bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract TMP104: Supporting People With Stroke in the Community Through Volunteering: An Innovative Collaboration Between Healthcare Professionals and General Public
Authors: Lo Suzanne H , Chau Janita P
Published: June 2021

Background and Purpose:
The recovery journey after stroke can be chronic and complicated. Studies found that stroke survivors had a lower self-efficacy in performing self-management. The purpose of this study was to explore the efficacy of supporting community-dwelling stroke survivors through volunteering by healthcare professionals and general public.

Methods:
The study was underpinned by Bandura’s constructs of self-efficacy and outcome expectation. A volunteer team of healthcare professionals and adult lay persons were recruited. Training manuals and a total of 10 scenario-based videos about home visiting and phone coaching respectively were developed. Training workshops were conducted for all volunteers. Practice sessions were conducted between the volunteers and stroke survivors. Semi-structured individual interviews were conducted with all volunteers about their experience of training, perceived challenges of volunteer services, and suggestions for improvement. The interviews were recorded and transcribed verbatim for thematic analysis.

Results:
A total of 13 volunteers (age range: 20-40 years) were recruited. Five were healthcare professionals (registered nurse or social worker). Four key themes were generated: (1) Continued community-based support to stroke survivors is crucial to address their chronic and complex physical and psychosocial challenges in recovery, (2) Collaboration between healthcare professionals and general public provided pragmatic and sustainable support to community-dwelling stroke survivors, (3) Support through home visiting and phone coaching was flexible and addressed the transportation problems common in stroke survivors, and (4) Psychosocial support was becoming more important in chronic stage of stroke recovery.

Conclusions:
The findings supported that collaboration between volunteer healthcare professionals and stroke survivors would provide an innovative and sustainable approach to support community-dwelling stroke survivors’ recovery in long term. The evidence will inform development and implementation of volunteer services and hence building community capacity to support recovery of stroke survivors.
Abstract TMP105: Location Does Matter: Comparing the Location of Blood Pressure Management in an Intensive Care Unit Setting
Authors: Siaron Kathrina B , Cortes Michaela , Venkatachalam Aardhra , Stutzman Sonja , Ahmed Khalid M , Olson Daiwai M
Published: June 2021

Background and Purpose:
Blood pressure (BP) management is a vital part of acute stroke care. Both over- and under-correction of BP are associated with increased morbidity and mortality. Non-invasive BP (NIBP) and intra-arterial BP (ABP) measurements are commonly used, yet both methods yield inconsistent results. Measurement error can hinder optimal clinical management in neurological conditions where BP directly affects cerebral perfusion pressures. Discrepancy in clinical decision-making associated with BP measurement is rarely reported. This prospective, non-randomized, cross-sectional study aims to address the gap by correlating simultaneous within-subject BP readings from multiple sites.

Methods:
NIBP was simultaneously measured from 4 sites (both arms, both wrists) and ABP (when available) in 80 intensive care unit subjects. Correlation matrices and repeated measures ANOVA were used to explore for differences in BP by measurement site.

Results:
Of 80 subjects, 41 were male, mean age = 52.8, and mean BMI = 30. Pearson Correlation Coefficients for SBP ranged from 0.67 to 0.83; DBP from 0.77 to 0.84; and MAP from 0.76 to 0.88. (Figure 1). SBP differences ranged from 0 to 57 mmHg and MAP differences ranged from 0 to 36 mmHg. One-way repeated measures ANOVA revealed significantly different values for SBP (p=0.0319); DBP (p=0.0002); and MAP (p=0.0001).

Conclusions:
BP values vary significantly when measured simultaneously in different sites. Unpredictable inter-site comparisons of BP warrant significant research in larger prospective trials. Nurses should consider standardizing a measurement site for consistent BP readings and better clinical decision-making.
Abstract TMP109: Cortico-Ponto-Cerebellar Structural Connectivity in Perinatal Stroke
Authors: Craig Brandon T , Hilderley Alicia , Carlson Helen , Kirton Adam
Published: June 2021

Introduction:
Perinatal stroke (PS) causes hemiparetic cerebral palsy and lifelong disability. As an early cerebrovascular injury, typically involving injury to motor systems, PS represents an ideal model for understanding motor system development. Emerging models demonstrate widespread network alterations but the role of the cerebellum is poorly defined. We used diffusion tractography to explore the development of the cortico-ponto-cerebellar (CPC) tract in children with PS, hypothesizing an association between non-dominant CPC diffusion metrics and motor ability.

Methods:
Retrospective, population-based, cross-sectional, controlled study. Participants aged 6-19 years with unilateral MRI confirmed perinatal arterial ischemic stroke (AIS; n=11) or periventricular venous infarction (PVI; n=20), and typically developing controls (TDC; n=31) had a 3T MRI including T1-weighted and diffusion imaging (32 directions; b=750s/mm
2
, 3 b0 volumes). Probabilistic tensor-based tractography was performed using the posterior limb of the internal capsule and contralateral middle cerebellar peduncle as regions of interest for seeding. Tensor-based outcomes were calculated including mean diffusivity (MD) and fractional anisotropy (FA). An asymmetry index (AI) was subsequently calculated (dominant / non-dominant values). PS participants completed motor assessments [Assisting Hand Assessment (AHA), Melbourne Assessment (MA), Box and Blocks Test (BBT)].

