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Hugh S. Markus - One of the best experts on this subject based on the ideXlab platform.
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risk factor profile of cerebral small vessel disease and its subtypes
Journal of Neurology Neurosurgery and Psychiatry, 2006Co-Authors: Usman Khan, Ahamad Hassan, Linda Porteous, Hugh S. MarkusAbstract:Background: The mechanisms of cerebral small vessel disease (SVD) are unclear. Both atherosclerosis and a non-atherosclerotic diffuse arteriopathy have been reported pathologically. Two pathological and radiological subtypes have been suggested: localised atherosclerotic disease in larger perforating arteries causing larger lacunar infarcts without Leukoaraiosis, and diffuse disease in smaller arterioles causing multiple smaller lacunar infarcts with Leukoaraiosis. If atherosclerosis were important in SVD as a whole or in one particular subtype, one would expect the risk factor profile to be similar to that of cerebral large vessel disease (LVD). Methods: Risk factor profiles were compared in Caucasian stroke patients with SVD (n = 414), LVD (n = 471) and 734 stroke-free Caucasian population controls. Patients with SVD were subdivided according to the presence or absence of confluent Leukoaraiosis, into isolated lacunar infarction (ILI) and ischaemic Leukoaraiosis (ILA). Results: Hypertension was commoner in SVD than LVD (odds ratio (OR) 3.43 (2.32 to 5.07); p<0.001) whereas hypercholesterolaemia (OR 0.34 (0.24 to 0.48); p<0.001), smoking (OR 0.63 (0.44 to 0.91); p = 0.012), myocardial infarction (OR 0.35 (0.20 to 0.59); p<0.001) and peripheral vascular disease (OR 0.32 (0.20 to 0.50); p<0.001) were commoner in LVD. Among SVD patients, age (OR 1.11 (1.09 to 1.14); p<0.001) and hypertension (OR 3.32 (1.56 to 7.07); p = 0.002) were associated with ILA and hypercholesterolaemia (OR 0.45 (0.28 to 0.74); p = 0.002), diabetes (OR 0.42 (0.21 to 0.84); p = 0.014) and myocardial infarction (OR 0.18 (0.06 to 0.52); p = 0.001) with ILI. Conclusion: SVD has a different risk factor profile from the typical atherosclerotic profile found in LVD, with hypertension being important. There are differences in the risk factor profile between the SVD subtypes; the association of ILI with hypercholesterolaemia, diabetes and myocardial infarction may be consistent with a more atherosclerotic aetiology.
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brief cognitive assessment for patients with cerebral small vessel disease
Journal of Neurology Neurosurgery and Psychiatry, 2005Co-Authors: Michael Osullivan, R G Morris, Hugh S. MarkusAbstract:Background: Cerebral small vessel disease is a common cause of cognitive impairment and vascular dementia. The cognitive deficit differs from that in Alzheimer’s disease, with greater executive/attentional dysfunction and relatively intact episodic memory. Objective: To develop brief assessment tools that are better adapted to the neuropsychological profile of cerebral small vessel disease. Methods: 32 subjects with ischaemic Leukoaraiosis (history of lacunar stroke and Leukoaraiosis on MRI), aged 50 to 84 years, and 17 age and education matched controls had a brief executive assessment, which took 20 minutes to administer, and a wide range of additional tests. The ability of the brief executive assessment to discriminate between groups—both individually and in combination—was evaluated and compared with that of the whole battery. Results: The brief executive assessment provided good sensitivity and specificity for identifying subjects with ischaemic Leukoaraiosis (sensitivity 88%, specificity 88%, using the optimal combination of scores). The best individual tests were trail making and digit symbol, which were both far more sensitive than the mini-mental state examination (MMSE). The ability to discriminate between groups was maintained in subjects with MMSE >27 and across the whole age range. The brief executive assessment performed well compared with the whole battery, with additional tests accounting for only a further 12% of between-group variance. Conclusions: The brief executive assessment was sensitive to deficits found in ischaemic Leukoaraiosis and discriminated them from the cognitive effects of healthy aging. The assessment has potential for bedside use and as a cognitive end point for clinical trials.
