bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract W P76: Parent Artery Curvature May Help Determine the Effectiveness of Flow Diverter Treatment
Authors: Dimapasoc Brando , Chien Aichi
Published: July 2021

Introduction:
Flow diverters (FDs) aim to treat intracranial aneurysms by altering intra-aneurysmal hemodynamics. Reports have suggested aneurysm and parent artery shape may affect flow reduction in FD-treatment. The purpose of this study is to gain insight into the way in which aneurysm shape and parent artery curvature influence the ability of FDs to redirect flow.

Hypothesis:
Aneurysm dome size and parent artery curvature affect FD-induced flow reduction within an aneurysm.

Methods:
FD models constructed based on the Pipeline Embolization Device with 35% area coverage, 30 um strand diameter, and 4 mm nominal diameter were implemented for hemodynamic simulation analysis. The flow reduction effects were tested using aneurysm models featuring different dome sizes and parent artery curvatures. Aneurysm blood flow was analyzed before and after FD stenting in regions of the aneurysm neck, body, and dome.

Results:
We found that aneurysms with higher parent artery curvature had increased systole flow volume entering aneurysms before and after stenting, regardless of aneurysm size, with pre-FD volume flow rates for curvatures of 20 and 30 degrees, respectively, 1.54 and 2.40 times those for 10 degree curvature. Furthermore, FD reduced flow less in aneurysms with higher curvature. For parent artery curvatures of 10, 20, and 30 degrees, overall reductions of flow volume entering the aneurysm were 91.1±0.56%, 88.2±1.2%, and 85.5±0.28%, respectively. 97.2% of models had more flow reduction at the aneurysm dome than neck. Figure 1 shows representative, post-FD flow in 10 and 30 degree parent arteries, with a greater volume flow rate in (b) depicted by denser streamlines. Aneurysm dome size was not found to have a significant effect on volume flow rate.

Conclusions:
We found that artery curvature may have a large influence on FD flow reduction, indicating that FD may be less effective at reducing blood flow entering aneurysms located within higher curvature arteries.
Abstract W P84: Post-ischemic Intra-arterial Infusion of Liposome-encapsulated Hemoglobin Suppresses Endothelial and Neutrophil Inflammatory Activation Accompanied by Maintaining Microvascular Perfusion in Rat Cerebral Ischemia Reperfusion Model
Authors: Shimbo Daisuke , Abumiya Takeo , Shichinohe Hideo , Nakayama Naoki , Kazumata Ken , Houkin Kiyohiro
Published: July 2021

Background:
Liposome-encapsulated hemoglobin (LEH) containing human hemoglobin (Hb) is an artificial oxygen carrier with 1/40th the size of erythrocytes. We previously demonstrated that post-ischemic intra-arterial (IA) infusion of LEH for 2 hours can reduce ischemia reperfusion (I/R) injury in the rat transient MCAO model (2013, ISC Honolulu). In the present study we examine whether short-time (15-minute) infusion of LEH can also have the same effect on I/R injury and explore the mechanism of the effect.

Methods:
Male SD rats were subjected to 2-hour MCAO and then were divided into three groups: 1) LEH group (n=9) infused with LEH (20 ml/kg) through the recanalized internal carotid artery for 15 minutes, 2) vehicle group (n=8) infused with saline (20 ml/kg) in the same manner as the LEH group, and 3) control group subjected to recanalization only (n=8).

Results:
Compared with the control and vehicle groups, the LEH group showed significantly better neurological score, smaller infarction and brain edema, and less Evans blue leakage (p<0.01). MPO expression, MMP-9 expression and activity, and ICAM-1 expression in the LEH group were also significantly lower than those in the control and vehicle groups (p<0.01). LEH visualized by immunostaining with anti-human Hb antibody in the LEH group was distributed in significantly more microvessels (p<0.01) compared with rat erythrocyte visualized by immunostaining with anti-rat Hb antibody in the control group (Figure).

Conclusions:
Short-time IA infusion of LEH can reduce I/R injury like long-time infusion. This therapeutic approach is likely to suppress endothelial and neutrophil inflammatory activation accompanied by maintaining microvascular perfusion because of LEH’s small size compared with erythrocyte.
Abstract W P96: Optogenetic Neuronal Stimulation Enhances Neurotrophin Expression in the Contralesional Motor Cortex After Stroke
Authors: Cheng Michelle Y , Wang Eric H , Bart Corinne L , Bautista Alex R , Woodson Wyatt J , Sun Guohua , Fenno Lief , Deisseroth Karl , Steinberg Gary K
Published: July 2021

Objective:
Functional recovery after stroke has been observed and is currently attributed to both brain remodeling and plasticity. One form of cortical reorganization involves the balance of interhemispheric interactions between ipsilesional and contralesional cortex. Stimulation of ipsilesional primary motor cortex (iM1) has been shown to be beneficial, however, the role of the contralesional M1 (cM1) remains controversial. Recently we showed that optogenetic stimulations of iM1 post-stroke promote functional recovery. In this study, we investigate the role of contralesional cortex in recovery by optogenetically stimulating iM1 or cM1 and examine the involvement of activity-dependent neurotrophins.

Methods:
Thy-1-ChR2-YFP line-18 transgenic male mice were used. Mice underwent stereotaxic surgery to implant a fiber cannula in either iM1 or cM1, followed by an intraluminal middle cerebral artery suture occlusion. Optogenetic stimulation began at day5 post-stroke and continued until day14 post-stroke. Sensorimotor behavior tests were used to assess their recovery at day 0, 2, 7, 10 and 14 post-stroke. Mice were sacrificed at day15 post-stroke and neurotrophin expressions were examined using quantitative PCR.

