January 2019

Introduction:
Vascular contributions to cognitive impairment and dementia (VCID) are a major factor in the overall clinical burden of dementia. Besides aging, metabolic disorders such as type 2 diabetes complicate understanding of underlying mechanisms. Despite the complexity,
we hypothesize that pathological changes in cerebrovascular extracellular matrix (ECM) are an underlying component of VCID that can be therapeutically targeted to reduce neurodegeneration and improve outcomes
. One such ECM component, the terminal domain V (DV) of perlecan, greatly reduces amyloid toxicity and enhances angiogenic cerebrovascular remodeling.

Methods:
DV’s mechanism and therapeutic potential in facilitating Aβ clearance were examined in an
ex vivo
model of isolated mouse brain capillaries in normal and high glucose environments. We also determined the cerebrovascular changes in a comorbidity mouse model of VCID (diabetic APP/PS1 knock in (db/AD)) that is associated with hemorrhages, aneurysms, Aβ deposition, cognitive decline and increased mortality.

Results:
DV (300 and 600 nM) doubled the transport of fluorescently tagged hAβ1-42 over 24 hours from the bath (abluminal) to luminal side of the brain capillaries. One of Aβ’s known transport proteins, P-glycoprotein (P-gp), also increased in total protein expression and in transport activity in the presence of DV. At 3-6 months in db/AD mice, we observed a decrease in BBB proteins (claudin-5) indicating an altered cerebrovascular function correlating with DV expression increase during the asymptomatic angiogenic stage. At 9-12 months, cognitive changes were associated with altered cerebrovascular protein expression in PECAM, Collagen IV, and DV correlating with the aberrant two-photon vascular imaging, increased saccular aneurysms, and microhemorrhages.

Conclusion:
These data show that DV increases cerebrovascular Aβ clearance through P-gp. Increased DV expression correlates with early cerebrovascular changes induced by angiogenic-remodeling in a diabetic co-morbid mouse model of VCID. Lower DV expression is associated with aberrant vasculature that contribute to increased mortality, suggesting that DV ‘replacement therapy’ could represent a novel therapeutic for VCID.