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Spontaneous intracerebral hemorrhage (SICH) remains a devastating form of stroke. Prior use of antiplatelets or warfarin before SICH is associated with poor outcomes, but the effects of direct oral anticoagulants (DOACs) remain unclear. This study aimed to clarify trends in prior antithrombotic use and to assess the associations between prior use of antithrombotics and in-hospital mortality using a multicenter prospective registry in Japan. In total, 1085 patients were analyzed. Prior antithrombotic medication included antiplatelets in 14.2%, oral anticoagulants in 8.1%, and both in 1.8%. Prior warfarin use was significantly associated with in-hospital mortality (odds ratio [OR] 5.50, 95% confidence interval [CI] 1.30–23.26, P < 0.05) compared to no prior antithrombotic use. No such association was evident between prior DOAC use and no prior antithrombotic use (OR 1.34, 95% CI 0.44–4.05, P = 0.606). Concomitant use of antiplatelets and warfarin further increased the in-hospital mortality rate (37.5%) compared to warfarin alone (17.2%), but no such association was found for antiplatelets plus DOACs (8.3%) compared to DOACs alone (11.9%). Prior use of warfarin remains an independent risk factor for in-hospital mortality after SICH in the era of DOACs. Further strategies are warranted to reduce SICH among patients receiving oral anticoagulants and to prevent serious outcomes. [ABSTRACT FROM AUTHOR]

Background: Major advances have been made in stroke treatment and prevention in the past decades. However, the burden of stroke remains high. Identification of novel targets and establishment of effective interventions to improve stroke outcomes are, therefore, needed. Recent research highlights the contribution of the gut microbiota to stroke pathogenesis. Summary: Compositional and functional alterations of the gut microbiota, termed dysbiosis, are linked to stroke risk factors, such as obesity, metabolic diseases, and atherosclerosis. In acute cerebral ischemia, the gut microbiota plays a key role in bidirectional interactions between the gut and brain, referred to as the microbiota-gut-brain axis. Gut dysbiosis prior to ischemic stroke affects outcomes. Additionally, the brain affects the gut microbiota during acute ischemic brain injury, which in turn impacts outcomes. Interactions between the gut microbiota and stroke pathogenesis are mediated by several factors including bacterial components (e.g., lipopolysaccharide), gut microbiota-related metabolites (e.g., short-chain fatty acids and trimethylamine N-oxide), and the immune and nervous systems. Clinical studies have reported that patients with acute ischemic stroke exhibit gut dysbiosis, which is associated with host metabolism and inflammation, as well as functional outcomes. Modulation of the gut microbiota or its metabolites improves conditions related to stroke pathogenesis, including inflammation, cardiometabolic disease, atherosclerosis, and thrombosis. Key Messages: Accumulating evidence indicates that the gut microbiota plays a possible role in stroke pathogenesis. Modulation of the gut microbiota may provide a novel therapeutic strategy for the treatment and prevention of stroke. [ABSTRACT FROM AUTHOR]

Survivin, a member of the inhibitors of apoptosis protein gene family, inhibits the activity of caspase, leading to a halt of the apoptotic process. Our study focused on the neuroprotective effect of survivin after transient middle cerebral artery occlusion (MCAO) with intraparenchymal administration of an adeno‐associated virus (AAV) vector. His‐tagged survivin was cloned and packaged into the AAV‐rh10 vector. Four‐week‐old Sprague–Dawley rats were injected with 4 × 109 vg of AAV‐GFP or AAV‐His‐survivin into the right striatum and were treated 3 weeks later with transient MCAO for 90 min. Twenty‐four hours after MCAO, functional and histological analyses of the rats were performed. The result showed that rats that had been treated with AAV‐green fluorescent protein (GFP) and those that had been treated with AAV‐His‐survivin did not show a significant difference in neurological scores 24 hr after MCAO, however, infarction volume was significantly reduced in the AAV‐His‐survivin group compared to that in the AAV‐GFP group. Although the neutrophil marker myeloperoxidase did not show a significant difference in the ischemic boundary zone, cells positive for active caspase‐3 and terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labeling were significantly decreased in the AAV‐His‐survivin group. In conclusion, survivin overexpression in the ischemic boundary zone induced by using an AAV vector has the potential for amelioration of ischemic damage via an antiapoptotic mechanism. Rats were injected with 4×109 vg of adeno‐associated virus (AAV)‐green fluorescent protein (GFP) or AAV‐His‐survivin into the right striatum and were treated three weeks later with transient middle cerebral artery occlusion (MCAO) for 90 minutes. Twenty‐four hours after MCAO, functional analysis did not show significant difference. Histological analyses showed that AAV‐His‐survivin treatment significantly reduced the infarction volume and decreased apoptotic markers in the ischemic boundary zone, but not the neutrophil infiltration. [ABSTRACT FROM AUTHOR]

Aims: White matter lesions (WMLs) are involved in the pathological processes leading to cognitive decline and dementia. We examined the mechanisms underlying the exacerbation of ischemia‐induced cognitive impairment and WMLs by diet‐induced obesity, including lipopolysaccharide (LPS)‐triggered neuroinflammation via toll‐like receptor (TLR) 4. Methods: Wild‐type (WT) and TLR4‐knockout (KO) C57BL/6 mice were fed a high‐fat diet (HFD) or low‐fat diet (LFD), and subjected to bilateral carotid artery stenosis (BCAS). Diet groups were compared for changes in gut microbiota, intestinal permeability, systemic inflammation, neuroinflammation, WML severity, and cognitive dysfunction. Results: In WT mice, HFD induced obesity and increased cognitive impairment and WML severity compared with LFD‐fed mice following BCAS. HFD caused gut dysbiosis and increased intestinal permeability, and plasma LPS and pro‐inflammatory cytokine concentrations. Furthermore, HFD‐fed mice had higher LPS levels and higher neuroinflammatory status, including increased TLR4 expression, in WMLs. In TLR4‐KO mice, HFD also caused obesity and gut dysbiosis but did not increase cognitive impairment or WML severity after BCAS. No difference was found between HFD‐ and LFD‐fed KO mice for LPS levels or inflammatory status in either plasma or WMLs. Conclusion: Inflammation triggered by LPS–TLR4 signaling may mediate obesity‐associated exacerbation of cognitive impairment and WMLs from brain ischemia. [ABSTRACT FROM AUTHOR]

The role of metabolic diseases in ischemic stroke has become a primary concern in both research and clinical practice. Increasing evidence suggests that dysbiosis is associated with metabolic diseases. The aim of this study was to investigate whether the gut microbiota, as well as concentrations of organic acids, the major products of dietary fiber fermentation by the gut microbiota, are altered in patients with ischemic stroke, and to examine the association between these changes and host metabolism and inflammation. We analyzed the composition of the fecal gut microbiota and the concentrations of fecal organic acids in 41 ischemic stroke patients and 40 control subjects via 16S and 23S rRNA-targeted quantitative reverse transcription (qRT)-PCR and high-performance liquid chromatography analyses, respectively. Multivariable linear regression analysis was subsequently performed to evaluate the relationships between ischemic stroke and bacterial counts and organic acid concentrations. Correlations between bioclinical markers and bacterial counts and organic acids concentrations were also evaluated. Although only the bacterial counts of Lactobacillus ruminis were significantly higher in stroke patients compared to controls, multivariable analysis showed that ischemic stroke was independently associated with increased bacterial counts of Atopobium cluster and Lactobacillus ruminis, and decreased numbers of Lactobacillus sakei subgroup, independent of age, hypertension, and type 2 diabetes. Changes in the prevalence of Lactobacillus ruminis were positively correlated with serum interleukin-6 levels. In addition, ischemic stroke was associated with decreased and increased concentrations of acetic acid and valeric acid, respectively. Meanwhile, changes in acetic acid concentrations were negatively correlated with the levels of glycated hemoglobin and low-density lipoprotein cholesterol, whereas changes in valeric acid concentrations were positively correlated with the level of high sensitivity C-reactive protein and with white blood cell counts. Together, our findings suggest that gut dysbiosis in patients with ischemic stroke is associated with host metabolism and inflammation. [ABSTRACT FROM AUTHOR]

