bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract T P83: Strain Differences In Leptomeningeal Collateral Flow Dynamics Correlate With Differences In Stroke Outcome
Authors: Nishijima Yasuo , Akamtsu Yosuke , Lee Chih Cheng , Liu Jialing
Published: July 2021

Introduction:
Emerging evidences suggest that the collateral circulation plays a key role in the risk of stroke and the severity of infarction. The current study aimed to investigate the effect of the brain collateral circulation in acute phase of stroke and outcome in two inbred mouse strains that differ markedly in anatomical collateralization.

Methods:
Male C57BL/6 and Balb/C mice were subjected to permanent unilateral common carotid artery occlusion (CCAO) or temporary distal middle cerebral artery occlusion (dMCAo). Regional cerebral blood flow (rCBF) was assessed by laser doppler flowmetry. In vivo imaging of collateral blood flow and flow velocity was evaluated by doppler optical coherence tomography (DOCT). Infarct size and motor function was assessed at 24 hours and 1 week after dMCAo, respectively. DiI-labeling was used to reveal anastomoses and to determine vessel diameter.

Results:
The diameters of the ICA and ACA on the ischemic side in both strains markedly decreased at 24 hours after CCAO but recovered at 7 days, although the diameters of ICA, MCA and ACA are larger in the Balb/C compared to the C57BL/6 strain before and after CCAO. Balb/C mice exhibited significantly less leptomeningeal connecting collateral arteries compared to C57BL/6 (0.6±0.3 vs 11.3±0.4, p<0.001), coincided with a larger infarction and worse neurological outcomes after dMCAo compared to C57BL/6. During the acute phase of occlusion of the CCA or MCA, C57BL/6 mice also demonstrated a much more robust retrograde filling of several distal branches of the MCA from ACA compared to Balb/C mice.

Conclusion:
Our results demonstrate that anatomical insufficiency of the leptomeningeal collateralization is associated with an impaired collateral flow dynamics, resulting in reduced rCBF during the acute phase of MCA stroke, which might in part, contribute to the larger infarction observed in the Balb/C strain.
Abstract T P84: Neuroprotective Effect of Probenecid in a Rat Model of Transient Global Cerebral Ischemia-Reperfusion
Authors: Wei Rui-li , Xu Yan , Wang Jing-ye , Luo Ben-yan
Published: July 2021

Background and Purpose:
Probenecid (PROB) has been used for decades to treat gouty arthritis with few side effects and recent studies revealed that it is also a specific inhibitor of pannexin-1 channel. Panx1 channel was activated by ischemic injury and inhibition of the panx1 channel maybe efficacious in stroke treatment. However, the role of PROB in cerebral ischemia /reperfusion (I/R) injury remains unclear. The aim of this study was to investigate the role of PROB in the transient global cerebral I/R injury in rats and its protective mechanisms.

Methods:
Twenty minutes of transient global cerebral I/R was induced using the four-vessel occlusion (4-VO) method in rats. PROB was given in the different dose, time and administration routes to verify its neuroprotective effects. Neuronal death in the hippocampal CA1 region was observed using H & E staining 7 days after ischemia. Molecular mechanisms of activation of calpain-cathepsin pathway and inflammatory cells by I/R injury were also investigated.

Results:
Treatment with PROB (0.1, 1 and 10 mg/kg ) 10 min before ischemia protected against I/R-induced hippocampal CA1 neuronal death significantly, and 1 mg/kg has best protective effect. Post-insult treatment 2h after reperfusion also protected against neuronal death and prolonged use for continuous 7 days could improve its protective effects compared to the single use 6h after reperfusion.Furthermore,oral administration also had protective effect. Cathepsin B expression was inceased significantly in CA-1 region after ischemia and PROB treatment could inhibit its expression. Expression of both calpain-1 and hsp70 at 1d ,2d and 3d after reperfusion were upregulated, whereas the expression of calpain-1 was inhibited and hsp70 was strengthened by pre-treatment with PROB. Prolonged PROB treatment suppressed the activation of microglia and astrocytes, reduced the number of microglia in CA1 region.

Conclusions:
Our study indicates that PROB protects against transient global cerebral I/R injury administrated before ischemia and even 6h after reperfusion by reducing calpain-1 expression , inhibiting lysosomal rupture and the activation of the glia, which suggests RPOB may be a promising therapeutic drug for clinical treatment of ischemic cerebral injury.
Abstract T P86: Paradoxical Motor Recovery From a First Stroke By Re-opening a Sensitive Period With a Second Stroke
Authors: Zeiler Steven R , Hubbard Robert B , Gibson Ellen M , Ng Kwan , Zheng Tony , O'Brien Richard J , Krakauer John W
Published: July 2021

Background and Purpose:
After stroke, there is a time-limited period of increased responsiveness to training due to heightened plasticity, which is thought to be induced by ischemia itself. Using a mouse model we have previously shown that most training-associated recovery after a caudal forelimb area (CFA - rodent primary motor cortex) stroke occurs in the first week and is attributable to reorganization in the medial premotor area (also called agranular medial cortex - AGm). The idea of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and lead to paradoxically enhanced recovery from the first stroke. To test this prediction, we induced a second focal stroke in the medial premotor area of mice with incomplete recovery after a first focal stroke in CFA.

Methods:
C57Bl/6 mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance after which they underwent photocoagulation-induced stroke in CFA. After a 7 day post-stroke delay, the mice were then retrained for 21 days. A second photocoagulation-induced stroke was then induced in the medial premotor area and the mice were re-trained for 8 days after only a one-day delay.

Results:
Focal CFA stroke led to a decrement in skilled prehension. Training-associated recovery of prehension begun 7 days after stroke induction was incomplete even with 21 days of training. At post-stroke day 21, a second focal stroke in the medial premotor area was induced, which now led to a dramatic response to training with recovery to normal performance after 8 days of training.

