Publications by authors named "Masafumi Ihara"

284 Publications

Plasma mid-regional pro-adrenomedullin: A biomarker of the ischemic penumbra in hyperacute stroke.

Brain Pathol 2022 Aug 2:e13110. Epub 2022 Aug 2.

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

Reperfusion therapy has improved the outcomes of ischemic stroke but also emphasized the importance of ischemic penumbra. However, blood biomarkers are currently unavailable for this region. Adrenomedullin (ADM) is a neuroprotective peptide, secreted in a compensatory response to brain ischemia. We thus investigated whether an increase in mid-regional pro-ADM (MR-proADM), a stable peptide fragment of the ADM precursor, could act as a biomarker by predicting the ischemic penumbra in hyperacute ischemic stroke (HAIS). We prospectively enrolled consecutive HAIS patients (n = 119; median age, 77 years; male, 59.7%) admitted to our institutes from July 2017 to March 2019 and evaluated plasma MR-proADM levels within 4.5 h of onset. MR-proADM levels in HAIS were compared to healthy controls (n = 1298; median age, 58 years; male, 33.2%) in the Japan Multi-Institutional Collaborative Cohort Study from 2013 to 2017. Furthermore, we evaluated whether MR-proADM levels were associated with the penumbra estimated by clinical-diffusion mismatch (CDM) (National Institute of Health Stroke Scale [NIHSS] ≥8, diffusion ischemic core volume ≤25 ml), or magnetic resonance angiography-diffusion-weighted imaging mismatch (MDM) (NIHSS ≥5, a proximal vessel occlusion with core volume ≤25 ml, or a proximal vessel stenosis/distal vessel occlusion with core volume ≤15 ml). In a case-control study, multivariate logistic analysis showed a significant association between HAIS and MR-proADM ≥0.54 nmol/L (adjusted odds ratio, 7.92 [95% CI, 4.17-15.02], p < 0.001). Though MR-proADM levels in HAIS did not correlate with the ischemic core volume (r  = 0.09, p = 0.348), they were higher in HAIS with CDM (n = 34; 0.81 vs. 0.61 nmol/L, p < 0.001) or MDM (n = 26; 0.83 vs. 0.62 nmol/L, p = 0.002). These differences remained significant after adjusting baseline factors (adjusted odds ratio, 4.06 [95% CI, 1.31-12.55], p = 0.015 and 4.65 [1.35-16.11], p = 0.015, respectively). Plasma MR-proADM is elevated in HAIS, especially in those with a substantial penumbra, suggesting potential as a blood biomarker in this region.
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http://dx.doi.org/10.1111/bpa.13110DOI Listing
August 2022

Developing an Asymmetry Method for Detecting Postictal Hyperperfusion in Poststroke Epilepsy.

Front Neurol 2022 13;13:877386. Epub 2022 Jul 13.

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

Using dual single-photon emission computed tomography (SPECT) scanning, we recently found the postictal-interictal (P-I) subtraction method frequently detects prolonged postictal hyperperfusion in poststroke epilepsy (PSE) and thus may be valuable for auxiliary diagnosis. This study aimed to determine if the asymmetry method can localize hyperperfusion to reflect epileptic activity in PSE using a single postictal SPECT scan. Sixty-four patients with PSE who had undergone perfusion SPECT two times (postictal and interictal) were enrolled. We formulated a novel asymmetry method (subtraction analysis of reversed postictal SPECT from postictal SPECT, co-registered to magnetic resonance imaging) to identify paradoxical asymmetric increase, defined as a higher perfusion area adjacent to stroke lesions compared to the contralateral side. The postictal hyperperfusion area and detection rates were determined by the asymmetry and P-I subtraction methods independently. We subsequently calculated the sensitivity and specificity of the asymmetry method, compared to the gold standard P-I subtraction method. We also evaluated lateralization concordance between the asymmetry method and other clinical findings. Among 64 patients (median age, 75 years), prolonged postictal hyperperfusion was detected in 43 (67%) by the asymmetry, and 54 (84%) the P-I, method. The asymmetry method had high sensitivity (80%) and specificity (100%) in detecting postictal hyperperfusion, showing high lateralization concordance with seizure semiology (97%) and epileptiform electroencephalography findings (interictal/ictal epileptiform discharges or periodic discharges) (100%). The present study demonstrated the advantages of the objective asymmetry method for detecting prolonged hyperperfusion through using one postictal SPECT scan in PSE.
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http://dx.doi.org/10.3389/fneur.2022.877386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9334132PMC
July 2022

Complement 3 Is a Potential Biomarker for Cerebral Amyloid Angiopathy.

J Alzheimers Dis 2022 Jul 20. Epub 2022 Jul 20.

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

Background: Cerebral amyloid angiopathy is a cerebrovascular disease directly implicated in Alzheimer's disease pathogenesis through amyloid-β deposition. Growing evidence has shown a pivotal role of chronic neuroinflammation both in cerebral amyloid angiopathy and Alzheimer's disease.

Objective: The aim of this study was to investigate whether circulating levels of the complement 3, a crucial component of the innate immune system, are increased in patients with cerebral amyloid angiopathy.

Methods: Serum complement 3 levels were retrospectively measured by a sandwich enzyme-linked immunosorbent assay in a single-center cohort of patients with mild cognitive impairment. The diagnosis of cerebral amyloid angiopathy was based on the modified Boston criteria. Logistic regression analysis was performed to identify the predictive factors for cerebral amyloid angiopathy.

Results: We analyzed 55 mild cognitive impairment patients (mean age [standard deviation]: 76.3 [6.8] years; 33 [60% ] men). Complement 3 levels were significantly increased in cerebral amyloid angiopathy patients (n = 16) compared with those without cerebral amyloid angiopathy (n = 39) (median [interquartile range]: 0.43 [0.34-0.65] versus 0.35 [0.25-0.45], respectively; p = 0.040). Univariate and multivariate logistic regression analysis revealed that increased complement 3 levels were significantly associated with cerebral amyloid angiopathy. After selection of the best predictive model using stepwise selection, complement 3 was preserved as a significant independent predictive factor for cerebral amyloid angiopathy (odds ratio per 0.1 unit/mL increase [95% confidence interval]: 1.407 [1.042-1.899]; p = 0.026).