Results:
Paired-samples t-tests revealed MD was significantly higher for non-dominant versus dominant tracts across all groups (all p<0.001), while FA did not differ (all p>0.05). MD AI differed among groups (F(2,59)=10.117,
p
<0.001) such that MD AI was significantly lower (less symmetrical) in AIS (AI=0.912±0.04) compared to PVI (AI=0.960±0.05,
p
=0.01) and TDC (AI=0.977±0.03,
p
<0.001). FA AI did not differ between groups (F(2,59)=1.045,
p
=0.358). A positive association was observed between MD AI and BBT performance in the affected hand (r=0.439,
p
=0.019).

Conclusion:
CPC tractography in children with PS is feasible. Development of the CPC appears to be altered following perinatal stroke, the degree of which may relate to motor function.
Abstract TMP111: Risk Factors Associated With Watershed Stroke in Pediatric Patients Undergoing Fontan Operation
Authors: Duncan Jay , Tilley Jo A , Javed Mahnoor , Umejiego Johnbosco , Hamby Tyler , Acosta Fernando , Tam Vincent , Torres Marcela
Published: June 2021

Introduction:
Cardiac disease is one of the leading causes of stroke in children. In an effort to separate pulmonary and systemic circulations, patients with single ventricle physiology undergo the Fontan surgery. Watershed strokes have been reported as a complication of Fontan surgery but literature on its prevalence and associated risk factors is lacking.

Methods:
Retrospective review of records of patients who underwent Fontan operation at our center from 2007 to 2018. Demographic, clinical, imaging, and outcome data were documented for all patients. Key risk factors evaluated:cardiac diagnosis, presence of significant AV-valve regurgitation, poor ventricular function, cardio-pulmonary bypass (CPB) time, Hematocrits, mean arterial pressure (Map) and significance of post-operative resuscitation measured by cardiac index and vasoactive infusion score. Univariate logistic regression was used for analyses, and a p-value of <0.05 was considered statistically significant.

Results:
We identified 149 patients;14 (10%) had clinical evidence and radiographic confirmation of a watershed stroke. There were no arterial ischemic strokes.From all the variables analyzed (Table 1), patients with significant A-V valve regurgitation pre- and post-operatively, depressed single ventricular function, and underlying diagnosis of hypoplastic left heart syndrome (HLHS) were at a higher risk for watershed strokes. No other risk factors were identified. (Table 1). All had no significant motor deficits at discharge.

Conclusion:
At our center, watershed infarcts occurred in 10% of patients undergoing Fontan surgery. Cardiac disease diagnosis and factors associated to cardiac function were significant risk factors for watershed stroke rather than surgical related variables.
Abstract TMP113: Non-invasive Estimate of Intracranial Arterial Luminal Diameter in Children
Authors: Vaughan Jessica , Taylor Michael , Leach James L , Horn Paul , Vadivelu Sudhakar , Abruzzo Todd
Published: June 2021

Background:
Growth of the intracranial arteries facilitates the rapid increase in cerebral growth in the first 2 decades of life. In the age of cerebral endovascular treatment, many questions arise in the pediatric cohort regarding the safety and efficacy of these therapeutic approaches. Small arterial diameter may influence treatment selection in the very young, but to date little normative data is available to define vascular growth in infants and children.

Methods:
Subjects in this single-institution, retrospective cohort study were identified by MRI brain imaging keyword query as “normal” with age 0-18 years old at the time of the study. Medical records were reviewed to capture weight, length, and head circumference and exclude cerebrovascular or connective tissue disease risk factors. MRI T2-weighted images were measured to calculate the head circumference and arterial diameter in axial and coronal planes. A growth curve was created from the head circumferences and intracranial artery diameters to compare luminal caliber to age, sex and recorded growth parameters.

Results:
317 subjects (170 female, 147 male) are included in the analysis. Luminal diameter was observed to increase rapidly in all arterial segments over the first 3 years of life. Compared to weight and length, head circumference most closely correlated with arterial size. Head circumference growth is most rapid during the first 3 years, tracking closely with the rate of luminal growth. An example relationship between arterial diameter and head circumference is shown in Figure 1.

Conclusions:
This is the largest cohort of cerebral arterial luminal growth in childhood. We show that arterial diameter can be measured non-invasively on MRI brain and correlated to routinely measured growth parameters. A better understanding of normal arterial growth is essential to our treatment of cerebrovascular disease in children.
Abstract TMP114: Functional and Structural Network Reorganization in Higher-Order Language Following Neonatal Stroke
Authors: Emami Zahra , Dunkley Benjamin T , Westmacott Robyn , Robertson Amanda , Krishnan Pradeep , Bhathal Ishvinder , Moharir Mahendranath , MacGregor Daune , Pang Elizabeth W , Dlamini Nomazulu
Published: June 2021

Introduction:
Neonatal arterial ischemic stroke (NAIS) is a common form of pediatric stroke often affecting classical language areas in the brain’s left hemisphere. While children with NAIS can acquire basic language skills, adolescence typically reveals the emergence of deficits in higher-order language, such as syntactic language. The reorganization of functional and structural brain networks may provide insight into later-emerging language outcomes and serve as a biomarker in prognostication.

Methods:
A cross-sectional study of eight children with unilateral NAIS (5F; 12.3±3.3 years) and seven neurotypical children (2F; 13.4±2.7 years) was conducted. Participants listened to syntactically correct and incorrect sentences while magnetoencephalography was recorded, and task-related functional connectivity in the time window and frequency band of interest was determined. Structural connectivity between brain regions was investigated using DTI tractography, and language outcomes were assessed using neuropsychological tests.

Results:
An analysis of the syntactic language network (4-7 Hz, 1.2-1.4s) indicated that unlike the typical correlation between left-lateralized functional connectivity and language skill (
p
<0.01), good outcome in patients is correlated with bilateral frontal connectivity (p<0.01). Furthermore, patients exhibit a significant reduction in structural connectivity between the left and right supplementary motor area, compared with controls (
p
=0.007), and the bilateral structural connectivity of this region is positively correlated with measures of working memory and information processing (
p
=0.036).