Conclusions:
Together, these data indicate that new ischemia can re-open a sensitive period and mediate full recovery from a previous stroke. Future work will need to characterize what the critical molecular pathways are that ischemia triggers.
Abstract T P87: Hydrogen Sulfide Enhances Neurogenesis through the IRAK-1/GSK3β/AKT Signaling Pathways after Ischemic Stroke
Authors: Kamat Pradip K , Kalani Anuradha , Tyagi Neetu
Published: July 2021

Background and purpose:
Increasing evidence signifying that inflammation has an ample role in the ischemia and; neurogenesis is somehow affected by inflammation. Current approved therapy for stroke is limited and new strategies need to be investigated. Hydrogen sulfide (H2S) showed neuro-protective however, role of H2S in stroke-induced neurogenesis is not known. Therefore, the present study was to determine the role of H2S in ischemia induced neurogenesis. Methods: To perform this study; we employed 8-10 weak old C57BL/6 mice with following groups: WT-Sham; WT+ ischemia reperfusion (IR) for 7 days; IR+GYY4137 (H2S donor, 30μM for 7 days; Intra peritoneal injection); and Sham+ GYY4137 (30μM for 7 day). Ischemia was created by the middle cerebral artery occlusion, (MCAO) for 50 min followed by reperfusion for 7 days. The brain tissue from different groups was used for biochemical, infarct area molecular and immunohistochemistry analysis. Data were analyzed by one way ANOVA followed by Tukey test. Results: We found increased protein expression of IRAK-1 (F=3, 27.01; P<.005), GSK3β 9 (F=3, 89.47; P<.005), p-AKT (F=3, 89.47; P<.005) and reduced expression of AKT p-AKT(F=3, 112.2; P<.005) in I/R group as compared to sham that indicates alteration of inflammatory signaling pathways. Further, we also found decreased level of Nestin (F=3, 35.32; P<.005), GFAP (F=3, 95.14; P<.001), NeuN (F=3, 123.4; P<.001), TUJ-1 (F=3, 112; P<.005), MAP-2 (F=3, 31.54; P<.0001), IL-6 (F=3, 55.7; p<.05) and BDNF (F=3, 166.5; P<.005) in cortical region of I/R group which indicates loss of neuronal function. Additionally, immunohistochemistry assay also revealed the loss of Nestin (P<.05), BDNF (P<.05), MAP-2 (P<.05) along with increased GSK-3β (P<.005) expression in sub ventricular zone (SVZ) and hippocampal region. Further, GYY4137 treatment for 7 days in ischemic group significantly restored the Nestin, GFAP, IL-6, NeuN, TUJ-1, MAP-2 and BDNF levels via regulating IRAK-1/GSK3β/AKT signaling pathways. Conclusion: Present study clearly demonstrate that H2S plays an important role in ischemia induced neurogenesis as well as protecting neuronal function through inhibition of IRAK1/GSK3β/AKT signaling pathways.

Acknowledgement:
This work was supported by NTHL107640-NT.
Abstract T P91: Changes in Diffusion Measures Following Experimental Stroke and Rehabilitative Training
Authors: Weber Rachel A , Nie Xingju , Hui Edward S , Jensen Jens H , Falangola Maria F , Helpern Joseph A , Adkins DeAnna L
Published: July 2021

Diffusional kurtosis imaging (DKI) is an advanced diffusion MRI (dMRI) technique that can quantify several diffusion measures that are highly sensitive to microstructural changes in brain. Previously, we found enhanced sensitivity of DKI-derived diffusion metrics following acute stroke in the lesion core and peri-lesional area that correlated with infiltration of activated glia. Studies have demonstrated that skilled motor training after ischemic damage affecting the sensorimotor cortex (SMC) induces functional motor recovery and neural plasticity in the remaining motor cortex. In the current study, we investigated the relationship between dMRI measures and rehabilitation-induced forelimb functional recovery. Adult male rats (3-4 months old) were trained on a skilled reaching task and given an endothelin-1 (ET-1) induced unilateral ischemic stroke over the SMC. Animals then received 21 days of impaired forelimb rehabilitative training (RT) on a reaching task or no rehabilitative training (No-RT). All animals underwent MRI scans prior to injury, 5 days post-injury, and after 21 days of RT or No-RT procedures, using a 7T Bruker Biospec MRI scanner to acquire dMRI images. Diffusivity and diffusional kurtosis metrics were calculated with in-house software. Multi-slice regions-of-interest were drawn in the lesion core, peri-lesional remaining motor cortex and in the forelimb region of the SMC in the non-infarcted hemisphere. All animals had lesion-induced motor deficits following ET-1 strokes and RT improved reaching forelimb function compared to No-RT. Peri-lesional diffusional kurtosis measures remained significantly different between the lesion and non-lesion SMC at four weeks post-injury, at which time diffusivity differences were no longer detected. Fractional anisotropy of the corpus callosum, inclusive of areas with SMC interhemispheric connections was higher following RT versus No-RT. These data indicate that the kurtosis of peri-lesional motor cortex remains sensitive to chronic ischemic effects, unlike diffusivity measures, and that skilled motor RT likely alters white matter connectivity between the two hemispheres.
Abstract T P96: Controlled Brain Glucose Uptake and Metabolism by Ethanol: An Alternative Approach in Improving Stroke Outcome
Authors: Akbary Fauzia , Peng Changya , Asmaro Karam , Kochanski Ryan , Guthikonda Murali , Ding Yuchuan
Published: July 2021

Introduction:
Post-stroke oxygen deficit impairs oxidative phosphorylation of glucose. Surviving brain cells increase anaerobic glycolysis (hyperglycolysis) promoting reactive oxygen species (ROS) synthesis via lactic acidosis and NADPH oxidase (NOX) activation. Hyperglycemia present in 40% of stroke patients with or without diabetes perpetuates hyperglycolysis. Insulin, the only treatment to attenuate hyperglycemia-induced hyperglycolysis, is linked to increased risk of hypoglycemia and mortality. We showed that EtOH reduced ROS-mediated brain damage. Here, we studied whether hyperglycemia/hyperglycolysis-enhanced brain injury are ameliorated by reducing brain glucose uptake and metabolism rather than affecting blood glucose levels.

