Publications by authors named "Takao Urabe"

126 Publications

Microbleeds and clinical outcome in acute mild stroke patients treated with antiplatelet therapy: ADS post-hoc analysis.

J Clin Neurosci 2021 Jul 12;89:216-222. Epub 2021 May 12.

Department of Neurology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Japan.

Background And Purpose: In this post-hoc analysis using acute dual study dataset, the impacts of cerebral microbleeds (MBs) after mild stroke on clinical outcome were investigated.

Methods: The number of MBs on admission was categorized as 1) no MBs, 2) MBs 1-4, 3) MBs 5-9, and 4) MBs ≥ 10. The efficacy outcome was defined as neurological deterioration and stroke recurrence within 14 days. Safety outcomes included ICH and/or SAH as well as extracranial hemorrhages.

Results: Of the 1102 patients, 780 (71%) had no MBs on admission, while 230 (21%) had MBs 1-4, 48 (4%) had MBs 5-9, and 44 (4%) had MBs ≥ 10. The number of MBs was not associated with the neurological deterioration and/or stroke recurrence (p = 0.934), ICH and/or SAH (p = 0.743), and extracranial hemorrhage (p = 0.205). Favorable outcome was seem in 84% in the No MBs group, 83% in the MBs 1-4, 94% in the MBs 5-9, and 85% in the MBs ≥ 10 (p = 0.304). Combined cilostazol and aspirin therapy did not alter any rates of efficacy and safety outcomes among the no MBs, MBs 1-4, MBs 5-9, and MBs ≥ 10 groups compared to aspirin alone (all p > 0.05). By multivariate regression analysis, a history of ICH and diastolic blood pressure were the independent parameters to all of the MBs criteria (presence, MBs ≥ 5, and MBs ≥ 10).

Conclusions: MBs did not alter the clinical outcome at 3 months of onset. Elevated diastolic blood pressure and a history of ICH were the essential parameters related to the MBs.
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http://dx.doi.org/10.1016/j.jocn.2021.04.028DOI Listing
July 2021

Role of the Gut Microbiota in Stroke Pathogenesis and Potential Therapeutic Implications.

Ann Nutr Metab 2021 Jun 9:1-9. Epub 2021 Jun 9.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1159/000516398DOI Listing
June 2021

Cardiac and Echocardiographic Markers in Cryptogenic Stroke with Incidental Patent Foramen Ovale.

J Stroke Cerebrovasc Dis 2021 Aug 6;30(8):105892. Epub 2021 Jun 6.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan. Electronic address:

Objective: Some cardiac abnormalities could be a substrate for potential embolic source in cryptogenic stroke (CS). We evaluated whether cardiac and echocardiographic markers were associated with CS in patients with incidental patent foramen ovale (PFO) as defined using the Risk of Paradoxical Embolism (RoPE) score.

Materials And Methods: Among 677 patients enrolled in a multicenter observational CS registry, 300 patients (44%) had PFOs detected by transesophageal echocardiography. They were classified into probable PFO-related stroke (RoPE score>6, n = 32) and stroke with incidental PFO (RoPE score≤6, n = 268) groups, and clinical characteristics, laboratory findings, cardiac and echocardiographic markers (i.e. brain natriuretic peptide, left atrial [LA] diameter, ejection fraction, early transmitral flow velocity/early diastolic tissue Doppler imaging velocity [E/e'], LA appendage flow velocity, spontaneous echo contrast, atrial septal aneurysm, substantial PFO, and aortic arch plaques), stroke recurrence, and excellent outcome (modified Rankin scale score <2) at discharge were compared. Risk factors for low RoPE scores were determined using multiple logistic regression analysis.

Results: Higher brain natriuretic peptide levels (p = 0.032), LA enlargement (p < 0.001), higher E/e' (p = 0.001), lower LA appendage flow velocity (p < 0.001), non-substantial PFO (p = 0.021), and aortic arch plaques (p = 0.002) were associated with the low RoPE score group. Patients with high RoPE scores had excellent outcomes (58% versus 78%, p = 0.035). LA enlargement (age- and sex-adjusted odds ratio, 1.15; 95 % confidence interval, 1.00-1.32; p = 0.039) was an independent predictor of low RoPE scores.