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diffusion tensor mri correlates with executive dysfunction in patients with ischaemic Leukoaraiosis
Journal of Neurology Neurosurgery and Psychiatry, 2004Co-Authors: Michael Osullivan, Derek K Jones, Steven Williams, R G Morris, B Huckstep, Hugh S. MarkusAbstract:Background: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (Leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage. Objectives: To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters. Methods: 36 patients with ischaemic Leukoaraiosis (Leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. Results: On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ ( r = −0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function. Conclusions: Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.
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homocysteine is a risk factor for cerebral small vessel disease acting via endothelial dysfunction
Brain, 2004Co-Authors: Ahamad Hassan, Michael Osullivan, J Bamford, Beverley J Hunt, Rachel Bell, Reuben Dsouza, Steve Jeffery, Hugh S. MarkusAbstract:Cerebral small vessel disease (SVD) causes focal lacunar infarction and more diffuse ischaemia, referred to as Leukoaraiosis. Endothelial dysfunction has been proposed as a causal mechanism in the disease. Homocysteine is toxic to endothelium. We determined whether elevated homocysteine levels and the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for SVD as a whole, and for two different SVD subtypes: isolated lacunar infarction and ischaemic Leukoaraiosis. We also determined whether any association was mediated by endothelial dysfunction, as assessed by circulating endothelial markers. One hundred and seventy‐two Caucasian patients with SVD and 172 community controls of similar age and sex were studied. Serum homocysteine measurement and MTHFR genotyping was performed. Levels of intercellular adhesion molecule 1 (ICAM1) and thrombomodulin were measured in a subgroup. Mean homocysteine levels were higher in SVD than controls [14.55 µmol/l [95% confidence interval (CI) 13.78–15.35] versus 12.01 µmol/l (95% CI 11.42–12.64), P < 0.0005]. Homocysteine was a stronger risk factor in those with ischaemic Leukoaraiosis [12.92 (95% CI 4.40–37.98), P < 0.0005) per µmol increase in log homocysteine concentration ( P < 0.0005)] in comparison with isolated lacunar infarction [4.22 (95% CI 1.29–13.73), P = 0.02] after controlling for both conventional risk factors and age. The MTHFR 677T allele was a risk factor only in the ischaemic Leukoaraiosis group [odds ratio (OR) 2.02 (95% CI 1.31–3.1), P = 0.001]. Inclusion of the endothelial markers ICAM1 and thrombomodulin in a logistic regression model resulted in the association between homocysteine and SVD no longer being significant. In conclusion, hyperhomocysteinaemia is an independent risk factor for SVD, particularly ischaemic Leukoaraiosis, and this effect may be mediated via endothelial dysfunction. Homocysteine‐lowering therapy may be particularly effective in this subgroup.
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markers of endothelial dysfunction in lacunar infarction and ischaemic Leukoaraiosis
Brain, 2003Co-Authors: Ahamad Hassan, Dennis Briley, Michael Osullivan, Beverley J Hunt, Kiran Parmar, John Bamford, Martin M Brown, Dafydd J Thomas, Hugh S. MarkusAbstract:Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of Leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood samples. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic Leukoaraiosis, defined as a clinical lacunar stroke and Leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of Leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P ≤ 0.006). The ischaemic Leukoaraiosis group had a different endothelial marker profile, with lower levels of TFPI (P = 0.01) and a higher TF/TFPI ratio (P = 0.01) compared with the isolated lacunar infarction group. TM levels were associated with the number of lacunes (P = 0.008) and the Leukoaraiosis score (P = 0.03), but TF levels and the TF/TFPI ratio were associated only with the extent of Leukoaraiosis (P ≤ 0.02). These results suggest that there is evidence of chronic endothelial dysfunction in cerebral SVD, and endothelial prothrombotic changes may be important in mediating the ischaemic Leukoaraiosis phenotype. Therapies which help to stabilize the endothelium may have a role in this group of patients.