Results:
Repeated iM1 stimulations promoted functional recovery at day14 post-stroke, with improved motor performance on the rotating beam test (p<0.01). Real-time PCR revealed significant increases of neurotrophin expressions in contralesional M1 at day15 post-stroke, including brain-derived neurotrophic factor (BDNF) (p<0.05), nerve growth factor (NGF) (p<0.05) and neurotrophin 3 (NTF3) (p<0.05). BDNF and NTF3 expression were also significantly increased in the contralesional S1 of stimulated mice (p<0.05).

Conclusion:
Our data suggest that activity-dependent neurotrophins in the contralesional cortex may be an important mechanism mediating stroke recovery. Current studies include specific stimulation and inhibition of the iM1 or cM1 post-stroke to elucidate the neurocircuitry mediating stroke recovery. In addition, the expression of neurotrophins will be examined in these studies to elucidate their role in the recovery process.
Abstract 1: Improvement of Sensory Function Following Rehabilitation in Chronic Stroke Is Associated With Increased Cortical Thickness
Authors: Pundik Svetlana , Scoco Aleca , Skelly Margaret , McCabe Jessica , Daly Janis J
Published: July 2021

Introduction:
Loss of somatosensory function after stroke weakens the ability to adequately relate to our environment, thus significantly reduces quality of life. Neuroplastic processes of sensory recovery are poorly understood. The objective of this study was to identify cortical regions that undergo structural changes (measured by change in cortical thickness (CT)) during sensory recovery. The hypothesis was that for subjects who improve sensory acuity, CT change in regions of the bilateral sensory network correlates with change in sensory acuity.

Methods:
Chronic stroke survivors were treated with 12-weeks rehabilitation. Outcome measures were sensory acuity (monofilament), Fugl-Meyer upper limb coordination and CT (T1 Magnetic Resonance Imaging). CT change was calculated based on T1 images using Freesurfer longitudinal processing stream. General linear regression modeling identified cortical regions where change in CT was associated with change in sensory acuity after controlling for baseline sensory impairment and change in motor function. Cluster-wise correction for multiple comparisons was conducted using Monte-Carlo simulation at p<0.05.

Results:
Subjects, who improved in sensory acuity (n=18), were 55.8±13.7 year old; 10% female; 1.8±0.9 years after first ever stroke. Acuity improved from 43.9±14mm to 40.53±13mm (p=0.004). FM improved from 22.4±8 to 34.5±10 (p<0.0001). For the ipsilesional hemisphere, CT increase correlated with sensory improvement in lateral occipital gyrus (size=1543mm2; peak vertex coordinates in MNI space x=-10.9, y=-97, z=10.9, cluster wise p=0.0002) and in middle temporal gyrus (795mm2, x=-57.2, y=-56.5,z=0.9, p=0.002). For the contralesional hemisphere, increased CT was associated with improved monofilament acuity within supramarginal gyrus (930mm2 ; x=47.2, y=-43.0, z=43.2, p=0.0002) and middle temporal gyrus (974mm2; x=53.5, y=-59.6, z=-1.7; p= 0.0001).

Conclusion:
Rehabilitation produces modality-specific structural brain changes that can be measured by changes in cortical thickness. Improved sensation correlates with increased thickness in bilateral high-order association sensory cortices reflecting a complex nature of sensory rehabilitation.
Abstract 108: Long-Term Outcome of Giant Unruptured Intracranial Aneurysms
Authors: Torner James C , Piepgras David , Huston John , Meissner Irene , Brown Robert
Published: July 2021

Introduction:
Giant intracranial aneurysms are uncommon, have a high risk for rupture and are difficult to treat. The International Study of Unruptured Intracranial Aneurysms (ISUIA) prospective cohort included 187 patients with maximal diameter of 25 mm or greater. This analysis was to determine the long-term prognosis of these aneurysms both treated and untreated.

Methods:
Patients were enrolled into ISUIA at 61 centers from 1991-1998. A prospective cohort included the managed with observation, surgery or endovascular treatment. Patients were followed for a median of 9.2 years. Aneurysms were measured using a central reading of bi-planar cerebral angiography. Outcomes were determined prospectively and with central review.

Results:
187 patients with a maximum diameter of 25 mm were followed. The mean size was 30.3 mm, ranging from 25 to 63 mm. 39% of the aneurysms were surgically treated at baseline, 27% were endovascularly treated, and 32% were managed conservatively;3% had subsequent endovascular treatment and 5% surgical treatment. Patients with giant aneurysms were predominantly women (83%), had a baseline Rankin Score of in 93%, were located predominantly in the anterior circulation (internal carotid 44%, cavernous ICA 28%, middle cerebral 12%). 80% of the patients were symptomatic with cranial nerve deficit in 47% (III and VI nerves), mass effect in 16%, headaches in 44%, orbital pain in 21%, and vision loss in 25%. Smoking history was present in 67%, hypertension in 44%, vascular headaches in 29% and family history in 10%. 70 patients (39%) died during follow-up however 59% were still Rankin 1 or 2. Both surgical and endovascular treated patients had 60-64% good outcome and 34-36% mortality. Untreated patients had a 57% mortality. Subarachnoid hemorrhage occurred in 11 untreated patients and 12 treated patients with most occurring in the first year.