Conclusions:
The preliminary results suggest that reorganization of functional networks towards bilateral connectivity may support language outcome following early stroke. The supplementary motor area’s role in coordination of interhemispheric functions and in information processing may position it as a key structural region in supporting the compensatory reorganization of functional networks underlying language. Ultimately, measures of functional and structural networks may be used as a prognostic tool for language development in pediatric stroke in order to improve long-term outcomes.
Abstract TMP116: Intracranial Hemorrhage Rate in Familial Cerebral Cavernous Malformation Patients
Authors: Zafar Atif , Nelson Jeffrey , McCulloch Charles E , Zabramski Joseph , Akers Amy L , Mabray Marc C , Hart Blaine , Morrison Leslie A , Kim Helen
Published: June 2021

Background:
Familial cerebral cavernous malformations (FCCM) is an autosomal dominant disease caused by mutations in three genes:
CCM1
,
CCM2
, or
CCM3
. FCCM patients typically present with multiple brain CCMs that can increase in number and size over time, and can cause intracranial hemorrhage (ICH) and other disabling symptoms, e.g., seizures, headaches, and deficits. Rates and predictors of ICH events in FCCM are not well described. The purpose of this study was to estimate ICH event rates and predictors in a cohort of FCCM patients followed prospectively.

Methods:
We collected baseline and follow-up data in 316 FCCM patients enrolled from 4 sites in the Brain Vascular Malformation Consortium CCM Project, including age, sex, race, CCM gene, CCM symptoms, and CCM burden (total and large CCMs>5mm) at baseline. We initially recruited
CCM1
patients with the Common Hispanic Mutation (CHM), and later expanded to include other genetic types. We performed Kaplan-Meier survival analysis to estimate ICH event rates after enrollment, censoring at date of first treatment, death or last follow-up, out to 10 years. Cox regression analysis was performed to estimate hazard ratios (HR) of predictors, adjusting for age, sex, and family.

Results:
The majority of patients were female (63%) and of Hispanic ethnicity (83%). CCM gene mutation was known for 82%; 98% had
CCM1
mutations (94% with CHM), 1%
CCM2
, and 1%
CCM3
. At enrollment, mean age was 39±20 years (range: 1-85), 32% had a history of ICH event, 38% had seizures, and 60% had headaches. Mean number of total and large CCMs was 55±103 and 4±7, respectively. Mean follow-up was 4.1±2.7 years. During 1285 person-years (PY) of follow-up, there were 31 ICH events for a rate of 2.4 per 100 PY (95% CI: 1.7-3.4) overall, 4.0 (2.5-6.6) in prior ICH patients, and 1.6 (1.0-2.8) in patients without prior ICH (HR=2.4, 95% CI: 1.2-4.9). ICH-free survival was not statistically significantly different by sex (HR=1.2, 95% CI: 0.6-2.8), age (HR=1.0 per decade, 0.8-1.2), total lesions (HR=1.2 per doubling, 0.9-1.5), or large lesions (HR=1.3 per doubling, 1.0-1.7).

Conclusions:
FCCM patients with prior history of ICH events are at higher risk for re-hemorrhage during follow-up. Additional studies are needed to identify predictors of ICH risk in FCCM.
Abstract TMP117: Subclinical Imaging Changes in Cerebral Cavernous Angiomas During Prospective Surveillance
Authors: Carrion-Penagos Julian , Polster Sean P , Zeineddine Hussein A , Fam Maged D , Girard Romuald , Koskimaki Janne , Lyne Sean , Romanos Sharbel , Zhang Dongdong , Srinath Abhinav , Cao Ying , Stadnik Agnieszka , Piedad Kristina , Awad Issam A
Published: June 2021

Introduction:
Studies on the natural clinical course of Cavernous Angioma (CA) have reported a <0.5% annual risk of symptomatic hemorrhage (SH). CAs, however, may undergo subclinical changes that can reflect lesional activity. We assess the frequency of asymptomatic hemorrhage or growth (AH) in CAs, and new lesion formation (NLF) during systematic longitudinal follow-up using magnetic resonance imaging (MRI), and correlate with prior SH.

Methods:
Patients with CA diagnosis were prospectively enrolled in IRB approved database from 09/2009 to 02/2019 (N=327). Imaging and clinical follow-up were recommended annually, or sooner with new symptoms. Patients with 1 or more CA with maximum diameter >4 mm on T2 MRI, not excised or irradiated, and 1 or more clinical/imaging follow-up were included (N=192). New AH and SH were assessed per prospectively articulated criteria, and rates were estimated per lesion-year and patient-year, and NLF in familial cases.

Results:
There were no demographic or disease confounders among cases included and excluded from the study cohort, except for higher rates of prior SH and greater prevalence of cases with solitary lesion excluded because of surgical treatment. Total follow-up was 410 patient-years (2539 lesion-years). During prospective follow-up, the rate of AH was higher than the rate of SH (12.9% vs. 7.5% per patient-year and 2.1% vs. 1.2% per lesion -year, p=0.02 and p=0.01 respectively). Patients presenting with SH in the prior year had higher rate of AH than those presenting incidentally or with seizures (19.83% and 8.2% per patient-year respectively; p=0.003). A higher rate of NLF on T2 (p=0.0002) and SWI (p=0.0004) was also observed in patients with prior SH compared to stable patients. After an AH, 3 of 6 sporadic patients with solitary lesion and only 2 of 28 familial cases with multiple lesions underwent surgical resection of the lesion with AH.