Jonathan Rosand - One of the best experts on this subject based on the ideXlab platform.
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associations of radiographic cerebral small vessel disease with acute intracerebral hemorrhage volume hematoma expansion and intraventricular hemorrhage
Neurocritical Care, 2020Co-Authors: Simone Uniken M Venema, Sandro Marini, Bart H Brouwers, Andrea Morotti, Daniel Woo, Christopher D Anderson, Jonathan RosandAbstract:The aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH). CSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of Leukoaraiosis and cerebral atrophy using visual rating scales. The associations of Leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing. A total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0–25.3) mL. IVH was detected in 971 patients (38%). Neither Leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of Leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend < 0.001). Increasing grades of global atrophy were dose-dependently associated with lower ICH volumes (s (95% Confidence Interval [CI]) − 0.30[− 0.46, − 0.14], − 0.33[− 0.49, − 0.17], − 0.40[− 0.60, − 0.20], and − 0.54[− 0.76, − 0.32], for grades 1, 2, 3 and 4 compared to 0; all P < 0.001). The associations of Leukoaraiosis with ICH volume were consistent with those of atrophy, albeit not meeting statistical significance. Leukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while Leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.
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associations of radiographic cerebral small vessel disease with acute intracerebral hemorrhage volume hematoma expansion and intraventricular hemorrhage
Neurocritical Care, 2020Co-Authors: Simone Uniken M Venema, Sandro Marini, Bart H Brouwers, Andrea Morotti, Christopher D Anderson, Jonathan RosandAbstract:BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH). METHODS: CSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of Leukoaraiosis and cerebral atrophy using visual rating scales. The associations of Leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing. RESULTS: A total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0-25.3) mL. IVH was detected in 971 patients (38%). Neither Leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of Leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend < 0.001). Increasing grades of global atrophy were dose-dependently associated with lower ICH volumes (s (95% Confidence Interval [CI]) - 0.30[- 0.46, - 0.14], - 0.33[- 0.49, - 0.17], - 0.40[- 0.60, - 0.20], and - 0.54[- 0.76, - 0.32], for grades 1, 2, 3 and 4 compared to 0; all P < 0.001). The associations of Leukoaraiosis with ICH volume were consistent with those of atrophy, albeit not meeting statistical significance. CONCLUSIONS: Leukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while Leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.
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extensive Leukoaraiosis is associated with high early risk of recurrence after ischemic stroke
Stroke, 2014Co-Authors: Gyeongmoon Kim, Johanna Helenius, Natalia S Rost, Kwangyeol Park, Ross Avery, Jonathan Rosand, Bruce R RosenAbstract:Background and Purpose—The integrity of white matter tracts connecting different parts of the brain is important for rapid compensation for the lost function from ischemic stroke. Impaired white matter reserve capacity secondary to Leukoaraiosis may facilitate detection of new symptomatic ischemic events that would otherwise remain inconspicuous after an initial ischemic stroke. We sought to identify whether the extent of Leukoaraiosis was a predictor of risk of early stroke recurrence. Methods—We used Cox regression analysis in consecutive patients with ischemic stroke to determine the relationship between Leukoaraiosis burden and symptomatic stroke recurrence within 90 days. We graded total Leukoaraiosis, periventricular Leukoaraiosis, and subcortical Leukoaraiosis using the Fazekas scale as mild (<2) and extensive (≥2) on fluid-attenuated inversion recovery images obtained within 72 hours of stroke onset in the hemisphere contralateral to acute stroke. Results—There were 106 recurrent events in 2378 pa...
