Ken Nagata

Dual Antithrombotic Therapy Increases Severe Bleeding Events in Patients With Stroke and Cardiovascular Disease A Prospective, Multicenter, Observational Study

Background and Purpose— We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries. Methods— A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition. Results— During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (P<0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative risk=1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative risk=1.37; 95% CI, 1.07 to 1.76). Conclusions— The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.

Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered l-DOPA

The aim of this study was to determine whether raphe-striatal serotonergic neurons of adult rats with extensive nigro-striatal dopaminergic denervation are induced by injection of exogenous L-DOPA to contain dopamine. Double-labeling immunofluorescence study was conducted. In the lesioned striatum of rats that received L-DOPA, serotonergic hyperinnervation was observed, and dopamine was detected in serotonergic varicose fibers. These findings suggest that striatal serotonergic hyperinnervation can compensate for the lost function of dopaminergic neurons.

Electroencephalographic correlates of blood flow and oxygen metabolism provided by positron emission tomography in patients with cerebral infarction

Quantitative EEG data were analyzed statistically with respect to cortical cerebral blood flow (CBF) and oxygen metabolism (CMRO2) measured by positron emission tomography in 47 patients with unilateral cerebral infarction. Relative value of the square root of average power was used as a percentage power fraction (PPF) for each frequency category. Power ratio index (PRI) was calculated by dividing the combined delta-PPF and theta-PPF by the combined alpha-PPF and beta-PPF. Delta-PPF, theta-PPF and PRI correlated negatively with regional CBF (rCBF) and CMRO2 (rCMRO2) whereas alpha-PPF and beta-PPF correlated positively. In the acute stage, delta-PPF, alpha-PPF and PRI correlated with rCBF at all but the frontopolar region whereas the correlation with rCMRO2 was poor. Alpha-PPF and PRI correlated also with rCMRO2 in the frontal, central, parietal and occipital regions while delta-PPF correlated with rCBF only in the parietal and occipital regions in the subacute stage. In the chronic stage, all EEG quotients correlated significantly with both rCBF and CMRO2 in the central and parietal regions. In the frontopolar region, only the theta-PPF correlated with rCBF throughout. In the comparison of hemispheric mean values, the correlations were always closer for the affected hemisphere than for the contralateral hemisphere. Although hemispheric mean CBF and CMRO2 were significantly lower in patients with cortical infarcts on CT than in those with small subcortical infarcts, there was no significant difference in the EEG data between the 2 groups.

Can PET Data Differentiate Alzheimer's Disease from Vascular Dementia?

Abstract: The present study endeavored to differentiate Alzheimers disease (AD) from vascular dementia (VaD) by comparing the metabolic and hemodynamic parameters. Positron emission tomographic (PET) studies were carried out in 13 patients with probable AD and 20 patients with VaD. PET findings were not included in the diagnostic criteria of AD or VaD. Using oxygen‐15 labeled compounds, cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), cerebral blood volume, and vascular transit time (VTT) were measured quantitatively during the resting state. To evaluate vascular reactivity (VR), CBF was also measured during 7% CO2 inhalation. Regional CBF from the parietal cortex positively correlated with the neuropsychological scores in both AD and VaD groups. The typical parietotemporal pattern of hypoperfusion and hypometabolism was observed in the AD group, whereas the frontal lobe including the cingulate and superior frontal gyri were predominantly affected in the VaD group. The occipital cortex was preserved in both groups. A significant increase of the OEF was found in the parietotemporal areas in the AD group. No significant prolongation was seen with VTT. There was a marked difference in VR between the two groups: VR was depleted in the VaD group, whereas VR was normal in the AD group. The increased OEF with preserved vascular reserve seen in AD may implicate participation of a vascular factor in the pathogenesis of AD, possibly at the capillary level. Thus, PET provides important functional information in discriminating AD from VaD by comparing the patterns of hypoperfusion and/or hypometabolism, and in the understanding of the underlying hemodynamic pathophysiology.