Conclusions:
Subclinical imaging changes are more common than SH during prospective follow-up of CAs. They are more common in patients presenting with prior SH, and likely reflect a more sensitive biomarker of CA instability. AH more likely provokes a surgical decision in cases with solitary lesion than in familial cases with multiple lesions.
Abstract TMP118: Clinical Outcomes of Surgical Resection After Stereotactic Radiosurgery Among Patients With Cerebral Arteriovenous Malformations
Authors: Bigder Mark G , Choudhri Omar , Gupta Mihir , Church Ephraim , Chang Steven , Han Summer , Do Huy , Marks Michael P , Steinberg Gary
Published: June 2021

Introduction:
Surgical treatment of arteriovenous malformations (AVMs), particularly higher grade lesions, can be aided by staged treatment consisting of stereotactic radiosurgery (SRS) followed by surgical resection in a delayed fashion. This strategy can be used to downgrade the AVM S-M grade, reduce blood flow through the AVM and often results in histopathological changes making AVMs more amenable to microsurgical resection. We present our 28-year clinical experience in managing AVMs with pre-operative SRS as a surgical adjunct.

Methods:
We retrospectively reviewed and analyzed records of all patients treated for cerebral AVMs between February 1991 and July 2019 at our institution. All patients that underwent SRS, with and without embolization, followed by microsurgery were included in the study. Of the 1245 cerebral AVM patients treated at our institution, 62 patients met eligibility criteria. Univariate and multivariate regression analysis was performed where appropriate to examine relationships between key variables and outcomes.

Results:
The majority of lesions (50%) were high grade (SM 4-5), 28.6% were intermediate (SM 3), while 21.4% were low grade (SM 1-2). Hemorrhage was the presenting sign among 22.6% of patients. Complete resection was achieved among 64.5%, 79% and 82% of patients after first, second and third surgical stages respectively; 16.1% of patients had partial resection requiring further treatment. Radiographic cure was achieved among 53 patients (85.5%), while 8 (12.9%) patients had residual AVM at last follow up. Six of 8 patients without radiographic cure received post-operative SRS. Thirty-seven patients (63.8%) had improved (26, 44.8%) or stable mRS scores (11, 19%), while 21 (36.2%) had a decline in mRS at final follow up compared to mRS at presentation; this includes 4 (6.9%) deaths due to hemorrhage, outside of the perioperative period, but occurring during follow up prior to AVM obliteration.

Conclusion:
SRS is a useful adjunct in the surgical management of cerebral AVMs. Multimodal therapy allowed for high obliteration rates with acceptable morbidity in this series of patients with predominantly high grade AVMs.
Abstract TMP120: Autoantigen(s) Trigger a Robust Immune Response in Cerebral Cavernous Malformations
Authors: Zhang Dongdong , Srinath Abhinav , Kinloch Andrew J , Shenkar Robert , Shen Le , Koskimaki Janne , Girard Romuald , Lightle Rhonda , Moore Thomas , Cao Ying , Penagos Julian C , Romanos Sharbel , Lyne Sean , Shi Changbin , Awad Issam A
Published: June 2021

Introduction:
Previous studies have reported robust inflammatory cell infiltration, selective synthesis of IgG, B-cell clonal expansion, and deposition of immune complexes and complement within Cerebral Cavernous Malformation (CCM) lesions. Furthermore,B-cell depletion has been shown to reduce the maturation of CCM in murine models. We hypothesize that specific autoantigen(s) within the lesional milieu trigger the pathogenetic immune responses in CCMs. This study aims to identify those putative autoantigen(s) using recombinant antibodies (rAbs) derived from plasma cells found in surgical human CCM lesions.

Methods:
CD138
+
plasma cells were laser captured from fresh frozen surgically resected human CCM lesions. Clonally expanded immunoglobulin heavy- and light-chain variable region pairs were cloned into IgG expression vectors and expressed as monoclonal antibodies. Purified rAbs were assayed by immunofluorescence with CCM lesion tissue and normal brain tissue sections. rAbs assayed by immunocytochemistry with human primary cell line were used to further define the staining pattern. The cell lysates were immunoprecipitated with rAb, after protein purification by SDS-PAGE, and analyzed by Mass spectrometry.

Results:
In normal brain tissue, rAbs stained endothelial cells with limited staining of glial cells. In CCM lesional tissue, rAbs stained endothelial cells, glial cells as well as structures in the acellular matrix adjacent to caverns. In cultured Human Brain Microvascular Endothelial Cells (HBMECs) and Human Astrocytes (HAs), rAbs co-localized with cytoplasmic components. After HBMEC and HA cell lysates were immunoprecipitated with rAb, a Coomassie Stain detected bands of approximately 50 kDa.

Conclusions:
Our results suggest that autoantigen(s) in human CCM lesions are cytoplasmic components present in lesional tissue as well as in normal brain tissue. Molecular level identification of the triggering antigen is still ongoing by mass spectrometry. Identification of the autoantigen(s) in the lesional milieu might explain the propensity of lesion development from leaky endothelium in the neuroglial parenchyma. Characterization of the autoantigen triggers will open new venues for therapy or vaccine in this disease.
Abstract TMP16: Standardized Iv- Thrombolysis Using Non-Contrast CT in Wake-Up or Unknown Onset Stroke
Authors: Kamal Haris , Barreto Andrew , Savitz Sean , Jagolino-Cole Amanda , Zha Alicia
Published: June 2021

Introduction:
Recent studies have shown that tPA can be safely administered beyond the standard 4.5hr window (
SW
) with good outcomes. However, patients were selected by multi-modal imaging, which is often unavailable outside of thrombectomy or comprehensive stroke centers (
CSC
). At our CSC, we developed a wake-up stroke (
WUS
) protocol based on a non-contrast CT. Safety and clinical outcomes are presented.

