bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 107: Rescue Tirofiban in Mechanical Thrombectomy for Acute Cerebral Large Artery Occlusion: A Multicenter Prospective Registry Study
Authors: Yang Ming , Huo Xiaochuan , Gao Feng , Wang Anxin , Zhang Xiaoli , Shi Hongchao , Chen Wenhuo , Wang Shouchun , Wang Yongjun , Miao Zhongrong
Published: January 2019

Background and Purpose:
Preferred rescue treatment has not yet been recommended for recanalization refractory stroke patients during mechanical thrombectomy (MT). We aim to evaluate the safety and efficacy of rescue tirofiban in acute ischemic stroke(AIS) patients undergoing MT.

Methods:
We derived data from the ANGEL study, a multi-centric, prospective registry study that included MT patients owing to proximal large-artery occlusionfrom June 2015 to December 2017. Patients in this study were dichotomized into tirofiban and non-tirofiban group according to whether rescue tirofiban was performed during and after MT. Safety (symptomatic intracerebral hemorrhage [sICH], ICH and thrombus distalization) and efficacy outcomes (artery recanalization and functional outcomes at 3-month follow-up) were compared between groups.

Results:
We included 662 patients from the entire 917 patients in the Registry. Among them, there were 230 in tirofiban group and 432 in non-tirofiban group, and 47 (7.1%) patients suffered sICH and 102 (15.4%) suffered ICH within post-MT 24 hours; 33 (5.0%) experienced thrombus distalization; 289 (43.7%) achieved functional independence and 135 (20.4%) died after three-month follow-up. No significant differences of safety outcomes on sICH, ICH thrombus distalization and efficacy outcomes on artery recanalization and long-term functional independence were found between tirofiban and non-tirofiban groupeither for the entire cohort, anterior circulation stroke(ACS) patients or posterior circulation stroke(PCS) patients (p>0.05 for all groups). Yet, rescue tirofiban was significantly correlated with long-term mortality reduction for PCS patients (adjusted hazard ratio 0.35 [0.14-0.92], p=0.03).

Conclusion:
Rescue tirofiban during and after MT was not associated with increased risk of safety outcomes on sICH, ICH and thrombus distalization for AIS patients, and was correlated with long-term mortality reduction for PCS.
Abstract 11: Stroke in the Young: Preliminary Results for Temporal Trends in the Age of Stroke Incidence in a Large, Bi-Racial Population
Authors: Kissela Brett M , Alwell Kathleen , Khoury Jane C , Moomaw Charles J , Woo Daniel , Adeoye Opeolu , Flaherty Matthew L , Khatri Pooja , Ferioli Simona , Demel Stacie L , Star Michael , De los Rios La Rosa Felipe , Walsh Kyle , Martini Sharyl , Mackey Jason , Jasne Adam , Slavin Sabreena , Broderick Joseph P , Kleindorfer Dawn O
Published: January 2019

Introduction:
Previously, we reported that stroke incidence in the young (age < 55) significantly increased in both blacks and whites over four study periods between 1993 and 2010. Here we further describe this temporal trend, adding data from 2015.

Methods:
The Greater Cincinnati/Northern Kentucky region includes 2 southern Ohio and 3 contiguous Northern Kentucky counties (estimated population, 1.3 M). Our study determined first-ever hospital-ascertained strokes that occurred in the population from 7/1/93 to 6/30/94 and in calendar years 1999, 2005, 2010, and 2015 by screening ICD9 (and ICD10, in 2015) codes of all inpatient and emergency department visits. Cases were abstracted by study nurses and verified by study physicians. Results for 2015 are preliminary. The denominator for the calculation of incidence rates (in those aged ≥20 years) was extracted from the U.S. Census Bureau website (www.census.gov). Age- and race -specific incidence rates with 95% confidence intervals (CI) were calculated assuming a Poisson distribution. We tested for differences in age trends using Student’s t-test, X
2
, and Poisson regression as appropriate.

Results:
The mean± SD age of stroke was 71.3±13.6 in 1993-94, 70.9±14.4 in 1999, 68.4±15.5 in 2005, 68.5±15.6 in 2010, and 68.7±15.4 in 2015 (p<0.0001 for trend). The proportion of all strokes under age 55 went from 12% to 15% to 20% to 22%, then 18% in 1993-94, 1999, 2005, 2010, and 2015, respectively. Poisson regression showed a shift toward younger strokes across the five periods studied (p<0.0001). Age-specific stroke incidence rates by study period are presented in the Table.

Discussion:
The disturbing trend of increasing stroke in the young (age < 55) has leveled off slightly since 2010 but is still of great public health significance as younger strokes carry the potential for greater lifetime burden of disability. Further study is needed to determine the reasons for these results, including examination of race-specific trends.
Abstract 111: Endovascular Thrombectomy May Be Safe and Effective in Patients With Large Core and Early Presentation
Authors: Sarraj Amrou , Hassan Ameer , Sitton Clark , Chen Peng R , Cai Chunyan , Cutter Gary , Pujara Deep , Imam Bita , Reddy Sujan , Kamal Haris , Ortega Gutierrez Santiago , Abraham Michael , Edgell Randall , McCullough Louise , Savitz Sean , Albers Gregory , Gupta Rishi , Grotta James
Published: January 2019

Background:
Large infarct cores on CT or CTP were an exclusion from most trials of Endovascular thrombectomy (EVT). However, large cores may be seen in occasional patients presenting within the early window (0-3 hours) and may not preclude potential benefit from thrombectomy. We studied clinical outcomes with thrombectomy in patients presenting with large cores measured by CT or CTP within 3 hours of last known well (LKW).

Methods:
From a multicenter prospective cohort study of imaging selection for EVT (SELECT), patients with a large ischemic core (CBF<30%) > 50cc or ASPECT≤5 presenting within 3 hours from LKW to imaging were identified. All patients received CT and CTP with mismatch determination by RAPID software. A blinded independent core-lab adjudicated all images. Good (90 day mRS 0-2) and safety (sICH and mortality) outcomes were compared between patients who received EVT and those with medical management (MM) only.

