Shotai Kobayashi

Electrophysiological correlates for response inhibition in a Go/NoGo task

OBJECTIVE Event-related brain potentials (ERPs) during a Go/NoGo task were investigated to elucidate the electrophysiological basis for executive and inhibitory control of responses. METHODS We studied Go/NoGo ERPs in 13 healthy subjects during a modified continuous performance test using high-density electroencephalogram (EEG) recording. We measured peak latency, amplitude, and topographic distribution of the components, and analyzed the neural sources using low-resolution electromagnetic tomography. RESULTS There were no differences between the Go and NoGo conditions in the latency, amplitude, scalp topography, or the electrical source localization of the P1 and N1 components. The N2 component was seen only in the NoGo ERP, and its source was located in the right lateral orbitofrontal and cingulate cortex. The NoGo-P3 component had larger amplitude and longer latency, and was more anteriorly localized than Go-P3; Go-P3 was located mainly in the medial part of the parietal cortex, whereas the NoGo-P3 activity was observed in the left lateral orbitofrontal cortex. CONCLUSIONS These results suggest that the lateral orbitofrontal and anterior cingulate areas play critical roles in the inhibitory control of behavior and that both hemispheres are involved in inhibitory cognitive function.

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in East Asians

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10−8) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10−31 and P = 1.3 × 10−35 for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Subcortical Silent Brain Infarction as a Risk Factor for Clinical Stroke

BACKGROUND AND PURPOSE No prospective studies have examined the rate of symptomatic ischemic or hemorrhagic stroke in patients with subcortical silent brain infarction (SSBI) who were otherwise neurologically normal at entry into the study. This report investigates SSBI, detected by MRI, as a clinical stroke risk factor. METHODS MRI scans were performed in 933 neurologically normal adults (30 to 81 years; mean age, 57.5 +/- 9.2 years) without history of cerebrovascular diseases who received our health screening of the brain 1 to 7 years before investigation. We obtained information of their clinical stroke onset through sending out a questionnaire for subjects. We detected SSBI (focal T2 hyperintensities larger than 3 mm with correlative T1 hypointensity), FWT2HL (focal white matter T2 hypertensity lesions similar to SSBI but without correlative T2-hypointensity), and PVH (periventricular hyperintensity) by MRI. Age, sex, family history of stroke, history of hypertension, diabetes mellitus, lipids, hematocrit, blood pressure, fasting blood sugar, smoking, alcohol habits, ischemic changes on electrocardiogram, and sclerotic changes of retinal arteries were included in the analysis. RESULTS Incidence of SSBI was 10.6% in all subjects. No cortical infarct was detected in this series. Multiple logistic regression analysis showed that hypertension (odds ratio [OR], 4.07; 95% CI, 2.57 to 6.45), diabetes (OR, 2.41; 95% CI, 1.20 to 4.85), alcohol habits > or = 58 g/day (OR, 2.58; 95% CI, 1.50 to 4.45), retinal artery sclerosis (OR, 2.14; 95% CI, 1.32 to 2.38), and age (OR, 1.77; 95% CI, 1.32 to 2.38) were significant and independent risk factors for SSBI. For FWT2HL, hypertension (OR, 4.49; 95% CI, 2.54 to 7.96) and age (OR, 2.08; 95% CI, 1.45 to 3.00) were also independent risk factors. Risk factors for PVH were age (OR, 3.46; 95% CI, 2.23 to 5.36), hypertension (OR, 3.06; 95% CI, 1.62 to 5.78), and retinal artery sclerosis (OR, 2.25; 95% CI, 1.02 to 4.96). We found 14 brain infarctions, 4 brain hemorrhages, and 1 subarachnoid hemorrhage during observation. Annual incidence of clinical stroke was higher in the subjects with SSBI than in those without focal lesions (10.1% versus 0.77%). ORs for clinical stroke onset were 10.48 for SSBI (95% CI, 3.63 to 30.21) and 4.81 for FWT2HL (95% CI, 1.13 to 20.58). The PVH did not relate to clinical stroke onset. CONCLUSIONS The strong association of SSBI, FWT2HL, and PVH with hypertension suggests a common underlying mechanism (presumably small-vessel vasculopathy). The SSBI showed the most significant association for clinical subcortical stroke. The FWT2HL was also a risk factor for the stroke but was less significant than SSBI. The subjects with SSBI should be considered at high risk for clinical subcortical brain infarction or brain hemorrhage.