Conclusions:
Giant intracranial aneurysms are typically symptomatic, and have a high risk of rupture early after diagnosis. Outcome was similar with surgical and endovascular treatment but post-procedure hemorrhage did occur.
Abstract 117: Stromal Cell-derived Factor-1 Gene Modified Endothelial Progenitor Cell Effectively Attenuated Ischemic Brain Injury in Mouse Model
Authors: Li Yaning , Tang Guanghui , Liu Yanqun , Chang Shuang , Song Yaying , Xu Jinmin , Yang Guo-Yuan , Wang Yongting
Published: July 2021

Background and purpose:
Stromal cell derived factor 1 (SDF-1, also know as CXCL12) is a chemokine that can attract stem cells. We have shown that post-acute SDF1 gene therapy promoted angiogenesis and neurogenesis after ischemic stroke. Transplantation of endothelial progenitor cells (EPC) alone was also beneficial for ischemic stroke recovery. However, it remains unclear whether SDF-1 gene modification of EPC (EPC-SDF-1) can further promote stroke recovery. Here we used lenti-virus (LV) to deliver SDF-1 or GFP gene into EPC, then delivered gene modified EPC cells after permanent middle cerebral artery occlusion (MCAO) to investigate the effect of EPC-SDF-1 on ischemic stroke recovery.

Methods and materials: Thirty-eight adult ICR male mice received EPC-SDF-1, EPC-GFP, LV-SDF-1, or PBS stereotactic injection into the peri-infarct area one week after MCAO. Brain atrophy volume, neurobehavioral tests and immunohistochemistry were performed to evaluate the effects of EPC-SDF-1 on angiogenesis and functional repair.

Results:
Brain atrophy volume was significantly reduced in both gene therapy and cell therapy groups 5 weeks after ischemia (p<0.05; LV-SDF-1 vs. PBS; EPC-GFP vs. PBS; EPC-SDF-1 vs. PBS; n=6), with a smaller atrophy volume in EPC-SDF-1 groups comparing to LV-SDF-1 (p<0.01) and EPC-GFP (p<0.001) group. Neurobehavioral tests including neurological deficits and rotarod test paralleled the result of atrophy volume, with neuronal function improved in all therapeutic groups 5 weeks after ischemic (p<0.001; LV-SDF-1 vs. PBS; EPC-GFP vs. PBS; EPC-SDF-1 vs. PBS; n=8-11), with a better outcome in EPC-SDF-1 group (EPC-SDF-1 vs. LV-SDF-1, p<0.05; EPC-SDF-1 vs. EPC-GFP, p<0.001). The number of CD31 positive blood vessels in peri-infarct area was significantly increased in LV-SDF-1 gene therapy (p<0.05, n=4) and EPC-SDF-1 cell therapy (p<0.001, n=4) group comparing to PBS control.

Conclusion:
Our results demonstrated that transplantation of SDF-1 gene modified EPC significantly increased angiogenesis after ischemic brain injury; reduced brain atrophy volume and improved the neurological outcomes of the animals. This in vivo data suggests that SDF-1 gene modification of EPC holds great potential in the treatment of ischemic stroke.
Abstract 126: Derivation and Validation of a Proposed Long Length of Stay (≥ 7 days) Score in Patients Hospitalized for Acute Ischemic Stroke
Authors: Ali Syed F , Chauhan Nabeel , Bianchi Nicolas , Singhal Aneesh B , Schwamm Lee H
Published: July 2021

Introduction:
Long length of stay (LLOS) is one of the main factors in the determination of high cost in hospitalized stroke patients. Our aim was to prospectively predict patients more likely to have a long length of stay using our hospitals Get with the guidelines (GWTG) ischemic stroke registry.

Methods:
We selected 5,400 patients from our database of which 3,400 (~70%) were used for the derivation cohort and 2,000 (~30%) were used for internal validation. For external validation, 730 patients were included from the University of Arkansas. Long length of stay was defined ≥ 7 days. A predictive score was developed using stepwise logistic regression, and its performance assessed using ROC curve analysis.

Result:
Patients with LLOS in the derivation cohort were more likely to female, self-pay, more often have diabetes mellitus, atrial fibrillation, heart failure, previous stroke and carotid stenosis, and more often presented with weakness. They were more likely to have received IV or IA thrombolysis and early antithrombotics, and had higher rates of pneumonia (18.8% vs. 2.6%) and UTI (16.7% vs. 5.3%). Independent predictors of LLOS were Medicare/Medicaid insurance, self pay, history of atrial fibrillation, CAD, previous stroke, carotid stenosis, higher NIHSS and altered level of consciousness at presentation. The LLOS score (Table 2) performed well on ROC analysis (Derivation cohort AUC=0.72, Internal validation AUC=0.73 and External validation AUC=0.77).

Conclusion:
Many factors play a role in determining the length of stay for AIS patients. Our study provides a scoring system that may help physicians predict which patients are more likely to have a prolonged hospital stay.
Abstract 129: Endovascular Therapy Demonstrates Benefit over IV-tPA based on 90-day NIHSS: A Longitudinal, Secondary Analysis of the IMS III Trial
Authors: Fan Liqiong , Yeatts Sharon D , Foster Lydia D , Khatri Pooja , Tomsick Thomas , Broderick Joseph P , Palesch Yuko Y
Published: July 2021

Introduction:
The IMS III trial was a randomized controlled trial designed to compare the add-on effect of endovascular therapy after IV-tPA. The primary outcome was mRS at 90 days. Secondary outcomes included NIHSS, which was evaluated repeatedly through 90 days.

Objective:
To evaluate the treatment effect of endovascular therapy over time on NIHSS.

Methods:
656 subjects were enrolled in the IMS III trial, including 434 subjects randomized to endovascular therapy and 222 to IV-tPA only. NIHSS evaluated at 40 min, 24 hours, Day 5 and Day 90 were included in the analysis. A mixed effects model was used to investigate the treatment effect on NIHSS over time, adjusting for relevant covariates including baseline stroke severity (NIHSS ≤19 vs ≥20). Model assumptions were held.