Background: Embolic stroke of undetermined source (ESUS) encompasses diverse embologenic mechanisms, which transesophageal echocardiography (TEE) is critical to detect. Specific markers related to each embolic source in ESUS is not fully studied. We focused on D-dimer levels, and explored the association of D-dimer with potential embolic sources (PES) identified on TEE in ESUS.Methods: Consecutive patients with ESUS were included in this study. Clinical characteristics including D-dimer levels were compared between ESUS patients with and without TEE, and among none of, one, and at least two PES in ESUS patients undergoing TEE. Factors related to elevation of D-dimer were analyzed.Results: A total of 211 patients (age, 69.3 ± 13.2 years; 149 males) with ESUS were enrolled. Of these, 115 received TEE, displaying significantly younger age and lower D-dimer levels than patients without TEE (P < 0.05), and 20 (17%), 61 (53%), and 34 (30%) patients were classified into none of, one, and ≥ two PES, respectively. On multiple logistic regression analysis, D-dimer levels were related to one PES (odds ratio [OR]: 9.01; 95% confidence interval [CI]: 1.00-81.51; P = 0.050) and PES ≥ two (OR: 9.76; 95% CI: 1.07-88.97; P = 0.043). Right-to-left shunt (RLS) with deep venous thrombosis (DVT)(OR: 13.94; 95% CI: 1.77-109.99; P = 0.012) and without DVT (OR: 3.90; 95% CI: 1.20-12.70; P = 0.024) were associated with elevation of D-dimer.Conclusions: D-dimer levels were higher in patients with PES. Among PES, RLS, with and without DVT, were associated with increase of D-dimer in ESUS. [ABSTRACT FROM AUTHOR]

Neuroinflammation contributes to the pathology and progression of Alzheimer's disease (AD), and it can be observed even with mild cognitive impairment (MCI), a prodromal phase of AD. Free water (FW) imaging estimates the extracellular water content and has been used to study neuroinflammation across several neurological diseases including AD. Recently, the role of gut microbiota has been implicated in the pathogenesis of AD. The relationship between FW imaging and gut microbiota was examined in patients with AD and MCI. Fifty-six participants underwent neuropsychological assessments, FW imaging, and gut microbiota analysis targeting the bacterial 16S rRNA gene. They were categorized into the cognitively normal control (NC) (n = 19), MCI (n = 19), and AD (n = 18) groups according to the neuropsychological assessments. The correlations of FW values, neuropsychological assessment scores, and the relative abundance of gut microbiota were analyzed. FW was higher in several white matter tracts and in gray matter regions, predominantly the frontal, temporal, limbic and paralimbic regions in the AD/MCI group than in the NC group. In the AD/MCI group, higher FW values in the temporal (superior temporal and temporal pole), limbic and paralimbic (insula, hippocampus and amygdala) regions were the most associated with worse neuropsychological assessment scores. In the AD/MCI group, FW values in these regions were negatively correlated with the relative abundances of butyrate-producing genera Anaerostipes , Lachnospiraceae UCG-004, and [ Ruminococcus ] gnavus group, which showed a significant decreasing trend in the order of the NC, MCI, and AD groups. The present study showed that increased FW in the gray matter regions related to cognitive impairment was associated with low abundances of butyrate producers in the AD/MCI group. These findings suggest an association between neuroinflammation and decreased levels of the short-chain fatty acid butyrate that is one of the major gut microbial metabolites having a potentially beneficial role in brain homeostasis. • FW imaging was performed to assess neuroinflammation. • FW in gray and white matter was higher in MCI and AD than in controls. • FW in gray matter was associated with cognitive impairment in the AD/MCI group. • FW in gray matter was related to decreased butyrate producers in the AD/MCI group. • Neuroinflammation appears to be linked to gut dysbiosis in AD and MCI. [ABSTRACT FROM AUTHOR]

• PGZ ameliorates insulin sensitivity and improves glucose intolerance in db/db mice. • PGZ prevents hemorrhagic infarction and preserves BBB integrity in db/db mice. • PGZ increases plasma APN levels. • PGZ may have neuroprotective effects against stroke via an APN-related mechanism. Pioglitazone (PGZ), a PPARγ agonist, has been used for diabetic patients as an insulin-sensitizing agent. Recent studies have demonstrated that PGZ increases adiponectin (APN) levels and provides vascular protection in ischemic conditions. This study was designed to assess the neuroprotective effects of PGZ against cerebral ischemia–reperfusion injury via an APN-related mechanism. Type 2 diabetic leptin-deficient mice (db/db) were administered PGZ for 1 week, and plasma insulin and APN levels were measured. These mice received a middle cerebral artery occlusion and reperfusion injury, and they were evaluated for the infarct volume and by immunohistochemistry and western blotting analysis at several time points after ischemia. PGZ-administered db/db mice showed improved insulin sensitivity, and the hemorrhagic rate and infarct volume were decreased (P < 0.05). In the PGZ-administered group, plasma APN levels increased compared with the vehicle group. In the db/db group, PGZ administration significantly suppressed inflammatory reactions and oxidative stress after reperfusion (P < 0.05). PGZ may be applicable for acute cerebral ischemia treatment in metabolic syndrome patients as well as antidiabetic agents. [ABSTRACT FROM AUTHOR]

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19–15.97; p < 0.001) was associated with AF ≤ 4 days, whereas a large infarction > 3 cm in diameter (OR 3.28; 95% CI 1.35–7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM. [ABSTRACT FROM AUTHOR]

Background: Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.Methods: This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.Results: After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.Conclusion: Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.Trial Registration: UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent inflammatory stimulus for the innate immune response via toll-like receptor (TLR) 4 activation. Type 2 diabetes is associated with changes in gut microbiota and impaired intestinal barrier functions, leading to translocation of microbiota-derived LPS into the circulatory system, a condition referred to as metabolic endotoxemia. We investigated the effects of metabolic endotoxemia after experimental stroke with transient middle cerebral artery occlusion (MCAO) in a murine model of type 2 diabetes (db/db) and phenotypically normal littermates (db/+). Compared to db/+ mice, db/db mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition, db/db mice presented increased infarct volumes and higher expression levels of LPS, TLR4, and inflammatory cytokines in the ischemic brain, as well as more severe neurological impairments and reduced survival rates after MCAO. Oral administration of a non-absorbable antibiotic modulated the gut microbiota and improved metabolic endotoxemia and stroke outcomes in db/db mice; these effects were associated with reduction of LPS levels and neuroinflammation in the ischemic brain. These data suggest that targeting metabolic endotoxemia may be a novel potential therapeutic strategy to improve stroke outcomes. [ABSTRACT FROM AUTHOR]

In Parkinson's disease (PD), nonmotor symptoms manifest before motor symptoms. In this report, we present a remarkable case of a semiprofessional painter with PD whose painting style dramatically changed from abstract painting to realism before he developed motor, psychiatric, and autonomic nerve disorders. This case suggests that certain types of visual creativity may be impaired in the very early, presymptomatic stages of PD. [ABSTRACT FROM AUTHOR]

We hypothesized that administration of cilostazol may clarify the occult atrial fibrillation (AF) during hospitalization in mild stroke patients, who has no history of AF. From our prospective non-cardioembolic stroke study, randomized to dual antiplatelet therapy using cilostazol and aspirin or aspirin alone trial (ADS), data on the presence or absence of AF were retrospectively analyzed. In the ADS, during hospitalization, as a routine examination, presence of AF was investigated using electrocardiogram (ECG), ECG monitoring and Holter ECG. Multivariate regression analysis was conducted to evaluate the independent parameters related to the AF. Clinical outcome at 3 months was evaluated using modified Rankin Scale (mRS) score. Data on 1194 patients (793 [66%] men; median age [interquartile range] of 69 [61–77] years, National Institutes of Health Stroke Scale score 2 [1–4], onset-to-admission 10.8 [4.7–20.5] hours) were retrospectively analyzed. AF was newly detected in 41 (3%) patients (3 by ECG, 21 by the ECG monitoring and 17 by the Holter ECG) during hospitalization. Patients treated with combined cilostazol and aspirin therapy frequently had the AF than those took aspirin alone (5% vs. 2%, p =.007). Multivariate regression analysis showed that cilostazol administration was one of the independent factors for new-AF (odds ratio 2.672, 95%CI: 1.205–5.927, p =.016). The frequency of mRS 0-1 was 68% in the new-AF group and 67% in the non-AF group (p = 1.000). Cilostazol therapy may increase the detectability of AF in acute non-cardioembolic stroke, though the new-AF was not related to clinical outcome at 3 months. • Cilostazol is often used for mild stroke patients without atrial fibrillation (AF). • Cilostazol stimulates vessels and cardiac system. • Retrospective analysis focused on 1194 patients without AF on admission. • Cilostazol administration was independently related to the new-AF detection. • Cilostazol may increase the detectability of AF in acute stroke patients. [ABSTRACT FROM AUTHOR]