Methods:
Suspected ischemic stroke patients between 12/2015-12/2018 who received tPA at our CSC based on the WUS protocol (Table 1) were identified. Our group instituted this protocol in 2015 based on 10 yrs of previously published retrospective and prospective safety data. This protocol has been utilized to treat both WUS and unknown onset (
UKN
) patients. We compared baseline characteristics, tPA metrics, and outcome data between the SW and WUS/UKN patients. Symptomatic ICH (
sICH)
was determined by SITS-MOST criteria.

Results:
At our center, 643 patients received tPA. Of these, 49 (7.6%) received tPA using the WUS protocol. Baseline characteristics were similar except WUS/UNK patients were less likely to have prior stroke history and more likely to go for endovascular therapy (Table 2). WUS/UKN patients had a median ASPECTS of 9 (IQR 7, 10) and had a mean last known well to arrival time of 9hrs. Length of stay, good functional outcome (mRS 0-2), and complications including sICH were comparable between SW and WUS/UKN patients.

Conclusions:
tPA appears safe and is potentially associated with comparable functional outcomes for select patients based on a non-contrast CT alone. Further studies are needed in the majority of stroke centers without multi-modal imaging capability.
Abstract TMP26: Extracellular Vesicles and Myelin Plasticity After Cortical Injury in Non-Human Primates
Authors: Go Veronica , Sarikaya Deniz , Medalla Maria , Rosene Douglas , Buller Benjamin , Moore Tara
Published: June 2021

Introduction:
Our laboratory demonstrated that monkeys treated after cortical injury with extracellular vesicles (EVs) derived from Mesenchymal Stem Cell (MSC) had enhanced recovery compared to controls. To identify the EV-mediated neuroplastic changes involved in improved recovery, we assessed markers of myelin damage and plasticity in brain and cerebrospinal fluid (CSF) of monkeys treated with EVs or vehicle.

Hypothesis:
MSC derived EVs enhance behavioral plasticity by reducing the post injury cascade of myelin damage and stimulating remyelination.

Methods:
Monkeys were given a unilateral cortical injury in the hand representation of M1. EVs were delivered IV 24 hours and 14 days later. Monkeys were tested on motor tasks for 14 weeks, and brains were harvested at completion. To quantify myelinated axons, we first used Spectral Confocal Reflectance (SCoRe) microscopy. To assess myelin damage, we measured accumulation of Myelin Basic Protein (MBP) in CSF from 24 hours to 14 weeks after injury. To assess myelin related gene expression changes, we used qPCR to assess MBP, BCAS1 as a marker of oligodendroglia engaged in new myelination, and Myelin Regulatory Factor (MyRF) a marker of oligodendrocyte regulation and differentiation. Additionally, we used IHC and stereology to quantify densities of BCAS1 and CC1 positive oligodendroglia.

Results:
Preliminary results show that EV treatment is associated with greater density of myelinated axons. In addition, longitudinal MBP levels in CSF gradually declined over 6 weeks, suggesting that EV treatment limited ongoing damage . PCR studies of perilesional brain tissue demonstrated a 4-fold increase in MyRF, as well as a 1.5-fold increase for BCAS1 and MBP in EV-treated monkeys relative to vehicle. Finally, increased densities of CC1+ and BCAS1+ cells approached significance in EV treated subjects.

Conclusions and Future Directions:
Our data suggests that MSC-EVs likely reduce the post injury cascade of myelin damage and promote remyelination, thus enhancing plasticity.

(Supported by R21-NS102991 & R21-NS111174).
Abstract TMP27: Par1 Mediates Protective Effect of 3K3K-APC After White Matter Stroke in Mice
Authors: Huuskonen Mikko T , Wang Yaoming , Montagne Axel , Dai Zhonghua , Nikolakopoulou Angeliki M , Lazic Divna , Sagare Abhay , Griffin John H , Zlokovic Berislav V
Published: June 2021

3K3A-APC is a recombinant variant of activated protein C (APC) with > 90% reduced anticoagulant activity but preserved cell signaling activity. Benefical effects are mediated by its antiapoptotic direct neuronal protective and vasculoprotective effects including protection of blood-brain barrier (BBB) integrity as well as anti-inflammatiory activity as shown in multiple animal models of large ischemic stroke (middle cerebral artery occlusion) and neurodegeneration. These preclinical studies led to a successfully completed phase II clinical trial of 3K3A-APC for ischemic stroke (RHAPSODY). RHAPSODY trial showed that 3K3A-APC is safe and may reduce hemorrhage in patients that were treated with tPA and/or thrombectomy standard of care therapy for stroke. Even though the protective effects of 3K3A-APC are well known to be mediated by biased signaling via protease activated receptor 1 (PAR1) activation, the role of PAR1 has not been studied in ischemic white matter stroke. In the present study, we used a mouse model of white matter stroke induced by injecting a vasoconstrictor
N
5
-(1-Iminoethyl)-L-ornithine (L-NIO) into the corpus callosum. Our results suggest that 4 hrs post-treatment with 3K3A-APC (0.2 mg/kg) reduced lesion volumes by about ~67% (cresyl violet staining and T2w MRI), which was associated with reduced BBB leakage (fibrinogen staining and DCE-MRI), and improved function of oligodendrocytes (OLS, Olig2+CNPase+) and oligodendrocyte precursor cell (OPCs, Olig2+PDGFRα+) at 1 and 7 days after stroke. Beneficial effects of 3K3A-APC were associated with reduced axonal damage on diffusion tensor MRI, and improved behavioral performance on adhesive removal and grid walking tests. We next showed that PAR1 is expressed in all major cell types in the white matter (e.g., OLS, OPCs, microglia and astrocytes) and that silencing PAR1 with small interfering RNA (siRNA) abolishes the protective effect of 3K3A-APC in this model. Taken together, our data suggest that 3K3A-APC is protective in ischemic white matter disease via PAR1 mediated signaling, which improves oligovascular integrity and neuronal survival.
Abstract TMP31: A Novel Shift of Notch Ligand, Dll4, Expression From Endothelial to Glial Cells in the Post-Stroke Brain May Contribute to Reparative Angiogenesis and Improved Functional Outcome
Authors: Kim Gab Seok , Stephenson Jessica M , Wu Ting , Gross Monica G , Herman Alexander M , Gutierrez Manuel C , Wythe Joshua D , Marrelli Sean P
Published: June 2021

