Publications by authors named "Kaori Miwa"

34 Publications

The bleeding with antithrombotic therapy study 2: Rationale, design, and baseline characteristics of the participants.

Eur Stroke J 2020 Dec 24;5(4):423-431. Epub 2020 Sep 24.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

Aims: The bleeding risk of current antithrombotic strategies in clinical settings, including recently developed agents, needs to be clarified.

Methods And Design: In an investigator-initiated, prospective, multicentre, observational study, patients with cerebrovascular or cardiovascular diseases who were taking oral antiplatelet or anticoagulant agents were enrolled. Compulsory multimodal magnetic resonance images were acquired at baseline to assess cerebral small vessel disease. Six-month follow-up will be performed for two years. The primary outcome is major bleeding as defined by the International Society on Thrombosis and Hemostasis.

Results: Between October 2016 and March 2019, 5306 patients (71.7 ± 11.2 years old, 1762 women) were enrolled. Previous intracranial haemorrhage was documented in 181 patients (3.4%), cerebrovascular disease (including asymptomatic) requiring antithrombotic therapy in 5006 patients (94.3%), and atrial fibrillation in 1061 patients (20.0%). At entry, 3726 patients (70.2%) were taking antiplatelet agents alone, including 551 (10.4%) using dual antiplatelet agents, 1317 (24.8%) taking anticoagulants alone, and the remaining 263 (5.0%) taking both. The leading antiplatelet agent was clopidogrel (2014 patients), and the leading combination of dual antiplatelet medication was clopidogrel plus aspirin (362). Use of direct oral anticoagulants (1029 patients, 19.4%) exceeded warfarin use (554, 10.4%). The number of pivotal bleeding events exceeded 200 in April 2020.

Conclusions: This study is expected to provide the incidence of bleeding complications of recent oral antithrombotics in clinical practice and identify their associations with underlying small vessel disease and other biomarkers. Novel risk stratification models for bleeding risk will be able to be created based on the study results.
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http://dx.doi.org/10.1177/2396987320960618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856591PMC
December 2020

A nomogram to predict unfavourable outcome in patients receiving oral anticoagulants for atrial fibrillation after stroke.

Eur Stroke J 2020 Dec 26;5(4):384-393. Epub 2020 Nov 26.

Neurology and Stroke Center, University Hospital Basel and University of Basel, Basel, Switzerland.

Introduction: It is unknown whether the type of treatment (direct oral anticoagulant versus vitamin K antagonist) and the time of treatment introduction (early versus late) may affect the functional outcome in stroke patients with atrial fibrillation. We aimed to develop and validate a nomogram model including direct oral anticoagulant/vitamin K antagonist and early/late oral anticoagulant introduction for predicting the probability of unfavourable outcome after stroke in atrial fibrillation-patients.

Patients And Methods: We conducted an individual patient data analysis of four prospective studies. Unfavourable functional outcome was defined as three-month modified Rankin Scale score 3 -6. To generate the nomogram, five independent predictors including age (<65 years, reference; 65--79; or 80), National Institutes of Health Stroke Scale score (0--5 points, reference; 6--15; 16--25; or >25), acute revascularisation treatments (yes, reference, or no), direct oral anticoagulant (reference) or vitamin K antagonist, and early (7 days, reference) or late (8--30) anticoagulant introduction entered into a final logistic regression model. The discriminative performance of the model was assessed by using the area under the receiver operating characteristic curve.

Results: A total of 2102 patients with complete data for generating the nomogram was randomly dichotomised into training ( = 1553) and test ( = 549) sets. The area under the receiver operating characteristic curve was 0.822 (95% confidence interval, CI: 0.800--0.844) in the training set and 0.803 (95% CI: 0.764--0.842) in the test set. The model was adequately calibrated (9.852;  = 0.276 for the Hosmer--Lemeshow test).

Discussion And Conclusion: Our nomogram is the first model including type of oral anticoagulant and time of treatment introduction to predict the probability of three-month unfavourable outcome in a large multicentre cohort of stroke patients with atrial fibrillation.
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http://dx.doi.org/10.1177/2396987320945840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856583PMC
December 2020

Magnetic Resonance Imaging-Guided Thrombolysis (0.6 mg/kg) Was Beneficial for Unknown Onset Stroke Above a Certain Core Size: THAWS RCT Substudy.

Stroke 2021 01 10;52(1):12-19. Epub 2020 Dec 10.

Department of Cerebrovascular Medicine (K.T., M. Inoue, S.Y., M.F.-D., K. Miwa, M. Shiozawa, K. Minematsu, M.K.), National Cerebral and Cardiovascular Center, Suita, Japan.

Background And Purpose: We determined to identify patients with unknown onset stroke who could have favorable 90-day outcomes after low-dose thrombolysis from the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg) database.

Methods: This was a subanalysis of an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients with stroke with a time last-known-well >4.5 hours who showed a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg intravenously or standard medical treatment. The patients were dichotomized by ischemic core size or National Institutes of Health Stroke Scale score, and the effects of assigned treatments were compared in each group. The efficacy outcome was favorable outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1.

Results: The median DWI-Alberta Stroke Program Early CT Score (ASPECTS) was 9, and the median ischemic core volume was 2.5 mL. Both favorable outcome (47.1% versus 48.3%) and any intracranial hemorrhage (26% versus 14%) at 22 to 36 hours were comparable between the 68 thrombolyzed patients and the 58 control patients. There was a significant treatment-by-cohort interaction for favorable outcome between dichotomized patients by ASPECTS on DWI (=0.026) and core volume (=0.035). Favorable outcome was more common in the alteplase group than in the control group in patients with DWI-ASPECTS 5 to 8 (RR, 4.75 [95% CI, 1.33-30.2]), although not in patients with DWI-ASPECTS 9 to 10. Favorable outcome tended to be more common in the alteplase group than in the control group in patients with core volume >6.4 mL (RR, 6.15 [95% CI, 0.87-43.64]), although not in patients with volume ≤6.4 mL. The frequency of any intracranial hemorrhage did not differ significantly between the 2 treatment groups in any dichotomized patients.

Conclusions: Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02002325. URL: https://www.umin.ac.jp/ctr; Unique Identifier: UMIN000011630.
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http://dx.doi.org/10.1161/STROKEAHA.120.030848DOI Listing
January 2021

Regional Differences in the Response to Acute Blood Pressure Lowering After Cerebral Hemorrhage.