Background: Cryptogenic stroke encompasses diverse emboligenic mechanisms and pathogeneses. Cerebral microbleeds (CMBs) occur differently among stroke subtypes. The association of CMBs with cryptogenic stroke is essentially unknown. Methods: CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for ESUS/CS) is a multicenter registry with comprehensive data including gradient-echo T2*-weighted magnetic resonance imaging of cryptogenic stroke patients who underwent transesophageal echocardiography. Patients' clinical characteristics were compared according to the presence and location of CMBs. Results: A total of 661 patients (68.7 ± 12.7 years; 445 males) were enrolled, and 209 (32%) had CMBs. Age (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00–1.04, p = 0.020), male sex (OR 1.85, 95% CI 1.18–2.91, p = 0.007), hypertension (OR 1.71, 95% CI 1.03–2.86, p = 0.039), chronic kidney disease (OR 1.64, 95% CI 1.11–2.43, p = 0.013), deep and subcortical white matter hyperintensity (OR 1.82, 95% CI 1.16–2.85, p = 0.009), and periventricular hyperintensity (OR 2.18, 95% CI 1.37–3.46, p = 0.001) were independently associated with the presence of CMBs. Aortic complicated lesions (OR 1.78, 95% CI 1.12–2.84, p = 0.015) were associated with deep and diffuse CMBs, whereas prior anticoagulant therapy (OR 7.88, 95% CI, 1.83–33.9, p = 0.006) was related to lobar CMBs. Conclusions: CMBs were common, and age, male sex, hypertension, chronic kidney disease, and cerebral white matter diseases were related to CMBs in cryptogenic stroke. Aortic complicated lesions were associated with deep and diffuse CMBs, while prior anticoagulant therapy was related to lobar CMBs. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis of unknown cause involving the brain and accompanied by prominent eosinophilia. Intracardiac thrombosis is a major cardiac complication of EGPA that may cause thromboembolism.Case Presentation: A 53-year-old man presenting with abulia (consciousness disturbance) and left upper limb paralysis was admitted to our hospital. His case was complicated by penetrating branches, small vessel infarcts, and endocardial thrombosis in the right and left ventricle. Cardiomyopathy was also observed. Sixteen days after admission, the patient died from intracranial hemorrhage. Brain autopsy revealed two major findings: 1) large hemorrhagic infarction caused by cardiac embolism; and 2) granuloma and eosinophil infiltration. Vasculitis was accompanied by eosinophil infiltration in the cortical blood vessels and granuloma.Conclusions: In this case study, we report autopsy findings of brain infarction in a patient with EGPA and endocardial thrombosis. The brain infarction was caused by the cardiac embolisms and vasculitis. [ABSTRACT FROM AUTHOR]

Background: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients.Methods: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke.Results: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups.Conclusions: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988. [ABSTRACT FROM AUTHOR]

White matter lesions due to cerebral hypoperfusion may be an important pathophysiology in vascular dementia and stroke, although the inherent mechanisms remain to be fully elucidated. The present study, using a mouse model of chronic cerebral hypoperfusion, examined the white matter protective effects of levetiracetam, an anticonvulsant, via the signaling cascade from the activation of cAMP-responsive element binding protein (CREB) phosphorylation. Mice underwent bilateral common carotid artery stenosis (BCAS), and were separated into the levetiracetam group (injected once only after BCAS [LEV1] or injected on three consecutive days [LEV3]), the vehicle group, or the anti-epileptic drugs with different action mechanisms phenytoin group (PHT3; injected on three consecutive days with the same condition as in LEV3). Cerebral blood flow analysis, Y-maze spontaneous alternation test, novel object recognition test, immunohistochemical and Western blot analyses, and protein kinase A assay were performed after BCAS. In the LEV3 group, SV2A expression was markedly increased, which preserved learning and memory after BCAS. Moreover, as the protein kinase A level was significantly increased, pCREB expression was also increased. The activation of microglia and astrocytes was markedly suppressed, although the number of oligodendrocyte precursor cells (OPCs) and GST-pi–positive-oligodendrocytes was markedly higher in the cerebral white matter. Moreover, oxidative stress was significantly reduced. We found that 3-day treatment with levetiracetam maintained SV2A protein expression via interaction with astrocytes, which influenced the OPC lineage through activation of CREB to protect white matter from ischemia. Unlabelled Image • White matter injury progresses in chronic cerebral hypoperfusion. • Levetiracetam (LEV) could upregulate CREB cascade via SV2A in white matter. • LEV keep the homeostasis in white matter, even in hypoperfused condition. • LEV could provide a broad therapeutic approach for vascular cognitive impairments. [ABSTRACT FROM AUTHOR]

Oligodendrocytes (OLGs) differentiate from oligodendrocyte-precursor-cells (OPCs) for myelination in white matter. This differentiation is maintained by cell–cell interactions through trophic factors such as brain-derived-neurotrophic-factor (BDNF). However, differentiation is impaired when white matter injury occurs in a chronic cerebral hypoperfusion model. Thus, we examined the effects of the interaction between astrocyte and oligodendrocyte lineage cells on myelination regarding the mechanism of impairment. A microcoil was applied to the bilateral common carotid arteries in male C57BL/6 mice as an in vivo cerebral chronic hypoperfusion model (BCAS model). A nonlethal concentration of CoCl2 was added to the primary cell culture from the postnatal rat cortex and incubated in vitro. White matter injury progressed in the BCAS model as myelin decreased. The numbers of OPCs and astrocytes increased after the operation, whereas that of OLGs decreased at day 28. BDNF continuously decreased until day 28. Differentiation was disrupted under the stressed conditions in the cell culture, but improved after administration of astrocyte-conditioned medium containing BDNF. Astrocytes with BDNF underwent differentiation, but differentiation was impaired under the stressed conditions due to the reduction of BDNF. We examined S100B regarding the mechanism of impairment. S100B is mainly expressed by mature astrocytes, and has neuroprotective and neurotoxic effects inside and outside of cells. GFAP-positive astrocytes increased in the corpus callosum in the BCAS model, whereas the number of mature astrocytes continued to decrease, resulting in reduced BDNF. The reduction in mature astrocytes due to the discharge of S100B in ischemic conditions caused the reduction in BDNF. Unlabelled Image • White matter injury progresses in chronic cerebral hypoperfusion. • White matter injury is caused by impairing oligodendrocyte lineage cells differentiation. • The reduction of brain derived neurotrophic factor which is expressed from astrocytes in mature stage is related to its impaired differentiation. • Decreasing mature astrocytes leads to the reduction of BDNF in white matter injury. [ABSTRACT FROM AUTHOR]

Current trends have suggested covert atrial fibrillation as a mechanism of cryptogenic stroke. However, etiological heterogeneity regarding the underlying embolic sources remains a critical issue in cryptogenic stroke. CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) is a multicenter observational registry of cryptogenic stroke patients admitted to participating hospitals, who underwent transesophageal echocardiography between April 2014 and December 2016. We obtained baseline characteristics, radiological and laboratory data, and echocardiographic findings, especially for embolic sources demonstrated on transesophageal echocardiography, and conducted comparisons according to CHADS 2 and CHA 2 DS 2 -VASc scores (0–1 vs. ≥2, respectively). This study was registered at http://www.umin.ac.jp/ctr/ (UMIN000032957). The study comprised 677 patients (age, 68.7 ± 12.8 years; 455 males; median National Institutes of Health Stroke Scale score, 2) with cryptogenic stroke. On multiple logistic regression analysis, large aortic arch plaque ≥4 mm (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.51–3.36; p < 0.001), with ulcerative or mobile components (OR, 2.37; 95%CI, 1.38–4.06; p = 0.002), was associated with CHADS 2 score ≥2. Large aortic arch plaque ≥4 mm (OR, 3.88; 95%CI, 2.07–7.27; p < 0.001) and ulcerative or mobile components (OR, 3.25; 95%CI, 1.44–7.34; p = 0.005) were linked to CHA 2 DS 2 -VASc score ≥2. The CHALLENGE ESUS/CS registry is a large TEE registry, and clarifies potential embolic etiologies of cryptogenic stroke using TEE. Large aortic arch plaques were associated with high CHADS 2 and CHA 2 DS 2 -VASc scores, and represented important embolic sources in cryptogenic stroke. Image 1 • CHALLENGE ESUS/CS registry is a large transesophageal echocardiography (TEE) registry for cryptogenic stroke patients. • CHALLENGE ESUS/CS registry clarified potential embolic sources. • Large aortic arch plaques were closely related to CHADS 2 and CHA 2 DS 2 -VASc scores. • Paroxysmal atrial fibrillation was linked to CHADS 2 and CHA 2 DS 2 -VASc scores. • Right-to-left shunt was inversely associated with CHA 2 DS 2 -VASc score. [ABSTRACT FROM AUTHOR]

