Bone marrow-derived mononuclear cells ameliorate neurological function in chronic cerebral infarction model mice via improvement of cerebral blood flow.

BACKGROUND AIMS: Stroke is a frequently observed neurological disorder that might lead to permanent and severe disability. Recently, various regenerative therapies have been developed, some of which have already been applied clinically. However, their outcomes have not been fully satisfactory. In particular, the development of regenerative therapies for chronic ischemic stroke is greatly needed. Herein intracerebral administration of bone marrow-derived mononuclear cells (BM-MNCs) was assessed as a potential treatment for chronic ischemic stroke using a severe combined immunodeficiency mouse model characterized by minimal vascular variation unrelated to immunodeficiency. METHODS: A reproducible model of permanent middle cerebral artery occlusion was prepared, and intracerebral BM-MNC transplantation was performed 14 days after stroke induction in the infarcted brain. RESULTS: Sensorimotor behavioral function and cerebral blood flow were significantly improved upon treatment with BM-MNCs compared to control medium injection. The transplanted cells exhibited characteristics of the vascular endothelium and microglia/macrophages. Significant angiogenesis and suppression of astrogliosis and microgliosis were observed in the affected brain. Messenger RNA expression analysis showed significant increases in anti-inflammatory cytokines, A2 astrocyte/anti-inflammatory microglia markers and vascular endothelial markers such as vascular endothelial growth factor and significant decreases in pro-inflammatory cytokines and A1 astrocyte/pro-inflammatory microglia markers following BM-MNC transplantation. CONCLUSIONS: These results suggest that intracerebral administration of BM-MNCs should be considered an effective cell therapy for chronic stroke.

Aging-related volume changes in the brain and cerebrospinal fluid using artificial intelligence-automated segmentation.

OBJECTIVES: To verify the reliability of the volumes automatically segmented using a new artificial intelligence (AI)-based application and evaluate changes in the brain and CSF volume with healthy aging. METHODS: The intracranial spaces were automatically segmented in the 21 brain subregions and 5 CSF subregions using the AI-based application on the 3D T1-weighted images in healthy volunteers aged > 20 years. Additionally, the automatically segmented volumes of the total ventricles and subarachnoid spaces were compared with the manually segmented volumes of those extracted from 3D T2-weighted images using the intra-class correlation and Bland-Altman analysis. RESULTS: In this study, 133 healthy volunteers aged 21-92 years were included. The mean intra-class correlations between the automatically and manually segmented volumes of the total ventricles and subarachnoid spaces were 0.986 and 0.882, respectively. The increase in the CSF volume was estimated to be approximately 30 mL (2%) per decade from 265 mL (18.7%) in the 20s to 488 mL (33.7%) in ages above 80 years; however, the increase in the volume of total ventricles was approximately 20 mL (< 2%) until the 60s and increased in ages above 60 years. CONCLUSIONS: This study confirmed the reliability of the CSF volumes using the AI-based auto-segmentation application. The intracranial CSF volume increased linearly because of the brain volume reduction with aging; however, the ventricular volume did not change until the age of 60 years and above and then gradually increased. This finding could help elucidate the pathogenesis of chronic hydrocephalus in adults. KEY POINTS: • The brain and CSF spaces were automatically segmented using an artificial intelligence-based application. • The total subarachnoid spaces increased linearly with aging, whereas the total ventricle volume was around 20 mL (< 2%) until the 60s and increased in ages above 60 years. • The cortical gray matter gradually decreases with aging, whereas the subcortical gray matter maintains its volume, and the cerebral white matter increases slightly until the 40s and begins to decrease from the 50s.

Association between proprotein convertase subtilisin/kexin type 9 and subclinical cerebrovascular disease in the community.

