Publications by authors named "Masafumi Ihara"

244 Publications

Left Ventricular Abnormality and Covert Atrial Fibrillation in Embolic Stroke of Undetermined Source.

J Atheroscler Thromb 2021 Jul 22. Epub 2021 Jul 22.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center.

Aims: The relationship between left ventricular (LV) function and AF detection in embolic stroke of undetermined source (ESUS) patients with insertable cardiac monitors (ICMs) remains unclear. We investigated the association between LV function and AF detection in patients with ESUS after ICMs implantation.

Methods: We enrolled patients with ESUS who underwent ICMs implantation from September 2016 to September 2020 using a single-center, prospective registry. LV systolic and diastolic functions were assessed on precordial echocardiography by LV fractional shortening (LVFS) and average E/e', respectively. Associations between characteristics of LV function and detection of AF by ICMs were analyzed.

Results: Participants comprised 101 patients (median age, 74 years; male, 62%). During a median follow-up period of 442 days (interquartile range (IQR), 202-770 days), AF was detected in 24 patients (24%). Median duration from ICMs implantation to AF detection was 71 days (IQR, 13-150 days). When LVFS and E/e' were dichotomized by cutoff value, each of low LVFS (<35.5%; adjusted hazard ratio (HR), 4.77; 95% confidence interval (CI), 1.77-12.9) and high E/e' (≥ 8.65; adjusted HR, 4.56; 95%CI, 1.17-17.7) were independently associated with AF detection after adjusting for age and sex. When patients were divided into four groups according to dichotomized LVFS and E/e', the combination of low LVFS and high E/e' was independently associated with AF.

Conclusions: In patients with ESUS after ICMs implantation, the LV characteristics of low LVFS and high E/e' were associated with AF detection.
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http://dx.doi.org/10.5551/jat.62994DOI Listing
July 2021

EXPRESS: Cerebral microbleeds development after stroke thrombolysis: A secondary analysis of the THAWS randomized clinical trial.

Int J Stroke 2021 Jul 20:17474930211035023. Epub 2021 Jul 20.

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

Background And Aim: We determined to investigate the incidence and clinical impact of new cerebral microbleeds (CMBs) after intravenous thrombolysis (IVT) in patients with acute stroke.

Methods: The THAWS was a multicenter, randomized trial to study the efficacy and safety of IVT with alteplase in patients with wake-up stroke or unknown onset stroke. Prescheduled T2*-weighted imaging assessed CMBs at 3-time points: baseline, 22â36 hours, and 7â14 days. Outcomes included new CMBs development, modified Rankin Scale [mRS] â¥3 at 90 days, and change in the National Institutes of Health Stroke Scale [NIHSS] score from 24 h to 7 days.

Results: Of all 131 patients randomized in the THAWS trial, 113 patients (mean 74.3±12.6 years, 50 female, 62 allocated to IVT) were available for analysis. Overall, 46 (41%) had baseline CMBs (15 strictly lobar CMBs, 14 mixed CMBs, and 17 deep CMBs). New CMBs only emerged in the IVT group (7 patients, 11%) within a median of 28.3 h, and did not additionally increase within a median of 7.35 days. In adjusted models, number of CMBs (relative risk [RR]1.30, 95%confidence interval [CI]: 1.17â1.44), mixed distribution (RR 19.2, 95%CI: 3.94â93.7), and CMBs burden â¥5 (RR 44.9, 95%CI: 5.78â349.8) were associated with new CMBs. New CMBs was associated with an increase in NIHSS score (p=0.023). Treatment with alteplase in patients with baseline â¥5 CMBs resulted in a numerical shift toward worse outcomes on ordinal mRS (median [IQR]; 4 [3â4] vs. 0 [0â3]), compared with those with <5 CMBs (common odds ratio 17.1, 95% CI: 0.76 â382.8). The association of baseline â¥5 CMBs with ordinal mRS score differed according to the treatment group (P interaction=0.042).

Conclusion: New CMBs developed within 36 h in 11% of the patients after IVT, and they were significantly associated with mixed-distribution and â¥5 CMBs. New CMBs development might impede neurological improvement. Furthermore, CMBs burden might affect the effect of alteplase.
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http://dx.doi.org/10.1177/17474930211035023DOI Listing
July 2021

[Cerebrovascular imaging to facilitate stroke reperfusion therapy in Japan].

Rinsho Shinkeigaku 2021 Jul 17. Epub 2021 Jul 17.

Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center.