Conclusion: Complement activation may play a pivotal role in cerebral amyloid angiopathy. Complement 3 may be a novel diagnostic biomarker for cerebral amyloid angiopathy.
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http://dx.doi.org/10.3233/JAD-220494DOI Listing
July 2022

Imaging Characteristics for Predicting Cognitive Impairment in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Front Aging Neurosci 2022 10;14:876437. Epub 2022 Jun 10.

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

Objectives: Patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) show various clinical symptoms, including migraine, recurrent stroke, and cognitive impairment. We investigated the associations between magnetic resonance imaging (MRI) markers of small vessel disease and neuropsychological tests and identified the MRI characteristics for predicting cognitive impairment in patients with CADASIL.

Methods: Subjects included 60 CADASIL patients diagnosed with genetic tests and registered in the Japanese CADASIL REDCap database between June 2016 and December 2020. Patient information including clinical data, modified Rankin Scale (mRS); MRI findings of small vessel disease including periventricular and deep white matter lesions (WML), lacunar infarcts, and cerebral microbleeds (CMBs); and neuropsychological tests, including the Japanese version of the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), and the Frontal Assessment Battery (FAB), were evaluated.

Results: Data from 44 CADASIL patients were eligible for this study, compared between patients with and without dementia. Regarding the neuroimaging findings, the Fazekas score of periventricular and deep WML was higher in patients with dementia (periventricular, = 0.003; deep, = 0.009). The number of lacunar infarcts was higher in patients with dementia ( = 0.001). The standardized partial regression coefficient (SPRC) in MoCA-J was 0.826 (95% CI, 0.723-0.942; = 0.005) for the number of CMBs. The SPRC in MMSE was 0.826 (95% CI, 0.719-0.949; = 0.007) for the number of CMBs. The SPRC for FAB decreased significantly to 0.728 (95% CI, 0.551-0.960; = 0.024) for the number of lacunar infarcts. Receiver operating characteristic (ROC) curves for dementia showed that in the number of lacunar infarcts, a cut-off score of 5.5 showed 90.9% sensitivity and 61.1% specificity. For the number of CMBs, a cut-off score of 18.5 showed 45.5% sensitivity and 100% specificity.

Conclusion: The characteristic MRI findings were that CADASIL patients with dementia had severe WML, both periventricular and deep, and a larger number of lacunar infarcts than those without dementia. The risk of dementia may be associated with ≥ 6 lacunar infarcts, ≥19 CMBs, or a Fazekas scale score of 3 in periventricular and deep WML.
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http://dx.doi.org/10.3389/fnagi.2022.876437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226637PMC
June 2022

Association Between Cerebral Microbleeds and Circulating Levels of Mid-Regional Pro-Adrenomedullin.

J Alzheimers Dis 2022 ;88(2):731-741

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

Background: Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored.

Objective: We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment.

Methods: In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (< 0.65 nmol/L) or high (≥0.65 nmol/L).

Results: The mean MR-proADM level was 0.515±0.127 nmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (p < 0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; p < 0.05).

Conclusion: High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients.
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http://dx.doi.org/10.3233/JAD-220195DOI Listing
July 2022

Evaluating the Potential Pathology and Short-Term Outcomes of Cryptogenic Stroke Using the Etiological Classification System.

J Atheroscler Thromb 2022 Jun 12. Epub 2022 Jun 12.

Department of Neurology, Juntendo University Urayasu Hospital.

Aim: Various embolic sources and pathogenetic mechanisms underlie cryptogenic stroke (CS). We investigated the association of etiological diversity with short-term outcomes in patients with CS using a modified atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D) (ASCOD) system.

Methods: Patients with CS who underwent transesophageal echocardiography were registered in this multicenter, observational study. In the modified classification system, O and D were inapplicable and thus excluded. Instead, atherosclerosis, small-vessel disease, cardiac pathology-CS classification was specifically constructed for the etiological diagnosis of CS. We utilized this system to explore the mechanism of CS by grading each pathology and evaluated its association with poorer modified Rankin Scale scores of 3-6 at hospital discharge.

Results: A total of 672 patients (68.7±12.8 years, 220 females) were analyzed. In the multiple logistic regression model, female sex (odds ratio [OR], 1.87 [1.15-3.04]; P=0.012), body mass index (OR, 0.93 [0.88-0.99]; P=0.025), National Institute of Health Stroke Scale score (OR, 1.16 [1.12-1.21]; P<0.001), CHADS2 score (OR, 1.56 [1.30-1.86]; P<0.001), D-dimer (OR, 1.04 [1.01-1.08]; P=0.015), diffusion-weighted image (DWI) lesion size (OR, 1.44 [1.10-1.89]; P=0.009), and S+C score (OR, 1.26 [1.03-1.56]; P=0.029) were associated with poor functional outcome at discharge whereas the S+C score was marginally associated with poor functional outcome after excluding 137 patients with a premorbid modified Rankin Scale score of ≥ 3.

Conclusions: The coexistence of small-vessel disease and cardiac pathology might be associated with poor in-hospital functional outcome in CS.
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http://dx.doi.org/10.5551/jat.63267DOI Listing
June 2022

Dedicated transthoracic echocardiography to identify apical thrombus causing recurrent cerebral embolism: a case report.

Acta Neurol Belg 2022 Jun 1. Epub 2022 Jun 1.

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

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http://dx.doi.org/10.1007/s13760-022-01995-0DOI Listing
June 2022

Risk Assessment of Cnm-Positive in Stroke Survivors (RAMESSES): Protocol for a Multicenter Prospective Cohort Study.

Front Neurol 2022 12;13:816147. Epub 2022 May 12.