BACKGROUND AND PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new target for reducing low-density lipoprotein cholesterol and incident cardiovascular disease, including stroke. However, the clinical relevance of circulating PCSK9 levels has been poorly elucidated in the general population, particularly in association with subclinical cerebrovascular disease including cerebral small vessel disease (CSVD) and intracranial artery stenosis (ICAS). METHODS: In community-dwelling Japanese men (n = 526) aged 46-82 years without a history of cardiovascular disease, the associations of serum PCSK9 levels with the prevalence of CSVD and ICAS were assessed using magnetic resonance imaging. CSVD included lacunar infarction, deep and subcortical white matter hyperintensity, periventricular hyperintensity and cerebral microbleeds. RESULTS: The median (interquartile range) age at baseline and serum PCSK9 levels were 69 (63-74) years and 240 (205-291) ng/ml, respectively. After adjusting for traditional cardiovascular risk factors including low-density lipoprotein cholesterol, multivariable Poisson regression with robust error variance revealed a significant association between PCSK9 levels (per 1 SD) and ICAS (relative risks 1.18, 95% confidence interval 1.02-1.37). Multivariable ordinal logistic regression for ICAS, with stenosis graded as mild (<50%) or moderate-severe (≥50%), revealed a similar association (common odds ratio 1.31, 95% confidence interval 1.04-1.64). However, no significant association was observed between serum PCSK9 levels and CSVD. CONCLUSIONS: Higher circulating PCSK9 levels were independently associated with an ICAS prevalence but not with CSVD prevalence. The quantification of circulating PCSK9 levels may help to identify individuals at high risk for cerebrovascular disease in the general population.

Control of Diabetes Mellitus and Long-Term Prognosis in Stroke Patients: The Shiga Stroke and Heart Attack Registry.

BACKGROUND: The relationship between diabetes control status and long-term prognosis after stroke incidence remains unclear. This study aimed to investigate the effect of diabetes status at admission on long-term survival in patients with first-ever stroke. METHODS: A retrospective cohort study was conducted based on the Shiga Stroke and Heart Attack Registry in Japan. Patients were classified according to their diabetes status and glycated hemoglobin (HbA1c) value at hospital admission into the following: (1) free of diabetes (no history of diabetes and HbA1c <6.5%); (2) good control (history of diabetes and HbA1c <7%; free of history and 6.5% ≤HbA1c <7%); and (3) poor control (with or without a history of diabetes and HbA1c ≥7%). Multivariable Cox regression models were used to evaluate the association between diabetes status and long-term survival from stroke onset. Additionally, we also evaluated the association between diabetes status and conditional survival, beginning 29 days after stroke onset. RESULTS: A total of 6,331 first-ever stroke patients were eligible for this study. Among study patients, the mean (±SD) age was 72.85 ± 13.19 years, and the mean (±SD) follow-up year was 2.76 ± 1.66 years; additionally, 42.09% of patients were women. Among patients with all strokes, considering the free-of-diabetes group as the reference group, the adjusted hazard ratio (95% confidence interval) for mortality was 1.26 (1.10, 1.44) in the good control group and 1.22 (1.05, 1.41) in the poor control group. Among patients with ischemic stroke, the adjusted hazard ratio was 1.24 (1.06, 1.46) in good control group and 1.27 (1.08, 1.50) in poor control group. After excluding patients who died within 28 days, the adjusted hazard ratio for conditional mortality in the poor control group was 1.31 (1.12, 1.54) among all stroke patients and 1.29 (1.08, 1.54) among ischemic stroke patients. No significant associations were observed between diabetic status and long-term mortality in intracerebral hemorrhage patients. CONCLUSIONS: The findings suggest that first-ever stroke patients with diabetes exhibited a higher risk of all-cause mortality than those without diabetes, particularly in the overall stroke and ischemic stroke populations. Additionally, in stroke populations after 28 days of onset, high risk of long-term mortality was stated in stroke patients with poor HbA1c control.

Epidemiology of Acute Aortic Dissection in a General Population of 1.4 Million People in Japan　- Shiga Stroke and Heart Attack Registry.

BACKGROUND: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease, with a reported incidence rate ranging from 2.5 to 7.2 per 100,000 person-years in several population-based registries in Western countries, but epidemiological data are lacking in Japan.Methods and Results: The Shiga Stroke and Heart Attack Registry is an ongoing multicenter population-based registry of cerebro-cardiovascular diseases. We enrolled patients who developed AAD, defined by any imaging examination method from 2014 to 2015 in Shiga Prefecture. Death certificates were used to identify cases that were not registered at acute care hospitals. The incidence rates of AAD were calculated by age categories and adjusted using standard populations for comparison. We evaluated differences in patient characteristics between Stanford type A-AAD and type B-AAD subtypes. A total of 402 incident cases with AAD were analyzed. The age-adjusted incidence rates using the 2015 Japanese population and the 2013 European Standard Population were 15.8 and 12.2 per 100,000 person-years, respectively. Compared with cases of type B-AAD, those with type A-AAD were older (75.0 vs. 69.9 years, P=0.001) and more likely to be women (62.3% vs. 28.6%, P<0.001). CONCLUSIONS: Population-based incidence rates of AAD in Japan appear to be higher than in previous reports from Western countries. Incident cases with type A-AAD were older and female predominance.