Imaging diagnosis is essential to perform appropriate reperfusion therapy for acute ischemic stroke. To equally perform reperfusion therapy all over in Japan, it is important to properly facilitate acute imaging evaluation for stroke suspected patients by medical staff not only in stroke-specialized hospitals but also in non-stroke-specialized hospitals. It is unique that CT and MRI are available in most of Japanese hospitals. Even in non-stroke-specialized hospitals, inpatients may suffer from in-hospital stroke. We review statements and recommendation items for a diagnostic imaging to appropriately perform reperfusion therapy based on major clinical trials, stroke guidelines and the current status of acute stroke imaging in Japan.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001603DOI Listing
July 2021

Impact of Renal Impairment on Intensive Blood-Pressure-Lowering Therapy and Outcomes in Intracerebral Hemorrhage: Results From ATACH-2.

Neurology 2021 Jul 1. Epub 2021 Jul 1.

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

Background And Objectives: The clinical impact of renal impairment on intracerebral hemorrhage (ICH) is unknown. This study sought to exploratory assess whether the estimated glomerular filtration rate (eGFR) affects clinical outcomes or modifies the efficacy of intensive systolic blood pressure (BP) control (target, 110-139 mmHg) against the standard (target, 140-179 mmHg) among patients with ICH.

Methods: We conducted post-hoc analyses of ATACH-2, a randomized, two-group, open-label trial. The baseline eGFR of each eligible patient was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. The outcome of interest was death or disability at 90 days. Multivariate logistic regression models were used for analysis.

Results: Among the 1000 patients randomized, 974 were analyzed. The median baseline eGFR was 88 (interquartile range: 68, 99) ml/min/1.73 m; 451 (46.3%), 363 (37.3%) and 160 (16.4%) patients had baseline eGFR values of ≥90, 60-89, and <60 ml/min/1.73 m, respectively. Compared with normal eGFR (≥90 ml/min/1.73 m), higher odds of death or disability were noted among those with eGFR values of <60 ml/min/1.73 m (adjusted odds ratio (OR) 2.02, 95% confidence interval (CI) 1.25-3.26) but not among those with eGFR values of 60-89 ml/min/1.73 m (OR 1.01, 95% CI 0.70-1.46). The odds of death or disability were significantly higher in the intensive arm among patients with decreased eGFR; the ORs were 0.89 (95% CI 0.55-1.44), 1.13 (0.68-1.89), and 3.60 (1.47-8.80) in patients with eGFR values of ≥90, 60-89, and <60 ml/min/1.73 m, respectively (p for interaction = 0.02).

Discussion: Decreased eGFR is associated with unfavorable outcomes following ICH. The statistically significant interaction between the eGFR group and treatment assignment raised safety concerns for the intensive BP-lowering therapy among patients with renal impairment.

Trial Registration Information: Clinicaltrials.gov (NCT01176565), first submitted on August 6, 2010. The first patient enrolled on May 2011.

Classification Of Evidence: This study provides Class II evidence that in spontaneous ICH, decreased eGFR identifies patients at risk of death or disability following intensive blood pressure control.
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http://dx.doi.org/10.1212/WNL.0000000000012442DOI Listing
July 2021

Echocardiographic predictors of cardioembolic stroke due to underlying atrial fibrillation: Reliable left atrial remodeling signs in acute stroke.

J Neurol Sci 2021 Aug 1;427:117514. Epub 2021 Jun 1.

Department of Neurology, National Cerebral and Cardiovascular Center, Japan.

Introduction: Atrial remodeling due to high-burden atrial fibrillation (AF) is associated with cardioembolic stroke (CES). As not all CESs is caused by AF, we analyzed the diagnostic values of each echocardiographic parameter to distinguish likely AF-related CES in acute stroke patients while in non-AF rhythm.

Methods: The data of consecutive patients with acute ischemic stroke in sinus rhythm between 2012 and 2015 were obtained. The echocardiographic parameters of patients with CES due to underlying AF (n = 61) and control patients (n = 319) with either large artery atherosclerosis or small-vessel occlusion were compared using receiver operating characteristic curves and logistic regression analyses. Each parameter was reassessed in acute stroke patients through a validation study using the same database with different periods of generalization.

Results: CES patients with underlying AF showed a significantly larger left atrial volume index (LAVi), higher mitral inflow E wave (E), and lower A wave (A) than the controls. The area under the curve (AUC) (95% confidence interval) for diagnosing CES due to underlying AF was significantly higher for LAVi/A than for LAVi (0.785 versus 0.696, P < 0.01). Among patients aged >60 years, the E/A ratio had the highest AUC (0.857) of the parameters. The cut-off values were ≥ 0.70 (sensitivity, 55.7%; specificity, 90.9%) and ≥ 0.82 (sensitivity, 71.4%; specificity, 84.1%) for LAVi/A and the E/A ratio, respectively, in patients >60 years. The cut-off values of all parameters showed similar trends in a validation study.

Conclusion: LAVi/A is a useful indicator for distinguishing CES patients with underlying AF regardless of age, and the E/A ratio is reliable among patients aged >60 years in evaluation during acute stroke admission.
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http://dx.doi.org/10.1016/j.jns.2021.117514DOI Listing
August 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

Conversion from cilostazol to OPC-13015 linked to mitigation of cognitive impairment.

