bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract W P94: Autologous Bone Marrow Derived Mononuclear Cells Attenuate Cerebral Edema and Inflammation in Intracerebral Hemorrhage
Authors: Suda Satoshi , Yang Bing , Xi Xiaopei , Schaar Krystal , Parsha Kaushik , Aronowski Jaroslaw , Savitz Sean I
Published: March 2022

Background:
Autologous bone marrow derived mononuclear cells (MNCs) improve functional recovery after ischemic stroke in rodent models. We now investigate the therapeutic effects of MNCs in intracerebral hemorrhage (ICH) and explore if MNCs impact the post-ICH inflammatory response.

Methods:
ICH was induced by stereotaxic infusion of 70 ul autologous whole blood into the left striatum in young male Long Evans rats. At 24 hrs after ICH, rats were randomized to receive an intravenous administration of autologous MNCs (10 million cell/kg) or saline. MNCs were isolated from the bone marrow harvest of the tibias at 22 hrs after ICH without causing limb impairment. A separate sham control group underwent the same surgical procedures but without the blood injection and the aspiration of bone marrow. At 3 days after randomization, brains were harvested to measure cerebral edema and various markers of inflammation in the perihematomal area.

Results:
Compared to the saline treated controls, MNCs significantly decreased brain water content in the ipsilateral hemisphere (p < 0.05, n = 3 in each group; Fig. 1). MNCs significantly reduced the number of neurotrophils and iNOS-positive microglia in the perihematomal area compared with saline-treated animals (P < 0.05, n = 3 in each group; Fig. 2). Moreover, MNCs reduced the expression of high-mobility group protein box-1 (HMGB1), S100β, matrix metalloproteinase 9 (MMP9), and aquaporin 4 (AQP4) in the perihematomal area compared with saline-treated animals (P < 0.05, n = 3 in each group; Fig. 3).

Conclusions:
We demonstrate for the first time that intravenously transplanted autologous MNCs can ameliorate brain edema and modulate the inflammatory responses after ICH. This is the first study to perform a bone marrow harvest and autologous infusion of MNCs after ICH. Functional behavioral tests are underway to assess the long-term effects of MNCs as a potential treatment for ICH.
Abstract 104: Good Collateral Status and Favorable Clinical Outcome in Acute Ischemic Stroke: First Systematic Review and Meta-analysis
Authors: Wee Patrick , Trivedi Anurag , Volny Ondrej , Qazi Emmad , d'Esterre Christopher , Hwan Ahn Seong , Demchuk Andrew , Goyal Mayank , Hill Michael , Menon Bijoy
Published: March 2022

Background:
Leptomeningeal collaterals preserve ischemic brain beyond an occluded artery until reperfusion is achieved. This systematic review and meta-analysis seeks to update current state of knowledge on the use of collateral imaging as a prognostic and patient selection tool in patients with acute ischemic stroke.

Methods:
We searched all published studies measuring collateral status in patients with acute ischemic stroke and its association with clinical outcome using MEDLINE, EMBASE and the Cochrane Systematic Review database between Jan 1951- May 2014. Imaging modality, collateral score type, time from stroke onset to evaluation and other parameters that assess study quality were collected. Association between collateral status and clinical outcome was estimated using random effects models. Meta-regression was then used to analyze heterogeneity.

Results:
Of 2,424 studies reviewed, 10 studies that fulfilled all inclusion/exclusion criteria, had all necessary data elements and reported adjusted point estimates were included in the final meta-analysis. Four studies used DSA to measure collaterals vs. 5 that used CTA and 1 dCTA; 6 studies included patients < 6 hours of symptom onset, 5 studies adjusted for reperfusion status while reporting point estimate while 5 studies used consensus reading. Pooled adjusted odds of good clinical outcome with good collateral status were 4.69 (95% CI 2.73-8.05) (Attached Figure 1). Only 36.3% of the variance in the pooled estimate is attributed to study heterogeneity (Q statistic p value=0.12). Meta-regression did not reveal any statistically significant difference in heterogeneity based on imaging modality (p=0.96), time from symptom onset to imaging (p=0.3), reperfusion status (p=0.82) or consensus reads (p=0.51). Begg’s test and funnel plot for small study effects suggests asymmetry (p<0.01).

Conclusion:
Collateral imaging is a reliable prognostic and patient selection tool in acute ischemic stroke.
Abstract 106: Validation Of The Unruptured Intracranial Aneurysm Treatment Score (UIATS) to Guide Management of Unruptured Intracranial Aneurysms
Authors: Etminan Nima , Brown Robert D , Beseoglu Kerim , Juvela Seppo , Morita Akio , Torner James C , Raymond Jean , Derdeyn Colin P , Raabe Andreas , Mocco J , Abdulazim Amr , Korja Miikka , Connolly E. Sander , Steinmetz Helmuth , Lanzino Giuseppe , Pasqualin Alberto , Rüfenacht Daniel , LeRoux Peter , Vajkoczy Peter , McDougall Cameron , Hänggi Daniel , Rinkel Gabriel J , Macdonald R Loch ,   UIATS Investigators
Published: March 2022

Objective:
We previously derived the Unruptured Intracranial Aneurysm Treatment Score (UIATS), designed using a multidisciplinary consensus approach among neurovascular specialists from diverse geographic and practice backgrounds. Here, we report on the development and validation of the final version of UIATS.