Loss of integrity of the blood-brain barrier (BBB) in ischemic stroke victims initiates a devastating cascade of events causing brain damage. Maintaining the BBB is important to preserve brain function in ischemic stroke. Unfortunately, recombinant tissue plasminogen activator (tPA), the only effective fibrinolytic treatment at the acute stage of ischemic stroke, also injures the BBB and increases the risk of brain edema and secondary hemorrhagic transformation. Thus, it is important to identify compounds that maintain BBB integrity in the face of ischemic injury in patients with stroke. We previously demonstrated that intravenously injected phosphorylated recombinant heat shock protein 27 (prHSP27) protects the brains of mice with transient middle cerebral artery occlusion (tMCAO), an animal stroke-model. Here, we determined whether prHSP27, in addition to attenuating brain injury, also decreases BBB damage in hyperglycemic tMCAO mice that had received tPA. After induction of hyperglycemia and tMCAO, we examined 4 treatment groups: 1) bovine serum albumin (BSA), 2) prHSP27, 3) tPA, 4) tPA plus prHSP27. We examined the effects of prHSP27 by comparing the BSA and prHSP27 groups and the tPA and tPA plus prHSP27 groups. Twenty-four hours after injection, prHSP27 reduced infarct volume, brain swelling, neurological deficits, the loss of microvessel proteins and endothelial cell walls, and mortality. It also reduced the rates of hemorrhagic transformation, extravasation of endogenous IgG, and MMP-9 activity, signs of BBB damage. Therefore, prHSP27 injection attenuated brain damage and preserved the BBB in tPA-injected, hyperglycemic tMCAO experimental stroke-model mice, in which the BBB is even more severely damaged than in simple tMCAO mice. The attenuation of brain damage and BBB disruption in the presence of tPA suggests the effectiveness of prHSP27 and tPA as a combination therapy. prHSP27 may be a novel therapeutic agent for ischemic stroke patients whose BBBs are injured following tPA injections. [ABSTRACT FROM AUTHOR]

Background: Enlarged perivascular spaces (PVS) are common magnetic resonance imaging (MRI) findings, whereas widespread enlarged PVS are extremely rare. Although most patients with widespread enlarged PVS remain asymptomatic, some develop neurological dysfunctions; however, it remains unclear whether these are the consequence of widespread enlarged PVS.Case Presentation: A 64-year-old female patient developed consciousness disturbance, cognitive dysfunctions, fluent aphasia, agraphia, acalculia, and left-right disorientation after suffering from bronchopneumonia. Brain MRI revealed unusually widespread enlarged PVS predominantly in the left cerebral hemisphere. Following bronchopneumonia treatment, her cognitive dysfunction, fluent aphasia, agraphia, acalculia, and left-right disorientation persisted despite improvement of her general condition. Furthermore, the hypoperfusion area on single photon emission computed tomography and slow wave sites on electroencephalography were consistent with the location of enlarged PVS, indicating that severe enlarged PVS impaired focal brain functions.Conclusions: This case suggested that widespread enlarged PVS could be a potential cause of neurological deficits. We propose that impaired perivascular circulation due to enlarged PVS might lead to focal brain dysfunction. [ABSTRACT FROM AUTHOR]

Background Unilateral spatial neglect (USN) is frequently found in ischemic stroke patients. Because USN is related to poor functional outcomes, evaluating recovery from USN after stroke is critical. Methods Patients with acute ischemic stroke with lesions in the right cerebral hemisphere on MRI and exhibiting left USN were administered the Behavior Inattention Test (BIT) at 1 and 3 weeks after admission. BIT improvement was defined as a ≥ 1-point increase in ≥ 4 of the 6 BIT subtests from 1 to 3 weeks, or a total BIT score ≥ 131 at 3 weeks. Factors associated with improvement of left USN were analyzed. Results Eighteen patients (8 men; mean age, 70 ± 12 years) were enrolled in this study. BIT was performed at 5.3 ± 0.7 and 18.2 ± 0.7 days after admission. Twelve patients were classified to the improvement (I) group, and 6 to the non-improvement (NI) group. BIT scores increased substantially from 76.6 ± 40.5 in the acute phase to 109.2 ± 43.3 in the subacute phase. The I group displayed higher BIT scores than the NI group in both acute and subacute phases ( P < 0.01 each). The degree of white matter lesions on the Fazekas scale was lower in the I group (0.6 ± 0.7) than in the NI group (1.7 ± 1.2, P = 0.028). Increased BIT scores correlated significantly with increased Mini Mental State Examination scores (r = 0.487, P = 0.040). Conclusions Amelioration of left USN might be related to white matter lesions and cognitive impairment. Sample size in the current study was small, limiting the generalizability of results, and larger studies are warranted in the future. [ABSTRACT FROM AUTHOR]

Background Clinical characteristics are important for determining the etiologies of embolic stroke, including patent foramen ovale and complex aortic plaques demonstrated on transesophageal echocardiography (TEE). This study sought to analyze the clinical signs of cryptogenic stroke (CS) without such embolic etiologies and to examine the association between CS and brain natriuretic peptide (BNP), which is currently unknown. Methods Patients with CS after routine examinations who underwent TEE were included in this single-center observational study. Patients were classified into the potential embolic sources (PES) group (patients having PES on TEE) and the no potential embolic source (NPES) group. Patients were also categorized according to the tertile of BNP. Results A total of 158 patients (age, 64.0 ± 13.9 years; 119 males) with CS were enrolled. The PES group had 108 (68%) patients, and the NPES group had 50 (32%). Hypertension was more common, and glucose, D-dimer, and BNP were higher in the NPES than in the PES group ( p < 0.05). NPES was independently associated with high-BNP tertile (OR: 5.61; 95% CI: 1.91 to 16.44; p = 0.002). Conclusions BNP, an indicator of cardioembolism, was closely associated with NPES. Cardiogenic mechanisms may be implicated in the etiology of CS without potential embolic etiologies on TEE. [ABSTRACT FROM AUTHOR]

Objective Large atheromatous aortic plaques (AAPs) have been associated with ischemic stroke. There is little evidence to guide the therapeutic strategy for ischemic stroke associated with large AAPs. This study sought to analyze the temporal profile of AAPs after rosuvastatin therapy in Japanese patients with acute ischemic stroke. Methods The Efficacy of Post-stroke Intensive Rosuvastatin Treatment for aortogenic Embolic stroke (EPISTEME) trial was a prospective, randomized, open-label study. Acute ischemic stroke patients with dyslipidemia and AAPs ≥4-mm-thick on transesophageal echocardiography (TEE) were enrolled and randomly allocated to either the group treated with 5 mg/day rosuvastatin or the control group. The primary endpoint was the changes in volume and composition of AAPs on repeat TEE after 6 months. High-echoic plaque area was analyzed using binary images. Results A total of 24 Japanese patients (rosuvastatin 12; control 12) were included in the primary analysis. Rosuvastatin substantially reduced low-density lipoprotein cholesterol (LDL-C) compared to control (−42.1% vs. 1.4%, P < 0.001). Percent changes of high-echoic plaque areas were significantly increased in the rosuvastatin group, while they were decreased in the control group (65.8% vs −14.7%, P < 0.001). There was a significant linear correlation between percent increase in high-echoic plaque area and LDL-C decrease (r = −0.434, P = 0.002). Conclusion Treatment with 5-mg rosuvastatin for 6 months might induce atheromatous aortic plaque stabilization together with marked LDL-C reduction in Japanese patients with ischemic stroke, which could provide evidence on which to base the therapeutic strategy for aortogenic brain embolism. [ABSTRACT FROM AUTHOR]

Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine. L-carnitine-treated rats exhibited significantly reduced escape latency in the Morris water maze task at 28 days after chronic hypoperfusion. Western blot analysis indicated that L-carnitine increased levels of phosphorylated high-molecular weight neurofilament (pNFH), concurrent with a reduction in phosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN), and increased phosphorylated Akt and mammalian target of rapamycin (mTOR) at 28 days after chronic hypoperfusion. L-carnitine reduced lipid peroxidation and oxidative DNA damage, and enhanced oligodendrocyte marker expression and myelin sheath thickness after chronic hypoperfusion. L-carnitine regulates the PTEN/Akt/mTOR signaling pathway, and enhances axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving WMLs and cognitive impairment in a rat chronic hypoperfusion model. [ABSTRACT FROM AUTHOR]

Patients with advanced-stage Parkinson's disease (PD) occasionally experience refractory depression or catatonic stupor. Electroconvulsive therapy (ECT) has been reported as a successful procedure for both severe psychosis and motor symptoms in patients with PD. Four patients with PD who were receiving ECT were quantitatively evaluated using the Unified PD Rating scale part III, Hoehn and Yahr scale, Barthel index, Neuropsychiatric Inventory, mini-mental state examination, Revised Hasegawa's Dementia scale, Beck's Depression Inventory, and Hamilton Rating Scale for Depression-17. We adopted the 'half-age' method, which is an age-based stimulus-dosing method. The patients showed improvement in symptoms of psychosis and motor symptoms without any adverse effects. The interval of improvement after ECT varied among patients. Of note, a decrease in psychiatric symptoms successfully alleviated the burden of caregivers. ECT may be useful to treat parkinsonism with refractory psychosis, major depression, or catatonic stupor, within the limitations of the patients enrolled. [ABSTRACT FROM AUTHOR]

Abstract: A rapidly progressive motor-dominant neuropathy associated with IgM monoclonal antibody against gangliosides with disialosyl residues, GD3, GD1b, GT1b, and GQ1b, in a 60-year-old Japanese man with mantle cell lymphoma is reported. Plasma exchange and chemotherapy for mantle cell lymphoma were performed for the neuropathy and mantle cell lymphoma. After therapy, the motor neuropathy dramatically improved concurrently with substantial reduction of the antibody activities especially in reaction to GD1b. This is the first case report of neuropathy with anti-disialosyl IgM antibodies associated with mantle cell lymphoma, and plasma exchange and chemotherapy were effective. [Copyright &y& Elsevier]

After coil embolization, recanalization in cerebral aneurysms adversely influences long-term prognosis. Proliferation of endothelial cells on the coil surface may reduce the incidence of recanalization and further improve outcomes after coil embolization. We aimed to map the expression of proliferating tissue over the aneurysmal orifice and define the temporal profile of tissue growth in a swine experimental aneurysm model. We compared the outcomes after spontaneous thrombosis with those of coil embolization using histological and morphological techniques. In aneurysms that we not coiled, spontaneous thrombosis was observed, and weak, easily detachable proliferating tissue was evident in the aneurysmal neck. In contrast, in the coil embolization group, histological analysis showed endothelial-like cells lining the aneurysmal opening. Moreover, immunohistochemical and morphological analysis suggested that these cells were immature endothelial cells. Our results indicated the existence of endothelial cell proliferation 1 week after coil embolization and showed immature endothelial cells in septal tissue between the systemic circulation and the aneurysm. These findings suggest that endothelial cells are lead to and proliferate in the former aneurysmal orifice. This is the first examination to evaluate the temporal change of proliferating tissue in a swine experimental aneurysm model. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We aimed to explore the association between abnormal glucose metabolism such as diabetes, prediabetes, and short-term prognosis in patients with acute ischemic stroke. Methods: Of 242 consecutive acute ischemic stroke patients, a 75-g oral glucose tolerance test was administered to 116 patients without previously diagnosed diabetes. One hundred forty patients were classified into diabetes, 52 patients were prediabetes (impaired glucose tolerance or impaired fasting glucose or both), and 50 patients were normal glucose tolerance (NGT). The association between each glycemic status and early neurological deterioration (END; increase in the NIH Stroke Scale (NIHSS) of ≥2 points during the first 14days after admission) or poor short-term outcome (30-day modified Ranking Scale [mRS] score 2–6) was evaluated. Results: In multivariable analysis, the risk of END was significantly higher in the diabetes group than in the NGT group (ORs=11.354; 95% CI, 1.492–86.415; p=0.019), even after adjustment for possible confounding factors (ORs=12.769; 95% CI, 1.361–119.763; p=0.026). Similar but insignificant associations were observed between prediabetes and NGT groups (ORs=6.369; 95% CI, 0.735–55.177; p=0.093). The risk of poor outcome (30-day mRS 2–6) was significantly higher in the diabetes group (ORs=3.667; 95% CI, 1.834–7.334; p<0.001) than in the NGT group, even after adjusting for confounding factors (ORs=3.340; 95% CI, 1.361–8.195; p=0.008). Similar but insignificant associations were observed between prediabetes and NGT groups (ORs=2.058; 95% CI, 0.916–4.623; p=0.08). Conclusion: In our patient population, both diabetes and prediabetes were associated with a poor early prognosis after acute ischemic stroke. [Copyright &y& Elsevier]

Abstract: Purpose: We examined the prevalence and risk of clinical symptoms in a large number of Japanese patients with Parkinson's disease (PD) (n = 1453; 650 males). Methods: Events were analyzed using Kaplan–Meier survival curves, logistic regression, and Cox proportional-hazards models. Results: The mean age (SD) was 67.7 (10.0), age of onset was 58.0 (11.5), and disease duration was 9.7 (6.6) years. The mean modified Hoehn and Yahr stage was 2.8 (1.2). Most patients (88.9%) received levodopa (547.7 (257.6) mg/day). A large proportion (81.3%) received dopamine agonists (136.2 (140.7) mg/day). About 23.4% received pain treatment 6.9 (5.1) years after the onset; females (p < 0.05) and patients with late-onset PD (≥60 years, p < 0.001) were more likely to be affected. About 44.7% of patients had wearing-off 7.5 (4.7) years after the onset, and it was more common in females (p < 0.001) and patients with early-onset PD (p < 0.001). Camptocormia was found in 9.5% of patients 8.1 (6.2) years after the onset, and it was more common in females (p < 0.05) and patients with late-onset PD (p < 0.05). About 28.6% of patients developed psychosis 9.0 (5.4) years after the onset, and it was more likely to occur in patients with late-onset PD (p < 0.001). Late-onset PD and cerebrovascular disease were also associated with increased risk of pneumonia. Conclusions: Considering that very few studies have assessed numerous clinical symptoms in the same report, these data provide a useful reference for the clinical course of PD. [Copyright &y& Elsevier]

Although challenging, neuroprotective therapies for ischemic stroke remain an interesting strategy for countering ischemic injury and suppressing brain tissue damage. Among potential neuroprotective molecules, heat shock protein 27 (HSP27) is a strong cell death suppressor. To assess the neuroprotective effects of HSP27 in a mouse model of transient middle cerebral artery occlusion, we purified a “physiological” HSP27 (hHSP27) from normal human lymphocytes. hHSP27 differed from recombinant HSP27 in that it formed dimeric, tetrameric, and multimeric complexes, was phosphorylated, and contained small amounts of αβ-crystallin and HSP20. Mice received intravenous injections of hHSP27 following focal cerebral ischemia. Infarct volume, neurological deficit scores, physiological parameters, and immunohistochemical analyses were evaluated 24 h after reperfusion. Intravenous injections of hHSP27 1 h after reperfusion significantly reduced infarct size and improved neurological deficits. Injected hHSP27 was localized in neurons on the ischemic side of the brain. hHSP27 suppressed neuronal cell death resulting from cytochrome c-mediated caspase activation, oxidative stress, and inflammatory responses. Recombinant HSP27 (rHSP27), which was artificially expressed and purified from Escherichia coli, and dephosphorylated hHSP27 did not have brain protective effects, suggesting that the phosphorylation of hHSP27 may be important for neuroprotection after ischemic insults. The present study suggests that hHSP27 with posttranslational modifications provided neuroprotection against ischemia/reperfusion injury and that the protection was mediated through the inhibition of apoptosis, oxidative stress, and inflammation. Intravenously injected human HSP27 should be explored for the treatment of acute ischemic strokes. [ABSTRACT FROM AUTHOR]

