Tomoya Mukai

Endothelial dysfunction is associated with the severity of cerebral small vessel disease.

The pathogenesis of cerebral small vessel disease, a disease that involves white matter lesions (WMLs) and cerebral microbleeds (CMBs), is thought to be associated with endothelial dysfunction. Flow-mediated dilation (FMD) has been used to measure endothelium-dependent vasodilation. The aim of this study was to investigate the association between endothelial function (as measured by FMD) and cerebral small vessel disease. Patients with a history of cerebrovascular disease and comorbidities were enrolled in this study (n=102; 69 males, 70.1±9.2 years). The patients were divided into two groups according to the severity of WMLs, which were assessed by Fazekas classification; grades 0 to 1 as mild WMLs group and grades 2 to 3 as severe WMLs group. A gradient-echo MRI was performed in 96 patients (94.1%) to evaluate whether CMBs were present. The patients in the severe WMLs group (n=40) were older (P=0.001), more frequently exhibited hypertension (P=0.045) and diabetes mellitus (P=0.026) and possessed lower FMD values (P<0.001) than the patients in the mild WMLs group (n=62). CMBs were observed in 30 patients (31.3%). Using receiver operating characteristic curves, the optimal FMD cutoff values for predicting the presence of severe WMLs and CMBs were 3.9% and 3.7%, respectively. On multivariate logistic analysis, FMD <4.0% (odds ratio 9.50; 95% confidence interval 3.55–28.83) was independently associated with severe WMLs. Additionally, FMD <3.8% (5.82; 2.23–16.50) was also associated with the presence of CMBs. Endothelial dysfunction as evaluated by FMD may be predictive of the severity of cerebral small vessel disease.

Modifications of tau protein after cerebral ischemia and reperfusion in rats are similar to those occurring in Alzheimer’s disease – Hyperphosphorylation and cleavage of 4- and 3-repeat tau

Epidemiological studies have suggested a close relationship between cerebral ischemia and Alzheimer’s disease (AD). To clarify the pathological association of tau dynamics in both diseases, we performed comprehensive studies on the posttranslational modification of tau in cerebral ischemia and reperfusion (I/R) in rats. The present study suggests that both 4-repeat and 3-repeat tau isoforms are hyperphosphorylated in cerebral I/R, similar to the case in AD. The generation of a 60-kDa Asp421-truncated tau in cerebral I/R preceded the emergence of a 17-kDa 3-repeat tau fragment and a 25-kDa 4-repeat tau fragment. The regional redistribution of tau from the neuropil to neuronal perikarya in our stroke model is thought to share similarity with that occurring in AD. In addition, immunofluorescence staining revealed the formation of axonal varicosities in cerebral I/R. Altered tau distribution may influence microtubule stability, disturbances in axonal transport, and the resulting formation of axonal varicosities. The staining profiles of granules in the ischemic cortex that were immunopositive for RD3, RD4, and AT8 in neuronal perikarya and that were argyrophilic on Gallyas-Braak staining were similar to those in AD. These findings suggest that transient cerebral ischemia shares a common pathology with AD, in the modification of tau protein.

Multiple Infarcts Are Associated With Long-Term Stroke Recurrence and All-Cause Mortality in Cryptogenic Stroke Patients.

Background and Purpose— Brain infarct patterns that are observed via diffusion-weighted imaging are useful for classifying stroke subtypes. However, it is unclear whether infarct patterns can predict long-term outcomes in cryptogenic stroke patients. Herein, we investigated the association between acute brain infarct patterns and long-term stroke outcomes in cryptogenic stroke patients. Methods— Acute cryptogenic stroke patients were consecutively enrolled between April 2008 and March 2012. Diffusion-weighted imaging ischemic lesion patterns were classified as single lesions, scattered lesions in one vascular territory, or multiple lesions in multiple vascular territories. Survivors (at discharge) were followed up for 3 years after stroke onset. Results— A total of 272 cryptogenic stroke patients (132 women; aged 72±13 years) were enrolled. Among these patients, 169 (62.1%) had a single lesion, 38 (14.0%) had scattered lesions, and 65 (23.9%) had multiple lesions. Next, 261 patients (96.0%) were evaluated to assess right-to-left shunting, and 61 patients (23.4%) exhibited right-to-left shunting. On patient admission, right-to-left shunting and increased D-dimer levels were independently associated with multiple lesions but not single or scattered lesions. During the follow-up period (median, 1093 days), 30 patients (11.0%) developed recurrent stroke and 35 patients (12.9%) died. Multivariate Cox proportional hazard analyses showed that multiple infarcts were independently associated with recurrent stroke and all-cause mortality (hazard ratio, 3.79; 95% confidence interval, 2.24–6.37; P<0.001). Conclusions— Multiple brain infarcts on diffusion-weighted imaging were independently associated with long-term stroke outcomes in cryptogenic stroke patients.