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

Introduction: The role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that (, the main pathogen of dental caries), harboring the gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive in the oral cavity on the risk of CMB development and cognitive decline.

Methods: Fifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years.

Discussion: The 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive in SVD including CMBs and intracerebral hemorrhage from the perspective of the "brain-oral axis" and provide guidance for novel prophylactic strategies against Cnm-positive -induced SVD.
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http://dx.doi.org/10.3389/fneur.2022.816147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133813PMC
May 2022

Randomised placebo-controlled multicentre trial to evaluate the efficacy and safety of JTR-161, allogeneic human dental pulp stem cells, in patients with Acute Ischaemic stRoke (J-REPAIR).

BMJ Open 2022 05 24;12(5):e054269. Epub 2022 May 24.

Department of Neurology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan.

Introduction: JTR-161 is a novel allogeneic human cell product consisting of dental pulp stem cells isolated from the extracted teeth of healthy adults. It is currently under development as a cell-based therapy for ischaemic stroke. The aim of this study is to evaluate the safety and efficacy of JTR-161 in patients with acute ischaemic stroke when given as a single intravenous administration within 48 hours of symptom onset.

Methods And Analysis: This is a first-in-human, randomised, double-blind, placebo-controlled, multicentre, phase 1/2 clinical trial to be conducted in Japan (from January 2019 to July 2021). Patients with a clinical diagnosis of anterior circulation ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS)score of 5-20 at baseline were enrolled. Patients previously treated with recombinant tissue-type plasminogen activator and/or endovascular thrombectomy were allowed to be enrolled. The study consists of three cohorts: cohorts 1 and 2 (each eight patients) and cohort 3 (60 patients). Subjects were randomly assigned to receive either JTR-161 or placebo in a 3:1 ratio in cohorts 1 and 2, and in a 1:1 ratio in cohort 3. The number of cells administered was increased sequentially from 1×10 (cohort 1) to 3 x 10 (cohort 2). In cohort 3, the higher tolerated dose among the two cohorts was administered. The primary endpoint is the proportion of patients who achieve an excellent outcome as defined by all of the following criteria at day 91 in cohort 3: modified Rankin Scale ≤1, NIHSS ≤1 and Barthel Index ≥95.

Ethics And Dissemination: The protocol and informed consent form were approved by the institutional review board at each participating study site. A manuscript with the results of the primary study will be published in a peer-reviewed journal.

Trial Registration Number: NCT04608838; JapicCTI-194570 and Clinical Trials. gov.
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http://dx.doi.org/10.1136/bmjopen-2021-054269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125710PMC
May 2022

Moyamoya disease: diagnosis and interventions.

Lancet Neurol 2022 08 20;21(8):747-758. Epub 2022 May 20.

Institute of Public Health, Kyoto Hokenkai Foundation, Kyoto, Japan.

Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.
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http://dx.doi.org/10.1016/S1474-4422(22)00165-XDOI Listing
August 2022

Clinical and imaging features of nonmotor onset seizure in poststroke epilepsy.

Epilepsia 2022 Aug 10;63(8):2068-2080. Epub 2022 Jun 10.

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

Objective: Motivated by the challenges raised by diagnosing poststroke epilepsy (PSE), especially in nonmotor onset seizure (non-MOS), we aimed to investigate the features of non-MOS, including seizure sequences, patient characteristics, and electrophysiological and imaging findings in PSE.

Methods: This observational cohort study enrolled patients with PSE whose seizure onset was witnessed. According to the International League Against Epilepsy (ILAE) 2017 seizure classification, we classified seizure-onset symptoms into the non-MOS and MOS groups. We compared the different clinical characteristics between the two groups.

Results: Between 2011 and 2018, we enrolled 225 patients with PSE (median age, 75 years), consisting of 97 (43%) with non-MOS and 128 (57%) with MOS. Overall, 65 (67%) of the patients without MOS had no subsequent convulsions. Multivariable logistic regression analysis showed significant associations of non-MOS with absence of poststroke hemiparesis (adjusted odds ratio [OR], 1.88; 95% confidence interval [CI], 1.03-3.42), frontal stroke lobe lesions (OR, 2.11; 95% CI, 1.14-3.91), and putaminal stroke lesions (OR, 2.51; 95% CI, 1.22-5.18) as negative indicators. Postictal single-photon emission computed tomography (SPECT) detected prolonged hyperperfusion in the temporal lobe more frequently in the non-MOS than in the MOS group (48% vs 31%; p = .02). The detection rate was higher than spikes/sharp waves in scalp electroencephalography, both in the non-MOS group (72% vs 33%; p < .001) and the MOS group (68% vs 29%; p < .001).

Significance: This study provides the clinical features of non-MOS in patients with PSE. Compared with the patients with MOS, patients with non-MOS showed less likely subsequent convulsive seizures, highlighting the clinical challenges. Postictal perfusion imaging and negative indicators of the non-MOS type may help diagnose and stratify PSE.
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http://dx.doi.org/10.1111/epi.17308DOI Listing
August 2022

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.

Brain 2022 06;145(6):1992-2007

University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Team ELEANOR, UMR 1219, F-33000 Bordeaux, France.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.
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http://dx.doi.org/10.1093/brain/awab432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255380PMC
June 2022

Impact of Seizure Recurrence on 1-Year Functional Outcome and Mortality in Patients With Poststroke Epilepsy.

Neurology 2022 Jul 4;99(4):e376-e384. Epub 2022 May 4.