Result:
After adjusting for age, time from symptom onset to initiation of IV tPA, and baseline stroke severity, a significant time by treatment interaction effect (p = 0.0137) was observed. Only NIHSS at Day 90 showed a significant treatment effect (p = 0.0473), with subjects in the endovascular arm having lower NIHSS compared to the IV- tPA arm (mean 7 vs 8).

Conclusion:
The IMS III trial demonstrated an endovascular treatment effect based on the secondary outcome of NIHSS. However, the magnitude of this treatment effect varied by time of assessment. It was only at Day 90 that the endovascular arm had a significantly lower NIHSS compared to those in the IV- tPA arm.
Abstract 144: Forced Aerobic Exercise Enhances Upper Extremity Task Practice in Patients with Stroke
Authors: Linder Susan , Rosenfeldt Anson , Alberts Jay
Published: July 2021

Introduction:
Aerobic exercise (AE) has been shown to improve cardiovascular health in individuals with stroke; however, the potential role of AE in enhancing neuroplasticity after stroke has not been systematically studied. We have implemented a forced exercise (FE) cycling intervention, initially developed for individuals with Parkinson’s disease, with a cohort of individuals with chronic stroke. We hypothesize that intensive AE training, when paired with repetitive task practice (RTP), will “prime” the central nervous system, to exploit the motor learning effects of task practice.

Hypothesis:
Individuals who perform FE followed by RTP will demonstrate greater improvements in motor and non-motor function compared to the voluntary rate aerobic exercise (VE) + RTP and RTP only groups. Individuals in both AE groups (FE and VE) will demonstrate greater improvements in VO2peak compared to the RTP only group.

Methods:
Fifteen individuals 6-12 months post-stroke were enrolled into one of the following groups: 1) Forced Exercise + RTP (FE + RTP); 2) Voluntary Exercise + RTP (VE + RTP); and 3) Time-matched RTP. Participants in the AE groups completed one 45-minute session of stationary cycling followed immediately by one 45-minute session of upper extremity RTP; however, the rate of cycling for the FE group was augmented to approximately 35% faster than their voluntary rate. All participants completed a total of 24 exercise sessions over an 8-week period.

Results:
While all three groups made significant improvements in motor function as measured by the Fugl-Meyer Assessment (p=.03), the FE+RTP group exceeded the VE+RTP and RTP only groups, approaching statistical significance (p=0.06), despite the two AE groups completing 44% less RTP practice time than the RTP group. Improvements in self-reported quality of life and depressive symptomology also improved across all three groups, with trends favoring the FE group. VO2peak improved by 1.1 and 2.68 mL/kg/min for the FE+RTP and VE+RTP groups, respectively; while VO2peak decreased by 0.85mL/kg/min in the RTP group.

Conclusion:
FE + RTP is a promising intervention to enhance motor and non-motor function, in addition to aerobic capacity in individuals 6-12 months after stroke.
Abstract 145: Outcome in Patients with Minor Stroke: The Effect of Itemized NIHSS Score Subsets
Authors: Yaghi Shadi , Willey Joshua Z , Andrews Howard , Boehme Amelia K , Quarles Leigh , Marshall Randolph S , Boden-Albala Bernadette
Published: July 2021

Background:
The use of the National Insitutes of Health Stroke Scale (NIHSS) to assess stroke severity in minor stroke is controversial. We hypothesized that patients with cortical signs on the itemized NIHSS subsets (neglect, visual, or language) will have a worse outcome than those without.

Methods:
Data was retrieved from the Columbia SPOTRIAS dataset. All patients with NIHSS between 0 and 5 within 12 hours from symptom onset who were not treated with intravenous thrombolysis were included. Patients were followed prospectively as part of the “Stroke Warning Information and Faster Treatment” Study. Poor outcome was defined as not being discharged home and analyzed using multivariable logistic regression. The primary predictor was cortical features on the itemized NIHSS. Individual components of the NIHSS score, treated as a dichotomous variable, as well as the admission NIHSS score were assessed in secondary analyses.

Results:
The sample included 894 patients, of which 162 (18%) were not discharged home. In multivariable regression analysis of baseline demographics, risk factors, median NIHSS, and cortical signs, only mean age (OR = 1.02, P<0.001) and NIHSS score (OR = 1.59, p<0.001) were associated with non-discharge home. In secondary analyses having any score on the following items predicted non-discharge home: Motor (OR = 2.40, p<0.001), LOC (OR = 6.67, p=0.004), and Ataxia (OR = 3.21, p<0.001). Other items from the NIHSS were not associated with discharge disposition. Motor deficits (AUC 0.623) appeared to be more predictive of discharge outcome than ataxia (AUC 0.569) and LOC deficits (AUC 0.517). In addition, the admission NIHSS had a fair correlation with discharge outcome (AUC 0.683).

Conclusion:
Deficits in LOC, motor weakness, and ataxia predict discharge outcome in patients with mild stroke, with the motor score being the most influential component. This may potentially alter treatment decisions in this population. The fair correlation between NIHSS score and discharge outcome suggests that certain factors not captured by the NIHSS score may contribute to discharge outcome in this patient population.
Abstract 146: Inpatient Rehabilitation Facility Care Reduces the Likelihood of Death and Rehospitalization After Stroke Compared with Skilled Nursing Facility Care
Authors: Prvu Bettger Janet , Liang Li , Xian Ying , Peterson Eric D , Bushnell Cheryl , Duncan Pamela W , Federspiel Jerome J , Stein Joel , Montalvo Cris , Lutz Barbara J , Hoenig Helen , Schwamm Lee H , Wu Jingjing , Stafford Judith , Thomas Laine
Published: July 2021

Introduction:
Accountable care and bundled payment initiatives have increased attention on inpatient post-acute care effectiveness. Empirical evidence for whether care at inpatient rehabilitation (IRF) or skilled nursing facilities (SNF) is associated with differential outcomes is limited.

