Takuya Kanamaru

Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation.

Valproic acid (VPA), widely used in clinical contexts for the treatment of seizures and bipolar mood disorder, has neuroprotective properties in cellular and animal models. However, the precise mechanisms underlying its neuroprotection against stroke remain unknown. In the present study, we explored the effect of VPA on experimental ischemic stroke. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion for 90 min, followed by reperfusion. The animals received a single injection of VPA (300 mg/kg) immediately, 90, or 270 min after the induction of ischemia. Vehicle-treated animals underwent the same procedure with physiological saline. Infarct volume and neurological symptoms were evaluated 24 h after reperfusion. Immunohistochemical staining for myeloperoxidase (MPO), microglia (Iba1), 4-hydroxy-2-nonenal (4-HNE), or 8-hydroxy-deoxyguanosine (8-OHdG) was performed. Ischemic boundary zone cell death was determined by TUNEL staining. VPA injected immediately or 90 min after ischemia induction significantly reduced infarct volume and improved neurological deficit compared with vehicle (P<0.05). VPA was ineffective when given 270 min after ischemia induction. VPA significantly reduced TUNEL-positive cells, MPO-positive cells, Iba1-positive cells, 4-HNE-positive cells, and 8-OHdG-positive cells compared with vehicle in the ischemic boundary zone (P<0.05). The therapeutic time window for single injection of VPA is between 0 and 90 min in this model. Our results demonstrate that single injection of VPA may have anti-inflammatory as well as antioxidative effects, leading to reduced cell death in ischemia-reperfusion injury.

Low Serum n-3 Polyunsaturated Fatty Acid/n-6 Polyunsaturated Fatty Acid Ratio Predicts Neurological Deterioration in Japanese Patients with Acute Ischemic Stroke

Background: Epidemiological and clinical trials have shown that n-3 polyunsaturated fatty acids (PUFAs) reduce the incidence of coronary heart disease or stroke. However, the association between PUFAs and acute-phase stroke has not yet been thoroughly studied. We investigated the impact of serum PUFAs on early neurological deterioration (END) in patients with acute ischemic stroke. Methods: In this retrospective study, we enrolled 281 Japanese patients (mean age: 75 ± 13 years; 165 males) with acute ischemic stroke diagnosed within 24 h of onset. General blood examinations, including PUFAs (n-3 PUFAs: eicosapentaenoic acid, EPA, and docosahexaenoic acid, DHA, and n-6 PUFAs: arachidonic acid, AA), were performed on admission. Other risk factors and comorbidities were also examined. END was defined as a ≥2-point increase in the National Institutes of Health Stroke Scale (NIHSS) score within a 72-hour period. Statistical significance between the END and non-END group was assessed using Wilcoxon rank sum tests or Students t tests for categorical variables. Multiple logistic regression analyses were performed to identify predictors of END. Results: END was observed in 75 patients (26.7%). Diabetes mellitus (p = 0.003), high-sensitivity C-reactive protein (hs-CRP) level (p < 0.001), prior stroke (p = 0.035), ischemic heart disease (p = 0.029), EPA/AA ratio (p = 0.003), DHA/AA ratio (p = 0.002), EPA+DHA/AA ratio (p = 0.002), diagnosis of small vessel disease (p = 0.004) and admission NIHSS score (p < 0.001) were significantly associated with END. We used separate multiple logistic regression analyses for the EPA/AA, DHA/AA and EPA+DHA/AA ratios, because EPA and DHA are considered covariant factors (r = 0.544; p < 0.0001). Multiple logistic regression analyses showed that END was positively associated with diabetes mellitus, hs-CRP level and NIHSS score on admission, and negatively associated with the EPA/AA ratio (odds ratio, OR: 0.18; 95% confidence interval, CI: 0.05-0.58; p = 0.003), DHA/AA ratio (OR: 0.045; 95% CI: 0.006-0.30; p = 0.001), EPA+DHA/AA ratio (OR: 0.45; 95% CI: 0.26-0.74; p = 0.002) and diagnosis of small vessel disease. Conclusions: Our data suggest that a low serum n-3 PUFA/n-6 PUFA ratio on admission may predict neurological deterioration in Japanese patients with acute ischemic stroke. Large-scale prospective studies are further required to clarify the role of PUFAs in the acute phase of ischemic stroke.

Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer's disease

Oxidative stress is known to play a prominent role in the onset and early stage progression of Alzheimers disease (AD). For example, protein oxidation and lipid peroxidation levels are increased in patients with mild cognitive impairment. Here, we created a double-transgenic mouse model of AD to explore the pathological and behavioral effects of oxidative stress. Double transgenic (APP/DAL) mice were constructed by crossing Tg2576 (APP) mice, which express a mutant form of human amyloid precursor protein (APP), with DAL mice expressing a dominant-negative mutant of mitochondrial aldehyde dehydrogenase 2 (ALDH2), in which oxidative stress is enhanced. Y-maze and object recognition tests were performed at 3 and 6 months of age to evaluate learning and memory. The accumulation of amyloid plaques, deposition of phosphorylated-tau protein, and number of astrocytes in the brain were assessed histopathologically at 3, 6, 9, and 12-15 months of age. The life span of APP/DAL mice was significantly shorter than that of APP or DAL mice. In addition, they showed accelerated amyloid deposition, tau phosphorylation, and gliosis. Furthermore, these mice showed impaired performance on Y-maze and object recognition tests at 3 months of age. These data suggest that oxidative stress accelerates cognitive dysfunction and pathological insults in the brain. APP/DAL mice could be a useful model for exploring new approaches to AD treatment.

Low free triiodothyronine predicts poor functional outcome after acute ischemic stroke

BACKGROUND AND PURPOSE The aim of this study was to investigate the association of admission serum thyroid hormone concentration with clinical characteristics and functional outcomes in patients after acute ischemic stroke. METHODS We retrospectively enrolled 398 consecutive patients admitted to our stroke center between July 2010 and April 2012. Serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) were evaluated upon admission. Neurological severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) upon admission and the modified Rankin Scale (mRS) upon discharge. Poor outcome was defined as a mRS score of 3-5 or death (mRS score 6). Separate analyses were conducted according to outcome and quartile serum FT3 concentration. RESULTS In total, 164 patients (41.2%) demonstrated a poor outcome. Age, male gender, blood glucose level, arterial fibrillation, dyslipidemia, smoking, NIHSS score, cardioembolic stroke type, and periventricular hyperintensities, but not FT4 or TSH, were significantly associated with poor functional outcome. Furthermore, poor functional outcome was independently associated with low FT3 (<2.29pg/mL). In comparisons between FT3 quartiles (Q1 [≤2.11pg/mL], Q2 [2.12-2.45pg/mL], Q3 [2.46-2.77pg/mL], Q4 [≥2.78pg/mL]), patients with poor outcomes were more frequent in Q1 than in Q4 after multivariate adjustment. Death was more frequent in Q1 than in Q4 after adjustment for risk factors and comorbidities, but this difference was non-significant after additional adjustment for age and NIHSS score. CONCLUSIONS Our data suggest that a lower FT3 value upon admission may predict a poor functional outcome in patients with acute ischemic stroke. Further large-scale prospective studies are required to clarify the role of thyroid hormone in the acute phase of ischemic stroke.

Intravenous transplantation of bone marrow-derived mononuclear cells prevents memory impairment in transgenic mouse models of Alzheimer's disease.