Neurology 2021 02 20;96(5):e740-e751. Epub 2020 Nov 20.

From the Department of Cerebrovascular Medicine (K. Toyoda, M.K., S.Y., K. Tanaka, K.M.), Center for Advancing Clinical and Translational Sciences (H.Y., M.F.-D., S.O.), and Department of Neurology (M.I.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Public Health Sciences (Y.Y.P., L.F.), Medical University of South Carolina, Charleston; Department of Neurology (Y.H.), St. Marianna University School of Medicine, Kawasaki; Department of Neurosurgery and Stroke Center (Y.S.), Kyorin University School of Medicine, Mitaka; Department of Neurosurgery (T.I.), Gifu University Graduate School of Medicine; Department of Neurosurgery (K.K.), Nakamura Memorial Hospital, Sapporo; Department of Neurology (H.H.), Tokyo Saiseikai Central Hospital, Japan; Department of Neurology (T.S.), Klinikum Frankfurt Höchst, Germany; Department of Neurology (B.-W.Y.), Seoul National University Hospital, South Korea; Beijing Tiantan Hospital (Y.W.), China; China Medical University (C.Y.H.), Taichung, Taiwan; and Zeenat Qureshi Stroke Research Center (A.I.Q.), University of Minnesota, Minneapolis.

Objective: To compare the impact of intensive blood pressure (BP) lowering right after intracerebral hemorrhage (ICH) on clinical and hematoma outcomes among patients from different geographic locations, we performed a prespecified subanalysis of a randomized, multinational, 2-group, open-label trial to determine the efficacy of rapidly lowering BP in hyperacute ICH (Antihypertensive Treatment of Acute Cerebral Hemorrhage [ATACH]-2), involving 537 patients from East Asia and 463 recruited outside of Asia.

Methods: Eligible patients were randomly assigned to a systolic BP target of 110 to 139 mm Hg (intensive treatment) or 140 to 179 mm Hg (standard treatment). Predefined outcomes were poor functional outcome (modified Rankin Scale score 4-6 at 90 days), death within 90 days, hematoma expansion at 24 hours, and cardiorenal adverse events within 7 days.

Results: Poor functional outcomes (32.0% vs 45.9%), death (1.9% vs 13.3%), and cardiorenal adverse events (3.9% vs 11.2%) occurred significantly less frequently in patients from Asia than those outside of Asia. The treatment-by-cohort interaction was not significant for any outcomes. Only patients from Asia showed a lower incidence of hematoma expansion with intensive treatment (adjusted relative risk [RR] 0.56, 95% confidence interval [CI] 0.38-0.83). Both Asian (RR 3.53, 95% CI 1.28-9.64) and non-Asian (RR 1.71, 95% CI 1.00-2.93) cohorts showed a higher incidence of cardiorenal adverse events with intensive treatment.

Conclusions: Poor functional outcomes and death 90 days after ICH were less common in patients from East Asia than those outside of Asia. Hematoma expansion, a potential predictor for poor clinical outcome, was attenuated by intensive BP lowering only in the Asian cohort.

Clinicaltrialsgov Identifier: NCT01176565.

Classification Of Evidence: This study provides Class II evidence that, for patients from East Asia with ICH, intensive blood pressure lowering significantly reduces the risk of hematoma expansion.
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http://dx.doi.org/10.1212/WNL.0000000000011229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884997PMC
February 2021

Left Atrial Size and Ischemic Events after Ischemic Stroke or Transient Ischemic Attack in Patients with Nonvalvular Atrial Fibrillation.

Cerebrovasc Dis 2020 11;49(6):619-624. Epub 2020 Nov 11.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

Background: The present study aimed to clarify the association between left atrial (LA) size and ischemic events after ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF).

Methods: Acute ischemic stroke or TIA patients with NVAF were enrolled. LA size was classified into normal LA size, mild LA enlargement (LAE), moderate LAE, and severe LAE. The ischemic event was defined as ischemic stroke, TIA, carotid endarterectomy, carotid artery stenting, acute coronary syndrome or percutaneous coronary intervention, systemic embolism, aortic aneurysm rupture or dissection, peripheral artery disease requiring hospitalization, or venous thromboembolism.

Results: A total of 1,043 patients (mean age, 78 years; 450 women) including 1,002 ischemic stroke and 41 TIA were analyzed. Of these, 351 patients (34%) had normal LA size, 298 (29%) had mild LAE, 198 (19%) had moderate LAE, and the remaining 196 (19%) had severe LAE. The median follow-up duration was 2.0 years (interquartile range, 0.9-2.1). During follow-up, 117 patients (11%) developed at least one ischemic event. The incidence rate of total ischemic events increased with increasing LA size. Severe LAE was independently associated with increased risk of ischemic events compared with normal LA size (multivariable-adjusted hazard ratio, 1.75; 95% confidence interval, 1.02-3.00).

Conclusion: Severe LAE was associated with increased risk of ischemic events after ischemic stroke or TIA in patients with NVAF.
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http://dx.doi.org/10.1159/000511393DOI Listing
March 2021

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

Lancet 2020 11 8;396(10262):1574-1584. Epub 2020 Nov 8.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers.

Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903.

Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024).

Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734592PMC
November 2020

Oral Carriage of Harboring the Gene Relates to an Increased Incidence of Cerebral Microbleeds.

Stroke 2020 12 5;51(12):3632-3639. Epub 2020 Nov 5.

Department of Neurology (S.H., S.S., S.T., H. Ishiyama, T.Y., S.I., H. Ikenouchi, Y.H., M.I.), National Cerebral and Cardiovascular Center, Suita, Japan.

Background And Purpose: Cerebral microbleeds (CMB) are associated with stroke and cognitive impairment. We previously reported a high prevalence of CMB in people with expressing Cnm, a collagen-binding protein in the oral cavity. is a major pathogen responsible for dental caries. Repeated challenge with harboring the gene encoding Cnm induced cerebral bleeding in stroke-prone spontaneously hypertensive rats. The purpose of this longitudinal study is to examine the relationship of -positive to the development of CMB.

Methods: We retrospectively investigated patients with stroke receiving oral microbiological examination and head 3T magnetic resonance imaging evaluations twice in the period 2014 to 2019, allowing >180-day interval. Patients with -positive were compared with those without. Quasi-Poisson regression models were used to explore associations between -positive and the increase in number of CMB between the 2 magnetic resonance imaging scans.