Methods:
Sprague-Dawley rats underwent a 2 h right middle cerebral artery occlusion (MCAO). EtOH (1.5 g/kg) or saline was injected IP upon reperfusion, then sacrificed 3 and 24 h later. Energy stores, hyperglycolysis-associated glucose uptake and metabolism, lactic acidosis, and oxidative stress were assessed via ADP/ATP ratio, NAD+/NADH ratio, Na+/K+ ATPase activity, levels of brain and blood glucose, glucose transporter GLUT 1 and 3, lactate, lactate dehydrogenase (LDH), ROS, phosphofructokinase-1 (PFK-1), NOX, and PFK-1 and NOX activity.

Results:
Ischemic rats showed significant (p<0.01) increase in ADP/ATP and NAD+/NADH ratios, and decrease in Na+/K+ ATPase activity indicating impaired metabolic and neural activity. Increased blood glucose and decreased brain glucose indicate hyperglycemic condition with hyperglycolysis. High levels of GLUT 1 and 3, lactate, LDH , PFK-1, NOX, and ROS support ROS associated hyperglycolysis. EtOH normalized these metabolic parameters to control levels, but only blood glucose remained higher. In sum, EtOH attenuates hyperglycemia-enhance brain injury by reducing glucose uptake and its hyperglycolytic-mediated metabolism under hyperglycemic condition.

Conclusion:
EtOH administered upon reperfusion is neuroprotective against ROS-mediated brain damage in acute ischemic stroke. It attenuates hyperglycemia-enhanced hyperglycolysis at the level of glucose uptake, utilization, and metabolism rather than reducing serum glucose levels.
Abstract W MP100: Applying Real-Time Location Systems to Acute Stroke Workflow: A Novel Quality Improvement Tool
Authors: Prater Adam , Bowen Meredith , Pavich Emily , Loehfelm Thomas , Anderson Aaron M , Belagaje Samir , Frankel Michael , Fountain A Jack
Published: July 2021

Background:
Real-Time Location Systems (RTLS) utilize tracking tags and detectors to locate objects or people. This technology has been implemented in healthcare, chiefly to track hospital assets, and a few healthcare systems have applied this technology to track patients in the emergency department. This pilot study tested the feasibility of RTLS to monitor the acute stroke workflow in a large, urban hospital.

Methods:
An asset tracking RTLS was installed in a large, urban hospital. A series of 21 acute stroke patients were tracked throughout the workflow process by a human observer and via RTLS asset tag attached to the patient’s hospital equipment. A Wi-Fi detector documented initial patient arrival times in the ER Hallway, radiofrequency/infrared (RFID/IR) detectors documented ER CT scanner and ER patient room times. Patient Arrival and departure times in the emergency room (ER) and radiology CT scanner were measured. Time differences between human observer and RTLS were calculated.

Results:
A total of 21 patients were tracked with RTLS. The mean time difference, interquartile range and standard deviation in minutes are as follows: initial arrival (mean 106, IQR 112, SD 197); CT arrival ( mean 1, IQR 1, SD 0.86); CT departure (mean 2, IQR 2, SD 1.13); patient return to ED (mean 1, IQR 1, SD 0.94).

Discussion:
Our data demonstrate that RTLS can provide accurate, real-time patient location information, and has the potential to provide data for quality improvement. Combination RFID/IR detectors provided accurate time information while the Wi-Fi detector, proved unreliable for initial arrival times. Our preliminary data supports the development of an unique RTLS system specifically designed to allow for complete visualization of the stroke workflow from patient arrival to treatment along with a dashboard user interface to facilitate treatment team coordination.
Abstract W MP111: The Impact of Fever on Presentation in Intracerebral Hemorrhage: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) Study
Authors: Lord Aaron S , Brown W. Mark , Moomaw Charles J , Langefeld Carl D , Sekar Padmini , James Michael L , Osborne Jennifer , Boehme Amelia K , Woo Daniel , Elkind Mitchell S
Published: July 2021

Background:
Fever on presentation has been demonstrated to be an independent predictor of poor-outcome after ICH. However, prospective data with post-discharge outcomes are limited.

Methods:
Associations between fever (≥38°C) on presentation and 3-month outcomes were sought among patients in ERICH, a multicenter, triethnic case-control study of ICH. Patients with missing CT or Glasgow Coma Score (GCS) and those lost to 3-month follow-up were excluded. Rates of fever on presentation were compared across admission characteristics, hospital complications, and 3-month outcomes. Additionally, a multivariate analysis was performed to determine factors associated with fever on presentation.

Results:
A total of 1644 patients out of 2276 enrolled by 12/31/2013 met inclusion criteria for the analysis. Fever on presentation with ICH was present in 2.4% of patients. In univariate analyses, fever was associated with (all data are % febrile in each group): ICH volume (<15mL: 1.7% , 15-30mL: 2.3%, 30-45mL: 4.7%, 45-60: 6.6%, >60: 2.9%, p=0.03), higher ED GCS (3-4: 1.8%, 5-12: 3.0% 13-15: 6.6%, p=0.004), and WBC > 10 (yes, 3.4% vs. no, 1.7% p=0.03). Additionally, borderline significance was seen with race (white 3.1%, black 2.9%, Hispanic 1.1%, p=0.06) and ICH Location (lobar 3.9%, primary IVH 3.8%, Deep 1.6%, Brainstem 2.2%, cerebellum 1.7%, p=0.06). Fever on presentation was not associated with 3-month outcomes (mRS 0-2: 2.1%;3-5:1.9%; 6: 3.2%, p=0.45). In a multivariate analysis, fever was associated with GCS (OR 0.9, 95% CI 0.83-0.97) and white or black race (reference Hispanic; white OR 3.0 95% CI 1.14-7.88; Black OR 2.68, 95% CI 1.04-6.96).