Conclusions: Abnormal cardiac substrate could be associated with CS occurrence in a subset of patients with PFO. Patients with CS who had incidental PFO may be at risk of cardioembolism.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105892DOI Listing
August 2021

Possible Neuroprotective Effects of l-Carnitine on White-Matter Microstructural Damage and Cognitive Decline in Hemodialysis Patients.

Nutrients 2021 Apr 14;13(4). Epub 2021 Apr 14.

Department of Neurology, Juntendo University Faculty of Medicine, Tokyo 113-8421, Japan.

Although l-carnitine alleviated white-matter lesions in an experimental study, the treatment effects of l-carnitine on white-matter microstructural damage and cognitive decline in hemodialysis patients are unknown. Using novel diffusion magnetic resonance imaging (dMRI) techniques, white-matter microstructural changes together with cognitive decline in hemodialysis patients and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent dMRI and laboratory and neuropsychological tests, which were compared across seven patients each in two groups according to duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment (NSTLC), and (2) long-term l-carnitine treatment (LTLC). Ten age- and sex-matched controls were enrolled. Compared to controls, microstructural disorders of white matter were widely detected on dMRI of patients. An autopsy study of one patient in the NSTLC group showed rarefaction of myelinated fibers in white matter. With LTLC, microstructural damage on dMRI was alleviated along with lower levels of high-sensitivity C-reactive protein and substantial increases in carnitine levels. The LTLC group showed better achievement on trail making test A, which was correlated with amelioration of disorders in some white-matter tracts. Novel dMRI tractography detected abnormalities of white-matter tracts after hemodialysis. Long-term treatment with l-carnitine might alleviate white-matter microstructural damage and cognitive impairment in hemodialysis patients.
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http://dx.doi.org/10.3390/nu13041292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070822PMC
April 2021

Different aspects of early and late development of atrial fibrillation during hospitalization in cryptogenic stroke.

Sci Rep 2021 Mar 29;11(1):7127. Epub 2021 Mar 29.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

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.
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http://dx.doi.org/10.1038/s41598-021-86620-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007744PMC
March 2021

Mucosal-Associated Invariant T Cells Are Involved in Acute Ischemic Stroke by Regulating Neuroinflammation.

J Am Heart Assoc 2021 Apr 18;10(7):e018803. Epub 2021 Mar 18.

Department of Neurology Juntendo University Faculty of Medicine Tokyo Japan.

Background Mucosal-associated invariant T (MAIT) cells have been associated with inflammation in several autoimmune diseases. However, their relation to ischemic stroke remains unclear. This study attempted to elucidate the role of MAIT cells in acute ischemic stroke in mice. Methods and Results We used MR1 knockout C57BL/6 (MR1) mice and wild-type littermates (MR1). After performing a transient middle cerebral artery occlusion (tMCAO), we evaluated the association with inflammation and prognosis in the acute cerebral ischemia. Furthermore, we analyzed the tMCAO C57BL/6 mice administered with the suppressive MR1 ligand and the vehicle control. We also evaluated the infiltration of MAIT cells into the ischemic brain by flow cytometry. Results showed a reduction of infarct volume and an improvement of neurological impairment in MR1 mice (n=8). There was a reduction in the number of infiltrating microglia/macrophages (n=3-5) and in their activation (n=5) in the peri-infarct area of MR1 mice. The cytokine levels of interleukin-6 and interleukin-17 at 24 hours after tMCAO (n=3-5), and for interleukin-17 at 72 hours after tMCAO (n=5), were lower in the MR1 mice. The administration of the suppressive MR1 ligand reduced the infarct volume and improved functional impairment (n=5). Flow cytometric analysis demonstrated there was a reduction of MAIT cells infiltrating into the ischemic brain at 24 hours after tMCAO (n=17). Conclusions Our results showed that MAIT cells play an important role in neuroinflammation after focal cerebral ischemia and the use of MAIT cell regulation has a potential role as a novel neuroprotectant for the treatment of acute ischemic stroke.
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http://dx.doi.org/10.1161/JAHA.120.018803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174378PMC
April 2021

Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.

BMC Neurol 2021 Feb 10;21(1):61. Epub 2021 Feb 10.

Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan.

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.
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http://dx.doi.org/10.1186/s12883-021-02098-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874473PMC
February 2021

Pioglitazone Prevents Hemorrhagic Infarction After Transient Focal Ischemia in Type 2 Diabetes.