From the Department of Neurology (H.Y., M. Kawamoto), Kobe City Medical Center General Hospital; Department of Neurology (T.T., K.F., M.I.), National Cerebral and Cardiovascular Center, Suita; Department of Neurology (S. Matsubara), Graduate School of Medical Sciences, Kumamoto University; Department of Neurology and Brain Bank for Aging Research (R. Motoyama, S. Murayama), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology; Department of Neurology (M.M.), Nakamura Memorial Hospital, Sapporo; Minami-ichijyo Neurology Clinic (M.M.), Sapporo; Department of Neurology (T.M.), St. Mary's Hospital, Fukuoka; Department of Neurology (Y.M.), National Hospital Organization Okayama Medical Center; Department of Neurology (J.S.), Toyota Memorial Hospital; Department of Neurology (K.K., A.S., R.T.), Kyoto University Graduate School of Medicine; Department of Preventive Medicine and Epidemiology (K.N.), National Cerebral and Cardiovascular Center, Suita; Department of Medical Informatics and Clinical Epidemiology (D.O.), Graduate School of Medical Science, Kyoto Prefectural University of Medicine; Department of Cerebrovascular Medicine (M. Koga, K.T.), National Cerebral and Cardiovascular Center, Suita; Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders (S. Murayama), Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita; Division of Neurology (R. Matsumoto), Kobe University Graduate School of Medicine; and Department of Epilepsy, Movement Disorders and Physiology (A.I.), Kyoto University Graduate School of Medicine, Japan.

Background And Objectives: The functional outcome and mortality of patients with poststroke epilepsy (PSE) have not been assessed in a prospective study. Previous reports have suggested that patients with PSE may suffer from prolonged functional deterioration after a seizure. In this study, we prospectively investigated the functional outcome and mortality of patients with PSE and analyzed the effect of seizure recurrence on the outcomes.

Methods: This is part of the Prognosis of Post-Stroke Epilepsy study, a multicenter, prospective observational cohort study, where 392 patients with PSE (at least 1 unprovoked seizure more than 7 days after the onset of the last symptomatic stroke) were followed for at least 1 year at 8 hospitals in Japan. This study included only PSE patients with a first-ever seizure and assessed their functional decline and mortality at 1 year. Functional decline was defined as an increase in modified Rankin Scale (mRS) score at 1 year compared with baseline, excluding death. The associations between the seizure recurrence and the outcomes were analyzed statistically.

Results: A total of 211 patients (median age of 75 years; median mRS score of 3) were identified. At 1 year, 50 patients (23.7%) experienced seizure recurrence. Regarding outcomes, 25 patients (11.8%) demonstrated functional decline and 20 (9.5%) had died. Most patients died of pneumonia or cardiac disease (7 patients each), and no known causes of death were directly related to recurrent seizures. Seizure recurrence was significantly associated with functional decline (odds ratio [OR] 2.96, 95% CI 1.25-7.03, = 0.01), even after adjusting for potential confounders (adjusted OR 3.26, 95% CI 1.27-8.36, = 0.01), but not with mortality (OR 0.79, 95% CI 0.25-2.48, = 0.68). Moreover, there was a significant trend where patients with more recurrent seizures were more likely to have functional decline (8.7%, 20.6%, and 28.6% in none, 1, and 2 or more recurrent seizures, respectively; = 0.006).

Discussion: One-year functional outcome and mortality of patients with PSE were poor. Seizure recurrence was significantly associated with functional outcome, but not with mortality. Further studies are needed to ascertain whether early and adequate antiseizure treatment can prevent the functional deterioration of patients with PSE.
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http://dx.doi.org/10.1212/WNL.0000000000200609DOI Listing
July 2022

Late-onset cerebral embolism after transcatheter aortic valve implantation under direct oral anticoagulant therapy.

J Stroke Cerebrovasc Dis 2022 Jul 28;31(7):106525. Epub 2022 Apr 28.

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

Ischemic stroke is a devastating complication of transcatheter aortic valve implantation (TAVI), mainly occurring in the early postoperative period. The risk of a transplanted heart valve (THV) thrombosis causing stroke may be underestimated in the late postoperative phase. We describe the case of a 92-year-old woman with delayed valve thrombosis causing stroke after TAVI, who developed recurrent strokes eight months after TAVI for severe aortic valve stenosis. Transesophageal echocardiography and cardiac computed tomography revealed a string-like thrombus attached to the implanted valve. With the administration of warfarin, the clot regressed, and the patient was discharged home without recurrence of stroke. Our case demonstrates the importance of THV thrombosis as an embolic source of stroke even in the late postoperative phase and provides a discussion on optimal antithrombotic therapy after TAVI.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2022.106525DOI Listing
July 2022

Endothelial BACE1: Bridging the Gap Between Hypertension and Alzheimer's Disease.

Authors:
Masafumi Ihara

Circ Res 2022 04 28;130(9):1342-1344. Epub 2022 Apr 28.

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

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http://dx.doi.org/10.1161/CIRCRESAHA.122.321078DOI Listing
April 2022

Impact of Previous Stroke on Clinical Outcome in Elderly Patients With Nonvalvular Atrial Fibrillation: ANAFIE Registry.

Stroke 2022 08 20;53(8):2549-2558. Epub 2022 Apr 20.

Department of Cerebrovascular Medicine (K.T., T. Yamaguchi), National Cerebral and Cardiovascular Center, Suita, Japan.

Background: We determined the long-term event incidence among elderly patients with nonvalvular atrial fibrillation in terms of history of stroke/transient ischemic attack (TIA) and oral anticoagulation.

Methods: Patients aged ≥75 years with documented nonvalvular atrial fibrillation enrolled in the prospective, multicenter, observational All Nippon Atrial Fibrillation in the Elderly Registry between October 2016 and January 2018 were divided into 2 groups according to history of stroke/TIA. The primary end point was the occurrence of stroke/systemic embolism within 2 years, and secondary end points were major bleeding and all-cause death within 2 years. Cox models were used to determine whether there was a difference in the hazard of each end point in patients with/without history of stroke/TIA, and in ischemic stroke/TIA survivors taking direct oral anticoagulants versus those taking warfarin.