Results:
Of 445 patients enrolled, 54 met criteria for large core and early presentation; 28 had ASPECT≤5 (17 EVT, 11 MM) and 40 had CTP >50 cc (26 EVT, 14 MM) and 14 on both CT and CTP. Median (IQR) age 66 years (60, 75), NIHSS 20 (18, 23), LKW to puncture 162 min (range 69-343). Baseline characteristics were similar between EVT and MM. Patients with large core whether on CT (ASPECT≤5) or CTP (CBF>50cc) had more frequent good outcome with EVT (30% overall, CT 35%, and CTP 27% vs 0% MM, p=0.04, Fig 1) Furthermore, EVT resulted in smaller average final infarcts (77 vs 202 ml, p=0.03), similar mortality (31% vs 29%, p=0.87) and sICH (16% vs 6%,p=0.34). In patients who achieved good outcome with thrombectomy, EVT resulted in smaller infarct growth 31 ml (10-58) vs 111 cc (67-233) in patients who had poor outcome, p=0.01. Outcome rates were similar if large core was defined as >70ml.

Conclusion:
Patients with large core infarct measured by CT or CTP presenting within 3 hours may benefit from EVT. Time may trump imaging in patients with large core who present early.
Abstract 115: Assessing the Concordance Between Stroke Rehabilitation Research Participants & ‘Real World’ Stoke Patients
Authors: Nelson Michelle
Published: January 2019

Stroke rehabilitation programs have been transformed to better align with stroke Clinical Practice Guidelines (CPGs), which prioritize randomized control trials as evidence-based best practices. However, a recent review of stroke rehabilitation randomized control trials (RCTs) found that the RCTS tended to include younger participants, excluded participants based on age related criteria, and often excluded individuals with comorbidities. The objective of this study was to determine the proportion of stroke patients that would meet the enrolment criteria of stroke rehabilitation randomized controlled trials. A retrospective chart audit was conducted for all patients discharged from a high intensity stroke rehabilitation unit for a one-year period (n=110). RCT exclusion criteria were extracted from a recent review that analyzed the study inclusion and exclusions of 428 RCTs (age, cognitive impairment, previous stroke, and comorbidities). These study exclusions were applied to the 110 patients to determine how many patients would have been eligible to participate in the RCTs. Patients admitted to the stroke rehab unit had a mean age of 67.4 years and an average of 6.2 co-morbidities. 60.1% of these patients would have been excluded from participating in the RCTs by one or more exclusion criteria. 5.5% of patients would have been excluded based on age, 84.5% of patients would have been ineligible for 54% of RCTs based on cognitive impairment, 28% of patients would have been ineligible for 36% of RCTs based on a previous stroke, and 4.2% of patients would have been excluded based on the presence of a CCI condition or stroke risk factor. Results highlight the difference between trial subjects and ‘real world’ patients. Based on our understanding of how people accumulate chronic conditions with age, it can be inferred that the high quality evidence may not reflect the clinical reality of stroke rehabilitation. Given the high prevalence of increased age and comorbidities among stroke rehabilitation patients, this study emphasizes the importance of including ‘typical stroke patients’ in research studies or supporting the use of alternative methodologies that addresses application of study results to older patients with comorbidities.
Abstract 116: MR PREDICTS@24H -- Multivariable Outcome Prediction After Endovascular Treatment for Acute Ischemic Stroke: Development and Validation of a Prognostic Model in Data From Seven RCTs
Authors: Chalos Vicky , Venema Esmee , Mulder Maxim , Roozenbeek Bob , Brown Scott , Demchuk Andrew , Majoie Charles B , Muir Keith , Davalos Antoni , Mitchell Peter , Bracard Serge , Hill Michael , White Phil , Campbell Bruce , Saver Jeffrey , Jovin Tudor , Goyal Mayank , van der Lugt Aad , Dippel Diederik W , Lingsma Hester
Published: January 2019

Background:
Even when the revascularization and clinical status of a patient after endovascular treatment (EVT) for acute ischemic stroke is known, outcome is still highly variable and difficult to predict. We aimed to develop and externally validate a prognostic model that can be applied within one day after EVT to predict functional outcome at three months (MR PREDICTS@24H).

Methods:
For model development we used data from patients in the treatment arms of seven randomized controlled trials within the HERMES collaboration. For external validation we used data from the MR CLEAN Registry, a Dutch ongoing prospective multicenter study for consecutive patients treated with EVT between March 2014 and June 2016 (n=1526). Primary outcome was the ordinal modified Rankin Scale (mRS) score three months after EVT. Eighteen pre- and post-procedural variables, assessed within one day after EVT, were analyzed with univariable ordinal logistic regression analysis (p<0.157) and multivariable ordinal logistic regression analysis with stepwise backward selection (p<AIC) and fixed effect for trial. From this model, we derived predicted probabilities of functional independence (mRS 0-2). Model performance was quantified with discrimination (c-statistic) and calibration.

Results:
The final model included nine variables: age, baseline stroke severity measured with the NIH Stroke Scale (NIHSS), diabetes mellitus, pre-stroke mRS, collateral score, occlusion location, revascularization grade, NIHSS 24 hours after EVT, and symptomatic intracranial hemorrhage. The model explained 62% of the variance in outcome and NIHSS 24 hours after EVT was the strongest predictor with 54% explained variance. The externally validated c-statistic was 0.84 for the prediction of the ordinal mRS and 0.91 for mRS 0-2, indicating very good model performance. Calibration for mRS 0-2 was also very good (intercept: 0.25 and slope: 0.99).