Delta-like 4 (Dll4) is a Notch receptor ligand classically thought to be expressed exclusively in endothelial cells. However, little is known about the cellular expression or functional role of
Dll4
following ischemic stroke. Here, we present novel findings that
Dll4
expression is shifted from endothelial cells to glial cells in the sub-acute stroke phase.

Method:
The permanent distal middle cerebral artery occlusion (dMCAO) model was performed to induce stroke. To investigate expression patterns of Dll4 protein and mRNA, immunostaining as well as single-cell RNA sequencing and single-cell fluorescent
in situ
hybridization were performed. To verify the role of endothelial
Dll4
, tamoxifen-inducible, endothelial-specific
Dll4
KO mice (Dll4iecKO) and
Dll4
fl/fl (“floxed-only”) female mice (3 mos) were injected with tamoxifen (n=4) at 24 and 48 hrs post-stroke. To determine the effect of Notch inhibition at different time points, DAPT (100 mg/kg) or vehicle was administered at 24 or 72 hours post-stroke (n=4-5). Behavioral tests (foot fault) were conducted at Post Stroke Day (PSD) 1, 3, 7, and 14 and functional angiogenesis was assessed at PSD 14.

Results:
Elevated expression of Dll4 protein was observed in the microvasculature of the peri-infarct cortex (piCtx) as early as PSD 1. By PSD 3, however, we discovered
Dll4
expression in microglia within the piCtx, with robust expression by PSD 14. Post-stroke deletion of endothelial
Dll4
resulted in significant improvement in neurological function and increased capillary density in piCtx[l1] . DAPT given at 24 hours post-stroke improved outcome and capillary density; however, DAPT given at 72 hours (when microglia
Dll4
expression is evident) appeared to worsen outcome.

Conclusions:
After stroke, expression of
Dll4
shifts from exclusively endothelial (PSD 1) to mixed endothelial/microglial (PSD 3) to primarily microglial (PSD 14). Notch inhibition beginning at 24 hours post-stroke or endothelial-only deletion of
Dll4
leads to increased angiogenesis and improved functional recovery. In contrast, Notch inhibition initiated at 72 hours post-stroke leads to worse outcome[l2] . These findings suggest a potential novel role of microglia in supporting reparative angiogenesis through Dll4/Notch signaling.
Abstract TMP37: The Biomakers Expression Following Reperfusion After Carotid Artery Stenting
Authors: Guo Fuqiang
Published: June 2021

Objective:
This study was to demonstrate the biomarkers (NSE,MMP9,S100B,HO-1,CO) in serum for their correlation with reperfusion after carotid artery stenting (CAS).

Methods:
In this study, a total of 44 patients who were diagnosed with carotid artery stenosis (symptomatic/ asymptomatic stenosis≥70%) by Digital Subtraction Angiography (DSA) and underwent CAS successfully, were selected as the operation groups. The patients’ blood samples were collected at three different time points: T1, prior to operation; T2, next morning after operation (24 hours); T3, three days after operation (72 hours); The second group of 30 patients, who were excluded for carotid artery stenosis by DSA, were assigned to be the control group; Blood samples of these patients were collected at T1. The concentrations of NSE, S100B, MMP9, HO-1 and CO in serum from patients of both groups were detected by ELISA.

Results:
(1) There was no significant difference between the control group and the operation group at T1 (P>0.05) on their concentrations of NSE, S100B, MMP9, HO-1 and CO in the serum. (2) All of the operations were implanted in stents successfully without complications and the reperfusion improved after CAS. The concentrations of NSE, S100B, MMP9 and CO in the serum decreased gradually.(T1: 378.53±187.74MU/ml, 20.04±9.27ng/ml, 3.28±1.62ng/ml, 2.21±1.98umol/l respectively; T2: 302.65±160.46MU/ml, 16.45±8.95ng/ml, 2.81±1.63ng/ml, 1.49±1.10umol/l respectively, T1 vs T2: P<0.01; T3: 280.60±159.22MU/ml, 12.62±8.32ng/ml, 2.59±1.55ng/ml, 1.22±1.04umol/l respectively,T1 vs T3: P<0.01). (3) The serum concentrations of HO-1 in the T2 increased when compared with T1 (P<0.05) and obviously increased in the T3 when compared with T1 (P<0.01).

Conclusions:
We concluded that the concentrations of NSE, S100B, MMP9 and CO in serum decreased with the improvement of cerebral reperfusion after CAS. NSE, S100B, MMP9 and CO can be used as biomarkers to evaluate the improvement of reperfusion after CAS. What’s more, the changes of HO-1 after CAS may be associated with hyper-perfusion syndrome.