Alzheimers Dement (N Y) 2021 27;7(1):e12182. Epub 2021 May 27.

Department of Neurology National Cerebral and Cardiovascular Center Suita Osaka Japan.

Introduction: Cilostazol may be a novel therapeutic agent for Alzheimer's disease. Its metabolite, OPC-13015, has a stronger inhibitory effect on type 3 phosphodiesterase than cilostazol.

Methods: We prospectively enrolled patients with mild cognitive impairment to whom cilostazol was newly prescribed. Patients underwent the Montreal Cognitive Assessment (MoCA) twice, at a 6-month interval. Plasma cilostazol, OPC-13015, OPC-13213, and OPC-13217 concentrations were determined using liquid chromatography-tandem mass spectrometry.

Results: MoCA score changes from baseline to the 6-month visit were positively correlated with ratios of OPC-13015 to cilostazol and total metabolites (= 19, = .005). Patients with higher ratios of OPC-13015 (≥0.18, median value; = 10) had significantly higher MoCA scores (= .036) than patients with lower ratios (the ratio <0.18, = 9). The absolute value of OPC-13015 concentration in blood was also higher in patients with preserved cognitive function (= .033).

Discussion: Blood OPC-13015 levels may be a predictive biomarker of cilostazol treatment for Alzheimer's disease.
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http://dx.doi.org/10.1002/trc2.12182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158162PMC
May 2021

Blind Exchange With Mini-Pinning Technique Using the Tron Stent Retriever for Middle Cerebral Artery M2 Occlusion Thrombectomy in Acute Ischemic Stroke.

Front Neurol 2021 19;12:667835. Epub 2021 May 19.

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

The usefulness of the blind exchange with mini-pinning (BEMP) technique has recently been reported for mechanical thrombectomy in patients with stroke owing to medium vessel occlusion (MeVO). The Tron stent retriever can be delivered and deployed through a 0.0165-inch microcatheter. This retriever has potential as an effective and safe treatment for acute ischemic stroke (AIS) due to occlusion of the M2 segment of the middle cerebral artery (MCA). Here, we report the outcomes of the BEMP technique using Tron stent retrievers for M2 occlusion thrombectomy. Consecutive patients with AIS owing to M2 occlusion who underwent the BEMP technique using 2 × 15-mm or 4 × 20-mm Tron stent retrievers were included. The technique involves deploying a Tron stent retriever through a 0.0165-inch microcatheter, followed by microcatheter removal and blind navigation of a 3MAX or 4MAX aspiration catheter over the bare Tron delivery wire until the aspiration catheter reaches the clot. A Tron stent retriever is inserted into the aspiration catheter like a cork and subsequently pulled as a unit. We assessed procedural outcomes [first-pass expanded thrombolysis in cerebral infarction (eTICI) score 2c/3 and 2b/2c/3], safety outcomes [symptomatic intracranial hemorrhage (sICH)], and clinical outcomes (good outcome rate defined as modified Rankin Scale score 0-2 at 90 days and mortality at 90 days). Eighteen M2 vessels were treated in 15 patients (six female, median age: 80 years, and median National Institutes of Health Stroke Scale score: 18). The BEMP technique was performed successfully in all cases. Whether to use a 3MAX or 4MAX catheter was determined by considering one of the following target vessels: dominant, non-dominant, or co-dominant M2 (3MAX, = 9; 4MAX, = 9). The first-pass eTICI 2c/3 and 2b/2c/3 rates were 47 (7/15) and 60% (9/15), respectively; sICH was not observed. Seven patients (47%) achieved good outcomes, and one patient (7%) died within 90 days. The Tron stent retriever was safely and effectively used in the BEMP technique for acute MCA M2 occlusion and can be combined with a 0.0165-inch microcatheter, which may be useful for treating MeVO, in general.
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http://dx.doi.org/10.3389/fneur.2021.667835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172139PMC
May 2021

New diagnostic algorithm for detection of covert Bow Hunter's Syndrome.

Int J Med Sci 2021 19;18(10):2162-2165. Epub 2021 Mar 19.

Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan.

Bow hunter's syndrome (BHS) should not be overlooked as a cause of cerebral infarction in the posterior circulation. However, covert BHS, which does not impair blood flow with simple rotation but only at certain angles, may make the diagnosis of BHS difficult. We propose a new algorithm to detect BHS or covert BHS. We recommend that BHS and covert BHS be detected by noninvasive duplex ultrasonography, which will allow for appropriate treatment.
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http://dx.doi.org/10.7150/ijms.56442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040409PMC
March 2021

Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase-II Trial: AdrenoMedullin for Ischemic Stroke Study.

J Stroke Cerebrovasc Dis 2021 Jun 1;30(6):105761. Epub 2021 Apr 1.

Department of Neurology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan. Electronic address:

Objectives: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke.