Conclusion:
Fever is relatively uncommon at admission and does not appear to be associated with poor outcomes.
Abstract W MP115: Patients With ICH Have Dynamic Electrocardiographic Changes Over Time
Authors: Gonzales Nicole R , Cai Chunyan , Bowry Ritvij , Ayish Doha , Pandurengan Renga , Sline M.Rick , Denktas Ali E , Ramanathan Sabarina , Barreto Andrew D , Wu Tzu-Ching , Ifejika Nneka , Sharrief Anjail Z , Sarraj Amrou , Savitz Sean I , Rahbar Mohammad H , Zhao Xiurong , Aronowski Jaroslaw , Grotta James C
Published: July 2021

Background:
Few studies have reported electrocardiographic (ECG) changes in patients with intracerebral hemorrhage (ICH). We performed a randomized controlled trial evaluating the safety of pioglitazone (PIO) versus placebo in patients with ICH (NCT00827892). Cardiac toxicity was evaluated with serial ECG.

Methods:
Patients enrolled into the Safety of Pioglitazone for Hematoma Resolution in ICH (SHRINC) trial were randomly allocated 1:1 to either placebo or PIO. Patients received escalating doses of PIO daily for 3 days (high-dose phase) beginning within 24 hours of symptom onset, followed by a 30mg maintenance dose for the duration of treatment. Serial ECGs were performed at baseline and on days 1, 2, 3 and 90. Zero inflated Poisson regression was used to model the relationship between treatment with PIO and the likelihood of observing new important ECG findings during the high-dose phase.

Results:
A total of 84 patients were enrolled in SHRINC (42 PIO, 42 placebo). At baseline, 60% of patients in both groups had important abnormal ECG findings, the most common being prolonged QT (Table 1a). During the high-dose phase, 51% in the PIO group and 46% in the placebo group developed at least one new important abnormal ECG finding (Table 1b). In multivariable analysis, after controlling for age, diabetes, baseline PTT, baseline systolic and diastolic blood pressure, PIO was not associated with the likelihood of developing any new important abnormal ECG findings, Rate Ratio 1.27, 95% CI (0.71, 2.28), p=0.42.

Conclusions:
ECG findings in this cohort of ICH patients were dynamic in the first 72 hours with most patients having abnormal ECGs at baseline and almost half of the cohort developing new findings. The addition of a placebo group allowed us to incorporate the natural history of ICH in our analysis to more clearly understand the effect of PIO. We did not find cardiac toxicity due to PIO as evidenced by ECG changes during the follow up period.
Abstract W MP117: Intracarebral Hemorrhage Volume Growth and Lipid Lowering Agent use: Pooled Analysis of Interact Studies
Authors: Priglinger Miriam L , Arima Hisatomi , Anderson Craig , Krause Martin ,   INTERACT Investigators
Published: July 2021

Background and rationale:
Despite several recent reviews of randomised trials, there remains controversy of the risks of intracerebral hemorrhage (ICH) associated with regular use of statins for prevention of cardiovascular disease, particular in populations with a high risk of ICH. We aimed to determine the risk of poor outcome and hematoma growth from use of lipid lowering agents among participants of the INTERACT substudies.

Design:
Pooled analyses of INTERACT 1 and 2, international, multicenter, prospective, open, blinded endpoint, randomized controlled trials, of patients with ICH (<6 hr) and elevated systolic BP (SBP 150-180 mmHg). Associations between lipid lowering treatment and clinical outcomes (n=3184) were estimated in analyses of co-variance. Digital images from CT substudies participants (n=1310) underwent blinded central analyses comparing measurements from standardized baseline and 24 hrs CTs. Associations between lipid lowering treatment and hematoma volume growth from baseline to 24 hrs were estimated in analyses of co-variance.

Results:
Among 204 patients (9%) with lipid lowering treatment at ICH onset, both death and dependency were higher after 90 days, but this was not significant with multivariable adjustment for baseline imbalances and confounding factors (p=0.783). In analysis of CT substudies, absolute ICH volume was larger among 124 patients (9%) with lipid lowering therapy compared to patients without prior therapy but again, multivariate-adjustment made this difference non-significant (9.2ml vs 6.8ml, p=0.13), with antithrombotic use being the main confounder.

Conclusion:
In the INTERACT studies, there was no association between lipid lowering use and adverse clinical outcomes.
Abstract W MP14: Detection of Early Ischemia Varies Extensively with Topography: Concurrent CT versus DWI ASPECTS
Authors: Liebeskind David S , Sheth Sunil A , Mehrkhani Farhad , Kamalian Shahmir , Scalzo Fabien , Johnson Mark S , Lev Michael H , Yoo Albert J
Published: July 2021

Background:
Numerous studies have compared CT with DWI ASPECTS, yet differences in timing between study acquisition may impart error or confound. We analyzed a large cohort of concurrently acquired CT and MRI to discern differences in regional variation in the ability to detect early ischemia.

Methods:
CT and DWI were acquired within 1 hour of each other during the first 8 hours after symptom onset and pooled from two large academic stroke centers for these analyses. Two raters independently scored CT ASPECTS and DWI ASPECTS at separate reading sessions. Modified DWI-ASPECTS (including only >20% per region) was also scored. Consensus readings were then utilized to compare regional ASPECTS across the 3 ASPECTS scales using the kappa statistic.