Sex Difference and Rupture Rate of Intracranial Aneurysms: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture. METHODS: We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal subarachnoid hemorrhage. RESULTS: We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/person-years [95% CI, 0.89-1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58-0.94]). Women were older (61.9 versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24% versus 17%), and larger sized aneurysms (≥7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio was 1.43 (95% CI, 1.07-1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02-1.90). CONCLUSIONS: Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differences in patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining the higher risk of aneurysmal rupture in women.

Seasonal Variation in Incidence of Stroke in a General Population of 1.4 Million Japanese: The Shiga Stroke Registry.

INTRODUCTION: The purpose of this study was to investigate seasonal variation in stroke incidence using data from a large-scale stroke registry of general population in current Japan. METHODS: Shiga Stroke Registry (SSR) is an ongoing population-based registry of stroke that occurred in the Shiga Prefecture in central Honshu, Japan. A total 6,688 cases of first-ever stroke, with onset dates ranging from 1 January 2011 to 31 December in 2013 were included in this study. Incidence rates of first-ever stroke in each season were estimated using the person-year approach and adjusted for age and sex using the Poisson regression models. RESULTS: From 2011 to 2013, we identified a total of 6,688 stroke cases (3,570 men, 3,118 women), of which 4,480 cases had ischemic stroke (2,518 men, 1,962 women), 1,588 had intracerebral hemorrhage (857 men, 731 women) and 563 had subarachnoid hemorrhage (166 men, 397 women). Age- and sex-adjusted incidence rates of total stroke were 151 (95% confidence interval [CI] 144-160, p = <0.001 vs. summer) in spring, 130 (95% CI 122-137) in summer, 141 (95% CI 133-149, p = 0.020 vs. summer) in autumn and 170 (95% CI 161-179, p = <0.001 vs. summer) in winter. Seasonal variation was more pronounced in intracerebral hemorrhage than in ischemic stroke. CONCLUSION: In the present large-scale stroke registry of general population, incidence rates of stroke were highest in winter and lowest in summer in current Japan.

Differential Association of Serum n-3 Polyunsaturated Fatty Acids with Various Cerebrovascular Lesions in Japanese Men.

BACKGROUND: An association between a high intake of marine-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) with a lower risk of coronary heart disease was previously reported. However, the association between n-3 PUFAs and cerebrovascular lesions remains unclear. We evaluated this association in a general-population-based sample of Japanese men. METHODS: Participants were community-dwelling men (40-79 years old) living in Kusatsu City, Shiga, Japan. Serum concentrations of n-3 PUFAs, defined as the sum of eicosapentaenoic and docosahexaenoic acids, were measured via gas-liquid chromatography between 2006 and 2008. Magnetic resonance imaging was used to assess cerebrovascular lesions (including intracerebral large-artery stenosis, lacunar infarction, and microbleeds) and white matter lesions between 2012 and 2015. Logistic regression adjusting for conventional cardiovascular risk factors was used to estimate the odds ratio of prevalent cerebrovascular lesions per 1 standard deviation higher serum concentration of n-3 PUFAs. RESULTS: Of a total of 739 men, the numbers (crude prevalence in %) of prevalent cerebral large-artery stenoses, lacunar infarctions, microbleeds, and white matter lesions were 222 (30.0), 162 (21.9), 103 (13.9), and 164 (22.2), respectively. A 1 standard deviation higher concentration of n-3 PUFAs (30.5 µmol/L) was independently associated with lower odds of cerebral large-artery stenosis (multivariable-adjusted odds ratio, 0.80; 95% confidential interval, 0.67-0.97). There were no significant associations of n-3 PUFAs with the other types of lesions. CONCLUSIONS: n-3 PUFAs may have protective effects against large-artery stenosis, but not small vessel lesions, in the brain.