Age-related decline of cerebral oxygen metabolism in normal population detected with positron emission tomography

Using positron emission tomography (PET), cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were measured in 32 healthy volunteers aged from 27 to 67 years. In bilateral putamen, left supratemporal, left infrafrontal and left parietal cortices, CMRO2 showed a significant decline during aging. The age-related decline of CBF was seen only at the left superior temporal cortex. The mean CMRO2 was significantly lower in the elder group (over 51 years old) than in the younger group (under 50 years old), whereas no significant difference in mean CBF between the two groups. The poor correlation of CBF to the age could be explained partly by the fact that CBF is easily influenced by the physiological, psychological and/or environmental factors. The age-related changes of CMRO2 were more marked in the association cortices of the left hemisphere than in that of the right hemisphere.

Activated brain regions in musicians during an ensemble: a PET study.

As in visual processing, we speculated that, in music processing, different brain regions would activate according to the mode of music listening. Using motets by a famous composer, we studied changes in regional cerebral blood flow (rCBF) with positron emission tomography associated with concentrating on the alto-part within the harmony (alto-part-listening condition) compared to listening to the harmony as a whole (harmony-listening condition). The alto-part-listening condition was associated with bilateral increases of rCBF in superior parietal lobules, precunei, premotor areas and orbital frontal cortices. Superior parietal lobules are likely to be responsible for auditory selective attention to the alto part within the harmony and the analysis of tone pitch on a mental score. The precuneus possibly participated in writing tones of the alto part on a mental score. Based on our findings, we propose that both auditory selective attention and analytic processing play an important role in concentrating on a certain vocal part within a harmony. During the harmony-listening condition, temporal poles, the anterior portion of the cingulate gyrus, occipital cortex and the medial surface of the cerebellum were bilaterally activated. Further studies are necessary to clarify the difference in music processing between musicians and nonmusicians.

Enhanced Connexin 43 immunoreactivity in penumbral areas in the human brain following ischemia

Astrocytes support neurons not only physically but also chemically by secreting neurotrophic factors and energy substrates. Moreover, astrocytes establish a glial network and communicate through gap junctions in the brain. Connexin 43 (Cx43) is one of major component proteins in astrocytic gap junctions. Heterozygote Cx43 KO mice and astrocyte specific Cx43 KO mice exhibited amplified brain damage after ischemic insults, suggesting a neuroprotective role for astrocytic gap junctions. However, some reports mentioned unfavorable effects of gap junctions in neuronal support. Therefore, the role of astrocytic gap junctions under ischemic condition remains controversial. Since these studies have been performed using animal models, we investigated the Cx43 expression in human brain after stroke. Brain slice sections were prepared from pathological samples in our hospital. Embolic stroke brains sectioned because of the stroke were considered as acute ischemic models. Multiple infarction brains sectioned because of pneumonia or cancer were considered as chronic models. We observed the levels of Cx43 in both lesioned and intact areas, and compared them with acute and chronic models. As the results, astrocytes were strongly activated in penumbral lesions both of acute and chronic ischemic models. The Cx43 immunoreactivity was significantly amplified in the penumbra of chronic model compared to that of the acute model. Neurons were well preserved in chronic model compared to acute model. These findings suggested that the brain may generate neuronal protection by increasing the levels of Cx43 and amplifying the astrocytic gap junctional intercellular communication under hypoxic condition.

Antithrombotic Therapy Influences Location, Enlargement, and Mortality from Intracerebral Hemorrhage

