ABSTRACT
BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)
Subject(s)
Embolic Stroke , Pyrazoles , Pyridones , Stroke , Humans , Aspirin , Double-Blind Method , Stroke/prevention & controlABSTRACT
BACKGROUND: Subcortical T2-weighted (T2w) lesions are very common in older adults and have been associated with dementia. However, little is known about the strategic lesion distribution and how lesion patterns relate to vascular risk factors and cognitive impairment. AIM: The aim of this study was to analyze the association between T2w lesion load and location, vascular risk factors, and cognitive impairment in a large cohort of older adults. METHODS: 1017 patients participating in a large prospective cohort study (INtervention project on cerebroVAscular disease and Dementia in the district of Ebersberg, INVADE II) were analyzed. Cerebral T2w white matter and deep grey matter lesions, the so-called white matter hyperintensities (WMHs), were outlined semi-automatically on fluid attenuated inversion recovery images and normalized to standard stereotaxic space (MNI152) by non-linear registration. Patients were assigned to either a low-risk or a high-risk group. The risk assessment considered ankle brachial index, intima media thickness, carotid artery stenosis, atrial fibrillation, previous cerebro-/cardiovascular events and peripheral artery disease as well as a score based on cholesterol levels, blood pressure and smoking. Separate lesion distributions were obtained for the two risk groups and compared using voxel-based lesion-symptom mapping. Moreover, we assessed the relation between lesion location and cognitive impairment (demographically adjusted z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery Plus, CERAD-NAB Plus) using voxel-based statistics (αâ¯=â¯0.05). RESULTS: A total of 878 out of 1017 subjects (86%) had evaluable MRI data and were included in the analyses (mean age: 68.2⯱â¯7.6 years, female: 515). Patients in the high-risk group were characterized by a significantly higher age, a higher proportion of men, a higher lesion load (pâ¯<â¯0.001), and a worse performance in some of the cognitive subdomain scores (pâ¯<â¯0.05). Voxels with significant associations to the subjects' cerebrovascular risk profiles were mainly found at locations of the corpus callosum, superior corona radiata, superior longitudinal fasciculus, internal and external capsule, and putamen. While several cognitive domains have shown significant associations with the participants' total lesion burden (pâ¯<â¯0.05), no focal WMH locations were found to be associated with cognitive impairment. CONCLUSION: Age, gender, several cognitive scores, and WMH lesion load were shown to be significantly associated with vascular risk factors in a population of older, but cognitively preserved adults. Vascular risk factors seem to promote lesion formation most severely at well-defined locations. While lesion load showed weak associations to some cognitive scores, no focal locations causing specific cognitive disturbances were identified in this large cohort of older adults.
Subject(s)
Cerebral Small Vessel Diseases/complications , Cerebral Small Vessel Diseases/pathology , Cognitive Dysfunction/etiology , Magnetic Resonance Imaging/methods , Neuroimaging/methods , White Matter/pathology , Aged , Cerebral Small Vessel Diseases/diagnostic imaging , Cerebral Small Vessel Diseases/physiopathology , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/physiopathology , Female , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , White Matter/diagnostic imagingABSTRACT
Background We have recently shown that the presence of headache in ischemic stroke is associated with lesions of the insular cortex. The aim of this post-hoc subgroup analysis was to investigate the association of specific headache features with stroke location in patients with acute ischemic stroke. Methods In this observational study, patients (mean age: 61.5, 58% males) with ischemic stroke and acute headache (n = 49) were investigated. Infarcts were manually outlined on 3D diffusion weighted magnetic resonance imaging (MRI) scans and transformed into standard stereotaxic space; lesions of the left hemisphere were mirrored in the x-axis to allow a voxel-wise group analysis of all patients. We analyzed the association of lesion location and the following phenotypical characteristics by voxel-based symptom lesion mapping: Headache intensity, different qualities of headache (pulsating, tension-type like and stabbing), and the presence of nausea, of cranial autonomic symptoms and of light or noise sensitivity. Results Headache intensity was associated with lesions of the posterior insula, the operculum and the cerebellum. "Pulsating" headache occurred with widespread cortical and subcortical strokes. The presence of "tension-like" and "stabbing" headache was not related to specific lesion patterns. Nausea was associated with lesions in the posterior circulation territory. Cranial-autonomic symptoms were related to lesions of the parietal lobe, the somatosensory cortex (SI) and the middle temporal cortex. The presence of noise sensitivity was associated with cerebellar lesions, whereas light sensitivity was not related to specific lesions in our sample. Conclusion Headache phenotype in ischemic stroke appears to be related to specific ischemic lesion patterns.