Materials And Methods: The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24 h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30 μg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). In the second cohort, patients will be assigned to the investigation treatment B (56 μg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10).

Results: Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups.

Conclusions: AM is expected to be a safe and effective treatment for ischemic stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105761DOI Listing
June 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

Diagnostic and prognostic blood biomarkers in vascular dementia: From the viewpoint of ischemic stroke.

Neurochem Int 2021 06 26;146:105015. Epub 2021 Mar 26.

Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan. Electronic address:

Reliable quantitative blood biomarkers are important in vascular dementia (VaD) because early diagnosis and therapeutic intervention are effective in preventing progression of dementia. Although many blood biomarkers for acute ischemic stroke (AIS) or VaD have been reported, there are few reliable blood biomarkers. VaD and AIS have similar pathological conditions that are associated with small vessel disease (SVD) such as oxidative stress, inflammation, endothelial dysfunction, and neuronal injury. Therefore, it may be possible to find superior blood biomarkers of VaD among AIS blood biomarkers. Owing to recent developments, noncoding RNAs such as microRNA and long noncoding RNA, which can be analyzed using a single drop of blood, are also particularly reliable VaD markers because they stably reflect brain tissue damage. A multimarker combining several blood biomarkers or artificial intelligence technology may also be beneficial to compensate for insufficiencies of a single blood biomarker. This review describes the blood biomarkers of VaD and how they are related to blood biomarkers of AIS.
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http://dx.doi.org/10.1016/j.neuint.2021.105015DOI Listing
June 2021

Taxifolin: A Potential Therapeutic Agent for Cerebral Amyloid Angiopathy.

Front Pharmacol 2021 12;12:643357. Epub 2021 Feb 12.

Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in the walls of cerebral vessels, leading to complications such as intracerebral hemorrhage, convexity subarachnoid hemorrhage and cerebral microinfarcts. Patients with CAA-related intracerebral hemorrhage are more likely to develop dementia and strokes. Several pathological investigations have demonstrated that more than 90% of Alzheimer's disease patients have concomitant CAA, suggesting common pathogenic mechanisms. Potential causes of CAA include impaired Aβ clearance from the brain through the intramural periarterial drainage (IPAD) system. Conversely, CAA causes restriction of IPAD, limiting clearance. Early intervention in CAA could thus prevent Alzheimer's disease progression. Growing evidence has suggested Taxifolin (dihydroquercetin) could be used as an effective therapy for CAA. Taxifolin is a plant flavonoid, widely available as a health supplement product, which has been demonstrated to exhibit anti-oxidative and anti-inflammatory effects, and provide protection against advanced glycation end products and mitochondrial damage. It has also been shown to facilitate disassembly, prevent oligomer formation and increase clearance of Aβ in a mouse model of CAA. Disturbed cerebrovascular reactivity and spatial reference memory impairment in CAA are completely prevented by Taxifolin treatment. These results highlight the need for clinical trials on the efficacy and safety of Taxifolin in patients with CAA.
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http://dx.doi.org/10.3389/fphar.2021.643357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907591PMC
February 2021

Macrosquare-wave jerks subsiding after hydrocephalus treatment in a thalamic hemorrhage patient.

Intern Med 2021 Mar 1. Epub 2021 Mar 1.

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

A 54-year-old man suddenly developed impaired consciousness and left hemiplegia due to a right thalamic hematoma. Emergent ventricular drainage for acute hydrocephalus improved the level of consciousness, but macrosquare-wave jerks (MSWJ) consisting of a right-ward intrusive saccade and corrective saccade appeared. The MSWJ disappeared on day 2 when follow-up CT revealed improvement of hydrocephalus. However, on day 36, after ventricular drainage was clamped, the MSWJ reappeared. After ventriculoperitoneal shunt, MSWJ again subsided. In this patient, hydrocephalus may have stretched the superior colliculus, thereby decreasing activity of the fixation neurons and then omnipause neurons, and eventually resulting in the reversible MSWJ.
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http://dx.doi.org/10.2169/internalmedicine.6293-20DOI Listing
March 2021

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

Early recurrent ischemic events after mechanical thrombectomy: effect of post-treatment intracranial hemorrhage.

J Neurol 2021 Aug 16;268(8):2810-2820. Epub 2021 Feb 16.

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

Objective: Patients with intracranial hemorrhages (ICH) after mechanical thrombectomy (MT) may have a higher risk of early recurrent embolism (ERE) because of delayed initiation of anticoagulants. We assessed the rate of ischemic events in the early period after MT and the association with post-MT ICH.

Methods: Patients who underwent MT in our institute were retrospectively reviewed. ERE was defined as recurrent ischemic stroke and systemic embolism within 14 days after MT. The association between ERE and parenchymal hematoma (PH) was assessed. Multivariable regression analysis and inverse probability of treatment weighting was used to adjust for differences in baseline characteristics between patients with and without PH.