Methods:
Data from the American Heart Association Get With The Guidelines-Stroke registry were linked with Medicare claims. We compared post-discharge mortality and a composite of all-cause rehospitalization or death for beneficiaries who received IRF or SNF care immediately after hospital discharge. Proportional hazards regression with inverse propensity weighting (IPW) was used to adjust for measured differences in demographic, clinical and hospital characteristics. Acknowledging the possibility of unmeasured differences between groups, an instrumental variable approach (IV=hospital-specific proportion of patients discharged to IRFs vs SNFs) was used to adjust for both measured and unmeasured confounding.

Results:
From 1,142 hospitals there were 34,574 AIS patients discharged to IRFs and 34,430 to SNFs. Patients receiving SNF vs IRF care were older (83 vs 79 years), had more comorbid illness, and higher unadjusted 7, 90, and 365 day mortality and rehospitalizations (Table). After IPW adjustment mortality and rehospitalization/mortality rates remained significantly better for patients with IRF vs SNF care (Table). Differences attenuated with IV analysis but IRF care continued to be associated with better outcomes (Table). Findings were similar in sensitivity analyses among patients with a NIHSS score.

Conclusions:
Receiving care at an IRF after AIS was associated with lower mortality and all-cause rehospitalization/death compared with SNF care even after rigorous adjustment for both measured and unmeasured differences in treatment selection. Further research is needed to discern the mechanisms for these potential differences between settings.
Abstract 148: Whole Exome Sequence Analysis of Cerebral White Matter Hyperintensities on MRI
Authors: Fornage Myriam , Bis Joshua C , Chouraki Vincent , Lin Li An , DeStefano Anita , Brody Jennifer A , Muzny Donna M , Metcalf Ginger A , Dahdouli Mahmoud , Psaty Bruce M , Gibbs Richard A , DeCarli Charles , Mosley Thomas H , Longstreth W.T. , Boerwinkle Eric , Seshadri Sudha ,   for the NeuroCHARGE Consortium
Published: July 2021

White matter hyperintensities (WMH) detected on MRI are commonly identified abnormalities in the adult brain, and are associated with a greater risk of stroke, dementia, and death. Genetic factors play a significant role in WMH etiology, yet, common genetic variants identified by GWAS explain little of the variance in WMH burden. Rare variants with larger effect on the phenotype may be identified from sequence analysis of the protein-coding region of the genome (exome). We sequenced the protein-coding regions of 16,541 genes in 2510 individuals of European or African ancestry from three NHLBI cohorts, and investigated whether putatively functional exomic variants were associated with WMH burden, either individually or in aggregate within a gene. Within each cohort, we used the SeqMeta R package to compute race-specific score statistics for each variant and genotypic covariance matrices within predefined gene regions. These were then combined by meta-analysis to generate single-variant and gene-based tests of association. Only missense, nonsense, and splice variants were included in the analyses. Analyses of 12,790 single variants with minor allele frequency (MAF)≥1% did not identify statistically significant associations based on a Bonferroni-corrected significance threshold. The most significantly associated variant was a common missense variant in the ELL gene (p=2.6x10-5). In the sequence kernel association test (SKAT), which included variants with MAF<5%, five genes were significantly associated with WMH burden (p<0.05/16,541). These have known function in phospholipid binding, transport, and signaling (3 genes); Abeta metabolism (1 gene); and have been previously implicated in microvascular complications of diabetes, hypertension, and obesity. Among 35 candidate genes mapping to five previously reported WMH GWAS loci, association of MRPL38 (chr17q25) was nominally significant by SKAT (p=0.011). This gene contained two missense variants (MAF~1%) also nominally significantly associated with WMH (p=0.040 and 0.017). This study suggests that rare and low frequency variants significantly influence WMH burden and that genes involved in cardiovascular health and disease play a role in WMH etiology.
Abstract 157: A Streamlined Hyperacute MRI Protocol Identifies IV tPA-Eligible Stroke Patients When Initial Clinical Assessment Favors Stroke Mimic
Authors: Goyal Manu , Hoff Brian , Williams Jennifer A , Buck Joshua , Heitsch Laura , Panagos Peter , Vo Katie D , Benzinger Tammie , Derdeyn Colin P , Lee Jin-Moo , Ford Andria L
Published: July 2021

Background:
The possibility of a stroke mimic (SM) challenges the initial clinical assessment of patients presenting with suspected acute ischemic stroke (AIS). When SM is deemed likely, IV tPA may be withheld, risking an opportunity to treat an AIS. Though not routinely used in the hyperacute setting, MRI may help in diagnosing stroke when SM is favored but not certain. We hypothesized that a streamlined, hyperacute MRI (HMRI) protocol would identify a small, but important, group of IV tPA-eligible AIS patients among those initially favored to have SM.

Methods:
A streamlined HMRI protocol was designed based on several identified barriers to rapid patient transport, MR image acquisition, and post-MRI tPA delivery. Treating neurologists were trained to only order HMRI when SM was favored and IV tPA was being withheld (Fig). Use of HMRI for tPA decision-making, as well as baseline variables, door-to-needle times (DNT), and discharge outcomes were compared before HMRI implementation (“Pre-HMRI”: 8/1/2011-7/31/2013) and after (“Post-HMRI”: 8/1/13-7/31/14).