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severity of Leukoaraiosis determines clinical phenotype after brain infarction
Neurology, 2011Co-Authors: Ethem Murat Arsava, Natalia S Rost, Jonathan Rosand, A Bayrlee, Mark Vangel, Karen L Furie, A G SorensenAbstract:Objective: To determine whether the extent of Leukoaraiosis, a composite marker of baseline brain integrity, differed between patients with TIA with diffusion-weighted imaging (DWI) evidence of infarction (transient symptoms with infarction [TSI]) and patients with ischemic stroke. Methods: Leukoaraiosis volume on MRI was quantified in a consecutive series of 153 TSI and 354 ischemic stroke patients with comparable infarct volumes on DWI. We explored the relationship between Leukoaraiosis volume and clinical phenotype (TIA or ischemic stroke) using a logistic regression model. Results: Patients with TSI tended to be younger (median age 66 vs 69 years, p = 0.062) and had smaller median normalized Leukoaraiosis volume (1.2 mL, interquartile range [IQR] 0.2–4.7 mL vs 3.5 mL, IQR 1.2–8.6 mL, p p = 0.004), along with infarct volume and infarct location. Conclusion: The probability of ischemic stroke rather than TSI increases with increasing Leukoaraiosis volume, independent of infarct size and location. Our findings support the concept that the integrity of white matter tracts connecting different parts of the brain could contribute to whether or not patients develop TSI or ischemic stroke in an event of brain infarction.
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silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy
Neurology, 2010Co-Authors: W T Kimberly, Natalia S Rost, Jonathan Rosand, Eric E Smith, Aaron J Gilson, Anand Viswanathan, Steven M GreenbergAbstract:We read the article by Kimberly et al.,1 who showed that small subacute infarcts were detected on MRI in patients with advanced cerebral amyloid angiopathy (CAA). The authors retrospectively detected 17 DWI-hyperintense lesions in 78 subjects with probable CAA, but found no lesions in 55 subjects with Alzheimer disease (AD) or mild cognitive impairment. An association was not found between Leukoaraiosis and the 17 ischemic lesions including 4 lesions found in the cortical gray matter. The distribution of microvascular lesions and the absence of their relation to Leukoaraiosis is notable since CAA is usually observed in the subarachnoid and intracortical vessels, frequently accompanied by Leukoaraiosis. In AD brains, cerebral microbleeds have shown occipital predominance and correspondence to parieto-occipital Leukoaraiosis.2 In addition, microinfarcts are typically found in the cortical borderzone with occipital predominance in …
Michael Osullivan - One of the best experts on this subject based on the ideXlab platform.
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brief cognitive assessment for patients with cerebral small vessel disease
Journal of Neurology Neurosurgery and Psychiatry, 2005Co-Authors: Michael Osullivan, R G Morris, Hugh S. MarkusAbstract:Background: Cerebral small vessel disease is a common cause of cognitive impairment and vascular dementia. The cognitive deficit differs from that in Alzheimer’s disease, with greater executive/attentional dysfunction and relatively intact episodic memory. Objective: To develop brief assessment tools that are better adapted to the neuropsychological profile of cerebral small vessel disease. Methods: 32 subjects with ischaemic Leukoaraiosis (history of lacunar stroke and Leukoaraiosis on MRI), aged 50 to 84 years, and 17 age and education matched controls had a brief executive assessment, which took 20 minutes to administer, and a wide range of additional tests. The ability of the brief executive assessment to discriminate between groups—both individually and in combination—was evaluated and compared with that of the whole battery. Results: The brief executive assessment provided good sensitivity and specificity for identifying subjects with ischaemic Leukoaraiosis (sensitivity 88%, specificity 88%, using the optimal combination of scores). The best individual tests were trail making and digit symbol, which were both far more sensitive than the mini-mental state examination (MMSE). The ability to discriminate between groups was maintained in subjects with MMSE >27 and across the whole age range. The brief executive assessment performed well compared with the whole battery, with additional tests accounting for only a further 12% of between-group variance. Conclusions: The brief executive assessment was sensitive to deficits found in ischaemic Leukoaraiosis and discriminated them from the cognitive effects of healthy aging. The assessment has potential for bedside use and as a cognitive end point for clinical trials.