Neurosci Res 2020 Dec 11. Epub 2020 Dec 11.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

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.
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http://dx.doi.org/10.1016/j.neures.2020.09.004DOI Listing
December 2020

Cilostazol Addition to Aspirin could not Reduce the Neurological Deterioration in TOAST Subtypes: ADS Post-Hoc Analysis.

J Stroke Cerebrovasc Dis 2021 Feb 2;30(2):105494. Epub 2020 Dec 2.

Department of Neurological Science, Nippon Medical School Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Japan.

Background: Our previous trial acute dual study (ADS) reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of short-term neurological worsening in non-cardioembolic stroke patients. Present post-hoc analysis investigated whether the impact of combined cilostazol and aspirin differed among stroke subtypes and factors associated with neurological deterioration and/or stroke recurrence.

Methods: Using the ADS registry, the rate of neurological deterioration, defined as clinical worsening and/or recurrent stroke, including transient ischemic attack was calculated. Stroke subtypes included large-artery atherosclerosis (LAA), small vessel occlusion (SVO), other determined etiology (Others), and undetermined etiology of stroke (Undetermined).

Results: Data of 1022 patients were analyzed. Deterioration was seen in 104 (10%) patients, and the rates were not markedly different between patients treated with DAPT vs. aspirin in any stroke subtypes: LAA, 19% vs. 11%, (p=0.192); SVO, 10% vs. 10% (p=1.000); Others, 6% vs. 6% (p=1.000); Undetermined, 11% vs. 8% (p=0.590). Diabetes mellitus was the independent factor associated with deterioration (odds ratio 4.360, 95% confidence interval 1.139-16.691, p=0.032) in the LAA group. Age (1.030 [1.004-1.057], p=0.026), systolic blood pressure (1.012 [1.003-1.022], p=0.010), and infarct size (2.550 [1.488-4.371], p=0.001) were associated with deterioration in SVO group, and intracranial stenosis/occlusion was associated with it in the Undetermined group (3.744 [1.138-12.318], p=0.030).

Conclusions: Combined cilostazol and aspirin did not reduce the rate of short-term neurological deterioration in any clinical stroke subtype. The characteristics of patients whose condition deteriorates in the acute period may differ based on the stroke subtypes.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105494DOI Listing
February 2021

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan.

Front Aging Neurosci 2020 14;12:216. Epub 2020 Jul 14.

Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan.

Objectives: Clinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed.

Methods: Subjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire.

Results: Based on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 ( = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan.

Conclusion: This questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.
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http://dx.doi.org/10.3389/fnagi.2020.00216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381163PMC
July 2020

Atrial Septal Aneurysm may Cause In-Hospital Recurrence of Cryptogenic Stroke.

J Atheroscler Thromb 2021 May 17;28(5):514-523. Epub 2020 Jul 17.

Department of Neurology, Juntendo University Urayasu Hospital.

Aims: Awareness of potentially embologenic diseases is critical to determining the prognosis of cryptogenic stroke. The clinical significance of atrial septal aneurysm (ASA) in cryptogenic stroke has not been fully studied. Therefore, we explored clinical characteristics and in-hospital recurrence in patients with ASA in cryptogenic stroke.

Methods: A multicenter observational registry of cryptogenic stroke patients was conducted. We obtained baseline characteristics, radiological and laboratory findings, and echocardiographic findings, especially of embolic sources on transesophageal echocardiography. The CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for embolic stroke of undetermined source/cryptogenic stroke) registry was recorded at http://www.umin.ac.jp/ctr/ (UMIN000032957). Patients' clinical characteristics were compared according to the presence of ASA, and factors associated with in-hospital stroke recurrence were assessed.

Results: The study included 671 patients (age, 68.7±12.7 years; 450 males; median National Institutes of Health Stroke Scale score, 2). ASA was detected in 92 patients (14%), displaying higher age (72.4±11.0 vs. 68.1 ±12.9 years, p=0.004), reduced frequency of diabetes mellitus (16% vs. 27%, p=0.030), higher frequency of right-to-left shunt (66% vs. 45%, p<0.001), and in-hospital stroke recurrence (8% vs. 3%, p=0.034). ASA was relatively associated with in-hospital recurrence (odds ratio 2.497, 95% confidence interval 0.959-6.500, p= 0.061).