Conclusion:
MR PREDICTS@24H, which can be applied within one day after EVT, accurately predicts functional outcome at three months. It may provide physicians, patients, and family members with improved outcome expectations and could guide physicians in personalizing their patients’ treatment and rehabilitation plans.
Abstract 117: Relationship Between Presence of Visceral Infarction and Functional Outcome Among Patients with Acute Ischemic Stroke
Authors: Piran Pirouz , Atalay Yahya B , Patel Praneil , Hung Peter , Finn Caitlyn , Gupta Ajay , Murthy Santosh B , Navi Babak B , Kamel Hooman , Merkler Alexander E
Published: January 2019

Background:
Evidence of visceral infarction is often found in patients with acute ischemic stroke, and appears to be more common among patients with embolic stroke subtypes. It remains uncertain whether there exists a relationship between visceral infarction and functional outcomes among patients with stroke.

Methods:
Among patients with acute ischemic stroke enrolled in the Cornell AcutE Stroke Academic Registry (CAESAR) from 2011 through 2016, we included those with a contrast-enhanced abdominal computed tomographic scan within 1 year of admission. Our outcome was ambulatory status at discharge from the acute stroke hospitalization, defined as walking without assistance, walking with assistance, and unable to walk. We used ordinal logistic regression to examine the association between visceral infarction and discharge ambulatory status after adjustment for demographics, stroke risk factors, stroke severity (NIH Stroke Scale score) and stroke subtype.

Results:
Among 2,116 ischemic stroke patients registered in CAESAR from 2011-2016, 228 had contrast-enhanced abdominopelvic computed tomographic imaging, of whom 40 (18%) had evidence of visceral infarction. Among the 188 patients without visceral infarction, 125 (66%) patients were discharged walking without assistance, 34 (18%) patients could walk with assistance, and 29 (15%) patients could not walk. In comparison, among the 40 patients with visceral infarction, 18 (45%) patients were discharged walking without assistance, 9 (23%) patients could walk with assistance, and 13 (33%) patients could not walk. After adjustment for demographics, stroke risk factors, stroke severity and stroke subtype, the presence of visceral infarction was associated with a worse ambulatory status (global OR for better ambulatory status, 0.3; 95% CI, 0.1-0.8).

Conclusions:
We found that the presence of visceral infarction, which is often incidentally detected on imaging among stroke patients, was associated with poor functional outcomes at the time of hospital discharge. These findings suggest that such incidental findings are not benign and are at the least a marker of poor outcomes.
Abstract 118: Predictors of Post-Stroke Depression in Ischemic Stroke Patients using the Patient Health Questionnaire-9
Authors: Fournier Lauren E , Zhang Xu , Bonojo Esther , Love Mary , Sanner Jennifer , Cooksey Gabretta , Hinojosa Evelyn , Okpala Munachi N , Savitz Sean I , Sharrief Anjail Z
Published: January 2019

Introduction:
Post-stroke depression (PSD), which affects one-third of stroke patients, is an important psychosocial consequence after stroke linked with higher stroke morbidity, mortality, and recurrence. Current guidelines do not direct when to screen for PSD. Using hospital and clinic PSD screening, we sought to identify predictors of PSD symptoms, factors associated with worsening PSD symptoms, and use of antidepressants in PSD.

Methods:
In a retrospective review of patients hospitalized with ischemic stroke from 01/2014-11/2016, patients completed a Patient Health Questionnaire-9 (PHQ-9) inpatient and again in clinic follow-up within 180 days (median 45 days). PHQ-9 score was categorized as no symptoms (0-4), mild (5-9), moderate (10-14) and severe (15-27). Baseline and follow-up data were analyzed by t-test and Fisher’s exact test for univariate analyses and logistic regression model for multivariable analyses.

Results:
Among 201 patients, depressive symptoms (PHQ-9 > 4) were seen in 30% of patients during hospitalization and 46% in clinic (54% of which had no symptoms inpatient). At follow-up, 64% of patients had stable/improved symptoms and 36% were worse by PHQ-9 category. In univariate analysis, clinic modified Rankin Scale (mRS) ≥2 (p=0.027) and clinic antidepressant prescription (p=0.0004) were associated with worsening PHQ-9 category. In logistic regression analysis, mRS ≥2 (p=0.022), posterior circulation stroke (p=0.029), and clinic antidepressant prescription (p=0.002) were associated with worsening.

Conclusions:
A substantial number of ischemic stroke patients develop or have worsening depression from hospitalization to follow-up. Post-stroke disability (mRs ≥2) and posterior circulation stroke were associated with worsening depression at follow-up. Worsening symptoms prompted a change in management in our clinic. Screening for PSD inpatient should be followed-up in clinic as both may impact treatment and outcomes.
Abstract 121: Machine Learning Prediction of Stroke Mechanism in Embolic Strokes of Undetermined Source
Authors: Sahu Ananya , Okin Peter M , Devereux Richard B , Weinsaft Jonathan W , Diaz Ivan , Salehi Omran Setareh , Gupta Ajay , Navi Babak B , Iadecola Costantino , Kamel Hooman
Published: January 2019

Introduction:
Embolic strokes of undetermined source (ESUS) are thought to arise mostly from occult cardiac sources or large-artery atherosclerotic lesions and, less frequently, other causes. The proportions of such mechanisms remains unclear.

Methods:
We trained a machine learning algorithm to distinguish non-lacunar strokes caused by cardiac embolism versus large-artery atherosclerosis or other known causes (e.g., dissection), then applied the algorithm to ESUS cases to determine the predicted prevalence of cardiac embolism, which we focused on since it is plausibly a potential target for anticoagulation. We used data from the Cornell Acute Stroke Academic Registry (CAESAR), which includes all acute strokes at our hospital from 2011-2016. All variables measured during echocardiography were pulled directly from our image server (Xcelera, Philips Healthcare) and used as features to train the algorithm. Stroke etiologies were adjudicated by a panel of neurologists using TOAST and ESUS criteria. We excluded patients with an ejection fraction <35% because it was highly collinear with a cardioembolic etiology. A gradient-boosted decision tree ensemble (XGBoost) was trained on a 90% random sample of patients with a known non-lacunar etiology. Random search and cross-validation were used to tune hyperparameters. Model performance was assessed in the 10% sample of held-out non-lacunar cases not used for model training. We then applied the final algorithm to the ESUS cases in our registry to determine the predicted label (cardioembolic or not).