Stem cell transplantation therapy is currently in clinical trials for the treatment of ischemic stroke, and several beneficial aspects have been reported. Similarly, in Alzheimers disease (AD), stem cell therapy is expected to provide an efficient therapeutic approach. Indeed, the intracerebral transplantation of stem cells reduced amyloid-β (Aβ) deposition and rescued memory deficits in AD model mice. Here, we show that intravenous transplantation of bone marrow-derived mononuclear cells (BMMCs) improves cognitive function in two different AD mouse models, DAL and APP mice, and prevents neurodegeneration. GFP-positive BMMCs were isolated from tibiae and femurs of 4-week-old mice and then transplanted intravenously into DAL and APP mice. Transplantation of BMMCs suppressed neuronal loss and restored memory impairment of DAL mice to almost the same level as in wild-type mice. Transplantation of BMMCs to APP mice reduced Aβ deposition in the brain. APP mice treated with BMMCs performed significantly better on behavioral tests than vehicle-injected mice. Moreover, the effects were observed even with transplantation after the onset of cognitive impairment in DAL mice. Together, our results indicate that intravenous transplantation of BMMCs has preventive effects against the cognitive decline in AD model mice and suggest a potential therapeutic effect of BMMC transplantation therapy.

Feasibility of using magnetic resonance imaging as a screening tool for acute stroke thrombolysis.

BACKGROUND Feasibility of performing MRI first for suspected hyperacute stroke patients in real-world practice has not been fully examined. Moreover, most past studies of reducing door-to-needle time (DNT) in intravenous thrombolysis were conducted using CT. The aim of this study was to evaluate the feasibility of an MRI-first policy and examine the effects of a quality improvement (QI) process for reducing DNT using MRI. METHODS From January 2014 to August 2015, consecutive acute stroke patients who were treated with thrombolysis were prospectively enrolled into the present study. In principle, multimodal 1.5T-MRI was performed first for patients with suspected acute stroke. A step-by-step QI process for decreasing DNT, including prenotification by the emergency medical service, limiting the MRI sequence, and introduction of a rapid examination tool, was also implemented during this period. Time metrics for thrombolysis were compared between specific time periods. RESULTS A total of 73 patients (27 women; median age 74years) were included in the present study. More than 80% of the patients were screened with MRI. More patients were managed with the MRI-first policy in the late phase (p=0.018). DNT (83min in the early phase, 68min in the middle phase, and 54min in the late phase, p<0.001) was significantly reduced across phases. The percentage of patients with DNT<60min increased significantly across time periods (p<0.001). CONCLUSION An MRI-first policy was feasible, and DNT was substantially reduced with a QI process. This process may be applicable to other hospitals.

Efficiency of the Penumbra 5MAX ACE Reperfusion Catheter in Acute Ischemic Stroke Patients

OBJECTIVE This study was performed to investigate whether the Penumbra 5MAX ACE is superior to other Penumbra systems. MATERIALS AND METHODS We performed a retrospective, single center analysis of patients with acute ischemic stroke with occlusion of the internal carotid artery or middle cerebral artery (M1 segment) who underwent endovascular therapy using a Penumbra system. The reperfusion success rate, puncture-to-revascularization time, and number of passes were assessed. Multivariate regression analysis was conducted to evaluate independent factors related to revascularization within 60 minutes. Successful revascularization was defined by a thrombolysis in cerebral infarction score ≥2b. RESULTS The Penumbra 5MAX ACE was used in 24 of the 40 patients (60%). Although the revascularization success rate was similar between patient groups (P = .229), the number of passes was significantly lower (1.5 ± .8 versus 2.6 ± 1.3, P = .006) and the puncture-to-revascularization time was shorter (50 ± 26 minutes versus 116 ± 69 minutes, P = .002) in patients treated with the Penumbra 5MAX ACE. The Penumbra 5MAX ACE was identified as an independent factor for early revascularization (odds ratio, 5.80; P = .041). Among patients with a premorbid modified Rankin Scale score of 0-1, a modified Rankin Scale score of 0-2 at 3 months was observed in 15 of the 19 patients (79%) treated with the Penumbra 5MAX ACE and in 8 of the 16 (50%) who were not (P = .072). CONCLUSION Acute revascularization therapy using the Penumbra 5MAX ACE can achieve rapid successful recanalization and tend to improve clinical outcomes.