Results: A total of 307 patients (median age, 78 years; female, 47%; median baseline National Institutes of Health Stroke Scale score, 19) were included. ERE was observed in 12 of 307 patients (8 strokes, 4 systemic embolisms; 3.9%). Median time from MT to ERE was 6.5 days (IQR, 3-8 days). PH occurred in 21 patients (6.8%). Median time from MT to initiating oral anticoagulants was longer in patients with PH (8 days) than in those without (3 days) (p < 0.01). In both unweighted and weighted multivariable analysis, PH was significantly associated with an increased risk of ERE (unweighted odds ratio, 10.60; 95% CI, 2.66-42.23; weighted odds ratio, 12.34; 95% CI, 2.49-61.07).

Conclusions: ERE occurred in about 4% of patients after MT. PH after MT was associated with delayed initiation of oral anticoagulants and an increased risk of recurrent ischemic events.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02251665.
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http://dx.doi.org/10.1007/s00415-021-10449-1DOI Listing
August 2021

A Nationwide Multi-Center Questionnaire Survey on the Real-World State and Issues Regarding Post-Stroke Complications in Japan.

J Stroke Cerebrovasc Dis 2021 Apr 8;30(4):105656. Epub 2021 Feb 8.

Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan. Electronic address:

Objectives: Post-stroke complications affect stroke survivors across the world, although data on them are limited. We conducted a questionnaire survey to examine the real-world state and issues regarding post-stroke complications in Japan, which represents a super-aged society.

Materials And Methods: In 2018, a nationwide multi-center questionnaire survey was conducted in the top 500 Japanese hospitals regarding the number of stroke patients treated. Three questionnaires regarding post-stroke complications were mailed to the doctors responsible for stroke management.

Results: Responses were obtained from 251 hospitals (50.2%). The chief doctors responsible for stroke management answered the questionnaires. The number of stroke patients in the departments of neurology and neurosurgery was 338.3 ± 195.3 and 295.8 ± 121.8. Hospitals were classified using the categories secondary (n =142) and tertiary hospitals (n = 106); most hospitals were acute hospitals. Dementia was the most common complication (30.9%), followed by dysphagia (29.3%), and apathy (16.3%). Dementia was thought to be more common by neurologists than neurosurgeons, while apathy and bladder-rectal disorder were thought to be more common by neurosurgeons than neurologists (p = 0.001). The most difficult complication to treat was dysphagia (40.4%), followed by dementia (33.9%), epilepsy (4.1%), and fall (4.1%). Dementia was considered to lack clinical evidence regarding treatment (32.8%), followed by dysphagia (25.3%), and epilepsy (14.1%). Epilepsy was considered to lack clinical evidence among hospitals with a larger number of stroke cases (p = 0.044).

Conclusion: This study revealed the current state and issues regarding post-stroke complications in Japan. Clinicians should be aware of the importance of post-stroke complications, although data on them remain unsatisfactory.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105656DOI Listing
April 2021

A case of hemichorea in RNF213-related vasculopathy.

BMC Neurol 2021 Jan 22;21(1):32. Epub 2021 Jan 22.

Department of Neurology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan.

Background: Internal carotid artery (ICA) stenosis has been recently reported to cause hemichorea, mainly in East Asia. The East Asian-specific p.R4810K variant of RNF213, a susceptibility gene for moyamoya disease (MMD), accounts for up to 25% of sporadic ischemic stroke with ICA stenosis cases in East Asia. However, as RNF213-related vasculopathy does not meet the diagnostic criteria for MMD, the creation of a new disease category has been suggested. Here, we report the first case of hemichorea in RNF213-related vasculopathy.

Case Presentation: An 81-year-old woman was admitted to our hospital with choreic movements in the periphery of the right extremities at rest. Though head magnetic resonance imaging showed no fresh or old cerebral infarction, I-iodoamphetamine-single photon emission computed tomography showed cerebral blood flow of < 80% in the anterior territory of the left middle cerebral artery (MCA) in a resting state and cerebrovascular reactivity of < 10% in the broader area supplied by the left MCA after acetazolamide challenge. Head magnetic resonance angiography and digital subtraction angiography revealed left ICA C1 portion stenosis with compromised collateral vessels. Involuntary movements resolved with haloperidol administration within 3 days, without apparent recurrence from continuation of the medication for a year. Genetic testing revealed the presence of the heterozygous RNF213 p.R4810K variant.

Conclusions: Chorea is thought to be caused by damage to circuitry connecting the basal ganglia with the cerebral cortex, as found in cases of MMD, which possess aberrant vessels in the basal ganglia. However, aberrant vessels and cerebral infarctions were not observed in the basal ganglia in the current case, decreasing the likelihood of a role in chorea. Alternatively, as RNF213 regulates vascular endothelial function and angiogenesis, dysregulation may impair the neurovascular unit and damage basal ganglia circuitry, contributing to the development of chorea. This case may renew interest in the concept of RNF213-related vasculopathy and the pathophysiological mechanisms behind chorea in ICA stenosis.
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http://dx.doi.org/10.1186/s12883-021-02061-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821645PMC
January 2021

Mid-regional pro-adrenomedullin is a novel biomarker for arterial stiffness as the criterion for vascular failure in a cross-sectional study.