Differences Between Subarachnoid Hemorrhage Seen in Daily Practice and Aneurysms That Rupture During Follow-Up.

[Figure: see text].

Neuropsychological outcomes after frontal lobectomy to treat intractable epilepsy.

OBJECTIVE: Frontal lobectomy is often used as a surgical treatment for frontal lobe epilepsy, especially when a large epileptogenic zone in the frontal lobe is inferred from preoperative evaluation. The frontal lobe is important for cognitive functions such as executive functions and verbal fluency, but the neuropsychological outcome after a frontal or prefrontal lobectomy that includes both the dorsolateral prefrontal cortex and ventral prefrontal cortex has not been studied thoroughly. In the present study, we evaluated neuropsychological outcomes after patients with frontal lobe epilepsy received a frontal or prefrontal lobectomy. METHODS: We retrospectively reviewed the data of patients with frontal lobe epilepsy who underwent a frontal or prefrontal lobectomy that includes both the dorsolateral prefrontal cortex and ventral prefrontal cortex at 16 years or older from October 2004 to December 2014, with a minimum postoperative follow-up of 24 months. We analyzed and compared neuropsychological outcomes, including executive functions, verbal fluency, intelligence, and memory, before and after the operation. RESULTS: Eighteen patients were 16 years or older and underwent pre- and postoperative (2 years after the operation) neuropsychological evaluations. Patients showed significant deterioration only on the Benton Visual Retention Test. Performance on tests of frontal lobe functions, such as executive function and verbal fluency, showed no significant deterioration. CONCLUSIONS: Overall cognitive performance, including functions widely thought to depend on the frontal lobe, is stable after a frontal or prefrontal lobectomy to treat frontal lobe epilepsy.

Relationship Between Step Counts and Cerebral Small Vessel Disease in Japanese Men.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) is a common subclinical feature of the aging brain. Steps per day may contribute to its prevention. We herein investigated the association between step counts and CSVD in a healthy Japanese male population. METHODS: We analyzed data from 680 men who were free of stroke and participated in this observational study. Seven-day step counts were assessed at baseline (2006-2008) using a pedometer. CSVD was assessed at follow-ups (2012-2015) based on deep and subcortical white matter hyperintensities (WMHs), periventricular hyperintensities, lacunar infarcts, and cerebral microbleeds on magnetic resonance imaging. Using a logistic regression analysis, we computed the adjusted odds ratios, with 95% CIs, of prevalent CSVD according to quartiles of step counts (reference: Q1). We also investigated the association between step counts and WMH volumes using a quantile regression. RESULTS: Steps per day were significantly associated with lower odds ratios, with the lowest at Q3 (8175-10 614 steps/day), of higher (versus low or no burden) deep and subcortical WMHs (odds ratio, 0.52 [95% CI, 0.30-0.89]), periventricular hyperintensities (0.50 [95% CI, 0.29-0.86]), and lacunar infarcts (0.52 [95% CI, 0.30-0.91]) compared with Q1 (≤6060 steps/day) but not cerebral microbleeds. An inverse linear association was observed between step counts and WMH volumes. These associations were independent of age and smoking and drinking status and remained consistent when adjusted for vascular risk factors. CONCLUSIONS: We found a J-shaped relationship between step counts and prevalent CSVD in healthy Japanese men, with the lowest risk being observed among participants with ≈8000 to 10 000 steps/day. Higher steps were also associated with lower WMH volumes.

Cerebrospinal fluid dynamics in idiopathic normal pressure hydrocephalus on four-dimensional flow imaging.