Method:
An international, multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 (39 panel members and 30 blinded external reviewers) specialists in the research and treatment of UIAs was convened. A web survey-based Delphi consensus process consisting of 7 rounds was utilized to rate numerous features of potential relevance in the assessment and treatment of UIAs and to develop the UIATS. Mean ratings were repeatedly used to determine statistical weight for each factor and then transformed into corresponding scores for every item to create the UIATS. For internal and blinded external validation, 30 representative cases of patients with UIAs were used to test the level of agreement (5 point Likert Scale) with treatment recommendations based on the UIATS.

Results:
The final UIATS system was designed in three domains (patient-, aneurysm - and treatment-related), comprising 13 different categories and 29 different features (Figure 1). Mean agreement based on Likert scores (5 indicating strong agreement and 1 indicating strong disagreement) was 4·2 for both reviewer cohorts, whereas mean agreement per case was 4·2 (panel members) and 4·5 (external reviewers) (p=0·017, Mann-Whitney-U Test).

Conclusion:
The final version of UIATS system was internally and externally validated by a large multidisciplinary group of neurovascular specialists, which suggests that the UIATS reflects contemporary decision-making regarding management of a patient with an UIA. The UIATS may aid clinicians in deciding on the appropriate management for an UIA.
Abstract 111: A Novel Role for Endogenous HGF in the Pathogenesis of Intracranial Aneurysms
Authors: Chalouhi Nohra , Peña-Silva Ricardo , Points Lauren , Mitchell Ian , Pierce Gary , Faraci Frank , Heistad Donald , Ballas Zuhair , Hasan David
Published: March 2022

Background and Purpose:
Inflammation plays a key role in formation and rupture of intracranial aneurysms. Because hepatocyte growth factor (HGF) modulates vascular inflammation, we sought to assess the role of endogenous HGF in the pathogenesis of intracranial aneurysms.

Methods:
Circulating HGF concentrations in blood samples drawn from the lumen of human intracranial aneurysms or femoral arteries were compared in 16 patients. Intracranial aneurysm and superficial temporal artery tissue samples from patients undergoing clipping (n=10) were immunostained with antibodies to HGF and its receptor c-Met. Intracranial aneurysms were induced in mice treated with PF-04217903 (a c-Met antagonist) or vehicle. Expression of inflammatory molecules was also measured in cultured endothelial, smooth muscle cells and monocytes treated with LPS in presence or absence of HGF and PF-04217903.

Results:
HGF concentrations were significantly higher in blood collected from human intracranial aneurysm (1076 ± 656 pg/ml) than in femoral arteries (196 ± 436 pg/ml, p0.05), but significantly increased the prevalence of subarachnoid hemorrhage and decreased survival in mice (P<0.05). HGF attenuated expression of markers of inflammation in human aortic endothelial cells (P<0.05), but not in human aortic smooth muscle cells or monocytes.

Conclusion:
Plasma HGF concentrations are higher in intracranial aneurysms. HGF and c-Met are expressed in intracranial aneurysms. HGF signaling through c-Met may decrease inflammation in endothelium and protect from intracranial aneurysm rupture. The findings of this study may have significant therapeutic implications for prevention of intracranial aneurysm formation and rupture.
Abstract 118: Effect of Interferon Regulatory Factor-1 on Vascular Dementia Using Mouse Chronic Cerebral Hypoperfusion Model
Authors: Wang Xiao-Li , Iwanami Jun , Mogi Masaki , Tsukuda Kana , Nakaoka Hirotomo , Bai Hui-Yu , Kukida Masayoshi , Chisaka Toshiyuki , Shan Bao-Shuai , Horiuchi Masatsugu
Published: March 2022

Objective:
Accumulation of inflammatory cells around the damaged blood vessels is an important feature of the pathophysiology of Binswanger disease due to hypoxic conditions. Recent reports indicate that expression of interferon regulatory factor (IRF)-1-dependent genes in neurons plays a role in ischemic neuronal death. However, the roles of IRF-1 in vascular dementia are not well investigated. Therefore, we assessed the effect of IRF-1 on cognitive function using vascular dementia mouse model by chronic cerebral hypoperfusion.

Methods:
Male 10-week-old C57BL/6 (wild-type; WT) and IRF-1-knockout (IRF-1KO) mice were used in this study. Chronic cerebral hypoperfusion mouse model was generated by bilateral common carotid artery stenosis (BCAS). Six weeks after BCAS, the mice were subjected to the Morris water maze test 5 times a day for 5 days. After the Morris water maze task, cerebral blood flow (CBF) was evaluated by laser speckle flowmetry. Expression of NADPH oxidase subunits and inflammatory cytokines in cortex and hippocampus were determined by real-time RT-PCR.

Results:
Body weight before and 6 weeks after BCAS operation did not differ in all groups. In the Morris water maze task, escape latency was significantly prolonged in sham-operated IRF-1KO mice compared with sham-operated WT mice. Moreover, BCAS-treated IRF-1KO mice exhibited more prolonged escape latency compared with sham-operated IRF-1KO and BCAS-treated WT mice. Although BCAS treatment reduced CBF in WT mice, there was no significant difference in CBF between sham-operated WT and IRF-1KO mice. On the other hand, after BCAS treatment, CBF was more markedly decreased in IRF-1KO mice than WT mice. In sham-operated groups, mRNA expression of NDADPH oxidase subunits and inflammatory cytokines in the brain did not differ between WT and IRF-1KO mice. In contrast, BCAS-treated IRF-1KO mice showed the tendency to increase mRNA expression of p22phox, p47phox, TNF-α and MCP-1 than BCAS-treated WT mice.