Sci Rep 2021 01 11;11(1):305. Epub 2021 Jan 11.

Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

We investigated the potential of mid-regional pro-adrenomedullin (MR-proADM) for use as a novel biomarker for arterial stiffness as the criterion for vascular failure and cardiometabolic disease (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome) compared with high-sensitivity C-reactive protein (hsCRP). Overall, 2169 individuals (702 men and 1467 women) were enrolled. Multiple regression analysis was performed to assess the association of MR-proADM and hsCRP with brachial-ankle pulse wave velocity (baPWV), adjusting for other variables. The diagnostic performance (accuracy) of MR-proADM with regard to the index of vascular failure was tested with the help of receiver operating characteristic curve analysis in the models. MR-proADM was significantly higher in participants with vascular failure, as defined by baPWV and/or its risk factors (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome), than in control groups. Independent of cardiovascular risk factors (age, drinking, smoking, body mass index, systolic blood pressure, lipid and glycol metabolism), MR-proADM was significantly associated with baPWV, and MR-proADM showed higher areas under the curve of baPWV than hsCRP showed. MR-proADM is more suitable for the diagnosis of higher arterial stiffness as the criterion for vascular failure than hsCRP. Because vascular assessment is important to mitigate the most significant modifiable cardiovascular risk factors, MR-proADM may be useful as a novel biomarker on routine blood examination.
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http://dx.doi.org/10.1038/s41598-020-79525-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801498PMC
January 2021

Head-to-head comparison of amplified plasmonic exosome Aβ42 platform and single-molecule array immunoassay in a memory clinic cohort.

Eur J Neurol 2021 May 23;28(5):1479-1489. Epub 2021 Jan 23.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Background And Purpose: Various blood biomarkers reflecting brain amyloid-β (Aβ) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort.

Methods: Using the same cohort (n = 68), the performances of the single-molecule array (Simoa) Aβ40, Aβ42, Aβ42/Aβ40 and the amplified plasmonic exosome (APEX) Aβ42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aβ+) participants.

Results: Compared to Simoa biomarkers, APEX-Aβ42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre-screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX-Aβ42 and 48.6% for Simoa-Aβ42/Aβ40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX-Aβ42 pre-screening does not increase the required number of initial participants.

Conclusions: With its high diagnostic performance, APEX is an ideal candidate for Aβ+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aβ+ participants whilst halving recruitment costs.
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http://dx.doi.org/10.1111/ene.14704DOI Listing
May 2021

Identifying large ischemic core volume ranges in acute stroke that can benefit from mechanical thrombectomy.

J Neurointerv Surg 2020 Dec 15. Epub 2020 Dec 15.

Neurology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Background: We aimed to identify the large ischemic core (LIC) volume ranges in acute ischemic stroke patients that can benefit from mechanical thrombectomy (MT).

Methods: Consecutive patients within 24 hours of onset of anterior circulation ischemic stroke with large vessel occlusion and ischemic core volumes of 70-300 mL were included from our single-center prospective database from March 2014 to December 2019. Subjects were divided into three groups by baseline ischemic core volume (A: 70-100 mL; B: 101-130 mL; C: >130 mL). We compared modified Rankin Scale (mRS) score 0-2 at 3 months and parenchymal hematoma between patients receiving MT and standard medical treatment (SMT), and determined clinically treatable core volume ranges for MT.

Results: Of 157 patients (86 women; median age, 81 years; median ischemic core volume, 123 mL), 49 patients underwent MT. In Group A (n=52), MT patients (n=31) showed a higher proportion of mRS 0-2 at 3 months (52% vs 5%, P<0.05) versus SMT, respectively. Group B (n=36) MT patients (n=14) also had a higher proportion of mRS 0-2 at 3 months (29% vs 9%, P=0.13) versus SMT, respectively. In Group C (n=69), only four patients received MT. The 95% confidence intervals for the probability of mRS 0-2 at 3 months in patients with MT (n=49) versus SMT (n=108) intersected at 120-130 mL.

Conclusions: Ischemic core volumes between 70 and 100 mL may benefit from MT. The treatable upper core limit is approximately 120 mL in selected patients with LIC of 70-300 mL.
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http://dx.doi.org/10.1136/neurintsurg-2020-016934DOI Listing
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

Cerebral Amyloid Angiopathy Presenting as Massive Subarachnoid Haemorrhage: A Case Study and Review of Literature.

