Keiji Igase

Interleukin-6 prevents ischemia-induced learning disability and neuronal and synaptic loss in gerbils

Interleukin-6 (IL-6) has been shown to have potent neurotrophic activity on peripheral and central neurons in vitro. However, it remains to be determined whether or not IL-6 rescues hippocampal CA1 neurons from lethal ischemia and prevents ischemia-induced learning disability. In the present in vivo study, we infused IL-6 continuously for 7 days into the lateral ventricle of gerbil starting 2 h before 3-min forebrain ischemia. IL-6 infusion prevented the occurrence of ischemia-induced learning disability in a dose-dependent manner as revealed by a step-down passive avoidance task. Subsequent light and electron microscopic examinations showed that pyramidal neurons in the CA1 region of the hippocampus as well as synapses within the strata moleculare, radiatum and oriens of the region were significantly more numerous in gerbils infused with IL-6 than in those receiving vehicle infusion. These findings suggest that IL-6 has a trophic effect on ischemic hippocampal neurons.

An 18-mer peptide fragment of prosaposin ameliorates place navigation disability, cortical infarction, and retrograde thalamic degeneration in rats with focal cerebral ischemia.

It was previously reported that prosaposin possesses neurotrophic activity that is ascribed to an 18-mer peptide comprising the hydrophilic sequence of the rat saposin C domain. To evaluate the effect of the 18-mer peptide on ischemic neuronal damage, the peptide was infused in the left lateral ventricle immediately after occlusion of the left middle cerebral artery (MCA) in stroke-prone spontaneously hypertensive (SP-SH) rats. The treatment ameliorated the ischemia-induced space navigation disability and cortical infarction and prevented secondary thalamic degeneration in a dose-dependent manner. In culture experiments, treatment with the 18-mer peptide attenuated free radical-induced neuronal injury at low concentrations (0.002 to 2 pg/mL), and the peptide at higher concentrations (0.2 to 20 ng/mL) protected neurons against hypoxic insult. Furthermore, a saposin C fragment comprising the 18-mer peptide bound to synaptosomal fractions of the cerebral cortex, and this binding decreased at the 1st day after MCA occlusion and recovered to the preischemic level at the 7th day after ischemia. These findings suggest that the 18-mer peptide ameliorates neuronal damage in vivo and in vitro through binding to the functional receptor, although the cDNA encoding prosaposin receptor has not been determined yet.

ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms.

Objective: To develop a risk score that estimates 3-year and 5-year absolute risks for aneurysm growth. Methods: From 10 cohorts of patients with unruptured intracranial aneurysms and follow-up imaging, we pooled individual data on sex, population, age, hypertension, history of subarachnoid hemorrhage, and aneurysm location, size, aspect ratio, and shape but not on smoking during follow-up and family history of intracranial aneurysms in 1,507 patients with 1,909 unruptured intracranial aneurysms and used aneurysm growth as outcome. With aneurysm-based multivariable Cox regression analysis, we determined predictors for aneurysm growth, which were presented as a risk score to calculate 3-year and 5-year risks for aneurysm growth by risk factor status. Results: Aneurysm growth occurred in 257 patients (17%) and 267 aneurysms (14%) during 5,782 patient-years of follow-up. Predictors for aneurysm growth were earlier subarachnoid hemorrhage, location of the aneurysm, age >60 years, population, size of the aneurysm, and shape of the aneurysm (ELAPSS). The 3-year growth risk ranged from <5% to >42% and the 5-year growth risk from <9% to >60%, depending on the risk factor status. Conclusions: The ELAPSS score consists of 6 easily retrievable predictors and can help physicians in decision making on the need for and timing of follow-up imaging in patients with unruptured intracranial aneurysms.

Initial experience in evaluating the prevalence of unruptured intracranial aneurysms detected on 3-tesla MRI.

Background: Given the very poor outcome of ruptured intracranial aneurysms, detection and treatment of unruptured intracranial aneurysms by a less invasive examination have become important. For this purpose, 3-tesla (3T) magnetic resonance imaging (MRI) is the most suitable candidate, owing to its high signal/noise ratio and frequency resolution. However, few reports have investigated the prevalence of intracranial aneurysms with high-tesla MRI. Here, we evaluated the prevalence of intracranial aneurysms and the effectiveness of a 3T MRI system in their detection. Methods: During a 1-year period, a total of 3,414 consecutive patients undergoing MR angiography with 3T MRI for the first time were enrolled. Diagnosis of intracranial aneurysm was made by two neuroradiologically trained medical doctors under complete blinding to patient information. When intracranial aneurysm was suspected, volume-rendering images were created for more accurate diagnosis. Results: Surprisingly, 317 unruptured intracranial aneurysms were identified in 286 of 3,414 cases (8.4%); 151 unruptured aneurysms (47.6%) occurred in the internal carotid artery, 85 (26.8%) in the middle cerebral artery, 54 (17.0%) in the anterior cerebral artery, and 27 (8.5%) in the posterior circulation. Of these, 152/317 (47.9%) were <3 mm, 104 (32.8%) ranged from 3 to 5 mm, 5 (11.0%) from 5 to 7 mm, and 26 (8.2%) were >7 mm. No significant difference in size was seen among the four locations.Conclusions: For the first time, this study assessed the detection rate of intracranial aneurysms using 3T MRI. Results showed a higher detection rate than previously documented. The reason for this higher rate is likely the improved ability of this modality to detect unruptured aneurysms in the internal carotid artery and those <3 mm.