Results: A total of 111 patients were identified; 21 (19%) with -positive and 90 (81%) without. Clinical history, including blood pressure and the use of antithrombotic agents, were comparable between the 2 groups. New CMB were more commonly observed in patients with -positive (52% versus 23%; =0.008). The incidence of CMB was significantly higher in the group with -positive , especially in deep areas, (incidence rate ratios [95% CI], 5.1 [1.9-13.6] for CMB in any brain region; 15.0 [5.4-42.0] for deep CMB), which persisted after adjusting for age, sex, hypertension, and renal impairment (4.7 [1.8-11.9] for CMB in any brain region; 13.9 [4.3-44.5] for deep CMB).

Conclusions: This study demonstrates that -positive is associated with an increased incidence of CMB. Treatment for -positive infection may be a novel microbiota-based therapeutic approach for stroke and cognitive impairment.
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http://dx.doi.org/10.1161/STROKEAHA.120.029607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678651PMC
December 2020

Cerebral embolism accompanied by remarkable diffusion-weighted imaging reversal in a 10 month-old infant with congenital heart disease.

eNeurologicalSci 2020 Sep 12;20:100260. Epub 2020 Aug 12.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, 6-1, Kishibe-shimmachi, Suita, Osaka 564-8565, Japan.

•The case of infant ischemic stroke with remarkable DWI reversal.•A mismatch between core volume and visually DWI lesion predicts DWI reversal.•Chronic hypoxia and early recanalization may contribute to large DWI reversal.•Mismatch between DWI-ASPECTS and core volume may occur in infant brain.
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http://dx.doi.org/10.1016/j.ensci.2020.100260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452634PMC
September 2020

Total small vessel disease score and functional outcomes following acute intracerebral hemorrhage.

J Stroke Cerebrovasc Dis 2020 Aug 13;29(8):105001. Epub 2020 Jun 13.

Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address:

Background: Individual cerebral small vessel disease (SVD) markers are independent predictors for poor prognosis following intracerebral hemorrhage (ICH), however, the impact of the cumulative SVD burden on outcomes remains unclear. We aimed to investigate the association between the global SVD burden and functional outcomes following ICH.

Methods: We retrospectively evaluated a consecutive cohort of patients with ICH who underwent brain magnetic resonance imaging and magnetic resonance angiography, from a prospective registry. We identified the presence and severity of the SVD markers (cerebral microbleeds, lacunar infarctions, periventricular hyperintensities, and deep white matter hyperintensities) and summed them to obtain the modified total SVD score (0-4). Poor functional outcomes were defined as a modified Rankin Scale score at discharge ≥ 3. A multivariate logistic regression model was used to assess the association between patient outcomes and the SVD score.

Results: A total of 144 patients were included (65.0 ± 12.2 years, 67.4% male). The modified total SVD score was potentially associated with poor functional outcomes (odds ratio [OR] 1.72, 95% confidence interval [CI] 0.97-3.03) after adjustment for age, sex, history of stroke, chronic kidney disease, prior use of antithrombotic agents, the National Institutes of Health Stroke Scale score on admission, the non-lobar location of ICH, and hematoma volume on admission. Moreover, among older patients (≥ 65 years), the SVD score was associated with poor outcomes (OR 3.11, 95% CI 1.01-9.55). Among those with supratentorial ICH, the score remained significant (OR 2.06, 95% CI 1.11-3.83).

Conclusions: The modified total SVD score may have predictive value for poor functional outcomes following ICH.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105001DOI Listing
August 2020

Sex Differences in Blood Pressure-Lowering Therapy and Outcomes Following Intracerebral Hemorrhage: Results From ATACH-2.

Stroke 2020 08 6;51(8):2282-2286. Epub 2020 Jul 6.

Department of Cerebrovascular Medicine (M.F.-D., M.K., S.Y., K.M., K.T.), National Cerebral and Cardiovascular Center, Suita, Japan.

Background And Purpose: Evidence regarding sex differences in clinical outcomes and treatment effect following intracerebral hemorrhage is limited. Using the ATACH-2 trial (Antihypertensive Treatment in Intracerebral Hemorrhage-2) data, we explored whether sex disparities exist in outcomes and response to intensive blood pressure (BP)-lowering therapy.

Methods: Eligible intracerebral hemorrhage subjects were randomly assigned to intensive (target systolic BP, 110-139 mm Hg) or standard (140-179 mm Hg) BP-lowering therapy within 4.5 hours after onset. Relative risk of death or disability corresponding to the modified Rankin Scale score of 4 to 6 was calculated, and interaction between sex and treatment was explored.

Results: In total, 380 women and 620 men were included. Women were older, more prescribed antihypertensive drugs before onset, and had more lobar intracerebral hemorrhage than men. Hematoma expansion was observed less in women. After multivariable adjustment, the relative risk of death or disability in women was 1.19 (95% CI, 1.02-1.37, =0.023). The relative risk of death or disability between intensive versus standard BP-lowering therapy was 0.91 (95% CI, 0.74-1.13) in women versus 1.13 (95% CI, 0.92-1.39) in men ( for interaction=0.11), with inconclusive Gail-Simmon test (=0.16).

Conclusions: Women had a higher risk of death or disability following intracerebral hemorrhage. The benefit of intensive BP-lowering therapy in women is inconclusive, consistent with the overall results of ATACH-2. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565.
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http://dx.doi.org/10.1161/STROKEAHA.120.029770DOI Listing
August 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

Tissue Plasminogen Activator for Cortical Embolism Stroke with Magnetic Resonance Perfusion Imaging: A Report of Two Cases.

Case Rep Neurol 2019 May-Aug;11(2):222-229. Epub 2019 Jul 16.

Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

Computerized tomography (CT) or magnetic resonance imaging (MRI) is indispensable for diagnosing acute ischemic stroke (AIS) patients who are candidates for recombinant tissue plasminogen activator (rt-PA) therapies, but further investigation concerning appropriate selection of therapy following advanced imaging including perfusion imaging has not yet been done. The 2018 AHA guidelines have recommended not to perform excessive time-consuming imaging before rt-PA. Here we describe two cases in which reperfusion therapy was decided based on advanced imaging. The first case was a 70-year-old woman with complaints of total aphasia and right unilateral spatial neglect. Her MRI revealed no apparent high signal area in diffusion-weighted image (DWI), and her magnetic resonance angiography (MRA) showed no large vessel occlusion. Subsequent perfusion-weighted image (PWI) analysis showed a unilateral perfusion deficit in the left middle cerebral artery (MCA) region. The other case was an 88-year-old man with complaints of minor unilateral spatial neglect, right conjugate deviation of the eyes, and dysarthria. His MRI also revealed no apparent high signal area in DWI, and MRA showed slight stenosis in the right middle MCA. Subsequent PWI analysis showed a unilateral perfusion deficit in the right MCA region. In both cases, intravenous rt-PA therapy was administered after the diagnosis of AIS and the patients responded well to the reperfusion therapy. When DWI is performed too early, detecting the ischemic core and differentiating between a diagnosis of stroke and stroke mimics is sometimes difficult. Evaluation of perfusion abnormalities in acute cases can be performed quickly, as shown in these cases. Although rt-PA can be given just by non-contrast CT with no hemorrhage, advanced imaging may be an option to identify difficult-to-diagnose patients who require reperfusion therapy.
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http://dx.doi.org/10.1159/000501547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738249PMC
July 2019

Magnetic Resonance Imaging Findings Related to Stroke Risk in Japanese Patients With Fabry Disease.

Stroke 2019 09 24;50(9):2571-2573. Epub 2019 Jul 24.

Department of Neurology (Y.Y., K.M., H.M.), Osaka University Graduate School of Medicine, Suita, Japan.

Background and Purpose- Stroke is the most frequent severe clinical event in patients with Fabry disease. We aimed to evaluate the cerebral magnetic resonance imaging findings of patients with Fabry disease and assess their association with future stroke risk after enzyme replacement therapy (ERT) induction. Methods- We retrospectively reviewed the magnetic resonance imaging findings of 25 patients with Fabry disease. Of these, 12 adult patients without prior stroke or ERT were enrolled to evaluate the association between baseline magnetic resonance imaging findings and stroke occurrence after ERT initiation. We assessed white matter hyperintensities, periventricular hyperintensities, and basilar artery diameter as neuroimaging markers. Results- The mean age of participants was 38.8±16.8 years. Fourteen patients (56.0%) were women. White matter hyperintensities and periventricular hyperintensities were observed in 15 and 13 cases, respectively. The mean basilar artery diameter was 3.2±0.55 mm. Two patients demonstrated old infarct lesions. Three of 12 patients in whom ERT was initiated had symptomatic stroke after baseline magnetic resonance imaging. Of these, 2 developed stroke within 6-month post-ERT initiation. The baseline basilar artery diameter was larger in patients who developed stroke than in those who did not (4.0±0.40 versus 2.9±0.49 mm, P=0.02). Conclusions- Basilar artery diameter may be associated with stroke risk after ERT initiation among Japanese patients with Fabry disease.
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http://dx.doi.org/10.1161/STROKEAHA.119.025528DOI Listing
September 2019

[Reliability of modified Rankin Scale assessment with a Japanese version of simplified modified Rankin Scale Questionnaire (J-RASQ)].

Rinsho Shinkeigaku 2019 Jul 27;59(7):399-404. Epub 2019 Jun 27.

Department of Neurology, National Cerebral and Cardiovascular Center.

Modified Rankin Scale (mRS) is widely used as an indicator of physical disability after the onset of stroke and a main evaluation scale in clinical stroke trials but sometimes has discrepancies among raters. We designed a Japanese version of simplified mRS questionnaire (J-RASQ) to evaluate mRS using closed question to assess the difference from the original. Currently there are no Japanese version of mRS questionnaire and its validity and reliability assessment has been warranted. Patients with planned visit to our hospital between 60 and 120 days after the onset of cerebral hemorrhage or infarction between August 2017 and March 2018 were recruited. J-RASQ was distributed before the outpatient visit to stroke patients, families or caregivers, and response was obtained. Thereafter, outpatient attending physicians qualified as stroke or neurological specialists evaluated mRS according to the Japanese version of guidance scheme for mRS. Subsequently, 130 patients (mean age, 72 ± 12 years old) were enrolled, and the difference between the two scale scores (mRS vs. J-RASQ) were statistically examined by the κ statistic and the weighted κ statistic. The κ statistic was 0.42 (95% CI, 0.31-0.52), and the weighted κ statistic calculated taking into account the extent of disagreement was 0.78 (95% CI, 0.70-0.86). We conclude that the J-RASQ appears to have decent reliability and is similar to the existing mRS.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001295DOI Listing
July 2019

Detection of Stenosis Progression in Intracranial Vertebral Artery Dissection Using Carotid Ultrasonography.

J Stroke Cerebrovasc Dis 2019 Aug 20;28(8):2201-2206. Epub 2019 May 20.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

Background: The purpose of this study was to assess whether carotid ultrasonography indices detect arterial stenosis progression in patients with vertebral artery (VA) dissection.

Methods: This was a retrospective, single-center, observational study that enrolled patients with intracranial VA dissection who were admitted from January 2011 to June 2017. Magnetic resonance angiography (MRA) was done on admission and followed up at a median 20 days after onset (interquartile range [IQR] 9-58 days), and ultrasonography was performed at a median of 22 (interquartile range 7-56) days. Peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV), and pulsatility index (PI) were measured by ultrasonography, and the ratio of each follow-up value to the baseline (follow-up/baseline) value was calculated. Two stroke neurologists categorized into 3 groups by morphological changes of the dissected vessel: patients with stenosis progression (progression group: P-group); those with no remarkable change or dilatation improved (stable group: S-group); and those with stenosis regression or dilatation enlargement (enlargement group: E-group). Ultrasonography indices were compared among the groups.

Results: Of the 42 patients who were enrolled to this study, 39 patients underwent ultrasonography and MRA on both admission and follow-up. The PI ratio was significantly higher in the P-group than in the S-group (1.96 ± .80 versus .98 ± .44, P = .02) and in the E-group (versus .65 ± .35, P < .01). There were no significant differences in the PSV ratio, EDV ratio, and MV ratio.