Abstract: Phosphodiesterase (PDE) exists in the cardiovascular system, adipose tissue and platelets, and its inhibition increases the cellular levels of cAMP, which could activate cAMP-responsive element binding protein (pCREB). The present study was designed to map the expression of PDE3A/B in the forebrain and define the time course of PDE3 expression in the ischemic boundary zone after ischemia. The number of PDE3A-positive cells (neurons and endothelial cells) remained unchanged, while PDE3B-positive cells gradually increased after ischemia/reperfusion. In the corpus callosum, PDE3B was expressed in oligodendrocytes, oligodendrocyte progenitor cells, and astrocytes. PDE3B-expressing astrocytes showed gradual increase after ischemia/reperfusion. In the cortex, the majority of PDE3B-expressing cells before ischemia were neurons, though few were astrocytes. Ischemic insult resulted in gradual increase in PDE3B-expressing astrocytes and neurons, with larger increase in astrocytes. Expression of brain derived neurotrophic factor (BDNF) and B-cell leukemia/lymphoma 2 protein (Bcl-2) was detected in pCREB-positive cells, not in PDE3B-positive cells. Our results demonstrated that ischemic insult increased PDE3B expression, but not PDE3A, and changed the number and type of cells in a time-dependent manner. The variation of PDE3B-expression in the brain might play a crucial pathophysiological role, and regulation of PDE3B production might protect against ischemic brain damage. [Copyright &y& Elsevier]

Background: Mobile or ulcerated aortic plaques (MUAPs) on transesophageal echocardiography (TEE) can cause aortogenic brain embolism. Aortic arch calcification (AoAC) on chest X-ray represents systemic atherosclerosis. This study focused on AoAC on chest X-ray and its link with atheromatous aortic plaques (AAPs) on TEE in stroke patients. The aim of the present study was to assess the relationship between AoAC and AAPs in unexplained stroke patients. Methods: A total of 178 patients (mean age: 64 ± 15 years; 115 males) with ischemic stroke who underwent TEE were enrolled. The patients were classified based on TEE findings: (1) AAPs <4 mm; (2) AAPs ≥4 mm, and (3) MUAPs. The extent of AoAC on chest X-ray was divided into 4 grades (0-3). Clinical characteristics including AoAC were compared among the 3 groups. Multiple logistic regression analysis was performed to identify the independent factors associated with MUAPs. An original diagnostic criterion was defined as a potential indicator of MUAPs in unexplained stroke patients. Results: 104 (58%) patients had AAPs <4 mm, 46 (26%) had AAPs ≥4 mm, and 28 (16%) had MUAPs. Older age (OR: 1.14; 95% CI: 1.06-1.24; p = 0.001), AoAC (OR: 2.35; 95% CI: 1.30-4.24; p = 0.005), and multiple infarctions in multiple vascular territories (VTs) demonstrated on diffusion-weighted imaging (DWI) (OR: 2.58; 95% CI: 1.35-4.92; p = 0.004) were independently associated with MUAPs. The CAM score was defined as consisting of the degree of AoAC (0-3 points), age (≥70 years: 1 point), and DWI findings (multiple infarctions in 1 VT: 1 point; 2 VTs: 2 points; more than 3 VTs: 3 points). The prevalence of MUAPs was substantially increased in patients with medium risk (CAM score 3-4, OR: 7.68; 95% CI: 2.89-20.44; p < 0.001) and high risk (CAM score 5-7, OR: 20.63; 95% CI: 5.12-83.06; p < 0.001). Conclusions: Older age, advanced AoAC, and multiple infarctions in multiple VTs are associated with aortogenic brain embolism. The CAM score can be useful for the diagnosis of aortogenic brain embolism. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The ratio of low- (LDL-C) to high- (HDL-C) density lipoprotein cholesterol serves as a positive predictor of atherosclerosis including coronary artery disease. We assessed the contribution of the LDL-C/HDL-C ratio to atheromatous aortic plaques (AAPs) in patients with unexplained ischemic stroke. One hundred thirty-seven patients (age, 65±14years; 87 male) with ischemic stroke underwent transesophageal echocardiography (TEE) and enrolled to the study. Patients were classified based on TEE findings: (1) AAPs<4mm in thickness; (2) AAPs≥4mm; and (3) mobile or ulcerated aortic plaques (MUAPs). We assessed clinical characteristics and biochemical findings, and investigated the relationship between AAPs and the LDL-C/HDL-C ratio of stroke patients. 84 (61%) patients had AAPs<4mm, 29 (21%) had AAPs≥4mm, and 24 (18%) had MUAPs. Older age (OR: 1.18; 95% CI: 1.08 to 1.30; p=0.001), and LDL-C/HDL-C ratio (OR: 2.94; 95% CI: 1.10 to 7.87; p=0.032) were significantly associated with MUAPs. The incidence of MUAPs substantially increased in patients with LDL-C/HDL-C ratios of >2.23 (p<0.001) when the ratios were divided into quartiles. The LDL-C/HDL-C ratio was closely associated with MUAPs. An elevated LDL-C/HDL-C ratio could be a positive predictor of aortogenic brain embolism. [Copyright &y& Elsevier]

Background Marchiafava-Bignami disease (MBD) is a rare neurologic complication of chronic alcohol consumption that is characterized by callosal lesions involving demyelination and necrosis. Various reversible neurologic symptoms are found in patients with MBD. Dysarthria and dysphagia are found in various neurological diseases. Case presentation We report a 51-year-old man with chronic alcoholism and malnutrition who progressively developed dysarthria and dysphagia. On admission, the patient was alert with mild cognitive dysfunction. The facial expression was flat, and there was weakness of the orbicularis oris bilaterally. The patient's speech was slurred, there was difficulty swallowing, and the gag reflex and palate elevation were poor. The jaw jerk reflex was brisk and the snout reflex was positive. Neither tongue atrophy nor fasciculation were found. Bilateral upper and lower limb weakness with increased bilateral upper limb reflexes and Babinski reflexes were found. Because he had progressive dysarthria and dysphagia with upper and lower motor neuron signs, the initial diagnosis was motor neuron disease. However, electrophysiological analysis was normal. The vitamin B1 level was 14 ng/mL (normal: >24 ng/mL), and MRI revealed hyperintense lesions in the splenium of the corpus callosum and the primary motor cortices bilaterally. After vitamin B therapy for 17 days, the neurological disorders alleviated concurrently with disappearance of the lesions on MRI, which led to the definitive diagnosis of MBD. Conclusions MBD presenting with these lesions can mimic motor neuron disease clinically. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to evaluate the contributions of embolic etiologies, patent foramen ovale (PFO) and atrial septal aneurysm (ASA) to the pathogenesis of ischemic stroke in patients with antiphospholipid syndrome (APS). We performed transesophageal echocardiography (TEE) examination for consecutive stroke patients who had been diagnosed with APS (APS group) to detect potential embolic sources. APS was diagnosed based on the modified Sapporo criteria. The control stroke group comprised age- and sex-matched cryptogenic stroke patients undergoing TEE. We assessed and compared the clinical characteristics and TEE findings between stroke patients with APS and control stroke groups. Among 582 patients, nine patients (nine women; mean age, 50 ± 18 years) were classified into the APS group. In 137 patients undergoing TEE, 41 age-matched female stroke patients were recruited to the control stroke group. Prevalences of PFO and ASA were significantly higher in the APS group than in the control stroke group (89 vs. 41 %, p = 0.027; 67 vs. 20 %, p = 0.015, respectively). Multiple logistic regression analysis showed that PFO (odds ratio (OR), 13.71; 95 % confidence interval (CI), 1.01-185.62; p = 0.049) and ASA (OR, 8.06; 95 % CI, 1.17-55.59; p = 0.034) were independently associated with the APS group. PFO and ASA were strongly associated with the APS group, and could thus represent potential embolic sources in ischemic stroke patients with APS. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion. The GLP-1 receptor agonist, exendin-4, has similar properties to GLP-1 and is currently in clinical use for type 2 diabetes mellitus. As GLP-1 and exendin-4 confer cardioprotection after myocardial infarction, this study was designed to assess the neuroprotective effects of exendin-4 against cerebral ischemia-reperfusion injury. Mice received a transvenous injection of exendin-4, after a 60-minute focal cerebral ischemia. Exendin-4-treated vehicle and sham groups were evaluated for infarct volume, neurologic deficit score, various physiologic parameters, and immunohistochemical analyses at several time points after ischemia. Exendin-4 treatment significantly reduced infarct volume and improved functional deficit. It also significantly suppressed oxidative stress, inflammatory response, and cell death after reperfusion. Furthermore, intracellular cyclic AMP (cAMP) levels were slightly higher in the exendin-4 group than in the vehicle group. No serial changes were noted in insulin and glucose levels in both groups. This study suggested that exendin-4 provides neuroprotection against ischemic injury and that this action is probably mediated through increased intracellular cAMP levels. Exendin-4 is potentially useful in the treatment of acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia is associated with decreased nitric oxide (NO) bioavailability and endothelial dysfunction, a phenomenon thought to have a major role in the altered cerebral blood flow evident in stroke. Therefore, strategies that increase endothelial NO production have potential utility. Vascular reactivity of the middle cerebral artery (MCA) from C57BL/6J wild-type (WT) mice, apolipoprotein-E knockout (ApoE−/−) mice, and mice treated with the phosphodiesterase inhibitor cilostazol (100 mg/kg) was analyzed using the tension myograph. Contractile responses to endothelin-1 were significantly enhanced in MCA from ApoE−/− mice compared with WT mice (P<0.01), an effect absent in cilostazol-treated ApoE−/− mice. Acetylcholine-induced relaxation (which is entirely NO-dependent) was significantly impaired in MCA of ApoE−/− mice compared with WT mice (P<0.05), again an effect prevented by cilostazol treatment. Endothelial NOS phosphorylation at Ser1179 was decreased in the aorta of ApoE−/− mice compared with WT mice (P<0.05), an effect normalized by cilostazol. Taken together, our data suggest that the endothelial dysfunction observed in MCA associated with hypercholesterolemia is prevented by cilostazol, an effect likely due to the increase in eNOS phosphorylation and, therefore, activity. [ABSTRACT FROM AUTHOR]