CD34+/CD144+ Circulating Endothelial Cells as an Indicator of Carotid Atherosclerosis

BACKGROUND The relationships between the number of circulating endothelial cells (CECs) or endothelial progenitor cells (EPCs) and indicators of carotid atherosclerosis, such as the intima-media thickness (IMT) and plaque score are not well characterized in patients with chronic ischemic stroke. The objective of this study was to investigate these relationships in patients with chronic ischemic stroke and in patients with risk factors for stroke. METHODS A total of 58 patients (69.6 ± 10.0 years, 21 females) with chronic ischemic stroke or with risk factors for stroke were included in this study. IMT was measured using an IntimaScope, and the numbers of CECs and EPCs were measured using flow cytometry. CECs and EPCs were defined as CD34+/CD144+ and CD34+/CD133+ cells, respectively. RESULTS The number of CECs in patients with large artery atherosclerosis was higher than that in patients with cardioembolism or small vessel occlusion (P < .05). In contrast, there were no significant differences in the number of EPCs between groups. A positive correlation was also observed between the plaque score and the number of CECs (r(2) = .139, P < .05, n = 36). Moreover, the number of CECs in patients with moderate and severe atherosclerosis (.32 ± .11/μL, n = 22) was higher than that in patients with no plaque and mild atherosclerosis (.25 ± .07/μL, n = 34, P < .05). CONCLUSIONS The number of CECs was high in patients with large artery atherosclerosis who experienced chronic ischemic stroke. And this number may reflect severity of carotid atherosclerosis.

Effects of Meteorological Conditions on the Risk of Ischemic Stroke Events in Patients Treated with Alteplase—HEWS-tPA

BACKGROUND Predicting a day that presents a high risk for the occurrence of ischemic stroke events may enable health professionals to prepare for emergency stroke therapy more properly. We evaluated the association between meteorological conditions and the frequency of ischemic stroke events in Japanese patients. METHODS Ischemic stroke patients (n = 299) who were treated with alteplase at 9 stroke hospitals in 3 restricted areas were examined. The daily rates of ischemic stroke events were compared with the daily mean thermo-hydrological index (THI), the atmospheric pressure, and the daily changes of these variables for the 6 days preceding an ischemic stroke event using Poisson regression analysis. RESULTS We trisected onset days based on the THI (low-temperature, intermediate-temperature, and high-temperature), atmospheric pressure (low-pressure, intermediate-pressure, and high-pressure), changes in THI for preceding 6 days from the previous day (cooler, unchanged-temperature, and warmer), and changes in atmospheric pressure (decreased-pressure, unchanged-pressure, and increased-pressure). The frequency of ischemic stroke was significantly higher on low-temperature or high-pressure days (risk ratio, 1.398, P = .022; risk ratio, 1.374, P = .039), on warmer-temperature days, and when atmospheric pressure varied from the day before (P < .05). There were significantly lower risks for ischemic stroke events on cooler-temperature days, and higher risks were associated with a variation in atmospheric pressure 3 days before the onset from 4 days before (P < .05). CONCLUSIONS There were higher risks for ischemic stroke events associated with low ambient temperature, high atmospheric pressure, increased temperature, and varied atmospheric pressure. Also, atmospheric pressure variation 3 days before may be associated.

The Association between Hyperintense Vessel Sign and Final Ischemic Lesion Differ in Its Location

BACKGROUND The hyperintense vessel sign (HVS) on fluid-attenuated inversion recovery images can frequently be detected in patients with acute cerebral infarction attributable to large artery stenosis or occlusion. The prognostic values and clinical characteristics of HVS remain to be elucidated. The aim of this study was to evaluate the association of HVS with ischemic lesions and severity of neurologic deficit. METHODS A total of 96 consecutive acute ischemic stroke patients (54 women, median age 76.5 [range 39-97] years), who had symptomatic severe stenosis or occlusion in the proximal middle cerebral artery that was detected with magnetic resonance angiography within 24 hours of onset, were enrolled. The extent of HVS was graded by a systematic quantitative scoring system (the HVS distribution score) based on Alberta Stroke Program Early Computed Tomographic Score. RESULTS An HVS was detected in 89 patients (93%) at admission, and the patients who displayed wider HVS distribution scores exhibited more severe neurologic deficits at admission (P<.05). The follow-up magnetic resonance imaging, which was obtained in 79 patients (82%), was performed an average of 13 days. The association between HVS distribution score and final ischemic lesions was strongly observed (n=67, P<.05) but not in the patients with intravenous thrombolysis (n=12, P=.06). CONCLUSIONS Although the distribution of HVS reflected final ischemic lesion, this association might not apply to the patients with the thrombolysis treatment. The interpretation of HVS distribution score with acute ischemic stroke patients should be discussed dependent on thrombolysis.