Visit-to-visit variability in systolic blood pressure is a novel risk factor for the growth of intracranial aneurysms.

Background: Although rupture of unruptured intracranial aneurysms (UIAs) is closely associated with UIA growth during follow-up, few studies have investigated how UIAs grow during observation. Hypertension appears to affect the formation of intracranial aneurysms. However, few studies have investigated the association of blood pressure variability with UIA growth. Visit-to-visit variability (VVV) in systolic blood pressure (SBP) is a newly defined concept which appears to be a good predictor of stroke. With this factor in mind, here we conducted a prospective analysis of the results of 2 years of observation of UIAs by magnetic resonance angiography (MRA) and sought to identify risk factors for UIA growth and rupture. Methods: From December 2006 through June 2010, two hundred patients with 212 UIAs were followed for 2 years. Patient ages ranged from 31 to 91 years. Putative risk factors for the growth of UIAs were evaluated. Subjects were divided into two groups: a UIA growth group consisting of patients whose UIAs increased by 1 mm or more in size or who developed subarachnoid hemorrhage (SAH), and an unchanged group. Brachial blood pressure values were recorded at the time of diagnosis and during follow-up in the outpatient clinic. All blood pressure values were then averaged, and the VVV of SBP was defined as the standard deviation (SD) of a minimum of 5 blood pressure measurements at outpatient visits. Results: UIA growth occurred in 20 patients and SAH occurred in 1 patient. Current smoking tended to be more prevalent in the UIA growth group (p < 0.01). Five of the 12 patients with multiple UIAs showed UIA growth within 2 years and multiplicity was a significant risk factor for UIA growth (p < 0.01). The mean baseline size in the UIA growth group was larger than that in the unchanged group (p = 0.01) and 7 of the 18 patients with large UIAs, categorized as having an initial diameter of 7 mm or more, had an increase in UIA size over the 2 years (p < 0.01). On multivariable logistic regression analysis, current smoking, multiplicity, and UIA size ≥7 mm were significant risk factors for UIA growth. Although no significant difference was seen between the UIA growth and unchanged groups in office SBP during the observation period, VVV in SBP was significantly higher in the UIA growth group than in the unchanged group, and it was significantly and independently associated with UIA growth. Conclusions: VVV in SBP is a novel risk factor for the growth of UIAs and may be a key factor for the prevention of UIA rupture. Future research is needed to confirm that SBP stability prevents UIA rupture.

Prevalence and Associated Clinical Factors of GERD (Gastro-Esophageal Reflux Disease) in Ischemic Stroke Patients

Purpose: Aspirin is protective against ischemic stroke, but its use is a significant risk factor for gastro-esophageal reflux disease (GERD). We investigated the prevalence and associated clinical factors of GERD in ischemic stroke patients treated with aspirin. Methods: We recruited 116 ischemic stroke outpatients who were receiving aspirin. Sixteen patients who had received proton pump inhibitors or H2 receptor antagonists within the previous month were excluded. The presence of GERD was defined using the GerdQ questionnaire, with a score of 8 or higher considered positive for GERD. Logistic regression analysis was conducted using variables which exhibited a significant correlation coefficient on two-group comparison as factors, with the presence or absence of GERD as the dependent variable. Results: Mean age of the 100 patients analyzed was 69.3 ± 8.9 years. The prevalence of GERD was 28%. Mean BW of patients with GERD was significantly higher than of those without GERD (P =0.02). The proportion of patients receiving angiotensin II receptor blockers (ARBs) was significantly lower in the GERD group (P=0.04). In contrast, no significant difference was seen in the proportion of patients receiving calcium channel blockers (CCBs). Multivariable logistic regression analysis showed that ARB disuse and increased BW were independent predictors of GERD. Conclusions: The prevalence of GERD was 28% in ischemic stroke patients treated with aspirin. Increased BW as well as ARBs disuse was independent risk factors of GERD. With all these factors, ARBs appear to be better suited than CCBs for use in patients with ischemic stroke with regard to the prevention of GERD. A comprehensive understanding of the relationship between ARBs and GERD prevalence awaits additional studies in a larger number of patients.