Conclusion:
These results suggest that IRF-1 has a protective effect on cognitive decline due to the prevention of CBF reduction, and the increases in NADPH oxidase and inflammatory cytokines in mouse chronic cerebral hypoperfusion model.
Abstract 122: Impact of Using Clinical Data to Profile Hospitals for 30-day Stroke Mortality: Data from the Ontario Stroke Audit
Authors: Reeves Mathew J , Hall Ruth , Li Shudong , Kapral Moira , Saposnik Gustavo , Austin Peter
Published: March 2022

Background:
Risk-adjustment models that use administrative data may not fully account for case-mix differences between hospitals. Supplementing these models with clinical data may improve their accuracy. We examined the impact of using data from a clinical registry in addition to administrative data on profiling Ontario hospitals for 30-day stroke mortality.

Methods:
Ontario Stroke Audit (OSA) data on 7006 acute stroke cases admitted to 54 Ontario hospitals between 2010-11 were obtained. We calculated 30-day risk-standardized mortality (RSMR) from an established risk adjustment model that relied on only hospital discharge data. This model (termed ADMIN) included age, sex, past medical history (including atrial fibrillation, stroke, diabetes, hypertension, heart disease), ambulance arrival, and stroke-type. We then modified this model to create a CLINICAL model by adding statistically significant clinical variables from the OSA data. In addition to the ADMIN model variables, the CLINICAL model included dysphagia, cognitive status, pre-stroke function, and stroke severity. We compared model performance (c-statistics, calibration [Hosmer-Lemeshow chi-square statistic (HLCS], Integrated Discrimination Improvement [IDI]), and hospital rankings (based on RSMR) using Spearman rank correlation.

Results:
Model performance was noticeably better for the CLINICAL model compared to the ADMIN model; discrimination was higher (c-statistic 0.82 vs. 0.70), calibration better (HLCS p= 0.08 vs <0.01) and predictive accuracy greater (IDI= 0.13, p <0.001). Comparison of RSMRs between the two models showed only moderate correlation (r = 0.653) with substantial variation for some hospitals (Figure).

Conclusions:
The addition of variables from clinical data to an established administrative data model had a marked effect on hospital rankings. These results suggest that clinical variables could have a meaningful impact on the accuracy of hospital report cards.
Abstract 128: Pittsburgh Outcomes After Stroke Thrombectomy Vertebrobasilar (POST VB) Score Predicts Outcomes After Endovascular Therapy for Basilar Artery Occlusions
Authors: Campbell David T , Rangaraju Srikant , Streib Christopher , Jadhav Ashutosh P , Jovin Tudor
Published: March 2022

Background:
Basilar artery occlusion (BAO) is associated with high rates of morbidity and mortality. Endovascular therapy offers improved outcomes, but the road to recovery is often protracted necessitating aggressive supportive care. We sought to develop a prognostic score incorporating these factors to predict outcomes after endovascular therapy for BAO.

Methods:
The derivation cohort was obtained from a previously utilized prospectively maintained database of patients with BAO treated endovascularly at our institution prior to June 2012 (N=59). Logistic regression was performed to identify any independent predictors of good outcome (90-day mRS, 0-2). Factors were weighted based on β-coefficients to derive the Pittsburgh Outcomes After Stroke Thrombectomy Vertebrobasilar (POST VB) score. The POST VB score was then validated in a similar cohort of patients with BAO treated endovascularly at our institution after June 2012 (N=30).

Results:
In the derivation cohort, independent predictors (P<0.1) of good outcome included final brainstem infarct volume (in cm3, β =-1.067, P<0.01) (but not infarct in other locations within the posterior circulation) and age (years, β=-0.114 P=0.011). The POSTVB score was calculated as age+10хfinal infarct volume. The Hosmer Lemeshow test of the model demonstrated a good fit (p=0.92). A POST VB <75 was associated with an 80% chance of good outcome compared with 0% with a score ≥125. POSTVB accurately predicted good outcomes in the derivation (AUC=0.89) and validation cohorts (AUC=0.88). Predictive accuracy was very similar across all groups.

Conclusions:
The POST VB score appears to accurately predict of outcome following endovascular therapy for acute stroke due to BAO and thus may aid in guiding post-interventional care. Our results await validation from larger prospectively acquired datasets.
Abstract 132: The Capillary Index and ASPECT Scores Are Strong Predictors of Patient Outcome In The Interventional Management of Ischemic Strokes
Authors: Labeyrie Paul Emile , Redjem Hocine , Blanc Raphaël , Bartolini Bruno , Ciccio Gabriele , Robert Thomas , Gilboa Boaz , Pistocchi Silvia , Fahed Robert , Abrivard Marie , Piotin Michel
Published: March 2022

Purpose:
The angiography-based capillary index Score (CIS) has recently emerged as a potential tool for assessing viable tissue. Our study aimed at correlating the CIS with patient outcomes.

Materials and Methods:
Based on our prospective gathered (December 2011 to April 2014) database, we analyzed the charts of patients who presented with anterior circulation acute ischemic stroke and elected for mechanical thrombectomy (MT). Patient age, NIHSS at admission, DWI-ASPECTS, pre-MT TICI score, CIS, post-MT TICI score, time from onset to reperfusion, 3-month mRS were analyzed. Patients were dichotomized into two groups: favorable (mRS≤2) and poor (mRS≥3) outcomes at 3-month follow-up. Univariate statistical analysis was carried out to determine which factors were the most determinant for patient outcome using the 3-month outcome. Then logistic regression analysis was performed to refine the results.