Front Aging Neurosci 2020 10;12:538456. Epub 2020 Nov 10.

Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.

Cerebral amyloid angiopathy (CAA) is characterised by the progressive accumulation of β-amyloid (Aβ) in the walls of cerebral capillaries and arteries representing a major cause of haemorrhagic stroke including lobar intracerebral haemorrhage (ICH) and convexity subarachnoid haemorrhage (SAH). Haemorrhaging from CAA predominantly involves smaller arteries rather than arterial aneurysm. Restricted bleeding into the subarachnoid space in CAA results in asymptomatic or mild symptomatic SAH. Herein, we present an autopsied case of massive SAH related to CAA. An 89-year-old male with a history of mild Alzheimer's disease (AD) and advanced pancreatic cancer with liver metastasis developed sudden onset of coma. Head CT illustrated ICH located in the right frontal lobe and right insula, as well as SAH bilaterally spreading from the basal cistern to the Sylvian fissure, with hydrocephalus and brain herniation. He died about 24 h after onset and the post-mortem examination showed no evidence of arterial aneurysm. The substantial accumulation of Aβ in the vessels around the haemorrhagic lesions led to the diagnosis of ICH related to CAA and secondary SAH, which may have been aggravated by old age and malignancy. This case suggests that CAA can cause severe SAH resembling aneurysmal origin and thus may be overlooked when complicated by atypical cerebral haemorrhage.
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http://dx.doi.org/10.3389/fnagi.2020.538456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683384PMC
November 2020

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

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

Neuronal densities and vascular pathology in the hippocampal formation in CADASIL.

Neurobiol Aging 2021 01 1;97:33-40. Epub 2020 Oct 1.

Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK. Electronic address:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral small vessel disease. Previous neuroimaging studies have suggested loss of hippocampal volume is a pathway for cognitive impairment in CADASIL. We used unbiased stereological methods to estimate SMI32-positive and total numbers and volumes of neurons in the hippocampal formation of 12 patients with CADASIL and similar age controls (young controls) and older controls. We found densities of SMI32-positive neurons in the entorhinal cortex, layer V, and cornu ammonis CA2 regions were reduced by 26%-50% in patients with CADASIL compared with young controls (p < 0.01), with a decreasing trend observed in older controls in the order of young controls> older controls ≥ CADASIL. These changes were not explained by any hippocampal infarct or vascular pathology or glial changes. Our results suggest notable loss of subsets of projection neurons within the hippocampal formation that may contribute to certain memory deficits in CADASIL, which is purely a vascular disease. It is likely that the severe arteriopathy leads to white matter damage which disconnects cortico-cortical and subcortical-cortical networks including the hippocampal formation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758782PMC
January 2021

Associations of equol-producing status with white matter lesion and amyloid-β deposition in cognitively normal elderly Japanese.

Alzheimers Dement (N Y) 2020 22;6(1):e12089. Epub 2020 Oct 22.

Department of Epidemiology Graduate School of Public Health University of Pittsburgh Pittsburgh Pennsylvania USA.

Introduction: Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti-oxidant and anti-amyloidogenic. We assessed the associations of equol with white matter lesion normalized to total brain volume (WML%) and amyloid beta (Aβ) deposition.

Methods: From 2016 to 2018, 91 cognitively normal elderly Japanese aged 75 to 89 underwent brain magnetic resonance imaging and positron emission tomography using C-Pittsburgh compound-B. Serum equol was measured using stored samples from 2008 to 2012. Equol producers were defined as individuals with serum levels >0. Producers were further divided into high (> the median) and low (≤ the median) producers.

Results: The median (interquartile range) WML% was 1.10 (0.59 to 1.61); 24.2% were Aβ positive, and 51% were equol producers. Equol-producing status (non-producers, low and high) was significantly inversely associated with WML%: 1.19, 0.89, and 0.58, respectively (trend  < .01). Equol-producing status was not associated with Aβ status.

Discussion: A randomized-controlled trial of equol targeting WML volume is warranted.
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http://dx.doi.org/10.1002/trc2.12089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580022PMC
October 2020

Postprandial cerebral infarction resolved by extracranial-intracranial bypass surgery.

eNeurologicalSci 2020 Dec 14;21:100283. Epub 2020 Oct 14.

Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.