Key words:
NSE; S100B; MMP9; CO; HO-1;reperfusion; carotid artery stenting
Abstract TMP46: Fostering Eating After Stroke (FEAST) Trial: A Randomized Controlled Trial of Non-Invasive Brain Stimulation for Improving Dysphagia After Stroke
Authors: Kumar Sandeep , Marchina Sarah , Langmore Susan , Pisegna Jessica , Wang Na , Palmisano Joseph , Massaro Joseph , Lioutas Vasileios-Arsenios , Schlaug Gottfried
Published: June 2021

Background:
Effective therapy for dysphagia recovery after stroke is currently lacking. We conducted a phase-2 RCT to investigate the effects of anodal transcranial direct current stimulation (atDCS) in reducing aspiration risk, improving diet, and analyzed its safety in the acute-subacute stroke phase.

Hypothesis:
Since swallowing has bi-hemispheric representation targeted atDCS to the unaffected hemisphere combined with swallowing exercises may improve dysphagia from a unilateral hemispheric infarction [UHI].

Methods:
This phase-2, double-blind, RCT enrolled subjects with dysphagia [penetration and aspiration (PAS) score ≥ 4], from an acute-subacute UHI [day 2-day 6 after stroke onset] and randomized them into 3 groups: low-dose atDCS [2 mA atDCS alternating with sham twice daily], high-dose atDCS [2 mA atDCS twice daily] or sham [twice daily]. All sessions were performed with standardized swallowing exercises for 20 minutes over 5 days. Major safety outcomes were incidence of seizures, worsening of neurological and swallowing functions and mortality; primary efficacy outcome was a change in PAS scores between day 1 and 5 of intervention; main dietary outcome was a change in dietary intake at 1 month using the Functional Oral Intake scale (FOIS).

Results:
Of the planned 99 subjects, 42 could be enrolled in the funding period. No group differences in pre-defined safety outcomes were observed. Mean (SD) change in PAS score from baseline to final session was -0.8 (±1.6) in sham, -0.8 (±1.5) in low-dose and -0.4 (±1.2) in high dose groups. Adjusting for baseline PAS, NIHSS scores and age, means (SE) were -0.96 (0.33) in sham, -0.81 (0.36) in low-dose and -0.34 (0.35) in high dose; there were no significant pairwise differences (p>0.40). Mean (SD) changes in FOIS scores from baseline to 1 month were: 2.1 (±1.7) in sham, 2.5 (±1.7) in low-dose and 2.9 (±1.2) in high dose. Adjusted means (SE) were 2.07 (0.35) in sham, 2.46 (0.38) in low dose and 3.05 (0.38) in high dose (pairwise p > 0.15).

Conclusion:
Application of atDCS to the unaffected hemisphere is safe in the acute-subacute stroke phase but did not decrease aspiration risk in this phase-2 RCT. Higher doses of atDCS were associated with better dietary scores but group differences were not statistically significant.
Abstract TMP50: Antihypertensive Medication Trends Among Individuals With History of Stroke and Hypertension: The National Health and Nutrition Examination Survey (NHANES) 2005 - 2016
Authors: Santos Daniel , Dhamoon Mandip S
Published: June 2021

Background:
Hypertension (HTN) is a well-established, modifiable stroke risk factor. National HTN management trends among stroke survivors may provide important insight into secondary preventive treatment gaps. We investigated the adequacy of blood pressure (BP) control among stroke survivors and national antihypertensive (ATH) treatment trends.

Methods:
The National Health and Nutrition Examination Survey (NHANES) is a large, nationally representative cross-sectional survey conducted in 2-year cycles in the U.S. Evaluations include interviews, medication lists, physical examinations, and blood samples. We included participants aged >=20 years with HTN and history of stroke from 2005 to 2016. HTN was defined by self-report, ATH use, or uncontrolled HTN (BP >140/90) on physical examination. ATH medications were classified into calcium channel blockers, beta blockers, diuretics, and ACE inhibitors/angiotensin receptor blockers (ACE/ARBs). We report weighted frequencies and means using NHANES methodology, estimating the proportion of those with stroke with HTN. For all other analyses we examined those with stroke and HTN, summarizing number and classes of ATH, frequency of uncontrolled HTN, and associations between ATH classes and BP control. We examined trends in ATH use over time.

Results:
Among an estimated 6.4 million adults with history of stroke from 2005-2016, 78.2% had HTN but only 69.6% reported having been prescribed ATH medication. Among those with history of stroke and HTN (n=4971136), 37.1% (33.5-40.8%) had uncontrolled HTN on examination with 80.4% taking ATH. Most commonly used ATH medications were beta blockers (43.8%, 40.3-47.3%) and diuretics (41.5%, 37.2-45.8%). ATH classes associated with uncontrolled HTN included ACE/ARB (56.0%) and beta blockers (42.6%). Examining trends over time, diuretics have become less commonly used (49.4% in 2005-2006 vs. 35.7% in 2015-2016) whereas other classes remain more constant.

Conclusion:
Using a national survey, we found significant under-treatment of HTN in those with history of stroke, and >1/3 had uncontrolled HTN. Since HTN is a major stroke risk factor, this data demonstrates a significant missed opportunity nationally for secondary stroke prevention.
Abstract TMP54: A VA Observational Study Examining the Benefit of Various Post-Ischemic Stroke/Tia Hypertension Goals in Preventing Recurrent Vascular Events
Authors: Sico Jason J , Hu Xin , Myers Laura , Arling Greg , Bravata Dawn
Published: June 2021

Introduction:
Joint National Committee (JNC)-8 goal blood pressure (BP) recommendation of < 140/90 mmHg has been supplanted by 2017 ACC/AHA goal of < 130/80 mmHg for patients with ischemic stroke/TIA. Understanding the potential benefit in preventing recurrent vascular events for patients reaching ACC/AHA BP goals is necessary to inform clinical care.