Conclusions: In patients with VA dissection, the PI ratio on ultrasonography is a promising index to detect stenosis progression.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.04.033DOI Listing
August 2019

Clinical and Radiological Characteristics of Intracranial Artery Dissection Using Recently Proposed Diagnostic Criteria.

J Stroke Cerebrovasc Dis 2019 Jun 19;28(6):1691-1702. Epub 2019 Mar 19.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.

Background: Data on the clinical and radiological characteristics of intracranial artery dissection (IAD) have remained limited. Our purpose was to reveal the clinical and radiological characteristics of IAD according to diagnostic criteria for IAD as recently reported by a group of international experts.

Methods: Patients were retrospectively enrolled using a prospective single-center stroke registry between 2011 and 2016. Baseline characteristics and radiological findings including conventional magnetic resonance imaging (MRI) sequences, magnetic resonance angiography (MRA), high-resolution 3-dimensional T1-weighted imaging (HR-3D-T1WI), and digital subtraction angiography were reviewed. We performed statistical comparisons to determine which findings from which modalities are useful.

Results: We identified 118 patients with suspected artery dissection, with 64 patients (median age, 51 [interquartile range, 45-56) years; 16 women) finally meeting the criteria for definite (n = 47), probable (n = 15), or possible (n = 2) idiopathic IAD. Ischemic stroke alone was found in 31 patients (48%) on admission. There were 36 patients (56%) suffering from hypertension and 39 (61%) with smoking history. The vertebral artery alone was the most affected in 42 patients (66%). Intramural hematoma (IMH) was more frequently detected on HR-3D-T1WI than on conventional MRI/MRA (odds ratio, 4.72; 95% confidence interval, 1.71-13.00). In 54 patients (84%), the modified Rankin Scale score after 3 months was 0-1.

Conclusions: Male dominance and age at IAD onset were similar to previous studies, and more than half had hypertension and smoking history. We confirmed that HR-3D-T1WI is useful for detecting IMH in the diagnostic criteria.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.02.019DOI Listing
June 2019

Effect of Enzyme Replacement Therapy on Basilar Artery Diameter in Male Patients With Fabry Disease.

Stroke 2019 04;50(4):1010-1012

Department of Neurology (K.M., M.S., H.M.), Osaka University Graduate School of Medicine, Japan.

Background and Purpose- The effect of enzyme replacement therapy (ERT) on cerebrovascular complications remains largely unexplored. We aimed to investigate the relationship between basilar artery (BA) diameter and long-term ERT in patients with Fabry disease. Methods- We obtained baseline magnetic resonance imaging data from 30 patients (40.5±16.3 years, male: 14) in the single institution; among them, 21 patients prospectively had follow-up magnetic resonance imaging assessments. The short axis of BA diameter was measured at the midpons level on axial T2-weighted images. Brain magnetic resonance imaging measurements included markers of cerebral small vessel disease (lacunas, white matter hyperintensities, and cerebral microbleeds). We assessed variables associated with baseline BA diameter and annual BA diameter change using linear regression analyses. Results- Hypertension, left ventricular hypertrophy, estimated glomerular filtration rate, and white matter hyperintensities correlated with the initial BA diameter. After a mean interval of 7.2±4.6 years, the annual BA diameter change correlated positively with severe white matter hyperintensities and inversely with the duration of ERT (β=-0.48, P=0.033). After stratifying patients by sex, a significant correlation between the duration of ERT and BA diameter was found only in men (β=-0.72, P=0.019). Conclusions- Our results show a possible relationship between ERT and changes in BA diameter. Future studies to elucidate the clinical impact of BA changes as a potential surrogate marker are needed.
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http://dx.doi.org/10.1161/STROKEAHA.118.024426DOI Listing
April 2019

A 9-Year Longitudinal Study of Basilar Artery Diameter.

J Am Heart Assoc 2019 03;8(5):e011154

1 Department of Neurology and Stroke Center Osaka University Graduate School of Medicine Suita, Osaka Japan.

Background Dilatation of the basilar artery ( BA ) has been recognized as a predictor of cardiovascular events ( CVE s). However, it is unclear if the longitudinal change in BA diameter (Δ BA ) is associated with CVE s. Methods and Results In a cohort of Japanese participants with vascular risk factors in an observational study, we evaluated the relationship of Δ BA to CVE s and the time course of the BA diameter. The short axis of the BA diameter was measured at the midpons level in T2-weighted images. Brain magnetic resonance imaging measurements included cerebral small-vessel disease, lacunars, and white matter hyperintensities. First, 493 patients were analyzed by the time-dependent Cox proportional hazards model to evaluate the association between Δ BA and CVE s, with adjustment for age, sex, vascular risk factors, and magnetic resonance imaging parameters. Second, we assessed the longitudinal Δ BA in 164 patients who underwent long-term follow-up magnetic resonance imaging, by linear regression analysis. In the mean follow-up of 8.7 years, 105 patients developed CVE s. A smaller Δ BA was independently associated with the high incidence of CVE s (hazard ratio, 0.36; 95% CI, 0.16-0.78; P=0.010; n=493). After a mean interval of 9.4 years, the average Δ BA was 0.41±0.46 mm (excluding patients with fetal-type circle of Willis). Progression of BA dilatation was associated with men but inversely associated with initial BA diameter and fetal-type circle of Willis (n=164). Conclusions BA diameter increased over time (excluding the patients with fetal-type circle of Willis), whereas Δ BA was inversely associated with the incidence of CVE s.
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http://dx.doi.org/10.1161/JAHA.118.011154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474931PMC
March 2019

Cortical Cerebral Microinfarcts on 3T Magnetic Resonance Imaging in Patients With Carotid Artery Stenosis.

Stroke 2019 03;50(3):639-644

From the Department of Neurology (J.T., K.M., S.O., K.T., T.S., M.S., H.M.), Osaka University Graduate School of Medicine, Japan.