Background: To determine whether the use of oral antithrombotic agents before the onset of intracerebral hemorrhage (ICH) affects hematoma features and early patient outcome. Methods: A retrospective, multicenter study involving 1,006 consecutive Japanese patients (607 men, 67 ± 12 years of age) hospitalized within 24 h after the onset of nontraumatic ICH was conducted. Results: One hundred and eighty patients were taking oral antiplatelet agents (17.9%, AP group), 67 were taking warfarin (6.7%, W group), and 21 were taking both (2.1%, W + AP group). After adjustment for age, sex, and known confounders, the taking of each kind of antithrombotic therapy was independently related to cerebellar hemorrhage; the odds ratios (OR) and 95% CI, with patients taking no antithrombotic agents as the reference group, were 2.31 (1.23–4.32) for the AP group, 2.90 (1.26–6.63) for the W group, and 3.43 (1.02–11.59) for the W + AP group. Similarly, the taking of each kind of antithrombotic therapy was independently related to hematoma enlargement within the initial 24 h (OR and 95% CI: AP group, 1.92, 1.10–3.34; W group, 4.80, 2.12–10.87; W + AP group, 4.94, 1.31–18.61) and mortality at 3 weeks post-ICH (OR and 95% CI: AP group, 2.70, 1.56–4.68; W group, 2.50, 1.05–5.96; W + AP group, 9.41, 2.78–31.88). Conclusions: Prior medication with antiplatelet agents, warfarin, or both was predictive of cerebellar hemorrhage, hematoma enlargement, and early death in Japanese ICH patients.

Regional correlations between the EEG and oxygen metabolism in dementia of Alzheimer's type

To determine the relationship between EEG slowing and cerebral hypometabolism in dementia, 10 patients with dementia of Alzheimers type (DAT) were evaluated with quantitative topographic EEG and positron emission tomography (PET). Power in each 1-Hz frequency band from 2-20 Hz, power ratio index, and normalised PET data from corresponding cortical sites were compared to data obtained from 20 normal volunteers. PET revealed significant parieto-temporal hypometabolism, and topographic EEG mapping and power spectrum analysis revealed a slowing of the background EEG that was most pronounced in the parietal-temporal areas. Correlation analysis between EEG power spectrum data and CMRO2 revealed significant negative correlations for frequencies below 8 Hz and significant positive correlations above 8 Hz in the parieto-temporal regions, which have previously been identified as the areas most severely affected by pathological changes associated with DAT. Correlation coefficients plotted as functions of frequency illustrated the relationships between EEG changes and reduced CMRO2, supporting previous views that EEG slowing in DAT may be related to hypometabolism in cortical regions most affected by the disease.

Blood Pressure Levels and Bleeding Events During Antithrombotic Therapy: The Bleeding With Antithrombotic Therapy (BAT) Study

Background and Purpose— A prospective, multicenter, observational cohort study was conducted to clarify the association between major bleeding events and blood pressure (BP) levels during follow-up before development of bleeding events in antithrombotic users. Methods— A total of 4009 patients taking oral antithrombotic agents for cardiovascular or cerebrovascular diseases (2728 men, 69±10 years old) were followed. Changes in systolic and diastolic BPs between entry and the last clinic visit before intracranial hemorrhage (ICH) or extracranial hemorrhage were assessed. Results— Over a median follow-up of 19 months, ICH developed in 31 patients and extracranial hemorrhage developed in 77. Entry BP levels were similar among patients with ICH, those with extracranial hemorrhage, and those without hemorrhagic events. Both systolic BP and diastolic BP were relatively high during follow-up as compared with the levels at entry in patients with ICH, whereas they showed plateaus in patients with extracranial hemorrhage and patients without hemorrhagic events. Average systolic BP levels between 1 and 6 months (hazard ratio, 1.45; 95% CI, 1.08 to 1.92 per 10-mm Hg increase) and between 7 and 12 months (hazard ratio, 1.47; 95% CI, 1.05 to 2.01) as well as average diastolic BP levels between 7 and 12 months (hazard ratio, 2.05; 95% CI, 1.15 to 3.62) were independently associated with development of ICH after adjustment for established ICH predictors. The optimal cutoff BP level to predict impending risk of ICH was ≥130/81 mm Hg using receiver operating characteristic curve analysis. Conclusions— An increase in BP levels during antithrombotic medication was positively associated with development of ICH, suggesting the importance of adequate BP control for avoiding ICH. BP levels did not appear to be associated with extracranial hemorrhage.