Results:
136 patients underwent both CT and DWI within 1 hour of each other in the setting of acute ischemic stroke. Regional involvement on DWI included caudate in 57%, lentiform in 73%, insula in 69%, internal capsule in 24%, M1 in 34%, M2 in 49%, M3 in 36%, M4 in 21%, M5 in 57% and M6 in 41%. The agreement between CT and DWI varied by region, from caudate kappa 0.616 (0.484-0.748), to lentiform 0.602 (0.457-0.748), insula 0.690 (0.558-0.822), internal capsule 0.374 (0.189-0.559), M1 0.583 (0.435-0.731), M2 0.515 (0.389-0.641), M3 0.421 (0.275-0.568), M4 0.453 (0.262-0.644), M5 0.388 (0.268-0.507) and M6 0.500 (0.366-0.634). Modified DWI-ASPECTS (>20% per region) and CT demonstrated overall better agreement, yet still markedly varied by region. In general, CT and DWI ASPECTS reveal good agreement in subcortical structures, whereas very limited agreement is noted in several cortical ischemic regions. Modified-DWI ASPECTS improves cortical agreement, yet remains poor in the internal capsule.

Conclusions:
Detection of early ischemia varies considerably depending on the location or topography depicted with either CT or MRI. Deep subcortical regions are best detected with either modality, whereas cortical regions exhibit marked distinctions. Modified DWI ASPECTS improves agreement with CT ASPECTS in cortical regions.
Abstract W MP18: NCCT ASPECTS Underestimates Infarct Core in Early Presenters with Poor Collateral Status
Authors: Yang Jun-Gyu , Hong Jeong-Ho , Kim Chang-Hyun , Chang Hyuk-Won , Menon Bijoy K , Sohn Sung-Il
Published: July 2021

Background and Purpose:
Noncontrast CT (NCCT) identifies early ischemic change that can predict irreversible ischemic injury. However DWI is more sensitive than NCCT in detection of early ischemic lesion. Our aim was to investigate the factors that influence discrepancy in early ischemic change detection between CT and DWI among good NCCT scan.

Methods:
We collected consecutive 167 ischemic stroke patients with occlusion of ICA and/or MCA M1 diagnosed by CTA and DWI within 6h of onset (last seen normal, LNT) between August 2004 and February 2013. Alberta Stroke Program Early Computed Tomography Score (ASPECTS) was used to evaluate discrepancy between lesions on NCCT and DWI MR. We identified 109 patients with a good NCCT scan defined as ASPECTS 6-10. Discrepancy between NCCT and DWI was when DWI ASPECTS was 0-5 and no discrepancy was when DWI ASPECTS was 6-10. Regional leptomeningeal collateral (rLMC) score by CTA was used to evaluate collateral status.

Results:
We reviewed 109 patients (mean age 67.5 ± 12.5 years) with median baseline National Institutes of Health Stroke Scale (NIHSS) 14 (interquartile range, 10-19). Discrepancy group (N=40, 36.7%) had shorter time from LNT to CT (median 98 vs 132 min, p=0.013), higher score of initial NIHSS (median 17 vs 13, p=0.013), lower rLMC score (median 10.5 vs 14, p<0.001). There was no significant difference from CT to DWI time (median 41 vs 40 min) between both groups. In a multivariable logistic regression analysis, time from LNT to CT (OR 0.99; 95% CI 0.99-1.00; P=0.05), rLMC score (OR 0.21; 95% CI 0.08-0.56; P=0.002) were independently associated with the discrepancy group.

Conclusion:
Discrepancy between CT and DWI is common in patients with acute anterior circulation ischemic stroke. This discrepancy is more apparent when patients present early and have poor collaterals.
Abstract W MP19: Diffusion-Weighted Imaging-Fluid-Attenuated Inversion Recovery Mismatch at 1.5T VS 3T MRI in Acute Ischemic Stroke
Authors: Seki Kenta , Koga Masatoshi , Sato Shoichiro , Homma Kazunari , Yoshimura Sohei , Miyazaki Yuichi , Nagatsuka Kazuyuki , Minematsu Kazuo , Toyoda Kazunori
Published: July 2021

Background and purpose:
Although the diffusion-weighted imaging (DWI)-fluid-attenuated inversion recovery (FLAIR) mismatch (DFM) can be a surrogate marker of stroke onset time, DFM at 3T MRI may represent different clinical implications from that at 1.5T MRI. We aimed to compare the prevalence of DFM between 1.5T and 3T MRI, and assess factors associated with the FLAIR lesion positivity, and analyze a sensitivity and a specificity of DFM to identify patients ≤ 4.5h of stroke onset.

Methods:
Consecutive patients with acute ischemic stroke who underwent 3T or 1.5T MRI including DWI and FLAIR ≤ 12h of onset were enrolled. Random allocation regarding the magnetic field strength was performed according to the MRI availability. More than two stroke neurologists judged whether there is DFM. We identified ischemic lesion corresponding to stroke symptom on DWI and then determined whether the FLAIR lesion positivity is negative, subtle (only slightly different from adjacent parenchyma) or evident (a clearly high signal). DFM was defined as the FLAIR negative or subtle corresponding to the DWI lesion.