Background and Purpose- Carotid artery stenosis is common in the elderly and contributes to cognitive impairment and dementia. Cortical cerebral microinfarcts (CMIs) play an important role in vascular cognitive impairment and dementia. We aimed to investigate the association between CMIs on 3T magnetic resonance imaging and clinical and radiological features, including plaque morphology, and cognitive function in patients with carotid stenosis. Methods- Eighty-nine patients with >30% carotid stenosis on ultrasound were prospectively enrolled, and underwent brain and carotid artery magnetic resonance imaging. CMIs were rated according to predetermined criteria based on 3D-double inversion recovery and fluid-attenuated inversion recovery images. Results- CMIs were identified in 26 patients (29%; median number 0, range 0-9). Poisson regression models adjusted for age and sex revealed that CMIs were associated with intraplaque hemorrhage (rate ratio, 1.95; 95% CI, 1.26-3.18), lacunar infarcts (rate ratio, 1.54; 95% CI, 1.00-2.44), and cortical infarcts (rate ratio, 3.22; 95% CI, 2.20-5.00). These associations were also observed in asymptomatic patients (n=64). Of 81 patients with unilateral carotid stenosis, the prevalence and number of CMIs were significantly higher in the hemisphere ipsilateral to the carotid stenosis than in the contralateral hemisphere ( P=0.005 and P<0.001, respectively). The presence of CMIs was associated with poor cognitive function. Conclusions- Our results indicate that vulnerable carotid plaque increases the risk of CMIs and subsequent cognitive impairment. Carotid atherosclerosis could be a potential therapeutic target for cognitive impairment.
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http://dx.doi.org/10.1161/STROKEAHA.118.023781DOI Listing
March 2019

Protective effects of oral anticoagulants on cerebrovascular diseases and cognitive impairment in patients with atrial fibrillation: protocol for a multicentre, prospective, observational, longitudinal cohort study (Strawberry study).

BMJ Open 2018 11 25;8(11):e021759. Epub 2018 Nov 25.

Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan.

Introduction: Non-valvular atrial fibrillation (NVAF) is known as a robust risk factor for stroke. Recent reports have suggested a risk of dementia with NVAF, but much remains unknown regarding the relationship between this mechanism and the potential protective effects of novel anticoagulants (direct oral anticoagulants (DOACs), or non-vitamin K oral anticoagulants).

Methods And Analysis: This study, the strategy to obtain warfarin or DOAC's benefit by evaluating registry, is an investigator-initiated, multicentre, prospective, observational, longitudinal cohort study comparing the effects of warfarin therapy and DOACs on cerebrovascular diseases and cognitive impairment over an estimated duration of 36 months. Once a year for 3 years, the activities of daily living and cognitive functioning of non-demented patients with NVAF will be assessed. Demographics, risk factors, laboratory investigations, lifestyle, social background and brain MRI will be assessed.

Ethics And Dissemination: This protocol has been approved by the ethics committee of the National Center for Geriatrics and Gerontology (No. 1017) and complies with the Declaration of Helsinki. Informed consent will be obtained before study enrolment and only coded data will be stored in a secured database. The results will be published in peer-reviewed journals and presented at scientific meetings to ensure the applicability of the findings in clinical practice.

Trial Registration Number: UMIN000025721.
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http://dx.doi.org/10.1136/bmjopen-2018-021759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254414PMC
November 2018

Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors.

Parkinsonism Relat Disord 2016 05 13;26:29-34. Epub 2016 Feb 13.

Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address:

Introduction: The aim of this study was to examine the association between mild parkinsonian signs (MPS), cerebral small-vessel disease (SVD), and total SVD burden in patients with vascular risk factors.

Methods: We performed a cross-sectional study among 268 patients with vascular risk factors but without parkinsonism or dementia (71.0 ± 7.8 years, 63% male). MPS was evaluated via Unified Parkinson's Disease Rating Scale Part III. Brain MRI was used to determine SVD (cerebral microbleeds [CMBs], lacunar infarctions [LIs], and white matter hyperintensities [WMH]). The presence of each SVD feature was indicated by the total SVD score. Logistic regression analyses were performed adjusting for age, sex, history of stroke, hypertension, diabetes mellitus, and dyslipidemia.

Results: In a multivariate analysis, we found that the presence of CMBs, deep CMBs, mixed (in the basal ganglia and thalamus) LIs, periventricular hyperintensities (PVH), and deep WMH (DWMH), and total SVD score were significantly associated with MPS, whereas strictly lobar CMBs and other LIs (in strictly basal ganglia or strictly thalamus) were not. We also found a significant association between mixed LIs, PVH, DWMH and total SVD score and gait/balance function, between PVH and rigidity, and between mixed LIs and bradykinesia. Among elderly participants (≥73years), the association of total SVD score, deep CMBs, mixed LIs, and PVH, with MPS remained significant.

Conclusion: Our results provide additional evidence that SVD including CMBs, and especially total SVD burden, might be a surrogate marker for MPS and support the contribution of hypertensive microangiopathy as the underlying etiology.
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http://dx.doi.org/10.1016/j.parkreldis.2016.02.011DOI Listing
May 2016

Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors.

J Alzheimers Dis 2016 ;49(2):503-13

Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan.

Background: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia.

Objective: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors.

Methods: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia.

Results: In the 643 subjects (age: 67.2 ± 8.4 years, male: 59% ; education: 12.9 ± 2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer's disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ɛ4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p = 0.043) and the highest tertile of tHcy (HR: 2.50, p = 0.047) for all-cause dementia remained significant.

Conclusions: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.
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http://dx.doi.org/10.3233/JAD-150458DOI Listing
September 2016

Echogenicity of medium-to-large carotid plaques predicts future vascular events.

Cerebrovasc Dis 2014 25;38(5):354-61. Epub 2014 Nov 25.

Stroke Division, Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Although the echolucent plaque in carotid stenosis is associated with future ischemic stroke, the predictive value of echogenicity in small and medium size carotid plaques on vascular events has not been thoroughly examined. Thus, we prospectively tested the hypothesis that plaque echogenicity of carotid atheroma can predict the future total cardiovascular events in patients with vascular risk factors.

Methods: Ultrasound assessment of carotid intima-media complex thickness (IMT) and plaque echogenicity using integrated backscatter (IBS) analysis was performed in 596 patients aged 40 or more, with any history of vascular events or with at least 1 risk factor, who were enrolled between 2001 and 2006 in the Osaka Follow-up Study for Carotid Atherosclerosis, part 2 (OSACA2). We followed the incidence of total cardiovascular events including cerebrovascular events, coronary heart disease (CHD), and peripheral artery disease (PAD) for 6.4 years. We divided the patients into two groups according to the IBS index above (echorich plaques) and under (echolucent plaque) the median value, and calculated the hazard ratios (HR) of the echolucent group compared with the echogenic group in the risk of cardiovascular events.