Methods:
This is a retrospective cohort of Veterans with stroke/TIA (N=39,053) who received their longitudinal outpatient primary care within a Veterans Administration Medical Center between 10/2014 and 9/2018. Patients were excluded (n=25,381) if they had missing or physiologically improbable BP values, died, or had less than 1 year of follow-up. Vascular events were defined as cerebrovascular-only, cardiovascular-only, and the composite of each. We calculated average SBP during 90 days after discharge and assessed it in categorical form (≤115 mmHg, 106-115 mmHg, 116-130, mmHg, 131-140 mmHg, and >140 mmHg) and continuous form. Multivariate COX proportional hazard regression was used to examine the relationship between average SBP groups and time to recurrent event 90 days after discharge up to 1 year. In multivariate logistic regression, we used continuous SBP along with its quadratic term to predict 1-year recurrent vascular event rates.

Results:
A total of 12,337 eligible patients were included in the final analysis. Compared to those with SBP > 140 mmHg, patients reaching ACC/AHA BP goal had significant lower risk of cerebrovascular recurrent events (HR=0.77, 95% CI=0.60-0.99) but not cardiovascular recurrence or both combined.

Conclusions:
In considering BP reached by 90-days, ACC/AHA BP guidelines showed protective effects on cerebrovascular event recurrence only.
Abstract TMP56: Prediction of Primary Stroke: A Secondary Analysis of the SPRINT Trial
Authors: de Havenon Adam H , Goldstein Eric , Lyden Stephanie , Majersik Jennifer
Published: June 2021

Background:
The Systolic Blood Pressure Intervention Trial enrolled patients aged 50 or older with at least one cardiovascular disease risk factor, but free of prior symptomatic stroke. Patients were assigned to two blood pressure reduction goals (<140 versus 120 mm Hg). There was not a significant difference in the rate of stroke, making this an ideal cohort to refine risk prediction of primary stroke, which is understudied in patients with adequate blood pressure control and a rigorously adjudicated outcome of stroke.

Methods:
The primary outcome is ischemic stroke. We fit Cox models to the primary outcome and evaluated all baseline demographic variables to determine which would be most predictive of stroke, which we then used to create a prediction score.

Results:
We included 9,361 patients with a mean (SD) age of 67.9 (9.4) years and 171 (1.8%) patients met the primary outcome of stroke. For our prediction model, we gave one point each for history of TIA, atrial fibrillation, congestive heart failure, or diabetes. Patients with 2 or more points were collapsed, making three possible scores of 0, 1, and 2, which had rates of stroke of 1.5% (117/8042), 3.2% (30/933), and 6.2% (24/386) (p<0.001). Compared to a score of 0, the hazard ratios for stroke of score 1 and 2 were 2.3 (95% CI, 1.6-3.5) and 4.6 (95% CI, 2.9-7.1) (both p<0.001) (Figure 1).

Conclusion:
A simple scoring system can improve prediction of ischemic stroke from 1.8% to 6.2% in patients with no prior history of stroke and excellent blood pressure control. This information could be used to improve patient selection for clinical trials or for identifying patients for more aggressive primary prevention strategies.
Abstract TMP57: The Influence of Telomere Length on Ischemic Stroke Risk and Phenotype
Authors: Yetim Ezgi , Topcuoglu Mehmet A , Yurur Kutlay Nuket , Tukun Ajlan , Oguz Kader K , Arsava Ethem M
Published: June 2021

Background:
Telomeres are specific nucleotide repeats that play a central role in control of DNA damage related to cell division and aging. The degree of telomere shortening that occurs as part of aging is associated with age-related non-cancer diseases like hypertension, diabetes mellitus and coronary artery disease. Although a number of studies have highlighted that a similar relationship might exist with ischemic stroke, contradictory reports are also present in the literature. In this study we investigated the association between telomere length and ischemic stroke, not only in terms of stroke risk in general, but also from the perspective of stroke etiology and severity.

Methods:
In a Caucasian cohort, telomere length was determined by Southern blot from peripheral blood leukocytes in 163 consecutive ischemic stroke patients, and 210 controls without any prior history of ischemic stroke. Univariate and multivariate analyses were performed to determine the contribution of telomere length to stroke risk, stroke etiology, admission NIHSS score and DWI lesion volume.

Results:
The median (interquartile range) telomere length was 7.0 (5.5-9.0) kb in the overall population. Expectedly, telomere length was negatively correlated with aging (r=-0.23; p<0.001). A short telomere length (i.e. lowest quartile; ≤5.5 kb) was significantly associated with ischemic stroke (OR 3.0, 95%CI 1.8-5.1) when adjusted for age, gender and cardiovascular risk factors. This significant relationship persisted for all stroke etiologies, except for other rare causes of stroke. There was no significant relationship between admission lesion volume and telomere length; however, patients with short telomeres presented with more severe strokes (NIHSS score ≥16) when adjusted for age, risk factors, stroke etiology and infarct volume (OR 7.0; 95%CI 1.7-28.7).

Conclusion:
Almost all etiologic subtypes of ischemic stroke are related to shortened telomere length, irrespective of the age of the subject. Furthermore, presence of short telomeres negatively influences the tolerance of brain to ischemia, thereby causing more severe clinical phenotypes in these patients in the setting of ischemic stroke.