Conclusions: The CHALLENGE ESUS/CS registry indicated that ASA was not rare in cryptogenic stroke, and ASA's clinical characteristics included higher age, reduced frequency of diabetes mellitus, and increased frequency of concomitant right-to-left shunt. ASA may be related to in-hospital stroke recurrence in cryptogenic stroke.
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http://dx.doi.org/10.5551/jat.56440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193779PMC
May 2021

Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan.

J Hum Genet 2020 Sep 13;65(9):771-781. Epub 2020 May 13.

Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.
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http://dx.doi.org/10.1038/s10038-020-0772-4DOI Listing
September 2020

Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial.

Stroke 2020 05 6;51(5):1530-1538. Epub 2020 Apr 6.

Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya (S. Yoshimura).

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; =0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; >0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; >0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.
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http://dx.doi.org/10.1161/STROKEAHA.119.028127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185058PMC
May 2020

Cilostazol uncovers covert atrial fibrillation in non-cardioembolic stroke.

J Neurol Sci 2020 06 21;413:116796. Epub 2020 Mar 21.

Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Department of Stroke Medicine, Kawasaki Medical School, Kurashiki, Japan.

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.
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http://dx.doi.org/10.1016/j.jns.2020.116796DOI Listing
June 2020

The effects of A1/A2 astrocytes on oligodendrocyte linage cells against white matter injury under prolonged cerebral hypoperfusion.

Glia 2020 09 28;68(9):1910-1924. Epub 2020 Feb 28.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

As oligodendrocyte precursor cells (OPCs) are vulnerable to ischemia, their differentiation to oligodendrocytes (OLG) is impaired in chronic cerebral hypoperfusion. Astrocyte-OLG interaction is important for white matter homeostasis. Recently, reactive astrocytes were separated into two types, A1 (cytotoxic) and A2 (neurotrophic). However, their role in prolonged cerebral hypoperfusion remains unclear. We analyzed the effects of interaction between A1-A2 astrocytes and OPC-OLG under hypoperfusion, focusing on mitochondrial migration. As an in vivo model, chronic hypoperfusion model mice were created by bilateral common carotid artery stenosis (BCAS) using microcoils. As a matching in vitro study, rat primary cells were cocultured with a nonlethal concentration of CoCl . At 28 days after hypoperfusion, the number of OPC and astrocytes increased, whereas that of OLG decreased. Increased astrocytes were mainly A1-like astrocytes; however, the number of A2-like type decreased. In cell culture, OPC differentiation was interrupted under mimic chronic ischemia, but improved after astrocyte-conditioned medium (ACM) was added. However, injured-ACM was unable to improve OPC maturation. Incubation with CoCl changed astrocytes from A2-like to A1-like, and mitochondrial migration was also reduced. A Trkβ agonist was able to maintain astrocytes from A1-like to A2-like even under hyperperfused conditions, and aided in OPC maturation and memory impairment via mitochondrial migration and drug effects in cell culture study and BCAS model. The reduction of A1-like astrocytes protects against white matter injury. Trkβ agonists may play an important role in the impairment under chronic ischemic conditions. Mitochondrial migration may be a broad therapeutic strategy for cerebrovascular diseases. MAIN POINTS: Prolonged cerebral hypoperfusion leads to impaired oligodendrocyte (OLG) maturation and increased numbers of A1 astrocytes. Mitochondria migration maintained A2 astrocyte morphology, mature OLG, and myelinated white matter in vivo/vitro.
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http://dx.doi.org/10.1002/glia.23814DOI Listing
September 2020

Cerebral Microbleeds and Chronic Kidney Disease in Acute Ischemic Stroke Patients with Atrial Fibrillation.

J Stroke Cerebrovasc Dis 2020 Apr 3;29(4):104650. Epub 2020 Feb 3.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Background: Cerebral microbleeds (CMBs) are associated with the risk of intracerebral hemorrhage in stroke patients with atrial fibrillation (AF). We investigated the association between CMBs and chronic kidney disease (CKD) in patients with acute ischemic stroke and AF.

Methods: We retrospectively examined consecutive patients with acute ischemic stroke and AF who underwent brain gradient-echo T2*-weighted magnetic resonance imaging. The number and distribution (lobar, deep or infratentorial, and mixed) of CMBs were assessed. Kidney function was assessed according to the estimated glomerular filtration rate (eGFR), which was calculated using a modified version of the Modification of Diet in Renal Disease equation.