Results:
Post-HMRI, 53 patients with suspected SM, who were otherwise IV tPA eligible, underwent HMRI (median MRI order to start time 29 min). Seven of 53 patients (13%) were subsequently diagnosed with AIS based on HMRI, of whom 4 received IV tPA; 3 were excluded from IV tPA due to blood pressure, symptom improvement, and change in last known normal time. Pre-HMRI, 158 patients were treated with IV tPA, of whom none received IV tPA aided by HMRI. Post-HMRI, 80 patients were treated with IV tPA, of whom 4 patients (5%) were treated with IV tPA utilizing HMRI results (0 vs 5%, p=0.012). In pre- and post-HMRI IV tPA-treated patients, DNT (39 vs 37 min, p=0.95), symptomatic hemorrhage rate (5 vs 2%, p=0.28), and favorable discharge location (85 vs 90%, p=0.32) did not differ.

Conclusions:
A streamlined HMRI protocol permitted IV tPA administration to a small, but significant, subset of AIS patients initially deemed to have a SM.
Abstract 189: ADAMTS13 Activity Predicts Response to Thrombolysis in the Acute Stroke Setting
Authors: Bustamante Alejandro , Llombart Victor , Boada Cristina , Penalba Anna , Simats Alba , García-Berrocoso Teresa , Pagola Jorge , Flores Alan , Ribó Marc , Molina Carlos , Montaner Joan
Published: July 2021

INTRODUCTION:
Biological markers predicting tPA response in acute stroke could be used for dose adjustments or early selection of patients for endovascular procedures. ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) inactivates Von Willebrand Factor by cleaving it, and its deficiency may generate prothrombotic diseases such as thrombotic thrombocytopenic purpura. We aimed to analyze ADAMTS13 activity in acute stroke patients and its relation to vessel patency among those treated with intravenous tPA.

METHODS:
Acute ischemic stroke patients (n=104) with documented arterial occlusion by transcranial Doppler (TCD), who received tPA within the first 4.5 hours after symptoms onset were recruited and compared with 38 age-matched healthy subjects. Samples were collected at baseline, before thrombolytic treatment, and ADAMTS13 activity was measured by ELISA and expressed as %. A temporal profile of ADAMTS13 activity was determined at 24 hours and 3 months in a subset of 10 patients. Recanalization was assessed 2 hours after tPA bolus by TCD, using thrombolysis in brain ischemia (TIBI) flow grading system. Logistic regression analysis was conducted to determine independent predictors of 2-hour recanalization in patients with proximal arterial occlusions.

RESULTS:
ADAMTS13 activity was consistently lower in stroke patients than in healthy controls (p<0.001), and remained lower at 24 hours and 3 months. For those patients who presented arterial recanalization at 2 hours, higher baseline ADAMTS13 activity (p=0.032) was noted. In logistic regression analysis from 72 patients with proximal MCA occlusion, ADAMTS13 activity >74.72% was an independent predictor of recanalization [OR=5.148 (1.463-18.111), p=0.011], together with early ischemic signs at baseline neuroimaging [OR=0.065 (0.006-0.712), p=0.025] and OCSP classification (TACI vs. PACI) [OR=0.072 (0.011-0.45), p=0.005].

CONCLUSIONS:
In stroke patients treated with tPA, ADAMTS13 activity may be used to monitor the treatment as well as to make decisions regarding more aggressive reperfusion therapies when the absence of a response to intravenous tPA is anticipated.
Abstract 205: Etiologic Ischemic Stroke Phenotypes in the NINDS Stroke Genetics Network
Authors: Ay Hakan , Arsava Ethem M , Brown Robert D. , Kittner Steven J , Lee Jin-Moo , McArdle Patrick F , Rexrode Kathryn M , Rosand Jonathan , Rundek Tatjana , Slowik Agnieszka , Worrall Bradford B , Meschia James F ,   Stroke Genetics Network Investigators
Published: July 2021

Background and Purpose:
NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of ischemic stroke subtypes. The goal of this analysis is to characterize the etiopathogenetic basis of ischemic stroke in the consortium.

Methods:
This analysis included 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries. 52 trained and certified adjudicators used the web-based Causative Classification of Stroke System for etiologic stroke classification through chart reviews to determine both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause in the presence of multiple etiologies) and causative subtypes in each subject. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases.

Findings:
The figure shows the distribution of etiologic categories. Overall, only 40% to 54% of cases with a given major ischemic stroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0·72, 95%CI:0·69-0·75) and phenotypic classifications (kappa 0·73, 95%CI:0·70-0·75).

Conclusions:
This study provides high quality data on etiologic stroke subtypes and demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes suggests that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke.
Abstract 28: Defining the Diagnosis of TIA: An Inter-rater Agreement Analysis of a New Precise Diagnostic Score (PREDISC)
Authors: Cereda Carlo W , Inoue Manabu , George Paul , Vora Nirali , Olivot Jean-Marc , Kemp Stephanie , Mlynash Michael , Albers Greg W
Published: July 2021