Results:
A total of 287 consecutive patients were elected for anterior circulation MT, 160 patients had a CIS and 138 of them had a complete follow-up including a 3-month mRS. They were (72 males, 67 females; mean age: 64). Sixty-nine out of the 138 patients (50.0 %) had a favorable outcome at 3-month. The 3-month mortality was 18.1%. Good reperfusion (TICI ≥ 2b) was obtained in 77.1% of the patients. The mean time from stroke onset to reperfusion was 5.9 hours. Univariate analysis showed that the statistically significant factors for a favorable 3-month outcome were the CIS and the NIHSS at admission (p<0.0001), a successful reperfusion (p=0.0002) and a high DWI-ASPECTS (p=0.0006). Patient age, time from onset to reperfusion and pre-MT-TICI score did not influence the 3-month patient outcomes. Logistic regression showed ASPECTS (p=0.0133, odd ratio=0.698) and CIS (p=0.036, odd ratio=0.564) to be the most determinant factors of patient outcomes.

Conclusions:
High initial CIS are associated with better outcomes in acute ischemic stroke patients who undergo MT arguing that, along with the infarct volume, the assessment of arterial collateral supply is a striking determinant of patient outcome.
Abstract 134: Relative MTT Predicts Subsequent Stroke in Symptomatic Carotid Occlusion
Authors: Powers William J , Videen Tom O , Derdeyn Colin P , Carpenter David A , Grubb Robert L
Published: March 2022

Relative mean transit time (MTT) is readily obtainable from dynamic susceptibility contrast MRI of the brain. While it has received much attention in acute ischemic stroke as a possible means to identify patients for reperfusion therapies, little has been done to determine if it has clinical significance outside the acute setting. To determine if relative MTT could be used to identify patients who are at high risk for subsequent stroke, we analyzed data from the St. Louis Carotid Occlusion Study. This prospective study was carried out from 1992-1997 to determine if PET measurement of oxygen extraction fraction could identify medically treated patients with recently symptomatic carotid artery occlusion at high risk for subsequent stroke. Sixty-eight of the participants in the study had quantitative PET measurements of cerebral blood flow (CBF) and cerebral blood volume (CBV). From these we calculated the MTT (CBV/CBF) in each middle cerebral artery territory and determined the MTT ratio of the ipsilateral to the contralateral hemisphere (I/C MTT ratio). Nine of the 68 participants had a subsequent ipsilateral ischemic stroke during mean follow-up of 2.6 years (range .5 - 5 years). The I/C MTT ratio was significantly associated with subsequent stroke as a continuous variable by Cox regression analysis (HR 65, 95%CI 7-613, p < .001). The maximum combination of sensitivity (.778) and specificity (.763) was obtained with a cutpoint of ≥ 1.387 which identified 7/9 subsequent strokes (PPV .333, NPV .957). Relative MTT shows great promise as a means to identify patients with large artery disease who are at high risk for subsequent stoke. These results need to be confirmed using MRI in a cohort receiving contemporary medical management.
Abstract 135: Angiogenic Factors and Response to Intensive Medical Management in Atherosclerotic Intracranial Arterial Stenosis
Authors: Gonzalez Nestor R , Connolly Mark J , Ooi Yinn Cher , Dusick Joshua , Bounni Firas , Liebeskind David S , Saver Jeffrey , Iruela-Arispe Luisa
Published: March 2022

Introduction:
Intracranial atherosclerotic steno-occlusive disease (ICASD) is the most common cause of stroke worldwide accounting for 33-67% of stroke in countries with predominantly Asian, Hispanic, and Black populations and at least 10% of all strokes in the US. In this study we test the hypothesis that circulating angiogenic factor profiles are associated with response to medical management.

Methods:
This is a prospective cohort of participants in the Angiogenic Factors in Intracranial Arterial Stenosis (ANFIS) Study, age 30-80, with a diagnosis of 70-99% ICASD of a major intracranial artery. All patients had optimization of medical management. Failure of medical treatment was defined as presence of TIA or strokes within 30 days of enrollment. Angiogenic factors were isolated in peripheral blood: HBEGF, VEGF, VEGF-D, TGFB1, TGFB2, PDGFAA, PDGFBB, Endostatin, Angiostatin, and VEGFR2. A correlation matrix was used to group highly correlated factors. Multivariable logistic-regression models were prepared to estimate risk of medical management failure.

Results:
Thirty patients (53% female) age 28-86 (mean 62.5) were enrolled. There were 10 (33.3%) failures of medical management. Age, gender, ethnicity and race were not significantly different between responders and failures of medical treatment. The multivariate analysis showed that higher VEGFD levels were associated with reduced failure (OR=0.26 95%CI 0.06-0.63, p=0.02) and higher HBEGF was associated with increased failure (OR=2.52 95%CI 1.28-7.34, p=0.03). The multivariate logistic model including VEGFD, HBEGF, female sex and black race had 90% sensitivity and 75% specificity (AUC 0.87) in predicting failure of management.

Conclusion:
In patients with severe (>70%) ICASD, elevated circulating HBEGF levels were associated with failure of medical treatment, while elevated circulating VEGFD levels were associated with protection from TIA/stroke. Further evaluation of the role of these factors in stroke prevention and potential collateral formation could elucidate new pathways for the treatment of intracranial atherosclerotic disease.
Abstract 142: Disability Trajectories Before And After Vascular Events: The Cardiovascular Health Study
Authors: Dhamoon Mandip S , Longstreth W T , Bartz Traci M , Elkind Mitchell S
Published: March 2022

Background:
Stroke may contribute to long-term functional decline apart from its acute effects on neurological function. Few studies have compared long-term disability trajectories before and after vascular events or considered the natural history of aging-related decline. We hypothesized that the increase in long-term disability would be steeper post-event than pre-event for stroke but not myocardial infarction (MI).