Results: Of 32 275 evaluable patients (13 793 women [42.7%]; median age, 81.0 years), 7304 (22.6%) had a history of stroke/TIA. The patients with previous stroke/TIA were more likely to be male and older and had higher hazard rates of stroke/systemic embolism (adjusted hazard ratio, 2.25 [95% CI, 1.97-2.58]), major bleeding (1.25, 1.05-1.49), and all-cause death (1.13, 1.02-1.24) than the other groups. Of 6446 patients with prior ischemic stroke/TIA, 4393 (68.2%) were taking direct oral anticoagulants and 1668 (25.9%) were taking warfarin at enrollment. The risk of stroke/systemic embolism was comparable between these 2 groups (adjusted hazard ratio, 0.90 [95% CI, 0.71-1.14]), while the risk of major bleeding (0.67, 0.48-0.94), intracranial hemorrhage (0.57, 0.39-0.85), and cardiovascular death (0.71, 0.51-0.99) was lower among those taking direct oral anticoagulants.

Conclusions: Patients aged ≥75 years with nonvalvular atrial fibrillation and previous stroke/TIA more commonly had subsequent ischemic and hemorrhagic events than those without previous stroke/TIA. Among patients with previous ischemic stroke/TIA, the risk of hemorrhagic events was lower in patients taking direct oral anticoagulants compared with warfarin.

Registration: URL: https://www.

Clinicaltrials: gov; Unique Identifier: UMIN000024006.
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http://dx.doi.org/10.1161/STROKEAHA.121.038285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311295PMC
August 2022

Internal Carotid Artery Tortuosity: Impact on Mechanical Thrombectomy.

Stroke 2022 Aug 11;53(8):2458-2467. Epub 2022 Apr 11.

Department of Cerebrovascular Medicine (J.K., M.S., M.K., K. Toyoda), National Cerebral and Cardiovascular Center, Suita, Japan.

Background: Although tortuosity of the internal carotid artery (ICA) can pose a significant challenge when performing mechanical thrombectomy, few studies have examined the impact of ICA tortuosity on mechanical thrombectomy outcomes.

Methods: In a registry-based hospital cohort, consecutive patients with anterior circulation stroke in whom mechanical thrombectomy was attempted were divided into 2 groups: those with tortuosity in the extracranial or cavernous ICA (tortuous group) and those without (nontortuous group). The extracranial ICA tortuosity was defined as the presence of coiling or kinking. The cavernous ICA tortuosity was defined by the posterior deflection of the posterior genu or the shape resembling Simmons-type catheter. Outcomes included first pass effect (FPE; extended Thrombolysis in Cerebral Infarction score 2c/3 after first pass), favorable outcome (3-month modified Rankin Scale score of 0-2), and intracranial hemorrhage.

Results: Of 370 patients, 124 were in the tortuous group (extracranial ICA tortuosity, 35; cavernous ICA tortuosity, 70; tortuosity at both sites, 19). The tortuous group showed a higher proportion of women and atrial fibrillation than the nontortuous group. FPE was less frequently achieved in the tortuous group than the nontortuous group (21% versus 39%; adjusted odds ratio, 0.45 [95% CI, 0.26-0.77]). ICA tortuosity was independently associated with the longer time from puncture to extended Thrombolysis in Cerebral Infarction ≥2b reperfusion (β=23.19 [95% CI, 13.44-32.94]). Favorable outcome was similar between groups (46% versus 48%; =0.87). Frequencies of any intracranial hemorrhage (54% versus 42%; adjusted odds ratio, 1.61 [95% CI, 1.02-2.53]) and parenchymal hematoma (11% versus 6%; adjusted odds ratio, 2.41 [95% CI, 1.04-5.58]) were higher in the tortuous group. In the tortuous group, the FPE rate was similar in patients who underwent combined stent retriever and contact aspiration thrombectomy and in those who underwent either procedure alone (22% versus 19%; =0.80). However, in the nontortuous group, the FPE rate was significantly higher in patients who underwent combined stent retriever and contact aspiration (52% versus 35%; =0.02).

Conclusions: ICA tortuosity was independently associated with reduced likelihood of FPE and increased risk of postmechanical thrombectomy intracranial hemorrhage.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT02251665.
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http://dx.doi.org/10.1161/STROKEAHA.121.037904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311296PMC
August 2022

Temporal Trajectory of Systolic Blood Pressure and Outcomes in Acute Intracerebral Hemorrhage: ATACH-2 Trial Cohort.

Stroke 2022 06 11;53(6):1854-1862. Epub 2022 Apr 11.

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

Background: To highlight the heterogeneity of acute temporal blood pressure (BP) changes in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) and associations with the outcomes of intracerebral hemorrhage.

Methods: One thousand patients with acute intracerebral hemorrhage, who had been randomized to intensive (110-139 mm Hg) or standard (140-179 mm Hg) systolic BP (SBP) lowering with intravenous nicardipine in ATACH-2 from 2011 to 2015, were analyzed about temporal changes in hourly maximum SBP up to 24 hours after randomization using group-based trajectory modeling. Outcomes included death or disability (modified Rankin Scale score 4-6) at 3 months, neurological deterioration within 24 hours (≥2-point decrease in Glasgow Coma Scale score or ≥4-point increase in National Institutes of Health Stroke Scale score), and acute kidney injury (≥0.3 mg/dL within 48 hours or ≥1.5-fold increase in serum creatinine) within 7 days after onset.

Results: Group-based trajectory modeling revealed 4 SBP trajectory groups: moderate SBP (from ≈190 mm Hg at hospital arrival to 150-160 mm Hg after randomization; n=298), moderate-to-low SBP (from ≈190 mm Hg to <140 mm Hg; n=395), high-to-low SBP (from >210 mm Hg to <140 mm Hg; n=134), and high SBP (from >210 mm Hg to 160-170 mm Hg; n=173). Patients with intensive treatment accounted for 11.1%, 88.6%, 85.1%, and 1.7% of each group, respectively. Compared with the moderate-to-low SBP group, the high-to-low SBP group showed increased risks of death or disability at 3 months (adjusted odds ratio, 2.29 [95% CI, 1.24-4.26]) and acute kidney injury (adjusted odds ratio, 3.50 [95% CI, 1.83-6.69]), while no increase in neurological deterioration was seen in this group (adjusted odds ratio, 0.48 [95% CI, 0.20-1.13]). The moderate SBP and high SBP groups showed no significant risk differences for such outcomes.