Results:
Among 1,758 patients with echocardiograms and an ejection fraction 35% or greater, 497 had a cardioembolic etiology, 240 a large-vessel etiology, and 78 another known etiology. Our XGBoost algorithm had an area under the curve of 0.83 (± 0.06) for classifying these non-lacunar strokes as cardioembolic versus non-cardioembolic. When applied to our 520 ESUS cases, the algorithm classified 16% as cardioembolic.

Conclusions:
An echocardiogram-based prediction algorithm that accurately distinguished known cardioembolic versus non-cardioembolic strokes predicted that about one-sixth of our ESUS cases were cardioembolic.
Abstract 122: Markers of Coagulation and Hemostatic Activation Identify Embolic Stroke of Undetermined Source (ESUS) Patients who are at Risk of Recurrent Thrombotic Events on Antiplatelet Therapy: A Validation Study
Authors: Sharashidze Vera , Rangaraju Srikant , Rathakrishnan Priyadharshi , Duncan Alexander , Hoskins Michael , Marmarchi Fahad , Belagaje Samir , Bianchi Nicolas , Belair Trina , Henriquez Laura , Monah Kaslyn , Nahab Fadi
Published: January 2019

Introduction:
Markers of coagulation and hemostatic activation (MOCHA) have previously been shown to identify ESUS patients who are more likely to have subsequent diagnosis of atrial fibrillation (AF) or malignancy. The objective of this study was to validate these results in a larger ESUS cohort.

Methods:
Consecutive ESUS patients seen in the Emory Clinic from January 1, 2017 to June 30, 2018 underwent outpatient cardiac monitoring and the MOCHA profile including serum d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex and fibrin monomer obtained ≥ 2 weeks after the index stroke. All patients were on antiplatelet therapy at the time of MOCHA testing and an abnormal MOCHA profile was defined as ≥ 2 elevated markers. Prespecified endpoints monitored during routine clinical follow-up included diagnosis of AF, malignancy, venous thromboembolism (VTE) or other defined hypercoagulable states.

Results:
During the study period, 113 ESUS patients (mean age 64 +/- 15 years, 63% female, 54% non-white) underwent prolonged cardiac monitoring (70% MCOT, 42% ILR) and MOCHA profile testing (median days from stroke 33, IQR 15-57). During a mean follow-up of 7 ± 4 months, AF, malignancy, VTE or other defined hypercoagulable state was identified in 30 (27%) patients; the 41 (36%) ESUS patients with an abnormal MOCHA profile were significantly more likely to have an endpoint than patients with a normal profile (59% vs 8%, p<0.0001). The absence of any elevated MOCHA tests (n=41) had 100% sensitivity for the prespecified endpoints.

Conclusion:
In this validation study, we found that the MOCHA profile identified ESUS patients more likely to have AF, malignancy, VTE or other defined hypercoagulable states during follow-up and may identify a subgroup of ESUS patients who could benefit from early anticoagulation; a normal MOCHA profile identifies ESUS patients who have a low risk of developing these endpoints on antiplatelet therapy.
Abstract 124: How to Preselect Stroke Patients for Enhanced ECG-Monitoring - Evaluation of Predictors of Paroxysmal Atrial Fibrillation in "Find-AFrandomised"
Authors: Weber-Krueger Mark , Protsenko Evgeny , Zapf Antonia , Wasser Katrin , Kermer Pawel , Hamann Gerhard F , Liman Jan , Gröschel Klaus , Wachter Rolf
Published: January 2019

Background:
Detecting concealed paroxysmal atrial fibrillation (pAF) is a major focus of the workup of ischemic-stroke-patients, but requires elaborate ECG-monitoring. We aimed to evaluate pre-specified predictors to determine stroke patients with an increased probability of underlying pAF. We applied cut-off-levels recently suggested by the German Stroke Society
1
.

Methods:
The Find-AF
RANDOMISED
-trial (NCT01855035) evaluated 3x10-day Holter-ECG vs. standard-care in 398 patients > 60 years with acute ischemic strokes. The primary endpoint was novel pAF after 6 months. 27 patients in the intervention arm (13.5 %) and 9 patients in the control arm (9.0 %) met the primary endpoint (p=0.002). We used Pearson’s Chi
2
-test and the Mann-Whitney-U-test, as applicable. In variables with p<0.05 we calculated the number-needed-to-screen (NNS). We also performed ROC-analyses to determine the areas-under-the-curve (AUC).

Results:
Table 1 shows known pAF-risk-factors in relation to whether patients had pAF. The absence of a clinical lacunar syndrome (p=0.007) or lacunar lesions (p=0.018), increased NIHSS-Score (p=0.003), frequent atrial premature beats (APB, p=0.003), prolonged supraventricular runs (p=0.01), enlarged left atria (p=0.07) and increased brain-natriuretic-peptide-levels (p=0.001) were associated with underlying pAF. Frequent APB differentiated best between those with and without pAF (area under the curve, AUC: 0.71).

Conclusions:
Several of the evaluated markers are useful to preselect stroke patients for enhanced ECG-monitoring. APB and comprehensive measures of both left atrial size and function (LAVI/a’) showed the highest AUC and should be used when preselecting stroke patients for prolonged ECG-monitoring.
Abstract 127: Premenopausal Cardiovascular Disease is Associated With Early Natural Menopause
Authors: Zhu Dongshan , Chung Hsin-Fang , Pandeya Nirmala , Dobson Annette , Mishra Gita
Published: January 2019

Introduction:
Early menopause has been associated with an increased risk of cardiovascular disease (CVD), but few studies have examined the converse, i.e., whether CVD events that occurred before menopause were linked to early natural menopause.