Methods:
In the Cardiovascular Health Study, 5888 Medicare eligible participants were followed for a mean of 13 years for vascular events and had annual disability assessments with an activities of daily living (ADL) and instrumental ADL scale, modified from the National Center for Health Statistics Supplement on Aging (range 0-12, scored by number of ADLs and IADLs which the participant could not perform, analyzed continuously). During follow-up, 382 participants had ischemic stroke and 395 had MI with >=1 post-event disability assessment. Generalized estimating equations models adjusted for baseline demographics, vascular risk factors, arthritis, cognition, and social support and included a test for different slopes of disability before and after event.

Results:
Participants had a mean of 4 disability assessments each pre- and post-stroke and MI. Stroke (0.88, 95% CI 0.57-1.20, p<0.0001) was associated with a greater acute increase in disability than MI (0.20, 0.06-0.35, p=0.006). The annual increase in disability before stroke (0.06 points per year, 0.002-0.12, p=0.04) more than tripled after stroke (0.15 additional points per year, 0.004-0.30, p=0.04). The annual increase in disability before MI (0.04 points per year, 0.004-0.08, p=0.03) did not change significantly after MI (0.02 additional points per year, -0.07-0.11, p=0.7).

Conclusions:
In this large population-based study, a trajectory of increasing disability became significantly steeper after stroke but not after MI. This worsening trajectory could be due to delayed cell dysfunction in the brain surrounding stroke, long-term inflammatory profile changes, progressive cardiovascular impairment, or silent recurrent infarcts. Stroke may be considered an ongoing, chronic condition with effects on function instead of a single discrete event.
Abstract 143: Race Differences in 1-year Outcomes after Stroke can be Largely Explained by Race Differences in Physical Functioning before Stroke
Authors: Roth David L , Sheehan Orla C , Haley William E , Rhodes J. D , Henry Michelle L , Howard George , Judd Suzanne E , Howard Virginia J
Published: March 2022

Background:
Several previous investigations, including the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, have demonstrated race and sex differences in long-term outcomes after stroke. However, it is largely unknown whether some of these post-stroke outcome disparities might actually reflect functional differences between the groups that were present before the stroke events.

Methods:
We examined data from 192 stroke survivors who were enrolled in the Caring for Adults Recovering from the Effects of Stroke (CARES) project. CARES is a REGARDS ancillary study that is examining the long-term effects of stroke on the REGARDS participants who experience a stroke and on their family caregivers. Functional abilities were assessed at baseline and after stroke using structured telephone interviews that included the 12-item Short Form Health Survey (SF-12). Stroke outcomes were measured during in-home examinations conducted approximately 1-year after their adjudicated stroke events. Outcome measures included the NIH Stroke Scale, Barthel index, and the subscales of the Stroke Impact Scale. Age, sex, and education were analyzed as covariates.

Results:
African Americans had significantly poorer covariate-adjusted 1-year outcomes than Whites on 8 of the 12 outcome measures examined. However, physical functioning before the stroke, as indexed by the Physical Component Summary (PCS) of the SF-12, was significantly lower in African Americans (adjusted Mean = 43.6) than Whites (adjusted Mean = 47.7; p = .005). When these pre-stroke PCS differences were added as additional covariates, many of the race differences in stroke outcome were no longer statistically significant.

Conclusions:
A substantial portion of the race differences in functional outcomes after stroke appear to reflect extensions of race differences in physical functioning that are present before stroke. In addition to ensuring adequate care after stroke to minority patients, disparities in stroke outcomes might also be further reduced by better risk factor modification and health promotion efforts for African Americans.
Abstract 155: Rate, Clinical features, Safety Profile and Outcome of Intravenous Thrombolysis for Acute Ischemic Stroke in Patients with Negative Brain Imaging
Authors: Mowla Ashkan , Kamal Haris , Mehla Sandhya , Shirani Peyman , Singh Karanbir , Farooq Salman , Crumlish Annmarie , Ching Marilou , Sawyer Robert N.
Published: March 2022

INTRODUCTION:
The exigent time demand for intravenous (IV) r-tPA administration in acute ischemic stroke (AIS) may not give the necessary time for thorough evaluation in patients presenting with AIS symptoms. As a result, IV thrombolysis of transient ischemic attack (TIA) or conditions mimicking stroke but with a subsequent different diagnosis might occur. In addition, IV r-tPA may sufficiently resolve ischemia such that subsequent brain diffusion weighted MR imaging (DWI-MRI) is negative in some patients. It would be expected that brain CT scan and the more sensitive DWI-MRI would be negative in all these cases. We sought to determine the rate, clinical characteristics, safety profile and outcome of brain imaging-negative patients treated with IV r-tPA for AIS in our large volume stroke center.

METHODS:
We retrospectively reviewed the medical records and brain imaging of patients who received IV rtPA for AIS within 4.5 hours of symptom onset from January 2006 to April 2014 at our center. A subset of patients with absence of acute infarct/ischemia on their follow- up brain imaging were identified. We recorded age, admission NIH stroke scale (NIHSS), discharge NIHSS, discharge modified Rankin Score (mRS), symptom onset to treatment time, clinical manifestations, discharge diagnosis and evidence of intracranial hemorrhage (ICH) on follow up images for these patients.