Subject(s)
Brain/pathology , Headache/etiology , Stroke/pathology , Adult , Aged , Brain/diagnostic imaging , Diffusion Magnetic Resonance Imaging , Female , Humans , Male , Middle Aged , Phenotype , Stroke/complications , Stroke/diagnostic imagingABSTRACT
BACKGROUND: Activated protein C (APC) resistance is the most common inherited prothrombotic disorder. The role of APC resistance in ischemic stroke is controversially discussed. OBJECTIVES: The aim of this single center follow up study was to investigate the effect of APC resistance on stroke recurrence and survival in stroke patients. PATIENTS/METHODS: We retrospectively identified 966 patients who had had an ischemic stroke or transitory ischemic attack (TIA) and in whom laboratory tests for APC resistance had been conducted. These patients were contacted to determine the primary outcomes of recurrent ischemic stroke or death. RESULTS: A total of 858 patients with an average follow up time of 8.48 years were included. APC resistance did not influence cumulative incidence functions for stroke free and total survival. In multivariate analyses, crude and adjusted hazard ratios for recurrent stroke as well as for death where not significantly increased in patients with APC resistance. This also applies to the subgroups of young patients, patients with cryptogenic stroke and patients with atrial fibrillation. CONCLUSION: APC-resistance is not a risk factor for subsequent stroke or death in patients with a first ischemic stroke or TIA. Testing for APC-resistance in stroke patients therefore cannot be routinely recommended.
Subject(s)
Activated Protein C Resistance/pathology , Protein C/metabolism , Stroke/mortality , Stroke/pathology , Activated Protein C Resistance/complications , Adolescent , Adult , Aged , Aged, 80 and over , Atrial Fibrillation/complications , Female , Follow-Up Studies , Humans , Incidence , Ischemic Attack, Transient/complications , Male , Middle Aged , Multivariate Analysis , Proportional Hazards Models , Protein C/chemistry , Protein C/genetics , Recurrence , Retrospective Studies , Risk Factors , Stroke/etiology , Young AdultABSTRACT
Progenitor cells (PCs) contribute to the endogenous repair mechanism after ischemic events. Interleukin-8 (IL-8) as part of the acute inflammatory reaction may enhance PC mobilization. Also, statins are supposed to alter number and function of circulating PCs. We aimed to investigate PC mobilization after acute ischemic stroke as well as its association with inflammatory markers and statin therapy. Sixty-five patients with ischemic stroke were enrolled in the study. The number of CD133+ PCs was analyzed by flow cytometry. Blood samples were drawn within 24 hours after symptom onset and after 5 days. The number of CD133+ PCs increased significantly within 5 days (p<0.001). We found no correlation between CD133+ PCs and the serum levels of IL-8, IL-6, or C-reactive protein (CRP). Multivariate analysis revealed that preexisting statin therapy correlated independently with the increase of CD133+ PCs (p=0.001). This study showed a mobilization of CD133+ PCs in patients with acute cerebral infarction within 5 days after symptom onset. The early systemic inflammatory response did not seem to be a decisive factor in the mobilization of PCs. Preexisting statin therapy was associated with the increase in CD133+ PCs, suggesting a potentially beneficial effect of statin therapy in patients with stroke.