Results: Of the 357 included patients, 105 (29.4%) had CMBs. CKD (eGFR < 60 mL/min/1.73 m) was found in 131 (36.7%) patients. Patients with CKD showed a higher prevalence of any form of CMB (41.2% versus 22.6%, P < .001), deep or infratentorial CMBs (19.9% versus 9.3%, P < .01), and mixed CMBs (14.5% versus 5.3%, P < .01) than those without CKD. After adjusting for age and other confounding factors, CKD was found to be independently associated with the presence of any form of CMB (odds ratio 1.89, P = .02) and mixed CMBs (odds ratio 3.10, P < .01). Moreover, moderate to severe CKD (eGFR < 45 mL/min/1.73 m) was independently associated with the presence of multiple CMBs (odds ratio 2.31, P = .04).

Conclusions: CMBs and CKD are common in acute ischemic stroke patients with AF, and CKD may be a risk factor for CMBs. Further longitudinal studies are needed to evaluate whether maintaining kidney function can prevent the development of CMBs.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104650DOI Listing
April 2020

Underlying embolic and pathologic differentiation by cerebral microbleeds in cryptogenic stroke.

J Neurol 2020 May 3;267(5):1482-1490. Epub 2020 Feb 3.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

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.
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http://dx.doi.org/10.1007/s00415-020-09732-4DOI Listing
May 2020

Eicosapentaenoic-to-Arachidonic Acid Ratio Predicts Mortality and Recurrent Vascular Events in Ischemic Stroke Patients.

J Atheroscler Thromb 2020 Sep 23;27(9):969-977. Epub 2020 Jan 23.

Department of Neurology, Juntendo University School of Medicine.

Aims: The ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) is related to major adverse events and death in cardiovascular diseases. The association between long-term prognosis of ischemic stroke and EPA/AA ratio has not been clarified.

Methods: Acute ischemic stroke patients who had undergone blood examinations for polyunsaturated fatty acids were enrolled. Major cardiovascular events, including recurrence of ischemic stroke, occurrence of cardiovascular and peripheral artery diseases and hemorrhagic stroke, and death, were analyzed, retrospectively. Cox proportional hazards regression analysis was used to explore factors, including clinical characteristics, laboratory data including EPA/AA ratio, and treatments associated with major cardiovascular events and death.

Results: A total of 269 patients (mean age, 70±13 years; 179 men) were enrolled. During follow-up (mean, 2.3 ±1.0 years), 64 patients exhibited major cardiovascular events and death (annualized rate, 10.5% per person-year). Multivariate Cox analysis revealed that EPA/AA ratio (hazard ratio, 0.26; 95% confidence interval, 0.07- 0.99; p=0.048) and statin therapy (hazard ratio, 0.43; 95% confidence interval, 0.25-0.73; p=0.002) correlated inversely with major cardiovascular events and death. In the Kaplan-Meier analysis, cumulative event-free rates were significantly lower among patients with EPA/AA ratio <0.33 and patients without statin therapy (p=0.006).

Conclusions: Low EPA/AA ratio at baseline and treatment without statins could predict mortality, recurrent ischemic stroke, cardiovascular and peripheral artery diseases, and hemorrhagic stroke among patients with acute ischemic stroke. The combination of baseline EPA/AA ratio and statin therapy could be critical in predicting the long-term prognosis of ischemic stroke patients.
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http://dx.doi.org/10.5551/jat.52373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508728PMC
September 2020

Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia.

J Cereb Blood Flow Metab 2020 12 7;40(12):2505-2520. Epub 2020 Jan 7.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

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 () and phenotypically normal littermates (). Compared to mice, mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition, 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 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.
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http://dx.doi.org/10.1177/0271678X19899577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820690PMC
December 2020

Analysis of Clinical Symptoms and Brain MRI of Heat Stroke: 2 Case Reports and a Literature Review.

J Stroke Cerebrovasc Dis 2020 Feb 26;29(2):104511. Epub 2019 Nov 26.

Department of Neurology, Juntendo Urayasu Hospital, Urayasu-city, Chiba, Japan.

Introduction: Heat stroke is defined as high body temperature causing multiple organ failure, psychological change, seizure, and consciousness disturbance, which lead to its high mortality rate. However, the involvement of brain injury is rare, and heat-stroke has only been reported in a few case reports or case series. The purpose of this case study was to evaluate the clinical symptoms and radiological features of heat stroke.

Methods: We reviewed our hospital records and previously published reports to find cases of heat stroke. We excluded those with unknown clinical features or radiological findings.