RESULTS:
A total of 637 patients received IV thrombolysis in our center during a 9.4 years period. Thirty seven (5.8%) were found to have no evidence of acute ischemia/infarct on their follow up imaging. DWI-MRI was available for 31 patients. Mean age was 65.2 ± 14, mean admission NIHSS was 8 and mean discharge NIHSS was 0. The mean time of symptom onset to IV thrombolysis was 2.5 hours. Twenty two (59%) had TIA or averted stroke and the rest had non-vascular stroke mimics. The most common stroke mimics were complicated migraine, seizure disorder and psychogenic disorders. No patient developed ICH on follow up brain imaging. All patients were functionally independent on discharge, mRS 0-1.

CONCLUSION:
IV thrombolysis is generally safe in patients with suspected AIS who have a follow -up negative brain imaging and delaying IV r-tPA administration in cases of doubt is not appropriate.
Abstract 162: Vagus Nerve Stimulation Enhances Neuroplasticity and Forelimb Recovery after Stroke in Aged Rats
Authors: Hays Seth A , Ruiz Andrea , Hulsey Daniel R , Khodaparast Navid , Bethea Thelma , Carmel Jason B , Rennaker Robert L , Kilgard Michael P
Published: March 2022

Background:
Advanced age is a leading risk factor for stroke and is associated with worse recovery. The goal of post-stroke rehabilitative therapies is to enhance neuroplasticity to support the recovery of motor function. Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitative training drives robust plasticity and results in significantly enhanced recovery of forelimb function in multiple models of brain injury in young rats. Advanced age may interfere with the benefits of VNS by reducing the capacity for plasticity. Here were evaluate the ability of VNS to drive neuroplasticity and improve forelimb recovery after stroke in aged subjects, and we examine mechanisms that may underlie recovery.

Methods:
In the first set of experiments, aged (16 mo. old) rats performed an automated forelimb task and then were trained for 5 days with (n = 2) or without VNS (n = 2) paired with forelimb movement. Movement representations were then assayed using ICMS. In the second set of experiments, aged rats were trained on the isometric force task and then received a cortical ischemic lesion and VNS cuff electrode. Rats underwent 6 weeks of rehabilitative training with (n = 8) or without paired VNS (n = 9). At the end of testing, rats received an injection of biotinylated dextran amine into the contralesional motor cortex to label corticospinal tract (CST) projections from the unlesioned hemisphere.

Results:
Early findings suggest that VNS paired with motor training results in a 244 ± 104% increase in forelimb representation compared to training alone in the motor cortex of aged rats. After stroke, VNS paired with rehabilitative results in significantly enhanced motor recovery compared to extensive rehabilitative training without VNS in aged rats. Rats that receive VNS+Rehab display 100 ± 7% recovery of forelimb strength compared to a 56 ± 14% recovery in rats that receive Rehab alone. Preliminary results indicate that VNS promotes increased connectivity of the CST from the unlesioned hemisphere to the denervated side of the spinal cord.

Conclusions:
VNS significantly enhances neuroplasticity and post-stroke recovery in aged rats. The VNS-dependent increase in recovery may be supported by reorganization of CST projections from the unlesioned motor cortex.
Abstract 164: IL-1a Enhances Angiogenic Neurorepair After Experimental Ischemic Stroke
Authors: Guell Kathleen , Pinteaux Emmanuel , Bix Gregory
Published: March 2022

Stroke is a major cause of death and disability worldwide. Unfortunately, all clinical trials that have targeted the primary cerebral ischemia (CI) injury mechanisms of oxidative stress and excitotoxicity have failed. However, CI also induces a potent local inflammatory response that leads to damage in the ischemic penumbra but may also, less acutely, initiate and sustain post-stroke repair processes such as angiogenesis. We hypothesize that the pro-inflammatory cytokine IL-1α promotes angiogenesis after stroke via generation of pro-angiogenic perlecan laminin globular domain 3 (LG3) protein fragments from the brain extracellular matrix. This is based on our previous observations that LG3 is rapidly and persistently generated after CI in vivo, and that IL-1α causes cells of the neurovascular unit to generate LG3
in vitro
. Importantly, the potential role of IL-1α in brain angiogenesis has not been previously studied. We now report that IL-1α activates primary brain endothelial cells (BECs)
in vitro
and significantly enhances several stages of BEC angiogenesis including proliferation and capillary tube-like structure morphogenesis. Furthermore, after experimental stroke (distal transient middle cerebral artery occlusion) in adult C57Bl6 mice, IL-1α levels are chronically (21 days) elevated (measured by qPCR and ELISA) suggesting that IL-1α is persists beyond the acute stroke phase to affect post-stroke angiogenic repair. Finally, IL-1α deficient mice have diminished post-stroke penumbral angiogenesis. Our results collectively suggest that inflammatory mediators such as IL-1α, in addition to their acute deleterious effects, may play an important and previously unrecognized role in post-stroke neurorepair that could be therapeutically exploited.
Abstract 167: Exosomes Derived from Mesenchymal Stromal Cells Promote Axonal Outgrowth
Authors: Zhang Yi , Chopp Michael , Katakowski Mark , Liu Xianshuang , Zhang Zheng Gang
Published: March 2022

Exosomes, small lipid microvesicles, transfer RNAs and proteins thereby mediating cell-cell communication. The present study investigated the effect of exosomes released from mesenchymal stromal cells (MSCs) on axonal outgrowth, that may play an important role in promoting brain repair after stroke.