Methods:
Pooled participant-level data (177 131 women) from nine studies that contributed to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE) consortium were included. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRR) and 95% confidence intervals (CI) for the associations between age at onset of non-fatal premenopausal CVD events (including coronary heart disease (CHD) and stroke events) and age at natural menopause. Age at menopause was categorised as <45 (early), 45-49, 50-51(reference), 52-53 and ≥54 years. Age at onset of premenopausal CVD events was grouped as <35, 35-39 and ≥40 years. Women who experienced no premenopausal CVD event were used as the reference group.

Results:
Overall, there were 1561 (0.9%) non-fatal premenopausal CVD events (including 1130 CHD and 469 stroke events). The mean age at onset of premenopausal CVD was 41.3 years (standard deviation: 8.2 years, median 44.0 years). Compared with women without experiencing any premenopausal CVD events, women who experienced premenopausal CVD, CHD or stroke before age 35 years had 2-fold increased risk of experiencing early menopause (<45 years), with adjusted RRR (95%CI) of 1.92 (1.17, 3.14), 1.86 (1.01, 3.43), 2.17 (1.43, 3.30) respectively, whereas women with premenopausal CVD after age 40 years were more likely to experience normal menopause at age around 51 years. The associations remained after adjusting for smoking status, BMI, educational level, race/ethnicity, age at menarche, parity, hypertension status and family history of CVD.

Conclusions:
In conclusion, women with premenopausal CVD events that occurred before age 35 years had twice the risk of having early menopause. Shared genetic and environmental factors, as well as compromised vasculature after CVD events may play a role.
Abstract 129: Brain-Heart Interaction After Stroke: Therapeutic Effects of Exosomes in Type 2 Diabetic Mice Subjected to Stroke
Authors: Venkat Poornima , Cui Chengcheng , Xu Jiang , Zacharek Alex , Yang Xiao-Ping , Chopp Michael , Wang Fengjie , Landschoot-Ward Julie , Chen Jieli
Published: January 2019

Aim:
Diabetes exacerbates post-stroke cardiac injury. We tested whether treatment with exosomes harvested from human umbilical cord blood derived CD133+/KDR+ cells (CD133+Exo) improves neurological, cognitive and cardiac functional outcome in type 2 diabetes mellitus (T2DM) stroke mice.

Methods:
Adult (3-4m), male, db/db (T2DM) mice were subjected to distal middle cerebral artery occlusion (dMCAo) and treated with PBS or CD133+Exo (3х10
10
, i.v.) at 3 days after stroke (n=8/group). Serum exosomal microRNA (miR) expression was measured. Echocardiography, neurological and cognitive tests were performed, and mice were sacrificed at 28 days after stroke.

Results:
1) Compared to T2DM-control, T2DM-stroke mice exhibit significantly decreased left ventricular ejection fraction (LVEF: db/db: 67.6±0.6%, db/db-dMCAo: 60.6±1.9%, p<0.05), significant cardiomyocyte hypertrophy, interstitial fibrosis, and decreased capillary density in heart indicating that stroke in T2DM mice induces cardiac dysfunction at 28 days after stroke. 2) Serum exosomal miR29b and miR126 expression was significantly decreased in T2DM-stroke mice compared to T2DM-control mice. CD133+Exo contain high levels of miR126 and miR29b. 3) CD133+Exo treatment in T2DM-stroke mice significantly promotes neurological functional recovery (foot-fault test), significantly improves cognitive outcome (Morris water maze (MWM) test and odor test), and significantly improves cardiac function (LVEF: db/db-dMCAo: 60.6±1.9%, db/db-dMCAo+CD133+Exo: 68.9±0.7%, p<0.05). 4) In T2DM-stroke mice with PBS or CD133+Exo treatment, cardiac function (LVEF) significantly correlates with cognitive outcome. 5) CD133+Exo treatment in T2DM-stroke mice significantly decreases myocardial fibrosis, decreases TGF-β and NOX2 expression, and increases heart tissue miR126 and miR29b expression, while decreasing expression of miR126 and miR29b target genes such as Spred-1 and DPP4.

Conclusions:
Stroke in T2DM mice induces significant cardiac dysfunction and CD133+Exo treatment improves neurological and cognitive outcome, and provides significant cardio-protection. The improvement in cardiac functional outcome highly correlates with cognitive functional recovery.
Abstract 13: Risk of Intracerebral Hemorrhage in Pregnancy and the Postpartum Period: A Population Based Analysis using a Cohort-Cross Over Design
Authors: Meeks Jennifer R , Bambhroliya Arvind B , Tyson Jon E , Miller Charles C , Sheth Sunil A , McCullough Louise D , Savitz Sean I , Vahidy Farhaan S
Published: January 2019

Introduction:
While there is a documented increased risk of thrombotic events; little is known regarding the risk of intracerebral hemorrhage (ICH) during pregnancy / postpartum period (PP). We explore the risk of ICH in PP utilizing a cohort crossover design in which patients serve as their own control.

Methods:
We utilized State Inpatient Databases for NY, FL (2005 - 2014) and CA (2005 - 2011), and identified patients with labor/delivery diagnoses using validated ICD-9 codes. The cohort crossover design included a 64wk case period (40wk pregnancy/labor/delivery, 24wk postpartum), followed by a 52wk interim period, and a 64wk crossover period. We excluded patients who were ≤ 12yr, missing linkage information, admitted for false labor, or had a prior ICH. Subsequent pregnancies were not included. We compared the rate of ICH during case and crossover periods and report absolute risk difference and rate ratio with 95% confidence interval (CI) estimated using conditional Poisson regression.

