Makiko Tanaka

Early CT Findings in Unknown-Onset and Wake-Up Strokes

Background: Approximately one quarter of the acute ischemic stroke patients notice the event at awakening. Such patients with stroke at awakening are usually excluded from thrombolysis, since the time of stroke onset cannot be definitely identified. We compared the hyperacute CT findings of awakening stroke patients with those of stroke patients with known onset to assess whether the time of stroke onset is shortly before awakening. Methods: Subjects were cardioembolic stroke patients who were consecutively admitted to our department within 3 h after the recognition of stroke during the period between January 2000 and March 2003. The patients were classified into three groups: group A with stroke of known onset, group B with stroke at awakening, and group C with stroke of unknown onset due to lack of a witness. The clinical and CT findings in each group were compared. Results: A total of 81 patients fulfilled the study criteria. There were 46 patients in group A, 17 patients in group B, and 18 patients in group C. There was no significant difference in CT findings between groups A and B. In group C, however, definite hypodense areas were more commonly found than in group A (56 vs. 0%; p < 0.001) or in group B (56 vs. 11%; p = 0.012). Conclusion: Based on our CT findings, stroke at awakening seems to be developing shortly before in a large subset of patients, making them potential candidates for acute stroke therapies.

Chronic kidney disease is associated with dementia independent of cerebral small-vessel disease

Objective: To determine whether chronic kidney disease (CKD) is associated with incident dementia independent of cerebral small-vessel disease (SVD) in patients with vascular risk factors. Methods: Using data from a Japanese cohort of participants with vascular risk factors in an ongoing observational study from 2001, we evaluated the association between CKD at baseline and incident dementia. Baseline brain MRI was used to determine SVD (lacunar infarction, white matter hyperintensities), medial-temporal atrophy, and subcortical atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE ε4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings. Results: Of the 600 subjects (mean age 68 ± 8.3 years, 57% male, 12.8 ± 2.6 years of education; CKD: 29%), 50 patients with incident dementia (Alzheimer disease: 24; vascular dementia: 18; mixed-type dementia: 5; other types: 3) were diagnosed during the median 7.5-year follow-up. CKD at baseline was associated with an increased risk of all-cause dementia in models adjusted for age, sex, educational level, and APOE ε4 allele. The associations of CKD at baseline remained significant even after additional adjusting for MRI findings and confounding variables (hazard ratio: 1.96 [1.08–3.58], p = 0.026). Conclusions: CKD is independently related to the risk of all-cause dementia in patients with vascular risk factors. Our results reinforce the hypothesis that CKD exerts deleterious effects on dementia incidence.

Relations of Blood Inflammatory Marker Levels With Cerebral Microbleeds

Background and Purpose— Cerebral microbleeds (CMB) are observed in the elderly and have been regarded as one of the manifestations of small vessel disease. Although inflammatory processes have attracted much attention not only in large-artery disease, but also in small vessel disease, their involvement in CMB remains to be determined. The purpose of this study is to clarify relations between inflammatory marker levels and CMB. Methods— Four hundred thirty-one patients without histories of cerebrovascular diseases were prospectively enrolled. The presence and number of CMB were assessed on gradient-echo magnetic resonance imaging. As common inflammatory markers, serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and interleukin-18 (IL-18) were evaluated. Results— CMB were found in 65 patients (15%). In 35 patients, at least one CMB was found in deep locations, but 30 patients had strictly lobar CMB. Levels of hsCRP, IL-6, and IL-18 were higher in patients with CMB than in those without. Logistic regression analyses showed that each 1SD increase in each inflammatory marker level was significantly associated with the presence of CMB after adjustment for age and sex, and after additional adjustment for cardiovascular risk factors, silent lacunar infarction, and white matter hyperintensity. The OR (95% CI) of hsCRP, IL-6, and IL-18 was 1.81 (1.35–2.46), 1.73 (1.18–2.61), and 2.41 (1.44–4.52), respectively. Furthermore, the inflammatory marker levels were associated with both deep and lobar CMB. Conclusions— Higher levels of hsCRP, IL-6, and IL-18 are associated with CMB, in both deep and lobar locations, suggesting the involvement of inflammation in CMB.

