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Background and Purpose: Antiphospholipid syndrome (APS) is one of the uncommon causes of ischemic stroke, and is associated with young and female patients. However, the significance of antiphospholipid antibody (aPL) in older ischemic stroke patients is uncertain. We aimed to examine the significance of aPLs in ischemic stroke in these older patients., Materials and Methods: A total of 739 patients with acute ischemic stroke within 7 days of initial symptoms were collected consecutively. Clinical and laboratory data were obtained from medical records. aPLs (lupus anticoagulant, anti-cardiolipin antibody, anti-β2glycoprotein-I antibody) were measured the day after admission and the presence of at least one antibody was regarded as positive aPL. Patients with positive aPL were rechecked after at least 12 weeks for confirmation of APS., Result: Of the 739 patients, 103 (13.9%) had at least one aPL initially. These patients were older, had more atrial fibrillation and higher levels of inflammatory markers. Among the 103 aPL positive patients, 41 remained positive at 3 months, 23 showed negative conversion, and 39 were not available for follow-up. Patients diagnosed with APS had higher numbers of aPL and had specifically anti-β2glycoprotein-I IgG antibody. The patients with aPLs did not differ significantly from the others in terms of stroke subtype., Conclusion: aPL was rather common in ischemic stroke patients regardless of age. Although the influence of transient positive aPL on ischemic stroke remains uncertain, two or more aPLs and the presence of anti-β2glycoprotein-I IgG may predict a diagnosis of APS.

Background: Atherosclerosis of the internal carotid artery (ICA) is an important cause of ischemic stroke. Artery-to-artery embolism is the major stroke mechanism in patients with atherosclerotic carotid disease. This study hypothesized that the atherosclerotic ICA geometry and plaque location would be associated with lesion pattern in patients with acute ischemic stroke., Methods: Ischemic stroke patients with symptomatic proximal ICA disease (> 50% diameter stenosis) were enrolled. The carotid plaque location was divided into high-apical and low-body types. The geometric parameters of the ICA (angles between arteries) were measured, and ischemic lesion patterns were classified according to the number, location, and size of the lesions. Factors associated with plaque location and lesion pattern, dichotomized by size, were investigated., Results: Of the 93 acute ischemic stroke patients enrolled, 31 had high-apical and 62 had low-body plaques. Hyperlipidemia was more prevalent and the common carotid artery (CCA)-ICA angle was wider (167.7 ± 10.4° vs 162.3 ± 9.8°, p = 0.019) in patients with low-body than high-apical plaques. Low-body plaques were more frequently associated with small scattered or cortical lesions (54.8% vs. 32.3%, p = 0.040), whereas high-apical plaques were more frequently associated with large lesions having additional lesions (38.7% vs. 11.3%, p = 0.002). The presence of low-body plaques (odds ratio: 3.106, 95% confidence interval: 1.105-8.728, p = 0.032) was independently associated with the small lesion-only pattern., Conclusions: Low-body plaques are more frequently associated with small scattered lesions, whereas high-apical plaques are more frequently associated with large lesions having additional lesions. A wide CCA-ICA angle is associated with low-body plaque of the carotid artery.