Conclusions: Data-driven observation using a group-based trajectory modeling approach may be useful to clarify the relationship between antihypertensive treatment, temporal SBP changes, and outcomes in acute intracerebral hemorrhage.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT01176565.
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http://dx.doi.org/10.1161/STROKEAHA.121.037186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126256PMC
June 2022

Transcriptomic mapping of the human cerebrovasculature.

Nat Rev Neurol 2022 06;18(6):319-320

Department of Molecular Innovation in Lipidemiology, National Cerebral and Cardiovascular Center, Suita, Japan.

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http://dx.doi.org/10.1038/s41582-022-00650-9DOI Listing
June 2022

P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study.

J Atheroscler Thromb 2022 Mar 5. Epub 2022 Mar 5.

Department of Neurology, National Cerebral and Cardiovascular Center.

Aims: We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA).

Methods: In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8-90 days) phases.

Results: Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19 2/2, 2/3, or 3/3). Multivariable receiver-operating characteristic analysis showed a greater area-under-the-curve (AUC) in predicting recurrence within 7 days, compared to 8-90 days (AUC, 0.79 versus 0.64; p=0.07), with a cut-off PRU of 254. Multivariable analysis showed high PRU (≥ 254), which had a comparable predictive performance for recurrent ischemic stroke within 7 days (odds ratio, 6.82; 95% CI, 2.23-20.9; p<0.001) to the CYP2C19 poor metabolizer genotype. The net reclassification improvement, calculated by adding high PRU (≥ 254) to a model including the CYP2C19 poor metabolizer genotype in the prediction of recurrence within 7 days, was 0.83 (p<0.001).

Conclusions: Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.
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http://dx.doi.org/10.5551/jat.63369DOI Listing
March 2022

Homonymous Hemianopsia Detected During a Meal.

Intern Med 2022 Feb 19. Epub 2022 Feb 19.

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

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http://dx.doi.org/10.2169/internalmedicine.9147-21DOI Listing
February 2022

The Association Between Standard Electrocardiography and Cerebral Small Vessel Disease in a Memory Clinic Study.

J Alzheimers Dis 2022 ;86(3):1093-1105

Department of Pharmacology, National University of Singapore, Singapore.

Background: P-wave terminal force in lead V1 (PTFV1) on electrocardiography has been associated with atrial fibrillation and ischemic stroke.

Objective: To investigate whether PTFV1 is associated with cerebral small vessel disease (CSVD) markers and etiological subtypes of cognitive impairment and dementia.

Methods: Participants were recruited from ongoing memory clinic study between August 2010 to January 2019. All participants underwent physical and medical evaluation along with an electrocardiography and 3 T brain magnetic resonance imaging. Participants were classified as no cognitive impairment, cognitive impairment no dementia, vascular cognitive impairment no dementia, and dementia subtypes (Alzheimer's disease and vascular dementia). Elevated PTFV1 was defined as > 4,000μV×ms and measured manually on ECG.

Results: Of 408 participants, 78 (19.1%) had elevated PTFV1 (37 women [47%]; mean [SD] age, 73.8 [7.2] years). The participants with elevated PTFV1 had higher burden of lacunes, cerebral microbleeds (CMB), and cortical microinfarcts. As for the CMB location, persons with strictly deep CMB and mixed CMB had significantly higher PTFV1 than those with no CMB (p = 0.005, p = 0.007). Regardless of adjustment for cardiovascular risk factors and/or heart diseases, elevated PTFV1 was significantly associated with presence of CMB (odds ratio, 2.26; 95% CI,1.33-3.91).

Conclusion: Elevated PTFV1 was associated with CSVD, especially deep CMB. PTFV1 in vascular dementia was also higher compared to Alzheimer's disease. Thus, PTFV1 might be a potential surrogate marker of brain-heart connection and vascular brain damage.
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http://dx.doi.org/10.3233/JAD-215413DOI Listing
January 2022

Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke: A CSPS.com Trial Post Hoc Analysis.

Neurology 2022 03 24;98(10):e983-e992. Epub 2022 Jan 24.

From the Departments of Cerebrovascular Medicine (K.T., K. Miwa, M.K., T.Y.), Data Science (K.O.), and Neurology (M.I.), National Cerebral and Cardiovascular Center, Suita; Department of Neurology (H.H.), Tokyo Saiseikai Central Hospital; Clinical Research Center for Medicine (S.U.), International University of Health and Welfare, Center for Brain and Cerebral Vessels, Sanno Medical Center; Department of Neurological Science (K.K.), Graduate School of Medicine, Nippon Medical School, Tokyo; Headquarters of the Iseikai Medical Corporation (K. Minematsu), Osaka; Department of Neurology (K.Y.), Ichinomiya Nishi Hospital; Department of Neurosurgery (Y.S.), Yuri Kumiai General Hospital, Yurihonjo; Department of Neurology (S.T.), Nitobe Memorial Nakano General Hospital; and Department of Neurology (K.K.), Tokyo Women's Medical University, Japan.

Background And Objectives: Long-term treatment with the combination of cilostazol with aspirin or clopidogrel showed a lower risk of stroke recurrence compared to aspirin or clopidogrel alone after high-risk noncardioembolic ischemic stroke in a randomized trial. We aimed to determine whether the effect of the dual medication compared to monotherapy on risk of recurrent ischemic stroke differs according to timing of starting medication after stroke onset.

Methods: In a subanalysis of the randomized controlled trial, patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone or a combination of cilostazol with aspirin or clopidogrel. They were divided into 3 groups according to the timing of starting trial treatment: between 8 and 14 days after stroke onset (8-14 days group), between 15 and 28 days after stroke onset (15-28 days group), and between 29 and 180 days after stroke onset (29-180 days group). The primary efficacy outcome was the first recurrence of ischemic stroke. Safety outcomes included severe or life-threatening bleeding.