Results:
Of 179 patients (women, 39%; 72±11 years) studied, 89 and 90 received 3T and 1.5T MRI, respectively. The median onset to MRI time (OMT) was 2.5h at both 3T and 1.5T MRI. The FLAIR positivity was negative in 51% at 3T vs. 30% at 1.5T, subtle in 22% vs. 27% and evident in 27% vs. 43%, respectively (p=0.015); thus DFM was identified in 73% vs. 57% (p=0.028). On ordinal logistic regression with backward stepwise selection, 3T MRI (OR 0.40, 95%CI 0.22-0.71) and infratentorial infarction (OR 0.29, 95%CI 0.12-0.68) were negatively, and OMT (per 1h, OR 1.18, 95%CI 1.07-1.30) was positively associated with the FLAIR lesion positivity. DFM ≤ 4.5h was more frequently observed at 3T than 1.5T MRI (80% vs. 60%, p=0.015). Using DFM, patients ≤ 4.5h of onset were detected with a sensitivity of 0.80, a specificity of 0.42, a positive predictive value of 0.77 and a negative predictive value of 0.46 at 3T MRI and 0.60, 0.53, 0.82 and 0.26, respectively, at 1.5T MRI.

Conclusions:
DFM was more frequently observed at 3T than at 1.5T MRI. Because the FLAIR lesion was associated with 1.5T rather than 3T, DFM at 3T may have different implications regarding time after stroke onset from that at 1.5T.
Abstract W MP23: Effect of Blood Pressure and Collateral Flow on Infarct Growth Rate
Authors: Oliveira-Filho Jamary , Pontes-Neto Octavio , Mehrkhani Farhad , Leslie-Mazwi Thabele M , Chaudhry Zeshan A , Shoamanesh Ashkan , Yoo Albert J , Wu Ona
Published: July 2021

Objectives:
To determine the effect of collateral flow and modifiable risk factors on infarct growth rate. Methods: Consecutive acute ischemic stroke patients admitted with witnessed-onset involving middle cerebral artery (MCA) stem (M1) occlusions underwent brain MRI before intra-arterial therapy. Admission CT angiography was graded for regional leptomeningeal collateral score (rLMC) and infarct volume was measured on diffusion-weighted MRI, both blinded to clinical data. Infarct growth rate was estimated as the ratio between admission infarct volume and time from symptom onset to MRI. Multivariable analysis was performed adjusting for age, sex, vessel occlusion location, smoking and arterial fibrillation. Results: We studied 98 patients over a 10-year period, age 66 +/- 17, median NIH Stroke Scale of 16. Most (36%) patients had isolated M1 occlusions, followed by M1/M2 segment occlusions (34%), M1/distal internal carotid (17%) and M1/distal carotid + anterior cerebral artery occlusions (12%). In the multivariable model, only admission systolic blood pressure (SBP) was significantly associated with infarct growth rate (6.3% lower infarct growth rate for every 10mmHg increase in SBP, 95% confidence interval = 0.3-12.1%, p=0.038). Collateral flow was associated with infarct growth rate among normotensive individuals (13% decrease in infarct growth rate for every 1 point increase in rLMC, 95% confidence interval = 3-23%, p=0.012), but not hypertensive individuals (p=0.019 for interaction). Conclusions: Infarct growth behavior is different between hypertensive and normotensive individuals. While acute high blood pressure is associated with decreased infarct growth rate in both groups, better collateral flow only limits infarct growth in normotensive individuals.
Abstract W MP33: Baseline Clinical and Infarct Characteristics as Predictors of Poor Outcomes in Patients Not Thrombolysed Due to Mild or Resolving Symptoms ("Too Good To Treat")
Authors: Ali Syed F , Siddiqui Khawja A , Cohen Abigail S , Ay Hakan , Singhal Aneesh B , Schwamm Lee H
Published: July 2021

Introduction:
A common reason for non-treatment of time eligible patients with IV tPA is mild symptoms in patients that are “too good to treat (TGTT)”. Several studies have reported poor outcomes in this group. We sought to identify patient and imaging characteristics associated with poor outcomes in this group.

Methods:
Using our institutional GWTG database, we analyzed 2,745 consecutive stroke admissions (01/2009 - 07/2013). Univariate and multivariable analysis were carried out to determine factors associated with the poor outcome of not being discharged home.

Results:
Of the total 2,745 patients, 306 (11.1%) presented within the window for IV tPA but did not receive the treatment due to symptoms too mild or rapidly improving. Of these, imaging characteristics were available in 238 patients. Among TGTT stroke patients, 62.6% were discharged home, 26.9% to IRF, 8.4% to SNF and 2.1% death/hospice. Patients with poor outcome were older, more often Hispanic, with more vascular risk factors, and higher NIHSS. Infarcts in both hemispheres, and in posterior+/- anterior circulation were more common with poor outcome. On multivariable analysis, increasing age, Hispanic ethnicity, higher NIHSS and bihemispheric stroke were associated with poor outcome, with a trend toward small vessel stroke subtype.

Conclusion:
A substantial percentage of patients deemed “too good” for IV tPA are still unable to be discharged home. Factors such as advanced age, higher NIHSS, bi-hemispheric infarction should be considered in tPA decision-making in potential TGTT patients. Large, multi-center prospective studies are needed to better identify potential biomarkers of poor outcomes in this group.
Abstract W MP45: RNA-seq Analysis of mRNA/miRNA in Rabbit Aneurysm Model Reveals Similar Expression Patterns to Human Intracranial Aneurysms
Authors: Holcomb Matthew , Ding Yong-Hong , Dai Daying , McDonald Robert , McDonald Jenniffer , Kallmes David , Kadirvel Ram
Published: July 2021

Background and Purpose:
Rabbit aneurysm models are used in the testing of embolization devices as well as elucidating the mechanisms human intracranial aneurysm growth and healing. We employed ribonucleic acid sequencing (RNA-seq) technology to identify genes relevant to induced rabbit aneurysm biology and compare these with genes related to human intracranial aneurysms to identify genes of potential clinical interest. This included sequencing micro RNA, which are important regulatory non-coding RNA.