Objective: Otaplimastat is a neuroprotectant that inhibits matrix metalloprotease pathway, and reduces edema and intracerebral hemorrhage induced by recombinant tissue plasminogen activator (rtPA) in animal stroke models. We aimed to assess the safety and efficacy of otaplimastat in patients receiving rtPA., Methods: This was a phase 2, 2-part, multicenter trial in stroke patients (19-80 years old) receiving rtPA. Intravenous otaplimastat was administered <30 minutes after rtPA. Stage 1 was a single-arm, open-label safety study in 11 patients. Otaplimastat 80 mg was administered twice daily for 3 days. Stage 2 was a randomized, double-blind, placebo-controlled study involving 69 patients, assigned (1:1:1) to otaplimastat 40 mg, otaplimastat 80 mg, or a placebo. The primary endpoint was the occurrence of parenchymal hematoma (PH) on day 1. Secondary endpoints included serious adverse events (SAEs), mortality, and modified Rankin scale (mRS) distribution at 90 days (clinicaltrials.gov identifier: NCT02787278)., Results: No safety issues were encountered in stage 1. The incidence of PH during stage 2 was comparable: 0 of 22 with the placebo, 0 of 22 with otaplimastat 40 mg, and 1 of 21 with the 80 mg dose. No differences in SAEs (13%, 17%, 14%) or death (8.3%, 4.2%, 4.8%) were observed among the 3 groups. Three adverse events (chills, muscle rigidity, hepatotoxicity) were judged to be related to otaplimastat., Interpretation: Intravenous otaplimastat adjunctive therapy in patients receiving rtPA is feasible and generally safe. The functional efficacy of otaplimastat needs to be investigated with further large trials. ANN NEUROL 2020;87:233-245., (© 2019 American Neurological Association.)

Background: Peripheral arterial disease (PAD) is an advanced form of atherosclerosis defined by an abnormal ankle-brachial index (ABI). However, the ABI provides no information about the location of atherosclerosis. We investigated the clinical implication of PAD confirmed using lower-extremity ultrasonography (LEUS), with consideration of the atherosclerosis location., Methods: Patients with acute ischemic stroke who underwent LEUS were enrolled. Patients with PAD were further divided into those with PAD at the proximal (above-popliteal artery, PADP) and distal (below-tibialis artery, PADD) segments. The clinical outcome was compared between patients with and without PAD, and between PADP and PADD. The atherosclerosis location in the cerebral artery was also compared between groups., Results: Among 289 patients, PAD was observed in 108 (37.4%) patients (43 had PADP and 65 had PADD). Patients with PAD were slightly older (P < .001) and had more significant carotid artery stenosis (30.6% versus 12.7%, P < .001) than those without. Patients with PAD had poor 3-month functional outcome than those without (modified-Rankin Scale score: 3 [interquartile range, 1-4] versus 2 [1-3], respectively, P = .003). Diabetes, high-stroke severity, and the presence of PADP (odds ratio, 3.893; 95% confidence interval, 1.454-10.425; P = .007) were independently associated with poor functional outcome at 3 months. Patients with PADP showed higher prevalence of extracranial stenosis than those with PADD (41.9% versus 23.1%; P = .038)., Conclusions: Our study suggests that subclinical PAD, especially PADP, is associated with poor functional outcome at 3 months after stroke onset. Interestingly, the location of cerebral atherosclerosis differed according to the location of PAD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Though several neuroprotective agents have been evaluated as potential treatments for acute ischemic stroke, none have demonstrated a definitive treatment efficacy, which remains elusive. HT047 is an herbal extract of Scutellaria baicalensis and Pueraria lobata, both of which have been widely used to treat ischemic stroke in traditional Korean medicine. The aims of this trial are to investigate whether HT047 can improve neurologic status, particularly motor function, in acute ischemic stroke patients, and to determine the safety of HT047., Methods: A multicenter, double-blind, randomized, placebo-controlled, 3-arm parallel group, phase II trial will be conducted in patients who have had an acute ischemic stroke within the past 14 days. The participating patients must have a Fugl-Meyer assessment (FMA) motor score ≤55, with arm or leg weakness, and Korean version of the National Institutes of Health Stroke scale (K-NIHSS) score of ≥4 and ≤15. Seventy-eight participants will be randomized in a 1:1:1 ratio and given high-dose HT047 (750 mg 3 times a day), low-dose HT047 (500 mg 3 times a day), or a placebo for 12 weeks. The primary endpoint is the change in FMA motor score between baseline and week 12. Secondary endpoints are as follows: the change in FMA motor score at weeks 4 and 8 from baseline; the change in FMA motor score at weeks 4, 8, and 12 from baseline according to the timing of treatment initiation (either within 1 week, or 1-2 weeks), or according to the presence of prognostic risk factors (hypertension, diabetes, dyslipidemia, etc); the change in K-NIHSS and Korean versions of the modified Rankin scale (K-mRS) and the modified Barthel index at weeks 4 and 12 from baseline; and the proportion of subjects at week 12 with a K-NIHSS score of 0 to 2, or with K-mRS scores of 0, ≤1, and ≤2., Discussion: This study is a 1st-in-human trial of HT047 to explore the efficacy and safety in acute ischemic stroke patients. The results will provide the appropriate dosage and evidence of therapeutic benefit of HT047 for stroke recovery., Trial Registration: ClinicalTrials.gov (NCT02828540) Registered July 11, 2016.