Results:
Over 3.3 million deliveries were identified, with 238 patients experiencing ICH during the case period. Those who died during the case / interim period or were in PP during the crossover period were removed from analyses. The overall rate of ICH during case vs. crossover period was 8.1 vs 2.5 per 100,000 deliveries / patients, resulting in an absolute risk difference and rate ratio (CI) of 5.5 (4.3 - 6.8) and 3.2 (2.4 - 4.2) respectively. During the case period, the majority of ICH occurred during the 3
rd
trimester and the first 12wks postpartum (Figure). Patients experiencing ICH during PP were more likely to be Black or Asian (compared to White), and had a history of hypertension, diabetes, coagulopathy, thrombocytopenia, or substance abuse (Table).

Conclusion:
Pregnancy confers a significantly higher risk of ICH that peaks during the 3
rd
trimester and continues into early postpartum. Further investigation is warranted to characterize individuals at a greater risk of ICH during PP.
Abstract 131: Delayed Egress of CD8 T Cells Contributes to Long-Term Pathology After Ischemic Stroke in Mice
Authors: Selvaraj Uma M , Torres Vanessa O , Kong Xiangmei , Plautz Erik J , Stowe Ann M
Published: January 2019

Introduction:
T cells are recruited to the ischemic brain within hours after stroke onset and can exhibit either protective or detrimental effects on recovery. Recent studies, including our data, confirm the persistence of immune cells in the brain weeks after stroke onset, including cytotoxic CD8 T cell egress, suggesting a longer-term role for the adaptive immune system during functional recovery after stroke.

Hypothesis:
We hypothesize that a delayed secondary egress of CD8 T cells into the ischemic brain negatively impacts functional recovery after transient ischemic stroke in mice.

Methods:
Male C57BL/6 mice (Jackson Labs, 8-14 wks) received a 60-min transient middle cerebral artery occlusion (tMCAo) and sacrificed 8, 14, or 30 days (d) post-tMCAo. Neuroinflammation was quantified using flow cytometry, infarct volume determined using MRI, and functional recovery quantified using rotarod behavioral test. In a second cohort, mice were randomized to CD8 T cell depletion (CD8
α
-specific antibodies; 400ug; 2.43 clone) or control (isotype antibodies; 400ug) treatment beginning 10d after tMCAo, with booster injections (200ug) every 3d thereafter. Mice were euthanized at 30d post-stroke.

Results:
Post-stroke mice exhibit a secondary influx of leukocytes at 14 and 30d after tMCAo. Ipsilesional CD4 T cell and CD8 T cell numbers were increased over the contralateral hemisphere at 14d (19-fold, p<0.0001 and 8-fold, p<0.001) and 30d (8-fold, p<0.01 and 7-fold, p<0.01) after stroke, respectively. Moreover, mice with higher ipsilesional CD4 T cells (R
2
=0.33, p=0.05) and CD8 T cells (R
2
=0.52, p<0.01) exhibited worse functional recovery. CD8 T cell-depleted mice had 2.5-fold (p=0.05) reduced leukocyte infiltration at 30d post-tMCAo. Specifically, macrophage, neutrophil, and CD4 T cell numbers were reduced in the ipsilesional hemisphere of the CD8 T cell-depleted mice. There were no significant differences between immune cell numbers in spleen.

Conclusions:
Our data confirm long-term CD4 T cell and CD8 T cell recruitment into the ipsilesional hemisphere that affect both immune cell numbers present in the brain and functional recovery through one month after stroke onset in mice.
Abstract 132: The Mammalian Target of Rapamycin Regulates Platelet Integrin Activation, Aggregation, and Ischemic Stroke
Authors: Campbell Robert , Denorme Frederik , Manne Bhanu K , Arajuo Claudia , Majersik Jennifer , Weyrich Andrew , Rondina Matthew
Published: January 2019

Rationale:
Platelets are critical cellular effectors in the development of ischemic stroke. Translational control pathways, such as the mammalian target of rapamycin (mTOR), are active in platelets, and can be targeted therapeutically, but have not been examined in stroke.

Objective:
To determine if activation of the mTOR pathway regulates platelet activation and the development of ischemic stroke following stroke
in vivo
.

Methods:
We generated mice lacking mTOR specifically in platelets (KO). We assessed mTOR activation, platelet aggregation, integrin activation, and clot retraction in KO and wild-type control mice (WT). In both KO and WT mice, we also performed a transient middle cerebral artery occlusion (tMCAO) stroke model (t=1h followed with reperfusion for 24hrs). Following tMACO, blood flow in the MCA and stroke infarct size were determined. We also examined mTOR activation in human platelets from individuals with ischemic stroke (n=5) and healthy controls (n=4).

Results:
We confirmed the absence of mTOR in KO platelets. In platelets from WT mice, the mTOR pathway is activatable, triggering platelet activation and clot retraction
in vitro
. In comparison, indices of mTOR activation, including pAKT and pS6K, were significantly (p<0.05) reduced in platelets from KO mice. Platelets from KO mice also had significant reductions in platelet aggregation (50% less), integrin αIIbβ3 activation (40% less), and clot retraction compared to WT mice. These differences were not due to alterations in platelet count. In the tMCAO model, KO mice had significantly smaller infarct sizes compared to WT mice (36.8±9.4mm
3
, n=7 vs. 80.3±8.1mm
3
, n=8; p<0.004). Smaller infarct sizes in KO mice were not due to differences in blood flow during the ischemia or reperfusion phase, which were similar to WT mice. In platelets from human ischemic stroke patients, the mTOR pathway was activated as p4EBP1, a downstream target of mTOR, was 1.72-fold higher compared to healthy controls.