Results: Of 1,879 patients, 498 belonged to the 8-14 days group, 467 to the 15-28 days group, and 914 to the 29-180 days group. There was a significant treatment-by-subgroup interaction for the recurrence of ischemic stroke between trial treatment and trichotomized groups. The recurrence of ischemic stroke was less common with dual therapy than with monotherapy in the 15-28 days group (annualized rate 1.5% vs 4.9%, respectively; adjusted hazard ratio 0.34 [95% CI 0.12-0.95]) and the 29-180 days group (1.9% vs 4.4%, respectively; 0.27 [0.12-0.63]) and similarly common in the 8-14 days group (4.5% for both; 1.02 [0.51-2.04]). Severe or life-threatening bleeding occurred similarly between patients on dual therapy and those on monotherapy in any of the trichotomized groups (crude hazard ratio 0.22 [95% CI 0.03-1.88] in the 8-14 days group, 1.07 [0.15-7.60] in the 15-28 days group, and 0.76 [0.24-2.39] in the 29-180 days group).

Discussion: Long-term dual antiplatelet therapy using cilostazol starting 15-180 days after stroke onset, compared to therapy started 8-14 days after onset, was more effective for secondary stroke prevention than monotherapy without increasing hemorrhage risk.

Trial Registration Information: ClinicalTrials.gov NCT01995370; UMIN Clinical Trials Registry 000012180.

Classification Of Evidence: This study provides Class II evidence that for patients with acute noncardioembolic stroke taking either aspirin or clopidogrel, the addition of cilostazol 15-180 days after stroke onset decreases the risk of recurrent ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000200064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967394PMC
March 2022

RNF213 p.R4810K Variant Carriers with Intracranial Arterial Stenosis Have a Low Atherosclerotic Burden.

J Atheroscler Thromb 2021 Dec 25. Epub 2021 Dec 25.

Department of Neurology, Osaka University Graduate School of Medicine.

Aim: The ring finger protein 213 gene (RNF213) p.R4810K variant is a major susceptibility gene for intracranial arterial stenosis in East Asia. We hypothesized that if intracranial arterial stenosis is induced by a non-atherosclerotic mechanism similar to moyamoya disease, the patients with RNF213 p.R4810K variant may have a lower cumulative atherosclerotic burden than the non-carriers.

Methods: A total of 112 participants with intracranial arterial stenosis were enrolled in this multicenter cross-sectional study. We compared the prevalence of atherosclerotic risk factors and three different cardiovascular risk scores (Essen Stroke Risk Score, Framingham Risk Score, and Suita Risk Score) between the RNF213 p.R4810K variant carriers and non-carriers. Patients with moyamoya disease were excluded from the study.

Results: The RNF213 p.R4810K variant carriers were younger than the non-carriers (P<0.001). The prevalence of each atherosclerotic risk factor was not significant, but it tended to be lower in the variant carriers. The Essen Stroke Risk Score (carriers: 2.3±1.5 vs. non-carriers: 2.9±1.5, P=0.047), Framingham Risk Score (10.7±6.4 vs. 15.3±6.2, P=0.001), and Suita Risk Score (35.4±15.8 vs. 48.7±15.2, P<0.001) were significantly lower in the variant carriers. Among the three risk scores, the Suita score showed the highest predictive accuracy for the variant carriers.

Conclusions: RNF213 p.R4810K variant carriers have a lower cumulative atherosclerotic burden than non-carriers among patients with intracranial arterial stenosis. New therapeutic approaches beyond the standard management of atherosclerotic risk factors are required to prevent the development of intracranial arterial stenosis.
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http://dx.doi.org/10.5551/jat.63379DOI Listing
December 2021

Mechanical Thrombectomy Up to 24 Hours in Large Vessel Occlusions and Infarct Velocity Assessment.

J Am Heart Assoc 2021 12 10;10(24):e022880. Epub 2021 Dec 10.

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

Background We retrospectively compared early- (<6 hours) versus late- (6-24 hours) presenting patients using perfusion-weighted imaging selection and evaluated clinical/radiographic outcomes. Methods and Results Large vessel occlusion patients treated with mechanical thrombectomy from August 2017 to July 2020 within 24 hours of onset were retrieved from a single-center database. Perfusion-weighted imaging was analyzed by automated software and final infarct volume was measured semi-automatically within 14 days. The primary end point was good outcome (modified Rankin Scale 0-2 at 90 days). Secondary end points were excellent outcome (modified Rankin Scale 0-1 at 90 days), symptomatic intracranial hemorrhage, and death. Clinical characteristics/radiological values including hypoperfusion volume and infarct growth velocity (baseline volume/onset-to-image time) were compared between the groups. Of 1294 patients, 118 patients were included. The median age was 74 years, baseline National Institutes of Health Stroke Scale score was 14, and core volume was 13 mL. The late-presenting group had more female patients (67% versus 31%, respectively; =0.001). No statistically significant differences were seen in good outcome (42% versus 53%, respectively; =0.30), excellent outcome (26% versus 32%, respectively; =0.51), symptomatic intracranial hemorrhage (6.5% versus 4.6%, respectively; =0.74), and death (3.2% versus 5.7%, respectively; =0.58) between the groups. The late-presenting group had more atherothrombotic cerebral infarction (19% versus 6%, respectively; =0.03), smaller hypoperfusion volume (median: 77 versus 133 mL, respectively; =0.04), and slower infarct growth velocity (median: 0.6 versus 5.1 mL/h, respectively; =0.03). Conclusions Patients with early- and late-time windows treated with mechanical thrombectomy by automated perfusion-weighted imaging selection have similar outcomes, comparable with those in randomized trials, but different in infarct growth velocities. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02251665.
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http://dx.doi.org/10.1161/JAHA.121.022880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075240PMC
December 2021

Postprandial cerebral infarction.