Blood Pressure Variability in Acute Ischemic Stroke: Influence of Infarct Location in the Insular Cortex

Background: The aim of this study was to elucidate the influence of insular infarction on blood pressure (BP) variability and outcomes according to the region of the insular cortex affected. Methods: A total of 90 patients diagnosed with acute unilateral ischemic stroke were registered. The BP variability was calculated over 24 h after admission (hyperacute) and for 2–3 days after admission (acute). Patients were classified into groups of right and left, and then right anterior, right posterior, left anterior, and left posterior insular infarction. Results: Patients with insular infarction showed a significantly larger infarct volume, higher modified Rankin scale scores, and lower SD and coefficient of variation (CV) of systolic BP in the hyperacute phase than shown by patients without insular infarction (p < 0.01, p < 0.01, p = 0.02, and p = 0.03, respectively). The SD and CV of systolic BP in the hyperacute phase showed significant differences among the 3 groups with right insular infarction, with left insular infarction, and without insular infarction (p < 0.05 and p < 0.05, respectively). There was a tendency for the systolic BP variability to be lower in patients with right anterior insular infarction than in patients with infarcts in other areas. Conclusion: The right insular cortex, especially the anterior part, might be a hub for autonomic nervous regulation.

Various meteorological conditions exhibit both immediate and delayed influences on the risk of stroke events: The HEWS–stroke study

We hypothesized that meteorological conditions on the onset day and conditions on the former days may play important roles in the modulation of physical conditions. Associations of meteorological factors and their changes in former days with stroke onset are of interest. We conducted a multicenter retrospective study to evaluate the frequency of stroke events and their interaction with meteorological conditions and their daily changes. Acute stroke patients (n = 3935, 73.5±12.4 years, 1610 females) who were admitted to 7 stroke hospitals in three restricted areas were enrolled in this study. Poisson regression models involving time-lag variables was used to compare daily rates of stroke events with mean thermo-hydrological index (THI), atmospheric pressure, and their daily changes. We divided onset days into quintiles based on the THI, atmospheric pressure, and their daily changes for the last 7 days. The frequencies of ischemic stroke significantly increased when THI varied either cooler or warmer from a previous day (extremely cooler, risk ratio (RR) 1.19, 95% confidence interval (CI) 1.05 to 1.34; extremely warmer, RR 1.16, 95% CI 1.03 to 1.31; r2 = 0.001 for the best regression, p = 0.001). Intracerebral hemorrhage frequencies significantly decreased on high-THI days (extremely high, RR 0.72, 95% CI 0.54 to 0.95; r2 = 0.013 for the best regression, p<0.001) and increased in high atmospheric pressure days (high, RR 1.31, 95% CI 1.04 to 1.65; r2 = 0.009 for the best regression, p<0.001). Additionally, even after adjusting for the THI on the onset day and its changes for the other days, intracerebral hemorrhage increased when THI got extremely cooler in 4 days prior (RR 1.33, 95% CI 1.03 to 1.71, r2 = 0.006 for the best regression, p<0.001). Various meteorological conditions may exhibit influences on stroke onset. And, when temperature cooled, there may be a possibility to show delayed influence on the frequency of intracerebral hemorrhage 4 days later.

A Case of Hypertensive Encephalopathy with Enlarged Optic Nerve Sheath Measured by Transorbital Sonography.

This case report describes our experience in using transorbital sonography to evaluate pathological changes in the central nervous system in hypertensive encephalopathy. A 49-year-old man with nausea, headache, and mild confusion was diagnosed with hypertensive encephalopathy by brain magnetic resonance imaging (MRI), which revealed vasogenic edema in the bilateral thalamus and the brain stem. Lumbar puncture showed no severe intracranial hypertension. Transorbital sonography showed an increase in the optic nerve sheath diameter (ONSD). Repeated examination revealed a return of the ONSD to an almost normal range after a reduction in blood pressure and a resolution of symptoms. An improvement in cerebral vasogenic edema was confirmed by brain MRI. ONSD might be related to the severity of cerebral vasogenic edema. Repeated measurement of ONSD by transorbital sonography may be useful to assess the pathological course and the effect of treatment in hypertensive encephalopathy.