OBJECTIVES: To evaluate complex CSF movements and shear stress in patients with idiopathic normal pressure hydrocephalus (iNPH) on four-dimensional (4D) flow MRI. METHODS: Three-dimensional velocities and volumes of the reciprocating CSF movements through 12 ROIs from the foramen of Monro to the upper cervical spine were measured in 41 patients with iNPH, 23 patients with co-occurrence of iNPH and Alzheimer's disease (AD), and 9 age-matched controls, using 4D flow imaging and application. Stroke volume, reversed-flow rate, and shear stress were automatically calculated. Relationships between flow-related parameters and morphological measurements were also assessed. RESULTS: Stroke volumes, reversed-flow rates, and shear stress at the cerebral aqueduct were significantly higher in patients with iNPH than in controls. Patients with pure iNPH had significantly higher shear stress at the ventral aspect of the cerebral aqueduct than those with co-occurrence of iNPH and AD. The stroke volume at the upper end of the cerebral aqueduct had the strongest association with the anteroposterior diameter of the lower end of the cerebral aqueduct (r = 0.52). The stroke volume at the foramen of Monro had significant associations with the indices specific to iNPH. The shear stress at the dorsal aspect of the cerebral aqueduct had the strongest association with the diameter of the foramen of Magendie (r = 0.52). CONCLUSIONS: Stroke volumes, reversed-flow rates, and shear stress through the cerebral aqueduct on 4D flow MRI are useful parameters for iNPH diagnosis. These findings can aid in elucidating the mechanism of ventricular enlargement in iNPH. KEY POINTS: • The CSF stroke volume and bimodal shear stress at the cerebral aqueduct were considerably higher in patients with iNPH. • The patients with pure iNPH had significantly higher shear stress at the ventral aspect of the cerebral aqueduct than those with co-occurrence of iNPH and AD. • The shear stress at the cerebral aqueduct was significantly associated with the diameter of the foramen of Magendie.

Two-Year Recurrence After First-Ever Stroke in a General Population of 1.4 Million Japanese Patients　- The Shiga Stroke and Heart Attack Registry Study.

BACKGROUND: Despite many effective strategies for the prevention of recurrent stroke, individuals who survive an initial stroke have been shown to be at high risk of recurrent stroke. The aim of this study was to investigate the current status of stroke recurrence after first-ever stroke using a population-based stroke registry in Japan.Methods and Results:As part of the Shiga Stroke and Heart Attack Registry, the Shiga Stroke Registry is an ongoing population-based stroke registry study that covers approximately 1.4 million residents of Shiga Prefecture, Japan. A total of 1,883 first-ever stroke survivors at 28 days was registered in 2011 and followed-up until the end of 2013. Recurrence was defined as any type of stroke after 28 days from the onset of an index event. Two-year cumulative recurrence rates were estimated using cumulative incidence function methods. Over a mean 2.1-year follow-up period, 120 patients experienced recurrent stroke and 389 patients died without recurrence. The 2-year cumulative recurrence rate was higher in patients with index ischemic stroke (6.8%) than in those with index hemorrhagic stroke (3.8%). CONCLUSIONS: Two-year cumulative recurrence rate after first-ever stroke remained high, particularly among patients with ischemic stroke, in the present population-based registry study in a real-world setting in Japan. Further intensive secondary prevention strategies are required for these high-risk individuals.

Intracranial Artery Stenosis and Its Association With Conventional Risk Factors in a General Population of Japanese Men.

Background and Purpose- Few community-based studies have reported the prevalence of intracranial artery stenosis (ICAS) assessed with magnetic resonance angiography. The aim was to determine the prevalence of ICAS using magnetic resonance angiography in a general population of Japanese men and to investigate the associations between ICAS and conventional cardiovascular risk factors. Methods- The Shiga Epidemiological Study of Subclinical Atherosclerosis randomly recruited and examined participants from Kusatsu City, Shiga, Japan, in 2006 to 2008 (baseline); 740 men returned for follow-up and underwent 1.5 T brain magnetic resonance angiography in 2012 to 2015. Participants were categorized as having no-ICAS, mild-ICAS (1 to <50%), or severe-ICAS (≥50%) in any of the arteries examined. After excluding the men with a history of stroke, 709 men were analyzed using multivariable logistic regression to assess independent associations of conventional cardiovascular risk factors with reference to the no-ICAS group. Results- The participants' mean age was 68.0 years. The age-standardized prevalences of mild and severe-ICAS were 20.7% and 4.5%, respectively (with the population of the 2010 Japanese vital statistics as the reference). Age, hypertension, diabetes mellitus, and dyslipidemia were associated with a higher prevalence of severe-ICAS after simultaneous adjustment for conventional cardiovascular risk factors. Conclusions- In a community-based sample of Japanese men, ICAS was estimated to be present in 25.2%, and related to metabolic risk factors, in addition to hypertension and age. These results support the importance of comprehensive management of conventional cardiovascular risk factors for stroke prevention.