Subject(s)
Adult Stem Cells/physiology , Antigens, CD/metabolism , Cerebral Infarction/pathology , Glycoproteins/metabolism , Peptides/metabolism , AC133 Antigen , Acute Disease , Adult , Aged , Aged, 80 and over , Cerebral Infarction/blood , Cerebral Infarction/immunology , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Inflammation Mediators/blood , Interleukin-6/blood , Interleukin-8/blood , Male , Middle Aged , Multivariate Analysis , Phosphopyruvate Hydratase/blood , Risk Factors , Young AdultABSTRACT
PURPOSE: The aim of this study was to investigate prospectively whether MRI plaque imaging can identify patients with asymptomatic carotid artery stenosis who have an increased risk for future cerebral events. MRI plaque imaging allows categorization of carotid stenosis into different lesion types (I-VIII). Within these lesion types, lesion types IV-V and VI are regarded as rupture-prone plaques, whereas the other lesion types represent stable ones. METHODS: Eighty-three consecutive patients (45 male (54.2%); age 54-88 years (mean 73.2 years)) presenting with an asymptomatic carotid stenosis of 50-99% according to ECST-criteria were recruited. Patients were imaged with a 1.5-T scanner. T1-, T2-, time-of-flight-, and proton-density weighted studies were performed. The carotid plaques were classified as lesion type I-VIII. Clinical endpoints were ischemic stroke, TIA or amaurosis fugax. Survival analysis and log rank test were used to ascertain statistical significance. RESULTS: Six out of 83 patients (7.2%) were excluded: 4 patients had insufficient MR image quality; 1 patient was lost-to-follow-up; 1 patient died shortly after the baseline MRI plaque imaging. The following results were obtained by analyzing the remaining 77 patients. The mean time of follow-up was 41.1 months. During follow-up, nâ=â9 (11.7%) ipsilateral ischemic cerebrovascular events occurred. Only patients presenting with the high-risk lesion types IV-V and VI developed an ipsilateral cerebrovascular event versus none of the patients presenting with the stable lesion types III, VII, and VIII (nâ=â9 (11.7%) vs. nâ=â0 (0%) during follow-up). Event-free survival was higher among patients with the MRI-defined stable lesion types (III, VII, and VIII) than in patients with the high-risk lesion types (IV-V and VI) (log rank test P<0.0001). CONCLUSIONS: MRI plaque imaging has the potential to identify patients with asymptomatic carotid stenosis who are particularly at risk of developing future cerebral ischemia. MRI could improve selection criteria for invasive therapy in the future.
Subject(s)
Carotid Stenosis/diagnosis , Magnetic Resonance Imaging/methods , Plaque, Atherosclerotic/diagnosis , Aged , Aged, 80 and over , Female , Humans , Male , Middle AgedABSTRACT
Although a relationship between depression and cardiovascular events has been suggested, past study results regarding the risk of stroke in relation to depression by subgroups are ambiguous. The aim of this study was to investigate the influence of depressive symptoms on risk of incident ischemic stroke in elderly according to age and sex. This prospective cohort study followed up 3852 subjects older than 55 years. Baseline depressive symptoms were defined by a score ≥ 5 on the Geriatric Depression Scale or antidepressant intake. The outcome measure was incident ischemic stroke within 6 years of follow-up. Multivariate Cox-proportional hazard models as well as cumulative survival analyses were computed. A total of 156 ischemic strokes occurred during the study period (24 strokes in the age-group<65 years and 132 strokes in the age-group ≥ 65 years). The distribution of strokes in sex-subgroups was 4.5% in men and 3.7% in women. The multivariate analysis showed an elevated stroke risk (Hazard Ratio (HR): 2.84, 95% CI 1.11-7.29, pâ=â0.030) in subjects from 55 to 64 years with depressive symptoms at baseline but not in subjects older than 65 years. In the multivariate analysis according to sex the risk was increased in women (HR: 1.62, 95% CI 1.02-2.57, Pâ=â0.043) but not in men. The Cox-regression model for interaction showed a significant interaction between age and sex (HR: 3.24, 95% CI 1.21-8.69, Pâ=â0.020). This study corroborates that depressive symptoms pose an important risk for ischemic stroke, which is particularly remarkable in women and patients younger than 65 years.