Results: Among 596 patients, carotid stenosis was found only in 87 patients. During the follow-up period, we observed 121 cardiovascular events including 63 cerebrovascular events, 45 CHD cases, and 13 PAD cases. The patients with incident cardiovascular events had larger plaque thickness and lower IBS index than those without incident vascular events. The relative risk of vascular events for echolucent versus echorich plaques was 1.45 (95% confidence interval [CI] 0.99-2.13, p = 0.058) after adjustment for risk factors and plaque thickness. In patients with plaque size above the median value (>2.1 mm), the relative risk of vascular events for echolucent plaques was 1.72 (95% CI 1.06-2.85, p = 0.029), but this association was not observed in patients with plaque size <2.0 mm.

Conclusions: The association between echogenicity of carotid plaque and incident vascular events is dependent on the plaque size. Echolucent medium-to-large plaques, but not small plaques, are associated with the risk of future total cardiovascular events. This finding suggests that measurement of echolucency in medium-to-large carotid plaques may improve selection of patients at high risk for total vascular events.
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http://dx.doi.org/10.1159/000365651DOI Listing
September 2015

Association of interleukin-6 with the progression of carotid atherosclerosis: a 9-year follow-up study.

Stroke 2014 Oct 19;45(10):2924-9. Epub 2014 Aug 19.

From the Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan (S.O., M.S., K.M., S.F., Y.Y., H.M.); Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan (H.Y.); and Department of Neurology, Tokyo Women's Medical University, Tokyo, Japan (K.K.).

Background And Purpose: Limited information is available on the long-term effects of interleukin-6 (IL-6) on systemic atherosclerosis. The purpose of the present study was to clarify the relationship between chronic elevation of IL-6 and the long-term progression of carotid atherosclerosis.

Methods: We prospectively evaluated 210 patients with ≥1 vascular risk factors for 9.0±1.0 years. Carotid mean-maximal intima-media thickness (mmIMT), the serum high-sensitivity C-reactive protein (hs-CRP) level, and the serum IL-6 level were measured at baseline and every 3 years. The associations between the progression of mmIMT and the long-term average levels of hs-CRP and IL-6 were analyzed.

Results: Carotid mmIMT increased throughout the study period (0.031±0.026 mm/y). Baseline mmIMT was significantly associated with baseline hs-CRP (P=0.002) and baseline IL-6 (P<0.001) levels. Progression of mmIMT was positively correlated with average hs-CRP (P=0.001) and average IL-6 (P<0.001) levels. When adjusted for age, sex, traditional risk factors, and baseline mmIMT, mmIMT progression remained significantly associated only with the average IL-6 level (standardized β=0.17; P=0.02), but not with the average hs-CRP level (standardized β=0.10; P=0.18).

Conclusions: Chronic elevation of serum IL-6 was associated with the progression of atherosclerosis in patients with vascular risk factors. IL-6 could be used as a quantitative marker and a potential therapeutic target for accelerated atherosclerosis.
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http://dx.doi.org/10.1161/STROKEAHA.114.005991DOI Listing
October 2014

Multiple or mixed cerebral microbleeds and dementia in patients with vascular risk factors.

Neurology 2014 Aug 11;83(7):646-53. Epub 2014 Jul 11.

From the Department of Neurology and Stroke Center (K.M., M.T., S.O., Y.Y., M.S., H.M.), Osaka University Graduate School of Medicine; and Department of Neurology (K.K.), Tokyo Women's Medical University, Japan.

Objective: To investigate whether cerebral microbleeds (CMBs) are independently associated with incident dementia in patients with vascular risk factors.

Methods: Using data from a Japanese cohort of participants with vascular risk factors in an observational study from 2001, we evaluated the association between CMBs at baseline and incident dementia. Baseline brain MRI was used to determine small-vessel disease (CMBs, lacunar infarcts, and white matter hyperintensities) and brain atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE ε4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings.

Results: Of the 524 subjects (mean age 68 ± 8.3 years, 57.6% male, 12.8 ± 2.6 years of schooling, 21.6% CMBs), 44 patients with incident dementia (20 Alzheimer disease, 18 vascular dementia, 3 mixed-type, and 3 other) were diagnosed during the median 7.5-year follow-up. In multivariate analysis, the presence of overall CMBs was not associated with an increased risk of incident all-cause dementia (p = 0.15). However, multiple CMBs (≥ 2) or mixed (lobar and deep) CMBs were associated with the increased risk of all-cause dementia, whereas strictly lobar CMBs showed no association with any dementia.

Conclusions: Multiple CMBs or mixed CMBs independently showed higher risk of all-cause dementia. Our results reinforce the hypothesis that CMBs exert deleterious effects on dementia incidence, suggesting that this association may be mediated by vascular burden.
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http://dx.doi.org/10.1212/WNL.0000000000000692DOI Listing
August 2014

Chronic kidney disease is associated with dementia independent of cerebral small-vessel disease.

Neurology 2014 Mar 19;82(12):1051-7. Epub 2014 Feb 19.

From the Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Japan.

Objective: To determine whether chronic kidney disease (CKD) is associated with incident dementia independent of cerebral small-vessel disease (SVD) in patients with vascular risk factors.

Methods: Using data from a Japanese cohort of participants with vascular risk factors in an ongoing observational study from 2001, we evaluated the association between CKD at baseline and incident dementia. Baseline brain MRI was used to determine SVD (lacunar infarction, white matter hyperintensities), medial-temporal atrophy, and subcortical atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE ε4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings.

Results: Of the 600 subjects (mean age 68 ± 8.3 years, 57% male, 12.8 ± 2.6 years of education; CKD: 29%), 50 patients with incident dementia (Alzheimer disease: 24; vascular dementia: 18; mixed-type dementia: 5; other types: 3) were diagnosed during the median 7.5-year follow-up. CKD at baseline was associated with an increased risk of all-cause dementia in models adjusted for age, sex, educational level, and APOE ε4 allele. The associations of CKD at baseline remained significant even after additional adjusting for MRI findings and confounding variables (hazard ratio: 1.96 [1.08-3.58], p = 0.026).

Conclusions: CKD is independently related to the risk of all-cause dementia in patients with vascular risk factors. Our results reinforce the hypothesis that CKD exerts deleterious effects on dementia incidence.
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http://dx.doi.org/10.1212/WNL.0000000000000251DOI Listing
March 2014

Basilar artery diameter is an independent predictor of incident cardiovascular events.