Two-Year Survival After First-Ever Stroke in a General Population of 1.4 Million Japanese　- Shiga Stroke Registry.

BACKGROUND: Stroke is one of the leading causes of disability and mortality in Japan. The aim of the present analysis was to determine the non-acute survival rate after first-ever stroke using data from a large-scale population-based stroke registry in Japan. Methods and Results: Shiga Stroke Registry is an ongoing population-based registry of stroke, which covers approximately 1.4 million residents of Shiga Prefecture in central Japan. A total of 2,176 first-ever stroke patients, who were registered in 2011, were followed up until December 2013. The 2-year cumulative survival rates were estimated using Kaplan-Meier method according to index stroke subtype. Cox proportional hazards models were used to assess predictors of all-cause death. During a 2-year follow-up period, 663 patients (30.5%) died. The 2-year cumulative survival rate after first-ever stroke was 69.5%. There was heterogeneity in 2-year cumulative survival according to stroke subtype: lacunar infarction, 87.2%; large artery infarction, 76.1%; cardioembolic infarction, 55.4%; intracerebral hemorrhage, 65.9%; and subarachnoid hemorrhage, 56.7%. Older age, male sex, medical history, higher Japan coma scale score on admission, and stroke subtype were associated with risk of all-cause death in ≤2 years. CONCLUSIONS: In the present population-based stroke registry with a real-world setting in Japan, 2-year cumulative mortality after first-ever stroke is still high (>30%), particularly for cardioembolic infarction, subarachnoid hemorrhage and intracerebral hemorrhage.

The JAGUAR Score Predicts 1-Month Disability/Death in Ischemic Stroke Patient Ineligible for Recanalization Therapy.

BACKGROUND AND PURPOSE: Most available scoring system to predict outcome after acute ischemic stroke (AIS) were established in Western countries. We aimed to develop a simple prediction score of 1-month severe disability/death after onset in AIS patients ineligible for recanalization therapy based on readily and widely obtainable on-admission clinical, laboratory and radiological examinations in Asian developing countries. METHODS: Using the Shiga Stroke Registry, a large population-based registry in Japan, multivariable logistic regression analysis was conducted in 1617 AIS patients ineligible for recanalization therapy to yield ß-coefficients of significant predictors of 1-month modified Rankin Scale score of 5-6, which were then multiplied by a specific constant and rounded to nearest integer to develop 0-10 points system. Model discrimination and calibration were evaluated in the original and bootstrapped population. RESULTS: Japan Coma Scale score (J), age (A), random glucose (G), untimely onset-to-arrival time (U), atrial fibrillation (A), and preadmission dependency status according to the modified Rankin Scale score (R), were recognized as independent predictors of outcome. Each of their ß-coefficients was multiplied by 1.3 creating the JAGUAR score. Its area under the curve (95% confidence interval) was .901 (.880- .922) and .901 (.900- .901) in the original and bootstrapped population, respectively. It was found to have good calibration in both study population (P = .27). CONCLUSIONS: The JAGUAR score can be an important prediction tool of severe disability/death in AIS patients ineligible for recanalization therapy that can be applied on admission with no complicated calculation and multimodal neuroimaging necessary, thus suitable for Asian developing countries.

Incidence, Management and Short-Term Outcome of Stroke in a General Population of 1.4 Million Japanese　- Shiga Stroke Registry.

BACKGROUND: This study determined the current status of the incidence, management, and prognosis of stroke in Japan using a population-based stroke registry.Methods and Results:Shiga Stroke Registry is an ongoing population-based registry that covers approximately 1.4 million residents of Shiga Prefecture. Cases of acute stroke were identified using standard definitions through surveillance of both all acute-care hospitals with neurology/neurosurgery facilities and death certificates in 2011. A total of 2,956 stroke cases and 2,176 first-ever stroke cases were identified. The age- and sex-adjusted incidence rate for first-ever stroke using the 2013 European Standard Population as standard was per 100,000 person-years: 91.3 for ischemic stroke, 36.4 for intracerebral hemorrhage, and 13.7 for subarachnoid hemorrhage. It was estimated that approximately 220,000 new strokes occurred in 2011 in Japan. Among the 2,956 cases, most stroke patients underwent neuroimaging, 268 received surgical or endovascular treatment, and 2,158 had rehabilitation therapy; 78 patients received intravenous thrombolysis. A total of 1,846 stroke patients had died or were dependent at hospital discharge, and 390 died within 28 days of onset. CONCLUSIONS: Incidence rates of stroke by subtypes were clarified and the total number of new strokes in Japan was estimated. More than half of stroke patients die or become dependent after a stroke. This study re-emphasized the importance of public health measures in reducing the burden of stroke in Japan.