Subject(s)
Brain Ischemia/complications , Depression/complications , Sex Characteristics , Stroke/complications , Stroke/epidemiology , Age Distribution , Age Factors , Aged , Female , Humans , Male , Middle Aged , Multivariate Analysis , Risk Factors , Sex Distribution , Survival AnalysisABSTRACT
BACKGROUND: Transient ischemic attack (TIA) patients are at a high vascular risk. Recently the ABCD2 score was validated for evaluating short-term stroke risk after TIA. We assessed the value of this score to predict the vascular outcome after TIA during medium- to long-term follow-up. METHODS: The ABCD2 score of 176 TIA patients consecutively admitted to the Stroke Unit was retrospectively calculated and stratified into three categories. TIA was defined as an acute transient focal neurological deficit caused by vascular disease and being completely reversible within 24 hours. All patients had to undergo cerebral MRI within 5 days after onset of symptoms as well as extracranial and transcranial Doppler and duplex ultrasonography. At a median follow-up of 27 months, new vascular events were recorded. Multivariate Cox regression adjusted for EDC findings and heart failure was performed for the combined endpoint of cerebral ischemic events, cardiac ischemic events and death of vascular or unknown cause. RESULTS: Fifty-five patients (32.0%) had an ABCD2 score < or = 3, 80 patients (46.5%) had an ABCD2 score of 4-5 points and 37 patients (21.5%) had an ABCD2 score of 6-7 points. Follow-up data were available in 173 (98.3%) patients. Twenty-two patients (13.8%) experienced an ischemic stroke or TIA; 5 (3.0%) a myocardial infarction or acute coronary syndrome; 10 (5.7%) died of vascular or unknown cause; and 5 (3.0%) patients underwent arterial revascularization. An ABCD2 score > 3 was significantly associated with the combined endpoint of cerebral or cardiovascular ischemic events, and death of vascular or unknown cause (hazard ratio (HR) 4.01, 95% confidence interval (CI) 1.21 to 13.27). After adjustment for extracranial ultrasonographic findings and heart failure, there was still a strong trend (HR 3.13, 95% CI 0.94 to 10.49). Whereas new cardiovascular ischemic events occurred in 9 (8.3%) patients with an ABCD2 score > 3, this happened in none of the 53 patients with a score < or = 3. CONCLUSIONS: An ABCD2 score > 3 is associated with an increased general risk for vascular events in the medium- to long-term follow-up after TIA.
Subject(s)
Ischemic Attack, Transient/diagnosis , Brain/pathology , Cerebrovascular Disorders/complications , Cohort Studies , Female , Follow-Up Studies , Humans , Ischemic Attack, Transient/mortality , Ischemic Attack, Transient/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Prognosis , Retrospective Studies , Risk , Time Factors , Ultrasonography, Doppler, TranscranialABSTRACT
The clock drawing test (CDT) is a widely used dementia screening instrument that assesses executive and visuospatial abilities; studies in patients with Alzheimer's disease (AD) suggest frontoposterior networks to be involved in clock drawing. Clock drawing errors are also often observed in dementia with Lewy bodies (DLB), but the functional neuroanatomical substrate of impaired clock drawing has not been firmly established in this disorder. The present study was designed to provide initial evidence for brain metabolic alterations associated with CDT performance in DLB. Twenty-one patients with DLB were enrolled. CDT ratings were correlated with the regional cerebral metabolic rate of glucose (rCMRglc) measured by (18)F-fluoro-2-deoxy-glucose positron emission tomography ((18)F-FDG PET) in the statistical parametric mapping software package SPM5, controlling for overall cognitive impairment as measured by the Mini-Mental-State Examination (MMSE) score. There was a significant negative association between test scores and rCMRglc in a left-hemispheric posterofrontal network including the temporoparietal and dorsal pre-motor cortices and the precuneus. The present study provides evidence for a direct association between frontoparietal dysfunction and impaired CDT performance in DLB. These findings also suggest that the CDT is an appropriate screening instrument for this disorder and that metabolic dysfunction, and therefore disease severity, is mirrored by performance on the test.
Subject(s)
Brain/diagnostic imaging , Cognition Disorders/etiology , Executive Function/physiology , Lewy Body Disease , Space Perception/physiology , Aged , Analysis of Variance , Brain Mapping , Cognition Disorders/diagnostic imaging , Female , Fluorodeoxyglucose F18 , Functional Laterality , Humans , Lewy Body Disease/complications , Lewy Body Disease/diagnostic imaging , Lewy Body Disease/pathology , Male , Mental Status Schedule , Middle Aged , Neuropsychological Tests , Photic Stimulation/methods , Positron-Emission Tomography/methodsABSTRACT
OBJECTIVES: 1) To investigate the neural substrate of impaired activities of daily living (ADL) in dementia with Lewy bodies (DLB) and 2) to explore, in the context of cognitive reserve, if hypometabolism was more pronounced in well-educated patients at the same level of everyday impairment. METHODS: Twenty-one patients with DLB underwent an extensive clinical evaluation including cerebral positron emission tomography with F-fluoro-2-deoxy-glucose scanning. First, brain areas were identified, where ADL performance and glucose metabolism were significantly correlated, controlling for individual differences in cognitive and motor dysfunction. Second, it was tested if there was a significant negative association between metabolism and years of education in brain regions associated with ADL performance. Again, a correction for cognitive and motor impairment was deployed. RESULTS: There was a significant association between glucose hypometabolism and impaired ADL performance in an extensive brain cluster located in the right temporoparietal cortex. Furthermore, schooling and metabolic rate were inversely associated in the right Brodmann area 19, controlling for ADL performance. CONCLUSIONS: The study suggests that 1) certain brain metabolic alterations are specifically associated with the loss of everyday competence, even if differences in cognition and motor function are taken into consideration and 2) well-educated patients can offset more brain damage until reaching the same degree of ADL impairment as their less educated counterparts. These results extend the literature on cognitive reserve to a region-specific effect on ADL performance.