Arterioscler Thromb Vasc Biol 2013 Sep 9;33(9):2240-4. Epub 2013 May 9.

Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.

Objective: Basilar arterial (BA) dolichoectasia is associated with cerebral small-vessel disease and stroke. However, the association between moderate dilation of the BA and cerebral small-vessel disease or subsequent cardiovascular events remains unclear. This study aims to clarify the factors related to BA diameter and to clarify whether the BA diameter is an independent predictor of cardiovascular events.

Approach And Results: The study subjects comprised 493 outpatients with atherosclerotic risk factors. BA diameter, lacunar infarct, severity of deep white matter hyperintensities, and intracranial steno-occlusive lesions were assessed with MRI and magnetic resonance angiography. Then, we prospectively evaluated the association between BA diameter and cardiovascular events. The BA diameter ranged from 1.1 to 5.2 mm, and only 0.8% of the patients had dolichoectasia. Male sex, the presence of lacunar infarcts, the severity of deep white matter hyperintensities, the fetal-type variation of the circle of Willis, and intracranial steno-occlusive lesions were independently associated with BA diameter. In the mean follow-up of 6.0 years, 91 patients developed cardiovascular events. BA diameter was independently associated with total cardiovascular events after adjusting for age, sex, and conventional risk factors (hazard ratio, 1.55 per 1 mm increase in BA diameter; P=0.009).

Conclusions: Increased BA diameter within the normal range is related to both large-vessel disease and cerebral small-vessel disease, and it could be a new predictor of cardiovascular events.
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http://dx.doi.org/10.1161/ATVBAHA.113.301467DOI Listing
September 2013

Association between interleukin-6 levels and first-ever cerebrovascular events in patients with vascular risk factors.

Arterioscler Thromb Vasc Biol 2013 Feb 21;33(2):400-5. Epub 2012 Nov 21.

Department of Neurology and Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan.

Objective: The objective of this study was to examine the association of inflammatory markers with risk of first-ever cerebrovascular events (CVEs), while simultaneously evaluating subclinical vascular disease.

Methods And Results: We enrolled 464 outpatients who had vascular risk factors without any preexisting cardiovascular disease. We examined the presence of silent lacunar infarction (SLI) by magnetic resonance imaging; carotid intima-media thickness by ultrasound; and measured high-sensitivity C-reactive protein, interleukin (IL)-6, and IL-18 at baseline, and assessed their associations with CVEs using Cox proportional hazards models of 4.8±2.6 years follow-up. We further calculated measures of reclassification and discrimination. In age- and sex-adjusted analysis, IL-6, but neither high-sensitivity C-reactive protein nor IL-18, was associated with CVEs. The association remained significant after adjustment for conventional risk factors, intima-media thickness, and SLI (hazard ratios: 1.80, per 1-SD increase in log IL-6, P=0.03). Compared with the patients with below median IL-6 without SLI, those with above median IL-6 and SLI had a higher risk of CVEs (hazard ratios: 4.14, P=0.0014). The combination of IL-6 and SLI resulted in the net reclassification improvement of 14.3% (P=0.04), and the integrated discrimination improvement gain of 2.1% (P=0.05).

Conclusions: IL-6 levels were independently associated with CVEs and could improve reclassification in those with SLI.
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http://dx.doi.org/10.1161/ATVBAHA.112.300350DOI Listing
February 2013

The relation between carotid plaque echogenicity and oxidative stress marker 8-iso-prostaglandin F2α.

Ultrasound Med Biol 2012 Mar 20;38(3):487-91. Epub 2012 Jan 20.

Neurology Department, Osaka University Graduate School of Medicine, Osaka, Japan.

Echolucent plaques are associated with high risk of ischemic cerebrovascular events. Oxidative stress has been implicated in the process of atherosclerotic plaque development from initiation to progression. We assessed the relation between carotid plaque echogenicity and urinary 8-iso-prostaglandin F2α, as an index of oxidative stress. This cross-sectional study was conducted prospectively on 290 consecutive outpatients. Each patient was evaluated for carotid plaque echogenicity using the gray-scale median at the maximal thickness plaque and urinary 8-iso-prostaglandin F2α using enzyme linked immunosorbent assay. By Pearson correlation analysis, we found significant negative linear relation between gray-scale median values and the urinary 8-iso-prostaglandin F2α levels (r = -0.133, p = 0.023). This correlation remained significant after adjustment for atherosclerotic risk factors, thickness of the maximal plaque and medication use (β = -0.137, p = 0.031). We herein show that higher levels of urinary 8-iso-prostaglandin F2α is associated with lower plaque echogenicity.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2011.11.016DOI Listing
March 2012

Cerebral microbleeds in patients with moyamoya-like vessels secondary to atherosclerosis.

Intern Med 2012 15;51(2):167-72. Epub 2012 Jan 15.

Department of Neurology, Osaka University Graduate School of Medicine, Japan.

Objective: Hemorrhagic risk is unknown in patients with moyamoya-like vessels associated with atherosclerotic intracranial cerebral artery occlusion. This study was undertaken to investigate the association between moyamoya-like vessels and cerebral microbleeds (CMBs) in patients with atherosclerotic steno-occlusive disease.

Methods: The study population comprised 34 patients with steno-occlusive lesions in the intracranial cerebral artery caused by atherosclerosis. We evaluated the presence of moyamoya-like vessels at the base of the brain by cerebral angiography, and the presence of CMBs by T2*-weighted MRI. Patients were divided into 2 groups: those with and those without moyamoya-like vessels; clinical histories and the incidence of CMBs were compared between the groups.

Results: Sixteen patients had moyamoya-like vessels. Twelve of 16 patients with moyamoya-like vessels had a history of ischemic stroke or transient ischemic attack, whereas only 1 patient had a history of symptomatic cerebral hemorrhage. The incidence of CMBs did not differ between the 2 groups (31% vs. 28%, p=0.82). The location of CMBs varied and was not associated with the site of moyamoya-like vessels.

Conclusion: CMBs were not associated with moyamoya-like vessels in patients with atherosclerotic cerebral artery occlusion. These patients may not have a high risk of cerebral hemorrhage.
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http://dx.doi.org/10.2169/internalmedicine.51.6429DOI Listing
August 2012