Distinguishing silent lacunar infarction from enlarged Virchow-Robin spaces : a magnetic resonance imaging and pathological study

Abstract We studied clinicopathological correlations between magnetic resonance imaging (MRI) appearances of postmortem brains and pathological findings in 12 patients to identify simple criteria with which to distinguish lacunar infarctions from enlarged Virchow-Robin spaces. In vivo MRI was also available for 6 of the 12 patients. We focused on small, silent, focal lesions including lacunar infarctions and enlarged Virchow-Robin spaces that were confirmed pathologically. From a total of 114 lesions, enlarged Virchow-Robin spaces were most often found in the basal ganglia and had a round or linear shape. Lacunar infarctions also were most frequent in the basal ganglia, but 47% of these were wedge-shaped. In the pathological studies, excluding lesions from the lower basal ganglia region, enlarged Virchow-Robin spaces were usually smaller than 2 × 1 mm. The shapes and sizes of the lesions determined by MRI (in vivo and postmortem) concurred with the pathological findings, except that on MRI the lesions appeared to be about 1 mm larger than found in the pathological study. When lesions from the lower basal ganglia and the brain stem regions are excluded, the sensitivity and specificity for discriminating enlarged Virchow-Robin spaces from lacunar infarctions are optimal when their size is 2 × 1 mm or less in the pathological study (79%/75%, respectively), 2 × 2 mm or less in both of the MRI studies: postmortem (81%/90%), and in vivo (86%/91%). In conclusion, we were able to differentiate most lacunar infarctions from enlarged Virchow-Robin spaces on MRI on the basis of their location, shape and size. We stress that size is the most important factor used to discriminate these lesions on MRI.

A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease

Several lines of evidence have suggested altered functions of the brain-derived neurotrophic factor (BDNF) in the pathogenesis of neurodegenerative diseases including Alzheimers disease (AD). In the search for polymorphisms in the 5′-flanking and 5′-noncoding regions of the BDNF gene, we found a novel nucleotide substitution (C270T) in the noncoding region. We performed an association study between this polymorphism and AD in a Japanese sample of 170 patients with sporadic AD (51 early-onset and 119 late-onset) and 498 controls. The frequency of individuals who carried the mutated type (T270) was significantly more common in patients with late-onset AD than in controls (P = 0.00004, odds ratio: 3.8, 95% CI 1.9–7.4). However, there was no significant difference in the genotype distribution between the patients with early-onset AD and the controls, although this might be due to the small sample size of the early-onset group. Our results suggest that the C270T polymorphism of the BDNF gene or other unknown polymorphisms, which are in linkage disequilibrium, give susceptibility to late-onset AD. We obtained no evidence for the possible interactions between the BDNF and apolipoprotein E (APOE) genes, suggesting that the possible effect of the BDNF gene on the development of late-onset AD might be independent of the APOE genotype.

Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model

Previous studies have suggested that intravenous transplantation of mesenchymal stem cells (MSCs) in rat ischemia models reduces ischemia‐induced brain damage. Here, we analyzed the expression of neurotrophic factors in transplanted human MSCs and host brain tissue in rat middle cerebral artery occlusion (MCAO) ischemia model. At 1 day after transient MCAO, 3 × 106 immortalized human MSC line (B10) cells or PBS was intravenously transplanted. Behavioral tests, infarction volume, and B10 cell migration were investigated at 1, 3, 7, and 14 days after MCAO. The expression of endogenous (rat origin) and exogenous (human origin) neurotorphic factors and cytokines was evaluated by quantitative real‐time RT‐PCR and Western blot analysis. Compared with PBS controls, rats receiving MSC transplantation showed improved functional recovery and reduced brain infarction volume at 7 and 14 days after MCAO. In MSC‐transplanted brain, among many neurotrofic factors, only human insulin‐like growth factor 1 (IGF‐1) was detected in the core and ischemic border zone at 3 days after MCAO, whereas host cells expressed markedly higher neurotrophic factors (rat origin) than control rats, especially vascular endothelial growth factor (VEGF) at 3 days and epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) at 7 days after MCAO. Intravenously transplanted human MSCs induced functional improvement, reduced infarct volume, and neuroprotection in ischemic rats, possibly by providing IGF‐1 and inducing VEGF, EGF, and bFGF neurotrophic factors in host brain.