Background:
the “gold standard” for the diagnosis of transient ischemic attack (TIA) is typically the final diagnosis of a neurologist. However, inter-rater agreement between physicians for the diagnosis of TIA is low, even among vascular neurologist. We developed a diagnostic scoring scale (PREDISC), which features well defined clinical and imaging parameters and investigated inter-rater agreement in patients with suspected TIA. Methods:fellowship-trained vascular neurologists, blinded to patient’s final diagnosis or outcomes, independently reviewed the history, clinical examination and MRI (including DWI and perfusion imaging) findings of patients with suspected TIA who were referred to our institution's TIA program. Each patient’s clinical manifestation and MRI findings were rated using the PREDISC score, an 8-point scale composed of a clinical score (0-4 points) and an Imaging score (0-4 points). The imaging score includes specific criteria for DWI positivity (4 points) as well as criteria for assessment of clinically relevant perfusion lesions (maximum 3 points for patients who are DWI negative). The final PREDISC score for confirmation that the event was caused by brain ischemia is determined as: 0-1 = unlikely, 2= possible, 3= probable, 4-8 = very likely. We assessed global agreement between the raters. Results: Three raters reviewed data from 114 patients. Using PREDISC all 3 raters scored a similar percentage of the clinical events as being “probable” or “very likely” caused by brain ischemia: 57%, 55% and 58%. Agreement was high for both total PREDISC Score (Intraclass correlation coefficient [ICC] of 0.94) and for the 4-point scale of TIA likelihood of diagnosis (AC1 agreement coefficient of 0.84). Agreement was excellent both on the clinical and imaging sub scores (ICC 0.88 and 0.95). Conclusion:Based on comparison with prior studies, inter-rater agreement for the diagnosis of TIA appears to be substantially improved with the PREDISC structured scoring system. This scale is the first to include specific criteria to assess the clinical relevance of DWI and perfusion lesions and supports the added value of MRI for assessing patients with suspected TIA. The diagnostic value of PREDISC should be confirmed in a prospective multicenter trial.
Abstract 30: Inhibited CaMKII Activity Decreases Hippocampal Neuronal Damage in Both Normothermic and Mild Therapeutic Hypothermic CA/CPR Mouse Model
Authors: Deng Guiying , Bayer K U , Traystman Richard J , Herson Paco S
Published: July 2021

Introduction:
Glutamate excitotoxicity is an important mechanism of ischemic neuronal damage, however inhibition of glutamate receptors has proven an unsuccessful strategy. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major downstream target of glutamate signaling. The aim of this study is to examine the neuroprotective potential of inhibition of autonomous CaMKII activity using novel peptide inhibitors (tatCN21,19o) and transgenic mice.

Methods:
C57BL/6 male wild-type (WT) and T286A mutant mice were subjected to 6 min of cardiac arrest and CPR. Mice were randomized to tatCN21 (1 mg/kg), tatCN19o (0.01,0.1,1 mg/kg) or control (tatSCR; 1 mg/kg), administered 30 min after CPR (iv). Separate experiments were performed to assess mild post-arrest hypothermia (rectal T = 34 ±0.2 °C for 1 hr after CPR). Hippocampal neuronal damage was analyzed 3 days after CA/CPR by H&E staining. Total CaMKII and Thr-286 phosphorylation levels were measured by western blot. Statistical analyses were performed using ANOVA and t tests, with P<0.05 considered significant.

Results:
Analysis of histological damage 72 hrs after CA/CPR showed that tatCN21 significantly reduced neuronal injury; 28.9±5.6% (n=11) compared to 55.4±4.0% (n=8, P<0.05) in tatSCR-treated mice. Mild hypothermia decreased damage from 55.4±4.0% (n=8) to 31.9±10.5% (n=6, P<0.05), which could be further reduced by tatCN21, reducing to 7.2±4.0% (n=4, P<0.05). Interestingly, the more potent tatCN19o decreased neuronal damage at all doses tested, reducing damage to 23.6±10.8% (n=7, P<0.05) for 1 mg/kg, 25.8±8.8% (n=8, P<0.05) for 0.1 mg/kg and 10.9±3.7% (n=8, P<0.05) for 0.01 mg/kg. Western blot analysis showed that CA/CPR significantly increases p-T286 CaMKII 3 (4.5±0.31, n=4,) compared to sham controls (0.91±0.14, n=4, P<0.05). Finally, T286A mutant mice had less neuronal damage after CA/CPR (4.0 ± 0.9%, n=8) compared to WT mice (28.9 ± 10.9%, n=8; P<0.05), indicating a role for autonomous CaMKII activity in CA/CPR-induced neuronal injury.

Conclusions:
The novel CaMKII inhibitors decrease neuronal damage under both normothermic and hypothermic condition following CA/CPR, indicating that inhibition of autonomous CaMKII activity is a promising new therapeutic approach.
Abstract 32: Direct Angiotensin II Type 2 Receptor Stimulation by Compound 21 Prevents Vascular Dementia
Authors: Iwanami Jun , Mogi Masaki , Tsukuda Kana , Wang Xiao-Li , Kukida Masanori , Nakaoka Hirotomo , Chisaka Toshiyuki , Bai Hui-Yu , Shang Bao-Shao , Horiuchi Masatsugu
Published: July 2021

Objectives:
Recent clinical evidence demonstrated that angiotensin II type 1 receptor blockers (ARBs) were associated with a significant reduction in the incidence and progression of dementia compared with angiotensin converting enzyme inhibitor. Therefore, we examined the possibility that direct angiotensin II type 2 (AT2) receptor stimulation by AT2 receptor agonist, compound 21 (C21), could prevent cognitive decline associated with hypoperfusion in the brain.

Methods:
We employed a bilateral common carotid artery stenosis (BCAS) model in mice as a model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. ARB, azilsartan (0.1 mg/kg/day) or C21 (10 μg/kg/day) was administered from 1 week before BCAS. Cerebral blood flow (CBF) was measured by laser speckle flowmetry and inflammatory cytokine levels were determined by real-time RT-PCR.