Conclusion:
These data demonstrate that inhibition of the mTOR pathway in platelets significantly reduces platelet activation and protects from ischemic stroke
.
Therapeutic targeting of the mTOR pathway in platelets may provide clinical benefit in the setting of ischemic stroke.
Abstract 133: Triggering Receptor Expressed on Myeloid Cells-2 Improves Post-stroke Neurological Function and Regulates Microglia/Macrophage Phenotype in Aged Female Mice
Authors: Kurisu Kota , Zheng Zhen , Hsieh Christine , Yenari Midori A
Published: January 2019

Background and Purpose:
We previously reported that triggering receptor expressed on myeloid cells-2 (TREM2) expression on microglia/macrophage activates its phagocytic function and promotes stroke recovery. Although its importance has been demonstrated, it is unclear whether there is a similar effect in females. Furthermore, TREM2 mutations have been linked to dementia. In the present study, we explored the influence of TREM2 deficiency in aged female mice subjected to middle cerebral artery occlusion (MCAO). We assessed histology, sensorimotor and cognitive functions along with post stroke immune responses.

Methods:
Age matched (≥8months) female TREM2 knockout (TREM2-KO) and Wild type (Wt) mice were subjected to permanent distal MCAO. Sensorimotor and cognitive (Y-maze test) functions and infarct size were assessed up to 14d after stroke (n=6/each). Microglial activation (isolectin B4, IB4 & CD68), phagocytosis (oil red O stain) and M1 (NO/iNOS) and M2 (arginase, Arg) markers 1,3,7 and 14d post MCAO.

Results:
At baseline, aged female mice lacking TREM2 had similar cognitive & sensorimotor function. However, post stroke, TREM2-KO females, compared to Wt, showed worsened cognitive (p<0.01) and neurological function (p<0.05). Female TREM2 knockout mice also had larger infarct volumes (p<0.05) and reduced phagocytic activity (p<0.01). Microglia/macrophage accumulation, which peaked by 7d, was significantly inhibited in TREM2-KO mice (p<0.01). TREM2-KO mice also showed fewer CD68+ phagocytes; however, iNOS positive CD68 cells were significantly increased at days 3 & 7 (p<0.05), while, Arg positive CD68 cells was significantly decreased at days 7 & 14 (p<0.05) in the TREM2-KO group, compared to the Wt group and suggests a M2 bias for TREM2.

Conclusions:
Similar to male mice, TREM2 seems to have beneficial properties in female mice. TREM2 deficient female mice had larger infarct sizes and worsened neurological performance. Microglial responses also seemed to suggest that TREM2 promotes beneficial and/or recovery pathways.
Abstract 134: Sex Differences in the Neuroprotective Effects of IAIP are Potentially Driven by Differences in Blood Brain Barrier Permeability after Stroke
Authors: Venna Venugopal Reddy , Urayama Akihiko , d'Aigle John , Lee Juneyoung , Lim Yow-Pin , McCullough Louise D
Published: January 2019

Introduction:
Stroke is a sexually dimorphic disease. There is growing evidence that there are sex differences in the response to drugs, both in experimental and in clinical studies. Increase in BBB permeability occurs after stroke, but little is known if BBB disruption and permeability differs in males and females. In our ongoing studies with Inter-alpha Inhibitor Protein (IAIP), we found that although IAIP is significantly efficacious in both sexes, it is more effective in males. Therefore, here we tested if the sex-specific differences in efficacy of IAIP is due to BBB permeability.

Methods:
Aged male and female mice (18-20 months; C57BL/6), were subjected to right middle cerebral artery occlusion (MCAO-60min) and randomly assigned to a vehicle/IAIP (30mg/kg) group. Infarcts were quantified at 7-days after stroke. Transport of IAIP across the BBB in vivo was directly investigated using
131
I-IAIP and
125
I-albumin (n=4/gp) at 6h & 24h after injection; Radioactivity was determined by a gamma counter. Brain and tissue uptake of
131
I-IAIP was determined by comparing to
125
I-albumin.

Results:
Aged males receiving IAIP had significantly reduced infarcts compared to vehicle treated mice in cortex (p=0.01), striatum (p=0.01) and in total hemispheric infarct (p=0.018) (n=8-10/grp). Female mice treated with IAIP also had a significant reduction in total infarct (p=0.04), but not in cortex or striatum. IAIP treated males had significantly lower mortality (p<0.05), but this was not seen in females. IAIP and albumin remained in the brain vascular space six hours after stroke in both sexes. However, at 24h, the brain distribution of
131
I-IAIP and
125
I-albumin in aged males was significantly higher than in shams, confirming brain entry. However, uptake of IAIP was only seen in males (P<0.05) and not in females.

Conclusions:
Our data demonstrates that 1) IAIP treatment is neuroprotective in both sexes, but more efficacious in males and 2) IAIP do not significantly cross the BBB early after stroke/reperfusion (6h), but crosses in a disruption-dependent manner at 24h, but only in males. This may be one explanation for the more robust neuroprotective effects seen in aged males vs. females. These studies may have far-reaching implications for other drug development strategies.
Abstract 135: A Clinical Validation Study of Anatomical Risk Scoring for Procedural Stroke in Carotid Artery Stenting
Authors: de Vries Evelien E , de Waard Djurre D , Huibers Anne E , Nederkoorn Paul J , van Dijk Lukas C , van der Lugt Aad , Koudstaal Peter J , Bonati Leo H , Brown Martin M
Published: January 2019

Introduction:
Vascular anatomy of aortic arch and supra-aortic arteries is often suggested to influence risk of carotid artery stenting (CAS). The expert opinion-based Macdonald anatomical risk score (MARS) was developed to predict difficulty of CAS in relation to 30-day stroke risk, and hereby aid in patient selection. We aimed to validate the MARS for procedural stroke after CAS.