Blood Pressure and Hypertension Are Associated With 7 Loci in the Japanese Population

Background— Two consortium-based genome-wide association studies have recently identified robust and significant associations of common variants with systolic and diastolic blood pressures in populations of European descent, warranting further investigation in populations of non-European descent. Methods and Results— We examined the associations at 27 loci reported by the genome-wide association studies on Europeans in a screening panel of Japanese subjects (n=1526) and chose 11 loci showing association signals (1-tailed test in the screening, P<0.3) for an extensive replication study with a follow-up panel of 3 Japanese general-population cohorts (n ≤24 300). Significant associations were replicated for 7 loci—CASZ1, MTHFR, ITGA9, FGF5, CYP17A1-CNNM2, ATP2B1, and CSK-ULK3—with any or all of these 3 traits: systolic blood pressure (P=1.4×10−14 to 0.05), diastolic blood pressure (P=1.9×10−12 to 0.05), and hypertension (P=2.0×10−14 to 0.006; odds ratio, 1.10 to 1.29). The strongest association was observed for FGF5. In the whole study panel, the variance (R2) for blood pressure explained by the 7 single-nucleotide polymorphism loci was calculated to be R2=0.003 for male and 0.006 for female participants. Stratified analysis implied the potential presence of a gene-age-sex interaction, although it did not reach a conclusive level of statistical significance after adjustment for multiple testing. Conclusions— We have confirmed 7 loci associated with blood pressure and/or hypertension in the Japanese. These loci can guide fine-mapping efforts to pinpoint causal variants and causal genes with the integration of multiethnic results.

Poststroke apathy and regional cerebral blood flow

BACKGROUND AND PURPOSE Although apathy has been reported as one of the neuropsychiatric symptoms following stroke, there have been no studies on regional cerebral blood flow (rCBF) in patients with apathy. In this study we estimated the severity of apathy using the Apathy Scale and examined its relationship to rCBF in 40 stroke patients (mean age, 71.4 years). METHODS Neuropsychiatric batteries were performed including the Apathy Scale, verbal intelligence and frontal function tests, a depression scale, and an assessment of activities of daily living. The cortical rCBFs were measured by the 133Xe inhalation method. RESULTS Twenty patients (50%) showed apathy. These patients showed significantly lower scores on verbal intelligence and frontal function tests and a significantly higher depression score than the nonapathetic group. On MRI images there was no relationship between the apathy score and specific regional distribution of lesions. The rCBFs of the bilateral hemisphere were significantly lower in the apathetic group than in the nonapathetic group. The apathetic group showed a significantly reduced rCBF in the right dorsolateral frontal and left fronto-temporal regions. Furthermore, the apathy score for all patients was significantly negatively correlated with rCBF in the same regions. CONCLUSIONS These findings demonstrate that apathy is a frequent symptom among elderly stroke patients and may be accompanied by cognitive impairments, depressive state, and frontal dysfunction. The hypoactivity in the frontal lobe and anterior temporal regions may contribute to symptoms of apathy after stroke.

Microbleeds Are Associated With Subsequent Hemorrhagic and Ischemic Stroke in Healthy Elderly Individuals

Background and Purpose— Cerebral microbleeds (MBs) are frequently detected in patients with stroke, especially those who experience intracerebral hemorrhage. However, the clinical significance of MBs in subjects without cerebrovascular disease is still unclear. We performed a prospective study to determine whether the presence of MBs provides useful prognostic information in healthy elderly individuals. Methods— We tracked 2102 subjects (mean age, 62.1 years) over a mean interval of 3.6 years after they voluntarily participated in the brain checkup system at the Shimane Institute of Health Science. An initial assessment was performed to document the presence of MBs and silent ischemic brain lesions and to map the location of the MBs. During the follow-up period, we obtained information about stroke events that occurred in each subject. Results— MBs were detected in 93 of the 2102 subjects (4.4%). Strokes occurred in 44 subjects (2.1%) during the follow-up period. They were significantly more common among subjects with MBs. Age and hypertension were independent risk factors for MBs. The presence of MBs was more strongly associated with a deep brain hemorrhage (hazard ratio, 50.2; 95% CI, 16.7 to 150.9) than ischemic stroke (hazard ratio, 4.48; 95% CI, 2.20 to 12.2). All hemorrhagic strokes occurred in deep brain regions, and they were associated with MBs located in the deep brain region. Conclusions— This longitudinal study demonstrated that the presence of MBs can be used to predict hemorrhagic and ischemic stroke, even in healthy elderly individuals.

Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for peroxynitrite-mediated oxidative stress in neurodegenerative diseases

Peroxynitrite can nitrate tyrosine residues of proteins. We examined nitrotyrosine‐containing proteins in cerebrospinal fluid of 66 patients with neurogenic disease by immunoblot analysis. Nitrated tyrosine residue–containing protein was observed in the cerebrospinal fluid and was concluded to be manganese superoxide dismutase (Mn‐SOD). The nitrated Mn‐SOD level was strikingly elevated in amyotrophic lateral sclerosis patients and was slightly increased in Alzheimers and Parkinsons disease patients, whereas an elevated Mn‐SOD level was observed only in progressive supranuclear palsy group. Ann Neurol 2000;47:524–527.