Results: We retrieved 2 cases of heat stroke from our hospital, which presented as extensive lesions on brain imaging that led to disseminated intravascular coagulation and death within a few days. In 21 previously reported cases of heat stroke, similar brain lesions were noted. These were classified as infarction/posterior reversible encephalopathy syndrome (PRES)-like lesions. The patients who developed PRES-like lesions and survived often developed cerebellar sequelae.

Conclusion: The mechanism of heat stroke is presumed to be multifactorial. Ischemic-like lesions result from hypovolemia and unusual coagulation, whereas PRES-like lesions are caused by direct heat and vasogenic edema due to hypercytokinemia. We need to consider the above mentioned conditions when evaluating heat stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.104511DOI Listing
February 2020

New Alzheimer's disease model mouse specialized for analyzing the function and toxicity of intraneuronal Amyloid β oligomers.

Sci Rep 2019 11 22;9(1):17368. Epub 2019 Nov 22.

Molecular Neurobiology Research Group and DAILAB, Biomedical Research Institute (BMRI), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1, Higashi, Tsukuba, Ibaraki, 305-8566, Japan.

Oligomers of intracellular amyloid β protein (Aβ) are strongly cytotoxic and play crucial roles in synaptic transmission and cognitive function in Alzheimer's disease (AD). However, there is currently no AD model mouse in which to specifically analyze the function of Aβ oligomers only. We have now developed a novel AD model mouse, an Aβ-GFP transgenic mouse (Aβ-GFP Tg), that expresses the GFP-fused human Aβ protein, which forms only Aβ oligomers within neurons throughout their life. The fusion proteins are expressed mainly in the hippocampal CA1-CA2 region and cerebral cortex, and are not secreted extracellularly. The Aβ-GFP Tg mice exhibit increased tau phosphorylation, altered spine morphology, decreased expressions of the GluN2B receptor and neuroligin in synaptic regions, attenuated hippocampal long-term potentiation, and impaired object recognition memory compared with non-Tg littermates. Interestingly, these dysfunctions have already appeared in 2-3-months-old animals. The Aβ-GFP fusion protein is bioactive and highly toxic, and induces the similar synaptic dysfunctions as the naturally generated Aβ oligomer derived from postmortem AD patient brains and synthetic Aβ oligomers. Thus, Aβ-GFP Tg mouse is a new tool specialized to analyze the function of Aβ oligomers in vivo and to find subtle changes in synapses in early symptoms of AD.
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http://dx.doi.org/10.1038/s41598-019-53415-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874556PMC
November 2019

Multiple cerebral infarction diagnosed as Eosinophilic Granulomatosis with Polyangiitis by autopsy.

BMC Neurol 2019 Nov 15;19(1):288. Epub 2019 Nov 15.

Department of Neurology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu, Chiba, 279-0021, Japan.

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.
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http://dx.doi.org/10.1186/s12883-019-1515-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857209PMC
November 2019

Clinical Characterization of Definite Autoimmune Limbic Encephalitis: A 30-case Series.

Intern Med 2019 Dec 21;58(23):3369-3378. Epub 2019 Aug 21.

Department of Neurology, Juntendo University School of Medicine, Japan.

Objective Limbic encephalitis (LE) is an inflammatory condition of the limbic system that has an acute or subacute onset. Several types of antibodies are related to the onset of LE, including anti-N-methyl D-aspartate receptor (NMDAR) antibodies and voltage-gated potassium channel (VGKC)-complex antibodies. However, the characteristics and prevalence of LE remain unclear, especially in Asian cohorts, due to the rarity. We aimed to survey their characteristics. Materials and Methods Data of 30 cases clinically defined as "definite autoimmune LE" (based on the standard criteria) were retrospectively collected. These patients were categorized into four subtypes: NMDAR (+) (n=8), VGKC (+) (n=2), antibodies related to paraneoplastic syndrome (n=2), and an antibody-negative group (uncategorized) (n=18). Results LE is rare in Japan, and affected only 30 of 16,759 hospital patients (0.2%) over a ten-year period. The NMDAR (+) group showed distinctive symptoms, while the other three groups had similar indications. Brain MRI indicated significant medial temporal lobe atrophy at one year follow up after discharge. The prevalence of cognitive dysfunction as a complication was 64% (9/14). First-line immunotherapy resulted in a good outcome. A drastic improvement was seen from 4.0±1.1 to 1.1+ on the modified Rankin Scale. A good treatment outcome was observed in all groups (NMDAR, VGKC, and uncategorized), suggesting the importance of an early clinical diagnosis and the early initiation of treatment. Furthermore, we reviewed 26 cases that were clinically diagnosed as definitive autoimmune LE in previous case reports. Conclusion Our findings show that the establishment of a clinical diagnosis based on the clinical criteria of definitive autoimmune LE is important for the initiation of immunotherapy.
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http://dx.doi.org/10.2169/internalmedicine.3029-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928500PMC
December 2019

Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

Circulation 2019 09 22;140(12):992-1003. Epub 2019 Aug 22.

Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan (K.H., H.I.).

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; =0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; =0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; =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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.039415DOI Listing
September 2019

Acute Aspirin Plus Cilostazol Dual Therapy for Noncardioembolic Stroke Patients Within 48 Hours of Symptom Onset.

J Am Heart Assoc 2019 08 26;8(15):e012652. Epub 2019 Jul 26.

Department of Neurological Science Graduate School of Medicine Nippon Medical School Tokyo Japan.

Background The aim of the present study was to investigate the efficacy and safety of antiplatelet (aspirin plus cilostazol) dual therapy for patients with noncardioembolic stroke within 48 hours of symptom onset. Methods and Results The ADS (Acute Aspirin Plus Cilostazol Dual Therapy for Non-Cardiogenic Stroke Patients Within 48 Hours of Symptom Onset ) study is an investigator-initiated, prospective, multicenter (34 hospitals in Japan), randomized, open-label, and aspirin-controlled trial. Acute stroke patients with noncardioembolic stroke within 48 hours of onset were studied. The subjects were randomly allocated to combination therapy with aspirin 81 to 200 mg plus cilostazol 200 mg (dual group) and single therapy with aspirin 81 to 200 mg (aspirin group) for 14 days. After the 14 days, all patients took the cilostazol 200 mg for 3 months. A primary efficacy outcome was defined as any one of the following occurring (neurological deterioration, symptomatic stroke recurrence, or transient ischemic attack) within 14 days. A primary safety outcome included intracerebral hemorrhage and subarachnoid hemorrhage. Between May 2011 and June 2017, 1201 patients (796 [66%] men; median age, 69 [61-77] years) randomized 1:1 to either the dual group or the aspirin group were analyzed. Initial National Institutes of Health Stroke Scale score was 2 (1-4) in both groups (P=0.830). A primary efficacy outcome was observed in 11% in the dual group and 11% in the aspirin group (P=0.853). A primary safety outcome occurred in 2 (0.3%) in the dual group and in 1 (0.2%) in the aspirin group (P=0.624). Conclusions Dual antiplatelet therapy using cilostazol and aspirin was safe but did not reduce the rate of short-term neurological worsening. Clinical Trial Registration URL: umin.ac.jp/ctr/index/htm. Unique identifier: UMIN000004950.
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http://dx.doi.org/10.1161/JAHA.119.012652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761671PMC
August 2019

Protective Role of Levetiracetam Against Cognitive Impairment And Brain White Matter Damage in Mouse prolonged Cerebral Hypoperfusion.

Neuroscience 2019 08 11;414:255-264. Epub 2019 Jul 11.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

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.
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http://dx.doi.org/10.1016/j.neuroscience.2019.07.015DOI Listing
August 2019

Large aortic arch plaques correlate with CHADS and CHADS-VASc scores in cryptogenic stroke.

Atherosclerosis 2019 05 20;284:181-186. Epub 2019 Mar 20.

Department of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan.

Background And Aims: 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.

Methods: 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 and CHADS-VASc scores (0-1 vs. ≥2, respectively). This study was registered at http://www.umin.ac.jp/ctr/(UMIN000032957).

Results: 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 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 CHADS-VASc score ≥2.

Conclusions: 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 and CHADS-VASc scores, and represented important embolic sources in cryptogenic stroke.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.03.009DOI Listing
May 2019

The Effects of Astrocyte and Oligodendrocyte Lineage Cell Interaction on White Matter Injury under Chronic Cerebral Hypoperfusion.

Neuroscience 2019 May 10;406:167-175. Epub 2019 Mar 10.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.neuroscience.2019.03.004DOI Listing
May 2019

Astrocyte-Derived Exosomes Treated With a Semaphorin 3A Inhibitor Enhance Stroke Recovery via Prostaglandin D Synthase.