Background and Purpose: In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence., Methods: In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding., Results: Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group., Conclusions: Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268., (© 2016 American Heart Association, Inc.)

Background: The incidence of ischemic stroke in young adults has been rising over recent decades, but there is still limited information on its risk factors, etiologies, and outcomes. Because these patients generally participate in social life, risk factors associated with lifestyle may have a great impact and need to be identified., Methods: The SKY (Stroke in Korean Young Adults) study is a multicenter case-control study and a prospective cohort study in 8 tertiary medical centers in the Republic of Korea. The case subjects are patients aged 18-44 years with first-ever ischemic stroke occurring within 1 month of stroke onset, and the control subjects are age- and gender-matched community controls. Our aim is to include 470 cases and 470 controls. The main objective of our study is to determine the risk factors and the causes of ischemic stroke in Korean young adults. Both well-documented risk factors and little-known lifestyle-related risk factors such as lifestyle habits and psychological distress including job strain will be evaluated by comparing cases and controls using a structured questionnaire. Secondary objectives are to determine the risks of mortality, recurrent vascular events, and poststroke epilepsy in these patients. Conditional logistic regression analysis will be used to estimate odds ratios and 95% confidence intervals., Conclusions: The SKY study is designed to obtain more insights into relatively little-known risk factors in young Korean adults with ischemic stroke. The results may also help identify the frequencies of uncommon etiologies and outcomes in these patients., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Stromal cell-derived factor-1α (SDF-1α) provides neurotrophic support to neurons. In this prospective study, we investigated the association between SDF-1α and long-term outcome in patients with acute ischemic stroke., Methods: This study included 104 patients with first-ever ischemic stroke, identified within 24 h of symptom onset. Serum samples were collected immediately after admission and 3 months thereafter, as well as from age- and sex-matched normal controls. The correlation between acute-stage serum SDF-1α and stroke severity were analyzed. Finally, the relationship between serum SDF-1α and long-term outcome was evaluated by multivariate analysis., Results: Serum SDF-1α levels were only higher in acute-stage stroke patients compared with the normal control group (p = 0.011). The serum SDF-1α level was increased in proportion to infarct volume (r = 0.220, p = 0.025) and initial National Institutes of Health Stroke Scale score (r = 0.275, p = 0.005). After adjustment for covariates, a high initial serum SDF-1α level (OR 1.167, p = 0.023) or second and third tertiles of SDF-1α level compared to first tertile (OR 4.644, p = 0.044 and OR 9.396, p = 0.025, respectively) were significantly associated with a favorable long-term outcome., Conclusions: This prospective study demonstrated a correlation between serum SDF-1α and favorable long-term outcome in patients with acute ischemic stroke., (Copyright © 2012 S. Karger AG, Basel.)