Materials and Methods:
Elastase-induced saccular aneurysms were created at the origin of the right common carotid artery (CCA) in 5 rabbits. Messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA) was isolated from the aneurysm and the control unoperated left CCA at 12 weeks and was processed using RNA-seq technology. The results from RNA-seq were analyzed using Ingenuity Pathway Analysis.

Results:
9396 genes were analyzed using RNA-seq, of which 649 (6.9%) were found to be significantly differentially expressed between aneurysm and control tissues (p < 0.05, false discovery rate 2). Of these, 500 were up-regulated in the aneurysm and 149 were down-regulated as compared to controls. Using the same criteria, 3 miRNA were identified as down regulated and 5 were identified as up regulated. Pathway analysis associated these genes with inflammatory response, cellular migration, and coagulation, among other functions and pathologies.

Conclusion:
RNA-seq next-gen analysis of rabbit aneurysms shows similarities to human intracranial aneurysms with respect to regulation of some key pathways.
Abstract W MP46: Novel In Vivo Assessment of Unruptured Intracranial Aneurysm Inflammatory Factors: Prospective Analysis of Intra-Aneurysmal Serum Inflammatory Markers in a University Hospital
Authors: Cordina Steve M , Gerthoffer William , Martino Anthony , Wilson Russell , Naritoku Dean K
Published: July 2021

Background:
There are known correlations between intracranial aneurysm size as well as underlying demographic risk factors that lead to aneurysm rupture. The treatment of unruptured aneurysms is predicated on this, however selecting which unruptured aneurysms should be treated can be difficult. It is thought that formation, growth and eventual rupture of aneurysms is due to an underlying inflammatory process, which has been shown in pathological studies to exist within aneurysmal walls. The inflammatory milieu within a live aneurysmal sac and its implications for aneurysmal rupture is not currently known.

Objective:
To determine the presence of inflammatory markers within unruptured aneurysm sacs.

Methods:
We analyzed prospectively collected data from a database of patients who presented for unruptured aneurysm coil embolization over the span of 25 months to a University Hospital. These patients had blood samples withdrawn from the aneurysm sac immediately prior to coil embolization. This blood was sent for testing, with controls provided by blood sampled from the aneurysm parent vessel. Complement C3 and C4 levels from the aneurysm and parent vessel were then compared using column tables with paired t-test analysis.

Results:
A total of 8 patients were enrolled. The mean age (± SD) of treated patients was 68 (±15.3) years and 7 (87.5%) were women. 5 aneurysms (62.5%) were in the anterior circulation. Aneurysm size ranged from 5mm to 14mm, mean size 8.9mm (± 3.1mm). 5 patients (62.5%) were white while 7 patients (87.5%) had history of hypertension. C3 and C4 analysis showed a consistent decrease of complement values within the aneurysm as compared to the parent vessel. (For C3, mean of differences [MD] was 9.375, 95% confidence interval [CI] 5.56-13.19. For C4, MD was 1.500, 95% CI 0.50-2.50.)

Conclusion:
There is an observed decrease in complement values within unruptured aneurysms, suggestive of ongoing classic complement pathway activation. This supports the aneurysm inflammation model, which shows complement deposition in aneurysm walls. Our data suggests that this process is ongoing in live unruptured aneurysms and could be possibly targeted in future aneurysm trials. Further investigation is needed.
Abstract W MP48: Measurement of Intracranial Aneurysm Growth
Authors: Yu Qianyi , Yang Xin , Cheng Tim , Liang Feng , Chien Aichi
Published: July 2021

Purpose:
The aim of this study is to develop a method to accurately measure 3-D growth of intracranial aneurysms using geodesic active contours segmentation and gradient descent registration algorithms. The method is expected to generate fast and reliable indication of aneurysm growth in clinical settings.

Method:
The geodesic active contours algorithm was implemented to perform 3-D aneurysm segmentation. 3-D CT Angiography images of 10 subjects with follow up aneurysm images were included in this study. Each subject had images acquired at two distinct time points (average time interval: 126.8 ± 80.1 days). 5 subjects were known to have aneurysm growth between the two time points (growth group). The other 5 subjects were known to have stable aneurysm sizes between the two time points (non-growth group). Segmentation and registration algorithms were used on images from all 10 subjects in an attempt to reproduce the diagnosis results. This study also included 7 sets of computer-built 3-D models and dimensions, for the purpose of validation.

Result:
Based on segmentation results, the growth group showed an average 21.7 ± 10.2% increase in aneurysm volume, and non-growth group showed an average 0.2 ± 1.3% increase in aneurysm volume. The difference in sample means between the growth group and non-growth group was statistically significant (p ≤ 0.05). For subjects in the growth group, the registration algorithm was able to identify and to label the growing region. For validation, segmentation and registration algorithms were also used on 7 sets of computer built models; growth was correctly labeled. The average runtime for processing segmentation under 4th Generation Intel Core i7-4500U Processor (3.0GHz) was 31.7 ± 38.4 seconds, and 45.2 ± 40.3 for registration. Input images had Signal-to-Noise Ratio (SNR) within a range of 1.8 to 5.9.

Conclusion:
Geodesic active contours segmentation and gradient descent registration offer an efficient way of measuring and monitoring intracranial aneurysm growth. Further improvements in algorithms are expected to reduce runtime and numerical errors.
Abstract W MP52: Treatment With N-acetyl-seryl-aspartyl-lysyl-proline Improves Neurological Functional Recovery in Diabetic Middle Aged Rats After Embolic Stroke
Authors: Zhang Li , Chopp Michael , Zhang Yanlu , Xiong Ye , Eapen Anita , Rhaleb Imane , Zhang Zheng Gang
Published: July 2021

Background and Purpose:
Diabetes mellitus (DM) is a common metabolic disease among middle-aged and older populations, which leads to an increase of stroke incidence and poor stroke recovery. The present study investigated the effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) on stroke recovery in middle aged DM rats after embolic stroke.