Background: The purpose of the present study was to assess the contribution of embolic etiologies, patent foramen ovale (PFO) and atrial septal aneurysm (ASA), to cerebral white matter lesions (WMLs) in ischemic stroke patients. Methods: Patients with acute ischemic stroke who underwent transesophageal echocardiography were prospectively studied to investigate the relationships between the prevalence of PFO and ASA and the degree of WMLs. The patients were classified into four groups based on transesophageal echocardiography findings: (1) the PFO group (patients having PFO but not ASA); (2) the ASA group (patients having ASA but not PFO); (3) the PFO-ASA group (patients having both PFO and ASA), and (4) the non-septal abnormalities group (non-SA group, patients with neither PFO nor ASA). Based on MRI findings, the patients were also subdivided into grades 0, 1, 2, and 3 according to the Fazekas classification. Results: 115 patients (age, 69 ± 11 years; 41 females) were enrolled; 49 (43%) were in the PFO group, 4 (3%) were in the ASA group, 23 (20%) were in the PFO-ASA group, and 39 (34%) were in the non-SA group. The PFO-ASA group had significantly increased WMLs compared to the other three groups (p = 0.004). On multiple logistic regression analysis, the coexistence of PFO and ASA was significantly associated with the degree of WMLs (odds ratio: 2.40; 95% confidence interval: 1.11–5.17; p = 0.026) when the PFO-ASA and non-SA groups were compared. Conclusions: The coexistence of PFO with ASA could play an important pathogenic role in WML severity. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. Performance at the Morris water-maze task, immunohistochemistry for bromodeoxyuridine, as well as serial neuronal and glial markers were analyzed until 28 days after hypoperfusion. There was a significant increase in the number of oligodendrocyte progenitor cells in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. The oligodendrocyte progenitor cells subsequently underwent cell death and the number of oligodendrocytes decreased. In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury. [ABSTRACT FROM AUTHOR]

This study was designed to examine the effect of adrenomedullin deficiency on cerebral infarction and the relationship between adrenomedullin and cyclic AMP–protein kinase A pathway in regulating reactive oxygen species (ROS). Adrenomedullin heterozygous and wild-type mice were subjected to 60-mins focal ischemia. We used adrenomedullin heterozygous mice because adrenomedullin homozygotes die in utero. Infarct volume, neurologic deficit scores, and immunohistochemical analyses were evaluated at several time points after ischemia. The infarct volume and neurologic deficit scores were significantly worse in adrenomedullin heterozygous mice. Significant accumulation of inducible nitric oxide, oxidative DNA damage, and lipid peroxidation was noted after reperfusion in adrenomedullin heterozygous mice. Treatment of wild-type mice with H89, a protein kinase A inhibitor, resulted in increased infarct size, and worsening of neurologic deficit score and other parameters to levels comparable to those of adrenomedullin heterozygous mice. In contrast, cilostazol, which increases cyclic AMP, rescued neurologic deficit and ROS accumulation in adrenomedullin heterozygous mice. This study showed that adrenomedullin downregulation results in increase in ROS after transient focal ischemia in mice. The results also indicated that adrenomedullin has an important function against ischemic injury through the cyclic AMP–protein kinase A pathway. [ABSTRACT FROM AUTHOR]

Abstract: Background: Adiponectin, an adipocyte-derived bioactive protein, provides vascular protection. Recent clinical studies have suggested that plasma adiponectin plays a role in cerebrovascular disease (CVD). The present study was designed to determine the serial changes in adiponectin expression in the brain and plasma after transient focal cerebral ischemia in mice. Methods: C57BL/6 mice (n =100) were subjected to 60 min of middle cerebral artery occlusion followed by 1, 3, 6, 12, 24, 48, 72 h and 7-day reperfusion. Plasma adiponectin levels were determined by ELISA kit, and expression of adiponectin was assessed by immunohistochemistry, western blot analysis, and reverse transcription-polymerase chain reaction. Results: Cerebral ischemia–reperfusion injury resulted in a transient rise in the acute phase and decrease in the late phase, in plasma adiponectin levels (P <0.05). The same insult resulted in upregulation of adiponectin expression, with two peaks at 3 and 24 h after reperfusion (P <0.05). Adiponectin protein was negligible in nonischemic contralateral hemispheres, but relatively high levels of the protein were detected in the ischemic hemisphere. Adiponectin mRNA was detected in neither nonischemic nor ischemic hemisphere. Adiponectin accumulated only in endothelial cells of ischemic brain in response to cerebral ischemia. Conclusions: Our results indicate that ischemic insult results in a transient rise in plasma adiponectin level during the acute phase, and that circulating adiponectin then accumulates in damaged vessels in the ischemic brain during the late phase. These findings suggest that time-targeting administration of adiponectin could be potentially useful in the treatment of stroke. [Copyright &y& Elsevier]

Abstract: This study assessed the time course of angiotensin (Ang) II type 1 and type 2 receptor expression after 60min of ischemia/reperfusion in mice treated with a nonhypotensive dose of valsartan, an angiotensin II type 1 receptor antagonist. We also examined the potential neuroprotective mechanisms mediated by angiotensin II type 2 receptor. Mice were divided into two groups (n =64, each): valsartan-treated and control, vehicle groups. Infarct volume and neurological deficit scores were evaluated at several time points after ischemia, while immunohistochemical analyses were performed at serial time points after reperfusion. Valsartan significantly reduced the infarct volume and improved the neurological deficit scores (P <0.05). Both angiotensin II type 1 and type 2 receptors were upregulated at 24h and peaked at 72h with type I receptors dominating in the ischemic penumbra of the vehicle group. Interestingly, angiotensin II type 2 receptor expression levels were significantly higher in the valsartan group than vehicle controls (P <0.001). Moreover, angiotensin II type 2 receptor upregulated phosphosignal transducer and activator of transcription-3, and B-cell lymphoma protein-2 (P <0.05). Our results indicated that angiotensin II type 2 receptor has antiapoptotic activity by activating the B-cell lymphoma protein-2 via the janus kinase/signal transducer and activator of transcription signaling pathway. [Copyright &y& Elsevier]