We investigated the effect of poly(ADP-ribose) polymerase (PARP) inhibitor on the levels of plasma and brain matrix metalloproteinase-9 (MMP-9) and the expression of nuclear factor kappa B (NF-kappaB) during experimental focal cerebral ischemia. The 3-aminobenzamide (3-AB), a PARP inhibitor, and saline were administered to 80 Sprague-Dawley rats [3-AB group; 5 rats for plasma sampling, 35 for brain sampling, and 40 for TTC staining] and to 85 rats (10, 35, and 40, respectively), respectively, 10 min before the occlusion of the left middle cerebral artery (MCAo) for 2 h. Infarct volume was measured by TTC staining, the serial levels of plasma and brain MMP-9 were measured by zymography just before and 2, 4, 8, 24, 48, and 72 h after MCAo, brain NF-kappaB activity was determined by Western blotting, and neutrophil infiltration was evaluated by assessing myeloperoxidase activity. Compared with control group, the levels of plasma and brain MMP-9, brain NF-kappaB, and MPO activities were significantly reduced in 3-AB group at each time point (p<0.05). Plasma MMP-9 increased maximally at 4h and then decreased rapidly, brain MMP-9 increased maximally at 24 h and persisted until 72 h, and NF-kappaB increased maximally at 24h and then decreased slowly in both groups. Therefore, the PARP inhibitor reduces the expression of MMP-9 and NF-kappaB and the infiltration of neutrophils in ischemic stroke.

Poly(ADP-ribose) polymerase (PARP) plays an important role in ischaemic cell death, and 3-aminobenzamide (3-AB), one of the PARP inhibitors, has a protective effect on ischaemic stroke. We investigated the neuroprotective mechanisms of 3-AB in ischaemic stroke. The occlusion of middle cerebral artery (MCA) was made in 170 Sprague-Dawley rats, and reperfusion was performed 2 h after the occlusion. Another 10 Sprague-Dawley rats were used for sham operation. 3-AB was administered to 85 rats 10 min before the occlusion [3-AB group (n = 85) vs. control group without 3-AB (n = 85)]. Infarct volume and water content were measured, brain magnetic resonance imaging, terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end-labelling (TUNEL) and Cresyl violet staining were performed, and immunoreactivities (IRs) of poly(ADP-ribose) polymer (PAR), cleaved caspase-3, CD11b, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), phospho-Akt (pAkt) and phospho-glycogen synthase kinase-3 (pGSK-3) were compared in the peri-infarcted region of the 3-AB group and its corresponding ischaemic region of the control group at 2, 8, 24 and 72 h after the occlusion. In the 3-AB group, the infarct volume and the water content were decreased (about 45% and 3.6%, respectively, at 24 h), the number of TUNEL-positive cells was decreased (about 36% at 24 h), and the IRs of PAR, cleaved caspase-3, CD11b, ICAM-1 and COX-2 were significantly reduced, while the IRs of pAkt and pGSK-3 were increased. These results suggest that 3-AB treatment could reduce the infarct volume by reducing ischaemic cell death, its related inflammation and increasing survival signals. The inhibition of PARP could be another potential neuroprotective strategy in ischaemic stroke.

During focal cerebral ischemia, matrix metalloproteinase-2 (MMP-2) can contribute to the loss of microvessel integrity within ischemic regions by degrading the basal lamina. MMP-2 is secreted in latent form (pro-MMP-2), but the activation of pro-MMP-2 in the ischemic territory has not been shown. Immunohistochemical and in situ hybridization studies of the expression of the direct activators of MMP-2, MT1-MMP and MT3-MMP, and the indirect activation system tissue plasminogen activator, urokinase (u-PA), its receptor (u-PAR), and its inhibitor PAI-1 after middle cerebral artery occlusion/reperfusion were undertaken in basal ganglia samples from 26 adolescent male baboons. The expressions of all three MMPs, u-PA, u-PAR, and PA1-1, but not tissue plasminogen activator, were increased from 1 hour after middle cerebral artery occlusion in the ischemic core. mRNA transcripts confirmed the increases in latent MMP-2, u-PA, u-PAR, and PAI-1 antigen very early after middle cerebral artery occlusion. The expression patterns are consistent with secretion of pro-MMP-2 and its activators in the ischemic core, perhaps from separate cell compartments. The rapid and coordinate appearance of pro-MMP-2 and its activation apparatus suggest that in the primate striatum this protease may participate in matrix injury during focal cerebral ischemia.