Multiple or mixed cerebral microbleeds and dementia in patients with vascular risk factors

Objective: To investigate whether cerebral microbleeds (CMBs) are independently associated with incident dementia in patients with vascular risk factors. Methods: Using data from a Japanese cohort of participants with vascular risk factors in an observational study from 2001, we evaluated the association between CMBs at baseline and incident dementia. Baseline brain MRI was used to determine small-vessel disease (CMBs, lacunar infarcts, and white matter hyperintensities) and brain atrophy. Cox proportional hazards analyses were performed for predictors of dementia adjusting for age, sex, APOE ε4 allele, educational level, baseline Mini-Mental State Examination score, cerebrovascular events, vascular risk factors, and MRI findings. Results: Of the 524 subjects (mean age 68 ± 8.3 years, 57.6% male, 12.8 ± 2.6 years of schooling, 21.6% CMBs), 44 patients with incident dementia (20 Alzheimer disease, 18 vascular dementia, 3 mixed-type, and 3 other) were diagnosed during the median 7.5-year follow-up. In multivariate analysis, the presence of overall CMBs was not associated with an increased risk of incident all-cause dementia (p = 0.15). However, multiple CMBs (≥2) or mixed (lobar and deep) CMBs were associated with the increased risk of all-cause dementia, whereas strictly lobar CMBs showed no association with any dementia. Conclusions: Multiple CMBs or mixed CMBs independently showed higher risk of all-cause dementia. Our results reinforce the hypothesis that CMBs exert deleterious effects on dementia incidence, suggesting that this association may be mediated by vascular burden.

Telomere-Nuclear Envelope Dissociation Promoted by Rap1 Phosphorylation Ensures Faithful Chromosome Segregation

Efficient chromosomal movements are important for the fidelity of chromosome segregation during mitosis; however, movements are constrained during interphase by tethering of multiple domains to the nuclear envelope (NE). Higher eukaryotes undergo open mitosis accompanied by NE breakdown, enabling chromosomes to be released from the NE, whereas lower eukaryotes undergo closed mitosis, in which NE breakdown does not occur. Although the chromosomal movements in closed mitosis are thought to be restricted compared to open mitosis, the cells overcome this problem by an unknown mechanism that enables accurate chromosome segregation. Here, we report the spatiotemporal regulation of telomeres in Schizosaccharomyces pombe closed mitosis. We found that the telomeres, tethered to the NE during interphase, are transiently dissociated from the NE during mitosis. This dissociation from the NE is essential for accurate chromosome segregation because forced telomere tethering to the NE causes frequent chromosome loss. The phosphorylation of the telomere protein Rap1 during mitosis, primarily by Cdc2, impedes the interaction between Rap1 and Bqt4, a nuclear membrane protein, thereby inducing telomere dissociation from the NE. We propose that the telomere dissociation from the NE promoted by Rap1 phosphorylation is critical for the fidelity of chromosome segregation in closed mitosis.

Chronic Middle Cerebral Artery Occlusion: A Hemodynamic and Metabolic Study with Positron-Emission Tomography

BACKGROUND AND PURPOSE: Chronic middle cerebral artery (MCA) occlusion is more common than generally thought. It is important to assess the cerebral hemodynamic status in patients with this chronic condition. We investigated the cerebral hemodynamic and metabolic disturbances in these patients in relation to the development of the collateral vasculature. MATERIALS AND METHODS: We studied 13 patients with chronic unilateral MCA occlusion who had a minor or no stroke by using positron-emission tomography (PET). PET was performed by the oxygen 15 (15O) gas steady-state inhalation method. The intracranial arteries were evaluated by digital subtraction angiography. We divided the patients into 2 subgroups according to whether they had a normal or increased oxygen extraction fraction (OEF) in the occluded MCA territory and compared the 2 groups. RESULTS: Of the 13 patients, 9 were classified into the normal OEF and 4 were classified into the increased OEF group. In the increased OEF group, the mean OEF values were also increased in the territories of the ipsilateral anterior cerebral artery, ipsilateral posterior cerebral artery, and contralateral MCA. The patients in the increased OEF group had more than 1 steno-occlusive lesion in the major intracranial arteries (P = .008). Three of the 4 patients in the increased OEF group also had vascular lesions in the collateral pathways to the MCA territory. CONCLUSION: Most patients with chronic MCA occlusion did not show severe hemodynamic impairment. Those with increased OEF tended to have other areas of severe hemodynamic impairment and other vascular lesions, especially in the collateral pathways.