Results:
Wild-type (WT) mice showed the significant prolongation of escape latency after BCAS and this cognitive impairment was attenuated by the pretreatment of azilsartan. Cognitive impairment was more marked in AT2 receptor knockout (AT2KO) mice, and preventive effect of azilsartan on cognitive decline was weaker in AT2KO mice than in WT mice, suggesting that improvement of cognitive decline by azilsartan may involve the stimulation of AT2 receptor. The significant impairment of spatial learning after BCAS in WT mice was attenuated by C21 treatment. CBF in the whole brain in the BCAS-treated group was significantly decreased compared with that in the sham group at 6 weeks after BCAS operation. This decrease was increased by treatment with C21. We assessed expression of inflammatory cytokines such as TNF-[[Unable to Display Character: ]]α and MCP-1 in the cerebral cortex. TNF-α and MCP-1 mRNA expression were significantly increased after BCAS operation, but significantly attenuated by treatment with C21. Azilsartan or C21 at these doses did not affect systolic blood pressure.

Conclusions:
These findings indicate that direct AT2 stimulation prevents ischemic vascular dementia induced by hypoperfusion at least in part through an increase in CBF, and reduction of inflammation. We expect that direct AT2 receptor stimulation could be a new therapeutic strategy for preventing and treating vascular dementia.
Abstract 42: Haptoglobin 2-2 Phenotype Is associated with Cerebral Salt Wasting Syndrome in Aneurysmal Subarachnoid Hemorrhage
Authors: Murthy Santosh B , Caplan Justin , Hadar Shalom , Ziai Wendy C , Levy Andrew P , Tamargo Rafael J , Nyquist Paul A
Published: July 2021

INTRODUCTION:
The Haptoglobin (Hp) phenotype has been shown to be a predictor of clinical outcomes in cerebrovascular disorders. We sought to determine if the Hp phenotype was predictive of cerebral salt wasting (CSW) following aneurysmal subarachnoid hemorrhage (SAH).

METHODS:
Patients admitted with a diagnosis of SAH were divided into three groups based on their genetically determined Hp phenotype: 1-1, 2-1, and 2-2. Outcome measures included CSW, delayed cerebral infarction (DCI) and favorable outcome -Glasgow Outcome score (GOS) of 4-5 at 30 days. CSW was diagnosed by a clinician, and met the following criteria: hyponatremia 4 liters in 12 hours with urine sodium > 40 mEq/L. Pearson’s Chi Square and Wilcoxon-Mann-Whitney tests were used for categorical and continuous variables respectively. Logistic regression was used to assess association between Hp phenotype and SAH outcomes.

RESULTS:
A total of 133 patients were included in the study. The distribution of Hp phenotype was- Hp 1-1: 29 (21.8%), Hp 2-1: 57 (42.9%), Hp 2-2: 47 (35.3%). The three Hp subgroups did not differ in terms of demographic variables, comorbidities or SAH characteristics. CSW occurred in 1 patient (3.4%) with Hp 1-1, 8 (14.0%) with Hp 2-1 and 15 (31.9%) with Hp 2-2 (p=0.004). In the multivariate analysis adjusted for age, sex, race, Hunt-Hess score and hydrocephalus, Hp 2-2 was associated with CSW (OR: 4.94 CI: 1.78-17.43, p=0.013) but Hp 2-1 was not (OR: 2.92, CI: 0.56-4.95, p=0.150). There were no associations between Hp phenotypes and favorable outcomes or DCI. CSW correlated strongly with development of DCI (OR: 7.16, OR: 2.48-20.62, p<0.001).

CONCLUSIONS:
Hp 2-2 phenotype was an independent predictor of cerebral salt wasting following SAH. There were no associations between Hp phenotype and DCI or good functional outcome.
Abstract 5: Role of Contralesional Hemisphere during Paretic Hand Movement Differs Based on Level of Motor Impairment
Authors: Stewart Jill C , Quinlan Erin B , Dodakian Lucy , McKenzie Alison , See Jill , Cramer Steven C
Published: July 2021

Introduction:
Paretic hand movements after stroke often correspond to activation in both the ipsilesional and contralesional hemispheres. Changes in intra- and interhemispheric connectivity have been reported but most studies have focused on individuals with limited motor impairment. The purpose of this pilot study was to examine connectivity between motor regions during paretic hand movement in a population with a range of motor impairment after stroke.

Methods:
Seventeen right-hand dominant individuals with hemispheric stroke (age 58.7±13.9; UE FM 34.3±12.3; days post-stroke 154.6±101.8) underwent functional MRI during paretic hand grasp/release. Data were extracted from 4 regions of interest (ROI) bilaterally: M1, dorsal premotor (PMd), supplementary motor (SMA), and visual association cortices. No participant had lesions in these cortical areas. These ROIs were included in a DCM analysis that focused on intrinsic connectivity during hand movement. Bayesian model selection was used to determine the optimal model from a set of bilateral (B), ipsilesional (IL), and contralesional (CL) models; Bayesian model averaging was used to extract coupling parameters across models.

Results:
Overall, individuals activated a bilateral network of motor regions during movement that included M1, PMd, SMA, basal ganglia, and cerebellum. There was variability between subjects as to the model that best fit the data: B for 3 subjects, IL for 6 subjects, and CL for 8 subjects. These three groups differed significantly in median UEFM scores (
p
=0.021; B=50, IL=34, CL=22) and number of blocks moved with the paretic hand in the Box & Blocks (
p
=0.03; B=35, IL=8, CL=0). Additionally, the direction and magnitude of M1-M1 coupling differed between the groups (
p
<0.016): CL M1 had a facilitatory influence on IL M1 in the B group (median=0.112) and CL group (0.469) but an inhibitory influence in the IL group (-0.524).

Conclusions:
Connectivity analysis revealed that the CL hemisphere plays a facilitatory role in some individuals and an inhibitory role in others that is related to level of motor impairment. Such variability in the role of the CL may have an impact on response to interventions aimed at altering communication between hemispheres during movement.