Stroke 2018 10;49(10):2483-2494

From the Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, Japan (K.H., Y.U., R.T., N.M., K.Y., N.H.).

Background and Purpose- Exosomes play a pivotal role in neurogenesis. In the peri-infarct area after stroke, axons begin to regenerate but are inhibited by astrocyte scar formation. The direct effect and underlying molecular mechanisms of astrocyte-derived exosomes on axonal outgrowth after ischemia are not known. Methods- Using a semaphorin 3A (Sema3A) inhibitor, we explored neuronal signaling during axonal outgrowth after ischemia in rats subjected to middle cerebral artery occlusion and in cultured cortical neurons challenged with oxygen-glucose deprivation. Furthermore, we assessed whether this inhibitor suppressed astrocyte activation and regulated astrocyte-derived exosomes to enhance axonal outgrowth after ischemia. Results- In rats subjected to middle cerebral artery occlusion, we administered a Sema3A inhibitor into the peri-infarct area from 7 to 21 days after occlusion. We found that phosphorylated high-molecular weight neurofilament-immunoreactive axons were increased, glial fibrillary acidic protein-immunoreactive astrocytes were decreased, and functional recovery was promoted at 28 days after middle cerebral artery occlusion. In cultured neurons, the Sema3A inhibitor decreased Rho family GTPase 1, increased R-Ras, which phosphorylates Akt and glycogen synthase kinase 3β (GSK-3β), selectively increased phosphorylated GSK-3β in axons, and thereby enhanced phosphorylated high-molecular weight neurofilament-immunoreactive axons after oxygen-glucose deprivation. In cultured astrocytes, the Sema3A inhibitor suppressed activation of astrocytes induced by oxygen-glucose deprivation. Exosomes secreted from ischemic astrocytes treated with the Sema3A inhibitor further promoted axonal elongation and increased prostaglandin D synthase expression on microarray analysis. GSK-3β and prostaglandin D synthase neurons were robustly increased after treatment with the Sema3A inhibitor in the peri-infarct area. Conclusions- Neuronal Rho family GTPase 1/R-Ras/Akt/GSK-3β signaling, axonal GSK-3β expression, and astrocyte-derived exosomes with prostaglandin D synthase expression contribute to axonal outgrowth and functional recovery after stroke.
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http://dx.doi.org/10.1161/STROKEAHA.118.021272DOI Listing
October 2018

Adequate Adherence to Direct Oral Anticoagulant is Associated with Reduced Ischemic Stroke Severity in Patients with Atrial Fibrillation.

J Stroke Cerebrovasc Dis 2019 Jun 12;28(6):1773-1780. Epub 2018 Oct 12.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.

Background: The impact of adherence to direct oral anticoagulants (DOACs) is unknown. We aimed to assess the effects of preceding anticoagulation treatment on neurologic severity at admission and functional outcomes at discharge in patients with atrial fibrillation (AF) who developed acute ischemic stroke.

Methods: We retrospectively assessed consecutive patients with acute ischemic stroke and AF. Adherence to DOACs was assessed using the 4-item Morisky Medication Adherence Scale. Associations between preceding DOAC treatment and stroke severity at admission and functional outcomes at hospital discharge were examined.

Results: Of 387 patients with AF and acute ischemic stroke, 248 (64.1%) were not administered an anticoagulant before stroke onset, 95 (24.5%) had subtherapeutic warfarin with an international normalized ratio less than 2 at the time of stroke, 16 (4.1%) had therapeutic warfarin, 6 (1.6%) had DOACs with nonadherence, and 22 (5.7%) had DOACs with adequate adherence. Multivariate analysis showed that DOAC treatment with adequate adherence was associated with lower odds of severe stroke (National Institute of Health Stroke Scale ≥10 at admission) (odds ratio, .24; 95% confidence interval, .03-.98; P = .04) and higher odds of excellent recovery (modified Rankin Scale score, 0-1 at discharge) (odds ratio, 4.89; 95% confidence interval, 1.51-20.6; P < .01) compared with no anticoagulation therapy.

Conclusions: Preceding DOAC treatment with adequate adherence has beneficial effects on stroke severity at admission and functional outcome at discharge in patients with AF. Hence, our results encourage an increased effort to bolster adherence to DOACs in patients with AF.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.09.019DOI Listing
June 2019