Methods:
Male Wistar rats at age of 13 months were subjected to nicotinamide (NTM) and streptozotocin (STZ) injection
.
Rats with confirmed hyperglycemia status were subjected to embolic middle cerebral artery occlusion (MCAO) 30d after STZ-NTM injection. AcSDKP (2.4mg/kg) or saline were subcutaneously infused for 3d starting at 1d after stroke (n=12/group).

Results:
AcSDKP treatment significantly improved neurological functional recovery measured by adhesive removal test, foot-fault test, and modified neurological severity score starting at 21d after MCAO compared with saline treated rats. In addition, AcSDKP substantially reduced spatial learning deficits measured by the Morris water maze (41±4 vs 33±3% of time spent in the correct quadrant) 35d after MCAO. AcSDKP treatment significantly reduced vascular and parenchymal fibrin deposition (43±9 vs 92±11/mm
2
) in the ipsilateral hippocampus and peri-infarct corpus callosum (CC), which was associated with reduction of IL-1 receptor associated kinase-1(IRAK1) immunoreactive vessels (95±13 vs 47±11/mm
2
) 7d after MCAO (n=4/group). AcSDKP treatment did not reduce infarct volume, but robustly increased myelinated axonal density (14±4 vs 8±3% in hippocampus, 36±6 vs 27±7% in CC) and oligodendrocyte density (71±18 vs 46±16/mm
2
in hippocampus, 526±113 vs 394±107/mm
2
in CC) 35d after MCAO (n=8/group). In vitro, high glucose increased protein level of IRAK1 and NF-κB in primary cerebral endothelial cells, whereas AcSDKP suppressed high glucose-increased IRAK1 and NF-κB protein levels by 50%.

Conclusions:
AcSDKP promotes ischemic brain repair by reducing neurovascular damage in the hippocampus and white matter, which likely contributes improvement of neurological functional recovery in middle-aged DM rats. IRAK1/NF-κB signals suppressed by AcSDKP may be involved these processes.
Abstract W MP6: SAVER I: Superselective Administration of VErapamil during Recanalization in Acute Ischemic Stroke. A Phase I Feasibility Study
Authors: Fraser Justin F , Maniskas Michael E , Alhajeri Abdulnasser , Bix Gregory J
Published: July 2021

Large vessel occlusive ischemic stroke results in high rates of morbidity and mortality. While intravenous t-PA and intra-arterial (IA) thrombectomy are mainstays in acute stroke therapy, clinical outcomes lag significantly behind improving rates of acute revascularization. Thus, there is a critical need for a novel adjunctive therapy to reduce stroke burden and to improve outcome. Previous neuroprotective drug studies failed due to long intervals between symptom onset and drug administration, lack of concordant thrombolytic revascularization, and lack of targeted administration to the affected vessel. Through a retro-engineered mouse model of large vessel stroke allowing concomitant recanalization and selective intra-arterial (IA) administration we previously evaluated verapamil, a calcium channel blocker (CCB) that is already safely injected intra-arterially (IA) for vasospasm. In this clinically relevant model, verapamil was highly neuroprotective when combined with vessel recanalization. Based on this data, we conducted a single-institution Phase I study to evaluate the feasibility and safety of superselective IA verapamil (10mg) administration immediately following mechanical thrombectomy. We collected information about demographics, location of the occlusion, last known normal time, time to and recanalization. Evaluation of CTA collateralization was performed using a previously a published grading scale (Souza et al. AJNR. 2012). The primary endpoint was symptomatic intracranial hemorrhage (ICH) within 24 hours post-procedure as defined by the Interventional Management Stroke (IMS) III Trial (Broderick et al. NEJM. 2013). Patients were monitored and graded at 3 months with the modified Rankin Score (mRS). Of the enrolled patients, none had a significant ICH, and none died as a direct result of the procedure. Clinical outcome results for patients were encouraging, and warrant further study. These results will be used to support a Phase II dose selection study.
Abstract W MP62: Vitamin D Status, Cerebral Ischemic Susceptibility, and Post-stroke Outcome
Authors: Turetsky Anya , Goddeau Richard P , Henninger Nils
Published: July 2021

Background:
Prevalence of vitamin D insufficiency is high in western countries and low vitamin D has been associated with neurovascular injury. To better understand how vitamin D status affects cerebral ischemic susceptibility we assess whether low serum 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, is predictive of the ischemic infarct volume and whether it relates to a worse outcome.

Methods:
We retrospectively analyzed prospective consecutive acute ischemic stroke patients that were evaluated from January 2013 to January 2014 at a tertiary referral center. All patients (n=96) had MRI-proven acute ischemic stroke. Multivariable linear and logistic regression analyses were used to test whether vitamin D represents an independent predictors of infarct volume and poor 90-day outcome (modified Rankin Scale score of >2).

Results:
There was a significant inverse correlation between infarct volume and serum 25(OH)D concentration in patients with lacunar (r=-.438; p=0.025) as well as non-lacunar (r=-.399; p=0.001) infarcts. Patients with ≥30 ng/mL had smaller infarct volumes than those with <30 ng/mL (Figure). The association of 25(OH)D with ischemic infarct volume was independent of other known predictors of the infarct extent (p<0.001). After adjustment, lower vitamin D (trichotomized as ≥30 vs 29-20 vs <20 ng/mL) was associated with a poor 90-day outcome (OR 9.46, 95%-CI 1.90-47.11, p=0.006).

Conclusion:
Low vitamin D independently predicts larger infarct volumes and a poor outcome following ischemic stroke. Though causality remains to be proven, our results highlight the need to further explore vitamin D as a promising biomarker for cerebral ischemic vulnerability and potential target for stroke prevention.