Deep cerebral microbleeds are negatively associated with HDL-C in elderly first-time ischemic stroke patients

BACKGROUND Cerebral microbleeds (CMBs) detected on T2*-weighted MRI gradient-echo have been associated with increased risk of cerebral infarction. We evaluated risk factors for these lesions in a cohort of first-time ischemic stroke patients. METHODS Presence of CMBs in consecutive first-time ischemic stroke patients was evaluated. The location of CMBs was classified by cerebral region as strictly lobar (lobar CMBs) and deep or infratentorial (deep CMBs). Logistic regression analysis was performed to determine the contribution of lipid profile to the presence of CMBs. RESULTS One hundred and sixteen patients with a mean age of 70±10years were recruited. CMBs were present in 74 patients. The deep CMBs group had significantly lower HDL-C levels than those without CMBs. In univariable analysis, advanced periventricular hyperintensity grade (PVH>2) and decreased HDL-C were significantly associated with the deep but not the lobar CMB group. On logistic regression analysis, HDL-C (beta=-0.06, p=0.002) and PVH grade >2 (beta=3.40, p=0.005) were independent determinants of deep CMBs. CONCLUSIONS Low HDL-C may be a risk factor of deep CMBs, including advanced PVH status, in elderly patients with acute ischemic stroke. Management of HDL-C levels might be a therapeutic target for the prevention of recurrence of stroke.

Utility of 3-Dimensional Ultrasound Imaging to Evaluate Carotid Artery Stenosis: Comparison with Magnetic Resonance Angiography

BACKGROUND We evaluated the utility of 3-dimensional (3-D) ultrasound imaging for assessment of carotid artery stenosis, as compared with similar assessment via magnetic resonance angiography (MRA). METHODS Subjects comprised 58 patients with carotid stenosis who underwent both 3-D ultrasound imaging and MRA. We studied whether abnormal findings detected by ultrasound imaging could be diagnosed using MRA. Ultrasound images were generated using Voluson 730 Expert and Voluson E8. RESULTS The degree of stenosis was mild in 17, moderate in 16, and severe in 25 patients, according to ultrasound imaging. Stenosis could not be recognized using MRA in 4 of 17 patients diagnosed with mild stenosis using ultrasound imaging. Ultrasound imaging showed ulceration in 13 patients and mobile plaque in 6 patients. When assessing these patients, MRA showed ulceration in only 2 of 13 patients and did not detect mobile plaque in any of these 6 patients. Static 3-D B mode images demonstrated distributions of plaque, ulceration, and mobile plaque, and static 3-D flow images showed flow configuration as a total structure. Real-time 3-D B mode images demonstrated plaque and vessel movement. Carotid artery stenting was not selected for patients diagnosed with ulceration or mobile plaque. CONCLUSIONS Ultrasound imaging was necessary to detect mild stenosis, ulcerated plaque, or mobile plaque in comparison with MRA, and 3-D ultrasound imaging was useful to recognize carotid stenosis and flow pattern as a total structure by static and real-time 3-D demonstration. This information may contribute to surgical planning.

Mismatch between TOF MR Angiography and CT Angiography of the Middle Cerebral Artery may be a Critical Sign in Cerebrovascular Dynamics

Purpose Although time-of-flight (TOF)-magnetic resonance angiography (MRA) can clearly depict intracranial arteries, the arterial flow of middle cerebral artery (MCA) is occasionally not detected. We evaluated this phenomenon with reference to cerebrovascular dynamics. Materials and Methods Seventeen patients with suspected occlusion of MCA or internal carotid artery on TOF-MRA were enrolled. All patients underwent CT angiography (CTA) and quantitative cerebral blood flow (CBF) examination for measurement of resting CBF and cerebrovascular reactivity (CVR). Depending on appearance, patients were categorized into three groups. Group A (n=6) had MCA delineation on both MRA and CTA, while groups B (n=6) and C (n=5) had no signal on MRA, but Group B had a MCA delineation on CTA. Results No significant difference between resting CBF and CBF after the administration of acetazolamide was seen among 3 groups. In contrast, mean CVR in group B was -19.7±18.1%, which was significantly lower than group A [36.4±21.7% (p<0.05)], but not than group C (21.4±35.2%). Furthermore, all patients in group B displayed a so-called steal phenomenon. Conclusion This study is the first to show that visualization of MCA on TOF-MRA closely correlates with CVR, and that a vascular pattern showing no MCA signal intensity on MRA but with MCA delineation on CTA indicates a critical cerebrovascular condition.

A double-blind, placebo-controlled, randomised clinical study of the effect of pork collagen peptide supplementation on atherosclerosis in healthy older individuals

Abstract We examined whether baPWV could be affected by pork collagen peptide (CP) ingestion. Seventy subjects were randomized into two groups (2.5 g/day CP and 2.5 g/day placebo). A significant reduction in baPWV was observed in the CP group compared to the placebo group. This study demonstrated that pork CP may contribute to the prevention of atherosclerosis in elderly.