Embryonic cortical neurons were cultured in a microfluidic culture device which separates somata and axons. Exosomes (3x109 particles/ml) harvested from MSCs were applied into the somal chamber. 24h in culture, exosomes increased axonal growth (396±8 vs 297±9 μm in non-treated axon, p<0.001, n=6). To examine whether miRNAs in exosomes mediate axonal growth, neurons were treated with exosomes with attenuated-Ago2, a key protein regulates miRNA biogenesis, derived from Ago2 knockdown MSCs. These exosomes abolished the axonal growth increased by exosomes from MSCs transfected with control siRNA (298±8 μm vs 396±11 μm in control, p<0.001, n=3), suggesting that miRNAs in exosomes mediate the exosome-enhanced axonal growth. We previously showed that the miR-17-92 cluster enhances axonal growth. Thus, we treated neurons with miR-17-92 cluster elevated-exosomes from MSCs transfected with a miR-17-92 vector. Compared to non-exosome treatment, neurons treated with exosomes from MSCs transfected with a control vector considerably increased axonal growth (406±8 μm, p<0.001, n=6). Moreover, neurons treated with miR-17-92 cluster elevated-exosomes exhibited further increases in axonal growth (595±10 μm, p<0.001, n=6). RT-PCR showed substantial elevation of individual members of the miR-17-92 cluster in axons of the neurons treated with the miR-17-92 cluster elevated-exosomes, which was associated with reduction of their target protein, PTEN, in axons. Western blots also showed that reduction of axonal PTEN by the miR-17-92 cluster elevated-exosomes activated PTEN downstream proteins mTOR and GSK3β, indicating that the miR-17-92 cluster delivered by exosomes targets the PTEN/GSK3β pathway in axons.

Conclusion:
The present study demonstrates that miRNAs in the exosomes can be delivered into neurons to promote axonal growth, which provides a novel therapy to enhance axonal growth.
Abstract 171: Four-dimensional Contrast-enhanced Ultrasonography for the Evaluation of Intraplaque Neovascularization in Carotid Artery Plaque
Authors: Oura Kazumasa , Ohba Hideki , Hitomi Jiro , Ogasawara Kuniaki , Kato Tadayoshi , Terayama Yasuo
Published: March 2022

Purpose:
The presence of intraplaque neovascularization has been identified as a factor in unstable plaque.

Contrast-enhanced carotid artery ultrasonography has been used for evaluating such neovascularizations.

However, it is difficult to define the inflow routes of a contrast agent into carotid artery plaque with conventional 2-dimensional (2D) ultrasonography.

We aimed to evaluate the distribution of intraplaque neovascularization with 4-dimensional (4D) contrast-enhanced carotid arterial ultrasonography.

Subjects:
The study included 29 patients with internal carotid artery stenosis (M:F =26:3, mean age:70.4 years) who were inpatients or outpatients of the Department of Neurology and Gerontology or the Department of Neurosurgery, and who were candidates for carotid endarterectomy.

Methods:
Four-dimensional contrast-enhanced ultrasonography was performed using the contrast agent Perflubutane prior to the undertaking of a carotid endarterectomy. The presence or absence of inflow of the contrast agent from the intimal side and adventitial side was observed using 2D and 4D modes and compared with the number of neovessels on the luminal side and outer wall side in a 2.5 mm
2
window of a pathological specimen obtained by surgery.

Results:
The number of neovessels on the intimal side in the pathological specimens was significantly higher in patients with inflow of the contrast agent from the intimal side (14.83±10.06/2.5 mm
2
) than in those without such inflow (6.60±5.296/2.5 mm
2
) (p=0.025, Mann-Whitney
U
test). In addition, the number of neovessels on the medial side in the pathological specimens was significantly higher in patients with inflow from the adventitial side (11.93±8.147/2.5 mm
2
) than in those without such inflow (5.57±5.585/2.5 mm
2
) (p=0.036, Mann-Whitney
U
test).

Conclusions:
Four-dimensional contrast-enhanced ultrasonography can be used to evaluate the distribution of neovessels in carotid artery plaque.
Abstract 174: In-vivo Assessment of the Impact of Regional Intracranial Atherosclerotic Lesions on Brain Arterial 3D Hemodynamics
Authors: Wu Can , Carroll Timothy J , Vakil Parmede , Honarmand Amir R , Ansari Sameer A , Markl Michael , Prabhakaran Shyam
Published: March 2022

Purpose:
To evaluate the feasibility of 4D flow MRI for the in-vivo assessment of the impact of regional stenotic lesions on intracranial arterial hemodynamics in patients with intracranial atherosclerotic disease (ICAD).

Method:
4D flow MRI data were acquired in 23 ICAD patients (13 male, 67±14 years) and 8 healthy volunteers (4 male, 60±11 years). The stenosed vessels were internal carotid artery (ICA, n=8), middle cerebral artery (MCA, n=11), and basilar artery (BA, n=7). 3D blood flow characteristics were visualized using time-integrated pathlines (Fig. 1a-c). Blood flow and peak velocity in the major intracranial arteries (ICA, MCA, PCA, and ACA) were quantified in manually positioned 2D planes (Fig. 1a). Asymmetry index (affected/non-affected for patients or left/right ratios for volunteers) of the blood flow (AI-F) and peak velocity (AI-V) were compared between patients and volunteers for the above 4 vessels.

Results:
The following indices were significantly different between volunteers and patients with ICA and MCA stenosis (Fig. 1d, e). For patients with ICA stenosis compared to volunteers, the indices measured for ICA location were: AI-F (0.48±0.23 vs. 0.99±0.05, P<0.001) and AI-V (0.64±0.23 vs. 0.96±0.12, P=0.004) and for MCA location were: AI-F (0.66±0.28 vs. 0.94±0.09, P=0.016). For patients with MCA stenosis compared to volunteers, the indices for MCA location were: AI-F (0.42±0.22 vs. 0.94±0.09, P<0.001) and AI-V (0.71±0.21 vs. 1.00±0.18, P=0.008). PCA flow and ACA velocity indices were altered suggesting collateral flow ipsilateral to the ICA or MCA stenosis. No difference was observed between volunteers and patients with BA stenosis.