J Clin Neurosci 2021 Dec 6;94:38-40. Epub 2021 Oct 6.

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

Some neurological diseases are accompanied by autonomic dysfunction. Postprandial hypotension (PPH) is one disorder accompanied by autonomic dysfunction. Although the major symptoms of PPH are fall and syncope, PPH is sometimes overlooked because of its non-specific symptoms, such as dizziness, nausea, and light-headedness. Because PPH could result in decreased cerebral perfusion pressure accompanied by a decrease in blood pressure, PPH may be linked to the risk of hemodynamic stroke or transient ischemic events, especially in patients with chronic cerebral large vessel occlusion/stenosis. Whether chronic cerebral large vessel occlusion or stenosis causes symptomatic ischemic events depends on the patient's compensatory collateral circulation and cerebral vasoreactivity. Therefore, we hypothesized that cerebral blood flow assessment could be essential for stratifying patients at high risk of postprandial cerebral infarction. However, there have been few reports on the association between cerebral blood flow and the occurrence of postprandial cerebral infarction. In a literature review, we identified seven cases of postprandial cerebral infarction. Postprandial cerebral infarction occurs in patients with chronic cerebral large vessel occlusion/stenosis accompanied by cerebral blood flow reduction. Non-pharmacotherapeutic and pharmacotherapeutic approaches could improve postprandial cerebral infarction; however, one patient with poor compensatory collateral circulation and reduced cerebral vasoreactivity experienced recurrent symptomatic episodes even with sufficient medical treatment and needed extracranial-intracranial bypass surgery. Physicians should be aware of PPH as it can complicate neurological disorders. Long-term blood pressure monitoring for the detection of PPH and cerebral blood flow assessment is needed in patients with cerebral large vessel occlusion/stenosis to prevent postprandial cerebral infarction.
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http://dx.doi.org/10.1016/j.jocn.2021.09.034DOI Listing
December 2021

Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model.

J Clin Invest 2021 11;131(22)

Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, Niigata University, Niigata, Japan.

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.
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http://dx.doi.org/10.1172/JCI140555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592543PMC
November 2021

Distinction in Prevalence of Atherosclerotic Embolic Sources in Cryptogenic Stroke With Cancer Status.

J Am Heart Assoc 2021 11 23;10(21):e021375. Epub 2021 Oct 23.

Department of Neurology Juntendo University Urayasu Hospital Chiba Japan.

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39-5.40) and CRP (C-reactive protein) (OR, 1.10; 95% CI, 1.01-1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01-1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60-10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09-4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11-4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.
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http://dx.doi.org/10.1161/JAHA.120.021375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751843PMC
November 2021

Influence of Renal Impairment and Genetic Subtypes on Warfarin Control in Japanese Patients.

Genes (Basel) 2021 09 28;12(10). Epub 2021 Sep 28.

Department of Neurology, National Cerebral and Cardiovascular Center, Osaka 564-8565, Japan.

The genotypes of vitamin K epoxide reductase complex 1 () and cytochrome P450 2C9 () can influence therapeutic warfarin doses. Conversely, nongenetic factors, especially renal function, are associated with warfarin maintenance doses; however, the optimal algorithm for considering genes and renal dysfunction has not been established. This single-center prospective cohort study aimed to evaluate the factors affecting warfarin maintenance doses and develop pharmacogenetics-guided algorithms, including the factors of renal impairment and others. To commence, 176 outpatients who were prescribed warfarin for thromboembolic stroke prophylaxis in the stroke center, were enrolled. Patient characteristics, blood test results, dietary vitamin K intake, and and genotypes were recorded. and genotyping revealed that 80% of the patients had and mutant AA genotypes. Multiple linear regression analysis demonstrated that the optimal pharmacogenetics-based model comprised age, body surface area, estimated glomerular filtration rate (eGFR), genotypes, vitamin K intake, aspartate aminotransferase levels, and alcohol intake. eGFR exercised a significant impact on the maintenance doses, as an increase in eGFR of 10 mL/min/1.73 m escalated the warfarin maintenance dose by 0.6 mg. Reduced eGFR was related to lower warfarin maintenance doses, independent of and genotypes in Japanese patients.
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http://dx.doi.org/10.3390/genes12101537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535514PMC
September 2021

A Nationwide Multi-Center Questionnaire Survey on the Real-World State and Clinical Management of Poststroke Dementia in Japan.

J Alzheimers Dis 2021 ;84(3):1103-1114

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

Background: Poststroke dementia (PSD) is a serious problem for stroke survivors. However, there is still limited data on the real-world state and clinical management of PSD worldwide, and several countries already have a super-aged society.

Objective: We conducted a nationwide questionnaire survey to examine the real-world state and management of PSD in Japan.

Methods: A survey was conducted in the top 500 Japanese hospitals regarding the number of stroke patients treated between July 2018 and August 2019. Thirteen questions regarding PSD were mailed to 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 median numbers of patients admitted annually with stroke in the departments of neurology and neurosurgery in the hospitals were 281.0 (interquartile range [IQR], 231.8-385.3) and 253.5 (IQR, 210.0-335.3), respectively, and most hospitals were acute care hospitals. Executive dysfunction was the most common cognitive dysfunction (10.9%), followed by amnesia (9.5%) and apathy (4.1%). Surprisingly, many stroke survivors lived alone at home (23.7%). Montreal Cognitive Assessment was significantly uncommon compared to Mini-Mental State Examination (p < 0.01). Furthermore, objective evaluation tests for behavioral and psychological symptoms of dementia were not often performed. Cognitive rehabilitation treatments were performed more often and earlier than drug treatments. The first drug of choice for PSD was predominantly donepezil (79.1%), followed by galantamine (6.1%), cilostazol (4.9%), memantine (2.5%), and rivastigmine (1.8%).

Conclusion: Our study provides real-world evidence for the state of clinical practice related to PSD in Japan.
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http://dx.doi.org/10.3233/JAD-215006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673533PMC
January 2022
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