Methods:
In this post-hoc analysis of the International Carotid Stenting Study (ICSS), 275 CAS patients with available pre-procedural CT angiography were included. CTA-based vascular anatomy was rated by two independent observers. Every possible combination of anatomy resulted in a risk score, which is divided in four categories of expected risk (low: <5.0; low-intermediate: 5.0–5.9; high-intermediate: 6.0–6.9; high: ≥7.0). Binomial logistic regression was used to assess the relation between anatomical risk scoring, as defined in the MARS, and procedural (<30 days) risk of any stroke. Differences between predefined age groups were also assessed.

Results:
Interobserver reliability for all anatomical risk factors was high (κ 0.76-0.84). In total, 16 strokes (5.8%) occurred in the procedural period. We observed no significant relationship between the MARS and risk of any procedural stroke, with the risk of stroke in the high-risk versus the low-risk MARS group being 9.1% vs 4.4%, respectively (
P
=0.49). A higher mean MARS was observed in patients ≥70 years compared to younger patients (4.6±1.5 vs 3.9±1.4,
P
<0.001), which was mainly explained by higher rates of arch atheroma (44% vs 20%,
P
<0.001).

Conclusion:
No clear association between anatomical difficulty, as defined in the MARS, and procedural any stroke risk could be found. Nevertheless, MARS is feasible and reliable based on CTA imaging. Currently running and future clinical trials and registries are recommended to include baseline CTA imaging of the carotid arteries in order to adequately determine the value of the MARS in selection of high-risk patients for CAS.
Abstract 138: Correlation of Cerebrovascular Reserve Assessed by Acetazolamide-stress SPECT With Collaterals on Arterial Spin-labeling MRI in Patients With Carotid Occlusive Disease
Authors: Kang Hyunkoo , Kim Yoone
Published: January 2019

Purpose:
We evaluated the correlation between cerebrovascular reserve (CVR) on acetazolamide (ACZ) -stress single photon emission computed tomography (SPECT) brain scans and collaterals on arterial spin-labeling (ASL) magnetic resonance imaging (MRI) in internal carotid artery (ICA) stenosis.

Materials and Methods:
86 patients with ICA stenosis (>70%) were enrolled in this study. Including pulsed ASL, MRI was acquired on a 3 tesla system. On ASL, late-arriving flow appears as serpiginous high ASL signal within cortical vessels, which has been termed arterial transit artifact (ATA). Images were interpreted for the presence of ATA. 82/86 ICA stenosis patients underwent SPECT imagings with Tc-99m-ECD in the resting and after ACZ challenge. We observed the presence of intracranial collaterals, which are manifested by ATA, on ASL brain perfusion scan. CVR based on rest-SPECT and ACZ-stress SPECT was calculated. With ACZ-stress SPECT, the 82 patients were grouped as either showing or not showing evidence of decreased CVR. We assessed the relationship between reduced CVR and intracranial collaterals shown as ATA on ASL brain perfusion.

Results:
In 61/86 (70%) of the ICA stenosis patients, ASL showed ATA in ipsilateral to the stenosis. With acetazolamide stress SPECT, the 27/82 (32%) patients showed evidence of decreased CVR. In 45/55 (81%) of the normal CVR group and 16/27 (59%) of the reduced CVR from the SPECT results, pulsed ASL showed ATA in ipsilateral to the stenosis. Significant positive relationship was observed between normal CVR group and ATA showing group in ICA stenosis patients on ASL brain perfusion (p=0.035, chi-square test).

Conclusion:
The ATA with ASL imaging as a noninvasive and no contrast demanding technique, can depict slow flow in excellent collateral vessels and has clinical utility in detecting CVR in patients with ICA stenosis.
Abstract 14: Is Low Heart Rate Variability, a Marker of Autonomic Dysfunction, the Missing Link Between Migraine With Visual Aura and Cardioembolic Stroke?
Authors: Trivedi Tushar , Androulakis Michelle , Redd Kolby T , Alonso Alvaro , Soliman Elsayed , Magnani Jared , Gottesman Rebecca , Rosamond Wayne , Sen Souvik
Published: January 2019

Introduction:
Migraine with visual aura (MA) has been associated with the risk of cardioembolic stroke (CES). Low heart rate variability (HRV), a marker of cardiac autonomic dysfunction, has been shown to be associated with atrial fibrillation (AF) and risk of stroke. We investigated the association between low HRV and MA. We also examined whether the MA associated CES risk can be explained by a low HRV.

Methods:
Participants in the Atherosclerosis Risk in Communities cohort were interviewed for migraine history in 1993-1995; during a subsequent follow-up visit (1996-1998) HRV was measured using 6-minute EKG. HRV indices were calculated using the standard deviation of RR intervals (SDNN), the mean of all normal RR intervals (MeanNN), the root mean square of successive differences of RR intervals (RMSSD), low (LF) and high (HF) frequency power, and the LF/HF ratio. All HRV measures were categorized into quintiles. Logistic regression models were used to estimate ORs adjusted for sociodemographic and comorbid confounders. Mediation analysis was conducted to test if HRV was a mediator of MA associated CES risk, using Barron-Kenny’s causal step tests.

Results:
Of 11,939 participants assessed for headache 426 reported MA. A total of 164 incident CES occurred over a 20-year follow-up period. After covariate adjustment, there was a strong evidence of an association between low HRV and MA. The lowest HRV quintile was associated with higher odds of MA compared with the highest quintile for SDNN (OR, 1.5, 95% CI, 1.1–2.3), RMSSD (OR, 1.4; 95% CI, 1.1–2.1), LF (OR, 1.3; 95% CI, 1.0–1.8), HF (OR, 1.5; 95% CI, 1.1–2.1), and LF/HF ratio (OR, 1.5; 95% CI, 1.1–2.0). The data also suggests HRV may be a potential mediator between MA and CES.

Conclusion:
MA was associated with low HRV, suggestive of chronic autonomic dysfunction among this population. Alongside prior findings showing HRV-AF, HRV-Stroke and AF-Stroke link, the association may provide the missing link between MA and Stroke (Figure).