Macrophage Imaging of Cerebral Aneurysms with Ferumoxytol: an Exploratory Study in an Animal Model and in Patients.

OBJECTIVE: The purpose of this study is to assess the validity and feasibility of macrophage imaging using an ultrasmall superparamagnetic iron oxide nanoparticle, ferumoxytol, in the cerebral aneurysmal wall in an animal model and in humans. MATERIALS AND METHODS: Engulfment of ferumoxytol by primary culture of macrophages and RAW264.7 cells was assessed. Uptake of ferumoxytol was evaluated histologically in a cerebral aneurysmal model in rats. In an exploratory clinical study of magnetic resonance macrophage imaging, 17 unruptured aneurysms in 17 patients were imaged using thin-slice gapless magnetic resonance images of 2D-gradient-recalled echo (2D-GRE) and 3D-T1-fast-spin echo sequences on day 0 and of the same sequences with infusion of ferumoxytol 24 hours after the first imaging. Pre- and postinfusion images were evaluated independently by 2 medical doctors. RESULTS: Engulfment of ferumoxytol was confirmed in vitro, but the amount of ferumoxytol uptake was independent of the activation state or the differentiation state. Ferumoxytol uptake in CD68-positive cells was observed in the cerebral arterial walls of 4 out of 15 (26.7%) experimentally induced aneurysms in rats. In a clinical study, 17 aneurysms were enrolled and 2 aneurysms were not assessed because of incomplete images. Eleven aneurysms without oral intake of recent anti-inflammatory agents of the remaining 15 aneurysms showed ferumoxytol uptake on 2D-GRE subtraction images, and the size of the aneurysms was significantly related to positive images. CONCLUSIONS: Ferumoxytol uptake was confirmed in cultured macrophages and in the cerebral aneurysmal wall in rats. Thin-slice gapless magnetic resonance imaging with ferumoxytol in human cerebral aneurysmal walls may reflect macrophages in the cerebral aneurysmal wall, but its application to small-sized lesions may be restricted.

Prediction model for 3-year rupture risk of unruptured cerebral aneurysms in Japanese patients.

OBJECTIVE: To build a prediction model that estimates the 3-year rupture risk of unruptured saccular cerebral aneurysms. METHODS: Survival analysis was done using each aneurysm as the unit for analysis. Derivation data were from the Unruptured Cerebral Aneurysm Study (UCAS) in Japan. It consists of patients with unruptured cerebral aneurysms enrolled between 2000 and 2004 at neurosurgical departments at tertiary care hospitals in Japan. The model was presented as a scoring system, and aneurysms were classified into 4 risk grades by predicted 3-year rupture risk: I, < 1%; II, 1 to 3%; III, 3 to 9%, and IV, >9%. The discrimination property and calibration plot of the model were evaluated with external validation data. They were a combination of 3 Japanese cohort studies: UCAS II, the Small Unruptured Intracranial Aneurysm Verification study, and the study at Jikei University School of Medicine. RESULTS: The derivation data include 6,606 unruptured cerebral aneurysms in 5,651 patients. During the 11,482 aneurysm-year follow-up period, 107 ruptures were observed. The predictors chosen for the scoring system were patient age, sex, and hypertension, along with aneurysm size, location, and the presence of a daughter sac. The 3-year risk of rupture ranged from <1% to >15% depending on the individual characteristics of patients and aneurysms. External validation indicated good discrimination and calibration properties. INTERPRETATION: A simple scoring system that only needs easily available patient and aneurysmal information was constructed. This can be used in clinical decision making regarding management of unruptured cerebral aneurysms.