Conclusion:
Our findings demonstrated the feasibility of 4D flow MRI to quantify the impact of a regional stenotic lesion on changes in other intracranial arterial hemodynamics. Quantitative hemodynamic markers may provide additional insight into the pathophysiology and risk stratification for ICAD patients.
Abstract 175: Vessel Wall Imaging at 3-Tesla in Patients with Symptomatic Intracranial Stenosis and Age-Matched Healthy Controls
Authors: Arteaga Daniel F , Donahue Manus J , Faraco Carlos C , Jordan Lori C , Siero Jeroen C , Hendrikse Jeroen , Strother Megan K
Published: March 2022

Purpose:
To translate a recently-proposed ultra-high field (7 Tesla) MRI protocol for assessing intracranial (IC) vessel wall morphology to the clinically available field strength of 3T to enable vessel wall imaging (VWI) routinely without contrast agent administration.

Methods:
Following protocol development, IC stenosis patients (n=16) and healthy volunteers (n=16) provided informed, written consent and underwent FLAIR, angiography, and a custom VWI protocol (3D turbo spin echo, TR=1500 ms; spatial resolution=0.5 mm isotropic, and anti-driven +90 equilibrium pulse). A board-certified neuroradiologist, blinded to clinical history, reviewed all images.

Results:
Vessel wall abnormalities were detected in all (12/16) participants with significant (>50%) flow-limiting stenosis on angiography.
Fig. 1
demonstrates changes for two individuals with VWI lesions. Two participants had advanced moyamoya disease and extensive collateralization on DSA, both of whom had corresponding findings on VWI.

Fig. 1: IC stenosis visualized by VWI and DSA. A) 57 yr/M with flow-limiting basilar artery stenosis. VWI (left) in the coronal plane shows hyperintense signal of a vessel wall lesion in the basilar artery (red arrow). AP projection from the left vertebral injection during DSA (right) shows stenosis in the same region (red arrow). B) 53 yr/M following L MCA territory stroke. VWI (left) demonstrates wall thickening (red arrow) of left distal ICA continuous in the left proximal MCA which corresponds to stenosis on DSA (right, AP view from L ICA injection).

Discussion:
We show that it is possible to perform VWI without contrast at 3T and still retain an acceptable image quality for discerning IC vessel abnormalities. Cerebrovascular reactivity (CVR) data were also acquired in all patients as part of an ongoing IC stenosis clinical trial; parallel work is focused on characterizing relationships between vessel wall disease and parenchymal reactivity.
Abstract 185: Safety and Outcomes of Intravenous Thrombolysis (IVT) in Dissection-related Ischemic Stroke: An International Multicenter Study and Comprehensive Meta-analysis of Reported Case Series
Authors: Tsivgoulis Georgios , Zand Ramin , Katsanos Aristeidis H , Sharma Vijay K , Goyal Nitin , Krogias Christos , Safouris Apostolos , Vadikolias Konstantinos , Chondrogianni Maria , Liantinioti Chrissoula , Alexandrov Anne W , Malkoff Marc D , Alexandrov Andrei V
Published: March 2022

Background&Purpose:
The safety and efficacy of intravenous thrombolysis (IVT) in dissection-related ischemic stroke (DRIS) has not been established. We sought to determine safety and recovery rates of IVT in DRIS using prospective, international, multi-center data and by conducting a comprehensive meta-analysis of reported case-series.

Subjects&Methods:
We analyzed consecutive DRIS patients treated with IVT according to national guidelines during a five-year period (2009-2013) at seven tertiary-care stroke centers. Pre-treatment NIHSS and modified Rankin Scores (mRS) at discharge were documented. Symptomatic intracerebral hemorrhage (sICH) was defined as imaging evidence of ICH with NIHSS increase of 4 or more points. Functional independence (FI) and favorable functional outcome (FFO) were defined as mRS 0-2 and 0-1. Recanalization of intracranial vessels was assessed using TIBI criteria. We also conducted a systematic review and meta-analysis of all available case-series reporting safety outcomes in IVT-DRIS using PRISMA guidelines.

Results:
A total of 39 DRIS patients (mean age 60±18 years; 59% men; Caucasians 51%, blacks 36%, Asians 13%; median NIHSS 13 points, IQR 9-17) received IVT. sICH, in-hospital mortality, complete recanalization, FFO and FI were 0% (adjusted Wald 95%CI: 0%-8%), 10% (3%-24%), 55% (40%-70%), 61% (45%-74%) and 68% (52%-81%). The pooled sICH and mortality rates in our meta-analysis including 10 case-series (234 IVT-DRIS patients) were 2% (0%-5%) and 4% (0%-8%). The pooled recanalization, FFO and FI rates were 45% (26%-67%), 41% (29%-54%) and 48% (61%-72%) respectively. We documented no heterogeneity (I squared statistic < 45%, p > 0.1 for Cohran Q test) between case-series reporting estimates of sICH, mortality, recanalization and FI. There was substantial heterogeneity for FFO (I squared statistic=61%; p=0.006). Subsequent meta-regression analysis identified baseline NIHSS as independent predictor of FFO (p<0.05) accounting for FFO variance across different studies.

Conclusions:
Our prospective, international data coupled with comprehensive meta-analysis results underscore IVT safety in DRIS while functional recovery rates compare favorably with overall IVT efficacy reported in phase III trials.