Crossed cerebellar diaschisis: a positron emission tomography study withl-[methyl-11C]methionine and 2-deoxy-2-[18F]fluoro-d-glucose

Objective: Crossed cerebellar diaschisis (CCD) is defined as a depression of blood flow and oxidative metabolism of glucose in the cerebellum contralateral to a supratentorial brain lesion, as detected with positron emission tomography (PET) and single photon emission computed tomography. We examined whetherl-[methyl-11C]methionine (MET) uptake is affected in CCD.Methods: In 12 patients with a unilateral supratentorial brain tumor, we evaluated the uptake of 2-deoxy-2-[18F]fluoroe-d-glucose (FDG) and MET in the cerebellar hemispheres by means of PET. Asymmetry index (AI) was defined as a difference in the average count between the ipsilateral and contralateral cerebellar hemispheres divided by the average count in both cerebellar hemispheres. Patients with AI of FDG PET more than 0.1 and those with AI equal to 0.1 or less than 0.1 were classified as CCD-positive and CCD-negative, respectively.Results: Six patients were CCD-positive and others were CCD-negative in the FDG PET study. Between CCD-positive and CCD-negative patients, mean AI of MET was not significantly different (0.017±0.023 and 0.014±0.039, respectively).Conclusions: Different from glucose metabolism, cerebellar MET uptake was not affected in CCD. The present study may indicate that cerebellar MET uptake is independent of suppression of cerebellar neuronal activity.

Basilar Artery Diameter Is an Independent Predictor of Incident Cardiovascular Events

Objective—Basilar arterial (BA) dolichoectasia is associated with cerebral small-vessel disease and stroke. However, the association between moderate dilation of the BA and cerebral small-vessel disease or subsequent cardiovascular events remains unclear. This study aims to clarify the factors related to BA diameter and to clarify whether the BA diameter is an independent predictor of cardiovascular events. Approach and Results—The study subjects comprised 493 outpatients with atherosclerotic risk factors. BA diameter, lacunar infarct, severity of deep white matter hyperintensities, and intracranial steno-occlusive lesions were assessed with MRI and magnetic resonance angiography. Then, we prospectively evaluated the association between BA diameter and cardiovascular events. The BA diameter ranged from 1.1 to 5.2 mm, and only 0.8% of the patients had dolichoectasia. Male sex, the presence of lacunar infarcts, the severity of deep white matter hyperintensities, the fetal-type variation of the circle of Willis, and intracranial steno-occlusive lesions were independently associated with BA diameter. In the mean follow-up of 6.0 years, 91 patients developed cardiovascular events. BA diameter was independently associated with total cardiovascular events after adjusting for age, sex, and conventional risk factors (hazard ratio, 1.55 per 1 mm increase in BA diameter; P=0.009). Conclusions—Increased BA diameter within the normal range is related to both large-vessel disease and cerebral small-vessel disease, and it could be a new predictor of cardiovascular events.

Serum inflammatory proteins and frontal lobe dysfunction in patients with cardiovascular risk factors

Background:  Recent studies have shown that the levels of circulating inflammatory markers are associated with cognitive decline and cerebral small‐vessel disease. Frontal lobe dysfunction is believed to be a relatively characteristic neuropsychological symptom in vascular cognitive impairment caused by cerebral small‐vessel disease. The purpose of this study was to investigate whether the levels of serum inflammatory markers are associated with frontal lobe dysfunction, particularly executive dysfunction.

Moderate Atheroma of the Aortic Arch and the Risk of Stroke

Background and Purpose: Severe atheroma ≧4 or 5 mm of the aortic arch is a risk factor for stroke. We investigated the most predictive characteristics of arch atheroma, including maximal plaque thickness, for subsequent cardiovascular events, and also examined whether moderate atheroma <4 mm is a risk of cerebral emboli.Methods: The maximal plaque thickness (MPT) and plaque morphologies of the aortic arch were evaluated by transesophageal echocardiography in 236 patients with ischemic stroke. We assessed the relationship between the incidence of cardiovascular events, recurrent stroke or myocardial infarction, and the characteristics of the atheroma. We also investigated the thickness of atheroma in patients with known causes of stroke (n = 148) and in patients with undetermined causes (n = 19).Results: Cardiovascular events occurred in 47 patients in the follow-up period with a mean of 3.5 years. MPT was a significant risk factor of the cardiovascular events, although plaque morphologies were not. For the receiver operator characteristics curve analysis, the suitable cutoff point of MPT associated with the cardiovascular events was 3.5 mm. Patients with MPT ≧3.5 mm had a higher risk of cardiovascular events than did those with MPT <3.5 mm. In addition, aortic atheroma with MPT ≧3.5 mm was more frequently observed in patients with undetermined causes of stroke than those with known causes at 68 vs. 39% (p = 0.024).Conclusions:MPT ≧3.5 mm is the best predictor of subsequent cardiovascular events and a possible cause of embolic stroke.