Subject(s)
Activities of Daily Living/psychology , Brain/diagnostic imaging , Cognition/physiology , Dementia/diagnostic imaging , Dementia/physiopathology , Lewy Body Disease/diagnostic imaging , Lewy Body Disease/physiopathology , Aged , Aged, 80 and over , Blood Glucose/metabolism , Brain/metabolism , Dementia/metabolism , Educational Status , Female , Fluorodeoxyglucose F18 , Humans , Image Processing, Computer-Assisted , Lewy Body Disease/metabolism , Male , Middle Aged , Neuropsychological Tests , Positron-Emission Tomography/methods , Radiopharmaceuticals , Regression AnalysisABSTRACT
BACKGROUND: Circulating progenitor cells (PCs) are considered to contribute to the remodeling of atherosclerotic plaques. Their surface receptor CXCR4 plays an important role in the recruitment of PCs to their target. This study compares the mobilization of PCs and their functional characteristics in asymptomatic subjects with stable and with unstable carotid plaques. This could provide insight into plaque remodeling and help to develop biomarkers for plaque stability. METHODS: In 31 subjects with asymptomatic carotid artery stenosis we analyzed the number of CD133+ PCs, VEGFR2+CD34+ PCs and the surface expression of CXCR4 on CD133+ PCs by flow cytometry. Subjects underwent bilateral carotid MRI in a 1.5-T scanner in order to allow the categorization of plaques, following the modified criteria of the American Heart Association. RESULTS: The number of CD133+ PCs and VEGFR2+CD34+ PCs showed no significant difference between subjects with stable and unstable carotid plaques. The expression of CXCR4 on CD133+ PCs was higher in subjects with unstable plaques than in subjects with stable plaques (p = 0.009). CONCLUSIONS: This study demonstrates an association between functional characteristics of circulating CD133+ PCs and plaque stability in subjects with asymptomatic carotid artery stenosis. The higher expression of CXCR4 on CD133+ PCs suggests a difference in the recruitment of PCs to the injured tissue in subjects with unstable plaques and subjects with stable plaques. As surface expression of CXCR4 on CD133+ PCs differs in subjects with unstable and with stable plaques, CXCR4 is a promising candidate for a serological biomarker for plaque stability.
ABSTRACT
INTRODUCTION: A number of studies has addressed the possible association between patent foramen ovale (PFO) and stroke. However, the role of PFO in the pathogenesis of cerebral ischemia has remained controversial and most studies did not analyze patient subgroups stratified for gender, age and origin of stroke. METHODS: To address the role of PFO for the occurrence of cerebral ischemia, we investigated the prevalence of right-to-left shunt in a large group of patients with acute stroke or TIA. 763 consecutive patients admitted to our hospital with cerebral ischemia were analyzed. All patients were screened for the presence of PFO by contrast-enhanced transcranial Doppler sonography at rest and during Valsalva maneuver. Subgroup analyses were performed in patients stratified for gender, age and origin of stroke. RESULTS: A right-to-left shunt was detected in 140 (28%) male and in 114 (42%) female patients during Valsalva maneuver, and in 66 (13%) and 44 (16%) at rest respectively. Patients with right-to-left shunt were younger than those without (P < 0.001). PFO was associated with stroke of unknown origin in male (P = 0.001) but not female patients (P > 0.05). After adjusting for age no significant association between PFO and stroke of unknown origin was found in either group. CONCLUSION: Our findings argue against paradoxical embolization as a major cause of cerebral ischemia in patients with right-to-left shunt. Our data demonstrate substantial gender-and age-related differences that should be taken into account in future studies.