Urinary albumin-to-creatinine ratio is associated with white matter lesions severity in first-ever stroke patients

BACKGROUND The presence of white matter lesions (WML) is an indicator of small vessel disease; however, the underlying pathological mechanisms are still unclear. We aimed to investigate the association of estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) with WML severity in first-ever stroke patients. METHODS We retrospectively enrolled 284 consecutive patients (177 male; median age 72years) admitted to our stroke center between May 2010 and January 2012. eGFR and UACR measurements were performed on admission. WML severity was assessed using the Fazekas classification. Severe WML was defined as a Fazekas grade of 2 or higher. The impact of eGFR and UACR on severe WML was evaluated using multiple logistic regression analysis. RESULTS Age (P<0.0001), sex (P=0.0094), eGFR (P=0.0173), UACR (P=0.0001), hypertension (P=0.0436), and brain natriuretic peptide (P=0.0354) were significantly associated with severe WML. On multivariable logistic regression analysis, high UACR (≥39.6mg/g creatinine, P=0.039), but not low eGFR (≤74ml/min/1.73m2, P=0.3672), was independently associated with severe WML. Comparisons between the UACR levels showed that severe WML was more frequent in the UACR ≥300mg/g creatinine group than in the UACR <30.0mg/g creatinine group after multivariate adjustment (OR, 2.25; 95% CI, 1.04-5.00; P=0.039). However, there was no significant association between eGFR and severe WML. CONCLUSIONS Our data suggest that high UACR, but not eGFR, is independently associated with severe WML.

Albuminuria predicts early neurological deterioration in patients with acute ischemic stroke

BACKGROUND Reduced glomerular filtration rate (GFR) and albuminuria have been independently associated with an increased risk of stroke and unfavorable long-term outcomes. However, the association between GFR, albuminuria, and early neurological deterioration (END) in patients with ischemic stroke has not been well studied to date. We therefore investigated the ability of estimated GFR (eGFR) and albuminuria to predict END in patients with acute ischemic stroke. METHODS We retrospectively enrolled 294 patients that were admitted to our stroke center with acute ischemic stroke between January 2011 and September 2012. General blood and urine examinations, including eGFR and urinary albumin/creatinine ratio (UACR) measurements, were performed on admission. Kidney dysfunction was defined by a low eGFR value (<60mL/min/1.73m2) and/or increased albuminuria (≥30mg/g creatinine). END was defined as a ≥2-point increase in the National Institutes of Health Stroke Scale (NIHSS) score within 7days after admission. RESULTS Kidney dysfunction was diagnosed in 200 of the 294 patients (68.0%). END was observed in 60 patients (20.4%). Age, blood glucose level on admission, UACR on admission, and NIHSS score on admission were significantly associated with END, while no relationship between eGFR on admission and END was identified. A multivariable logistic regression analysis showed that END was positively associated with high UACR (≥39.6mg/g creatinine) and a high NIHSS score (≥6 points). CONCLUSIONS Our data suggest that high UACR on admission may predict END in patients with acute ischemic stroke. Larger prospective studies are required to validate the correlation between albuminuria and END.

A case report of bilateral paramedian thalamic and occult midbrain infarctions without disturbance of consciousness

Bilateral paramedian thalamic infarction is well known to cause disturbances of consciousness, and there are a few reports of bithalamic paramedian stroke without alterations in consciousness [1–4]. Moreover, a thalamic lesion has been reported to cause vertical gaze palsy [5], but there are controversies about whether a thalamic lesion itself leads to vertical gaze palsy [6]. An alert patient with bilateral paramedian thalamic infarction is presented. Complete vertical gaze palsy with right adduction impairment was the sole manifestation of this patient, and follow-up magnetic resonance imaging (MRI) revealed slight extension of the lesions into the upper midbrain.