To investigate the frequency of cardiac valve regurgitation related with low dose dopamine agonists in patients with Parkinson's disease (PD), echocardiograms were analyzed in 527 consecutive PD patients (448 patients treated with dopamine agonists, 79 patients never treated with dopamine agonists as age-matched controls). The frequency of mild or above mild regurgitation of the aortic valve (AR) was significantly higher in the cabergoline group (13.7%, P < 0.05) compared with the controls (2.5%). Odds ratio adjusted by age and sex for AR was significantly higher in the cabergoline group (OR, 6.45; 95% CI, 1.46-28.60; P = 0.01): odds ratio was significantly higher in patients treated with higher daily doses (OR, 14.41; 95% CI, 3.08-67.38; P = 0.0007) and higher cumulative doses (OR, 15.29; 95% CI, 3.19-73.18; P = 0.0006). No statistical difference was identified in the frequency of the tricuspid and mitral regurgitation. None of the other dopamine agonist groups including pergolide gave higher frequency or higher odds ratio compared with the controls. None of our patients showed severe regurgitation or was operated for valvular heart disease. The question as to whether or not longer duration of low dose dopamine agonist treatment would yield the same results needs further studies. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Proving that right-to-left shunt (RLS) represents the precise causative mechanism in ischemic stroke patients with RLS is difficult. The aim of this study was to examine the frequency and clarify the clinical characteristics of paradoxical brain embolism (PBE). We prospectively enrolled consecutive acute ischemic stroke patients, who underwent transcranial Doppler and/or transesophageal echocardiography. For patients with RLS, diagnostic criteria for PBE were established as follows: 1) brain images suggesting embolic strokes; 2) presence of deep venous thrombus or pulmonary embolism; and 3) absence of any embolic sources. Patients were divided into 4 groups: patients meeting all 3 criteria (Definite); fulfilling 2 criteria (Probable); fulfilling 1 or 0 criteria (Possible); and patients without RLS (Non-RLS). A total of 240 subjects were analyzed for this study. The Definite group comprised 5% of patients, and displayed significantly more females (p = 0.038), and infarcts involving both anterior and posterior circulations (p < 0.001). Patients having neither hypertension nor diabetes mellitus also predominantly belonged to the Definite group (p < 0.001). Clinical characteristics of PBE are a female preponderance, infarcts affecting both anterior and posterior circulations, and an absence of risk factors. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to assess the influence of clusters of risk factors on the incidence of echolucent carotid plaque in stroke patients. Methods: A retrospective analysis of 413 stroke patients who had undergone carotid ultrasonography was performed. High-resolution B-mode ultrasonography was used to evaluate the characteristics of carotid plaque. We investigated the relationships between the incidence of echolucent carotid plaque and clustering of risk factors (hypertension, diabetes mellitus and hyperlipidemia) and stroke subtypes and transient ischemic attack (TIA). Results: Echolucent plaques were present in 10.5% of patients free of risk factors, in 18.8% with a single risk factor (NS), in 27.7% with two risk factors (p <0.01) and in 50.0% with three risk factors (p <0.001), and were significantly more common in patients with multiple risk factors (odds ratio 1.79; 95% CI, 1.05–3.06; p = 0.045). Echolucent plaques were observed in 41.2% of patients with atherothrombotic infarction, in 17.6% with lacunar infarction, in 11.5% with cardioembolic stroke, and in 25.0% with TIA, and were significantly more common in patients with atherothrombotic infarction than in those with lacunar infarction or cardioembolic stroke (p<0.001), or in those with TIA (p <0.05). Conclusions: The clustering of risk factors increased the incidence of echolucent carotid plaque. Patients with multiple risk factors were at increased risk of echolucent plaque, and these had a significant relationship with atherothrombotic infarction compared with other stroke subtypes and TIA. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Cerebral ischemia induces the expression of several growth factors and cytokines, which protect neurons against ischemic insults. Recent studies showed that granulocyte colony-stimulating factor (G-CSF) has a neuroprotective effect through the signaling pathway for the antiapoptotic cascade. The current study was designed to assess the neuroprotective mechanisms of G-CSF in ischemia/reperfusion injury using bone marrow chimera mice known to express enhanced green fluorescent protein (EGFP). Mice were subjected to ischemia/reperfusion and divided into two groups: those treated with G-CSF (G-CSF group) and vehicle (control group) (n=35 in each group). Immunohistochemistry and immunoblotting for antiapoptotic protein, nitrotyrosine, and inducible nitrate oxide synthase (iNOS) were performed. G-CSF significantly reduced stroke volume (34%, P<0.006). G-CSF upregulated Stat3, pStat3, and Bcl-2 (P<0.05), and suppressed iNOS and nitrotyrosine expression. In EGFP chimera mice, G-CSF decreased the migration of Iba-1/EGFP-positive bone marrow-derived monocytes/macrophages and increased intrinsic microglia/macrophages at ischemic penumbra (P<0.05), suggesting that bone marrow-derived monocytes/macrophages are not involved in G-CSF-induced reduction of ischemic injury size. Our study indicated that G-CSF exerts a neuroprotective effect through the direct activation of antiapoptotic pathway, and suggested that G-CSF is important for expansion of the therapeutic time window in patients with cerebral ischemia.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 402–413. doi:10.1038/sj.jcbfm.9600195; published online 27 July 2005 [ABSTRACT FROM AUTHOR]

This study was designed to investigate the neuroprotective effect of intrinsic and extrinsic erythropoietin (EPO) against hypoxia/ischemia, and determine the optimal time-window with respect to the EPO-induced neuroprotection. Experiments were conducted using primary mixed neuronal/astrocytic cultures and neuron-rich cultures. Hypoxia (2%) induces hypoxia-inducible factor-1α (HIF-1α) activity followed by strong EPO expression in mixed cultures and weak expression in neuron-rich cultures as documented by both western blot and RT–PCR. Immunoreactive EPO was strongly detected in astrocytes, whereas EPOR was only detected in neurons. Neurons were significantly damaged in neuron-rich cultures but were distinctly rescued in mixed cultures. Application of recombinant human EPO (rhEPO) (0.1 U/mL) within 6 h before or after hypoxia significantly increased neuronal survival compared with no rhEPO treatment. Application of rhEPO after onset of reoxygenation achieved the maximal neuronal protection against ischemia/reperfusion injury (6 h hypoxia followed 24 h reoxygenation). Our results indicate that HIF-1α induces EPO gene released by astrocytes and acts as an essential mediator of neuroprotection, prove the protective role of intrinsic astrocytic-neuronal signaling pathway in hypoxic/ischemic injury and demonstrate an optimal therapeutic time-window of extrinsic rhEPO in ischemia/reperfusion injury in vitro. The results point to the potential beneficial effects of HIF-1α and EPO for the possible treatment of stroke. [ABSTRACT FROM AUTHOR]

Background: Previous study showed that polymorphism of the NAD(P)H oxidase p22phox gene is associated with atherosclerosis, although others could not confirm such association. We investigated the association between p22phox C242T polymorphism and thrombotic cerebral infarction and the role of this polymorphism on superoxide-production activity in human neutrophils and promyelocytic HL-60 cells as a model system. Methods: PCR-RFLP analysis revealed that genotype and allele frequencies of C242T polymorphism in 120 patients with thrombotic cerebral infarction and 177 control subjects. The superoxide-production activity in neutrophils was determined by cytochrome c reduction assay. To clarify the role of p22phox C242T polymorphism on NAD(P)H oxidase activity, we used transgenic HL-60 cells transfected with expression plasmids carrying p22phox cDNAs with or without C242T polymorphism. Results: Genotype and allele frequencies of C242T polymorphism in patients and control subjects were not significantly different. The superoxide-production activity in neutrophils with T allele was higher than in neutrophils without T allele. Moreover, expression analysis showed that superoxide-production activity in p22phox C242T-expressing HL-60 cells were significantly higher than in p22phox-expressing HL-60 cells. Conclusions: We conclude that C242T of p22phox gene is not involved in thrombotic cerebral infarction but more likely in increased NAD(P)H oxidase activity in phagocytes. [Copyright &y& Elsevier]