A 51-year-old man with type 2 diabetes mellitus was admitted with a 2-month history of repeated episodes of transient aphasia and right hemiparesis after food intake. His blood pressure (BP) fell when the neurological deficits developed. The fall in BP after each meal was confirmed by 24-h ambulatory blood pressure monitoring (ABPM), which established the diagnosis of postprandial hypotension (PPH). Diffusion-weighted magnetic resonance imaging of the brain showed multiple high-intensity lesions at the borderzone between the anterior and middle cerebral artery (MCA) territories in the left hemisphere. Digital subtraction angiography showed tapered occlusion at the origin of the left internal carotid artery (ICA). Despite sufficient antiplatelet therapy and medication for PPH, the transient symptoms remained. Positron emission tomography scanning using H O showed decreased cerebral blood flow with increased oxygen extraction fraction in the left MCA territory. As the symptomatic left ICA occlusion was intractable, an extracranial-intracranial (EC-IC) bypass surgery was conducted without any perioperative complications. Although PPH remained, cerebrovascular ischemic events including repeated transient ischemic attack disappeared for 2 months after surgery. The coincidence of stroke with ABPM-proved transient hypotension suggested that the brain infarcts were caused by hemodynamic changes related to PPH co-existent with the chronic left ICA occlusion. ABPM is useful in evaluating hemodynamic infarcts associated with BP fluctuation, and should be considered for patients with chronic ICA occlusion. In addition, EC-IC bypass may be a treatment option for symptomatic chronic ICA occlusion due to PPH.
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http://dx.doi.org/10.1016/j.ensci.2020.100283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575838PMC
December 2020

Treatment Outcomes by Initial Neurological Deficits in Acute Stroke Patients with Basilar Artery Occlusion: The RESCUE Japan Registry 2.

J Stroke Cerebrovasc Dis 2020 Nov 4;29(11):105256. Epub 2020 Sep 4.

Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan.

Background And Purpose: We hypothesized that the relationships between treatments and outcomes in acute basilar artery occlusion (BAO) are different, depending on the severity of initial neurological deficits.

Methods: Of 2420 ischemic stroke patients with large vessel occlusion in a prospective, multicenter registry in Japan, patients with acute BAO were enrolled. Subjects were divided into two severity groups according to the baseline NIH Stroke Scale score: severe (≥10) and mild (<10) groups. The primary effectiveness outcome was favorable outcome, defined as modified Rankin Scale score 0-3 at 3 months. Safety outcomes included any intracranial hemorrhage (ICH) within 72 h. Outcomes in each group were compared between patients who received endovascular therapy (EVT) and those with standard medical treatment (SMT).

Results: In this study, 167 patients (52 female; median age 75 years) were analyzed. The favorable outcome was seen in 93 patients (56%) overall. In the severe group (n = 128), the proportion of favorable outcome was higher in patients who received EVT (60/111, 54%) than those with SMT (2/17, 12%, P < 0.01). In the mild group (n = 39), the rates of favorable outcome were comparable between the EVT (13/18, 72%) and SMT patients (18/21, 86%, P = 0.43). No significant differences in the rates of any ICH were seen among any groups.

Conclusions: In acute BAO stroke with severe neurological deficit, independent ambulation was more frequently seen in patients who received EVT than those with SMT. Patients with mild neurological deficits showed similar rates of independent ambulation between the two treatment selections.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105256DOI Listing
November 2020

A Prospective Longitudinal Study on the Relationship Between Glucose Fluctuation and Cognitive Function in Type 2 Diabetes: PROPOSAL Study Protocol.

Diabetes Ther 2020 Nov 5;11(11):2729-2737. Epub 2020 Sep 5.

Division of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.

Introduction: Although the risk of dementia among patients with type 2 diabetes mellitus (T2DM) is double that of those without T2DM, the mechanism remains to be elucidated and the glycemic goal to prevent progression of cognitive impairment is unclear. Results from cross-sectional studies suggest that glucose fluctuations are associated with impairment of cognitive function among T2DM patients. Therefore, the aim of the longitudinal study described here is to evaluate the relationships between glucose fluctuation indexes assessed by continuous glucose monitoring (CGM) and cognitive function among elderly patients with T2DM.

Methods: This will be a prospective, single-center, 2-year longitudinal study in which a total of 100 elderly patients with T2DM showing mild cognitive impairment (MCI) will be enrolled. Glucose fluctuations, assessed using the FreeStyle Libre Pro continuous glucose monitoring system (Abbott Laboratories), and results of cognitive tests, namely the Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale (ADAS), will be evaluated at baseline, 1-year visit and 2-year visit. The primary endpoint is the relationships between indexes of glucose fluctuation and change in MoCA and ADAS scores. Secondary endpoints are the relationships between the indexes of glucose fluctuation or cognitive scores and the following: indexes representing intracranial lesions obtained by magnetic resonance imaging and angiography of the head; Geriatric Depression Scale score; Apathy Scale score; carotid intima-media thickness assessed by echography; inflammatory markers; fasting glucose; glycated hemoglobin; blood pressure; and the development of cardiovascular and renal events.

Planned Outcomes: The current study is scheduled for completion in June 2022. The results could lead to the elucidation of novel glycemic goals to prevent the progression of cognitive impairment and/or of relationships between glucose fluctuations and cognitive function among T2DM patients. The findings of the study will be reported in publications and conference presentations.

Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN000038546).
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http://dx.doi.org/10.1007/s13300-020-00916-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547936PMC
November 2020
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