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diffusion tensor mri correlates with executive dysfunction in patients with ischaemic Leukoaraiosis
Journal of Neurology Neurosurgery and Psychiatry, 2004Co-Authors: Michael Osullivan, Derek K Jones, Steven Williams, R G Morris, B Huckstep, Hugh S. MarkusAbstract:Background: Cerebral small vessel disease is a common cause of vascular dementia. Both discrete lacunar infarcts and more diffuse ischaemic changes, seen as confluent high signal (Leukoaraiosis) on T2 weighted magnetic resonance imaging (MRI), occur. However, there is a weak correlation between T2 lesion load and cognitive impairment. Diffusion tensor MRI (DTI) is a new technique that may provide a better index of white matter damage. Objectives: To determine whether DTI measures are correlated more strongly with cognitive performance than lesion load on T2 weighted images, and whether these correlations are independent of conventional MRI parameters. Methods: 36 patients with ischaemic Leukoaraiosis (Leukoaraiosis plus a previous lacunar stroke) and 19 healthy volunteers underwent DTI, conventional MRI, and neuropsychological assessment. Results: On DTI, diffusivity was increased both within lesions and in normal appearing white matter. Mean diffusivity of normal appearing white matter correlated with full scale IQ ( r = −0.46, p = 0.009) and tests of executive function. These correlations remained significant after controlling for age, sex, brain volume, and T1/T2 lesion volumes. No significant correlation was identified between T2 lesion load and IQ or neuropsychological scores. Of conventional measures, brain volume correlated best with cognitive function. Conclusions: Diffusion tensor measurements correlate better with cognition than conventional MRI measures. They may be useful in monitoring disease progression and as a surrogate marker for treatment trials. The findings support the role of white matter damage and disruption of white matter connections in the pathogenesis of cognitive impairment in cerebral small vessel disease.
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homocysteine is a risk factor for cerebral small vessel disease acting via endothelial dysfunction
Brain, 2004Co-Authors: Ahamad Hassan, Michael Osullivan, J Bamford, Beverley J Hunt, Rachel Bell, Reuben Dsouza, Steve Jeffery, Hugh S. MarkusAbstract:Cerebral small vessel disease (SVD) causes focal lacunar infarction and more diffuse ischaemia, referred to as Leukoaraiosis. Endothelial dysfunction has been proposed as a causal mechanism in the disease. Homocysteine is toxic to endothelium. We determined whether elevated homocysteine levels and the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for SVD as a whole, and for two different SVD subtypes: isolated lacunar infarction and ischaemic Leukoaraiosis. We also determined whether any association was mediated by endothelial dysfunction, as assessed by circulating endothelial markers. One hundred and seventy‐two Caucasian patients with SVD and 172 community controls of similar age and sex were studied. Serum homocysteine measurement and MTHFR genotyping was performed. Levels of intercellular adhesion molecule 1 (ICAM1) and thrombomodulin were measured in a subgroup. Mean homocysteine levels were higher in SVD than controls [14.55 µmol/l [95% confidence interval (CI) 13.78–15.35] versus 12.01 µmol/l (95% CI 11.42–12.64), P < 0.0005]. Homocysteine was a stronger risk factor in those with ischaemic Leukoaraiosis [12.92 (95% CI 4.40–37.98), P < 0.0005) per µmol increase in log homocysteine concentration ( P < 0.0005)] in comparison with isolated lacunar infarction [4.22 (95% CI 1.29–13.73), P = 0.02] after controlling for both conventional risk factors and age. The MTHFR 677T allele was a risk factor only in the ischaemic Leukoaraiosis group [odds ratio (OR) 2.02 (95% CI 1.31–3.1), P = 0.001]. Inclusion of the endothelial markers ICAM1 and thrombomodulin in a logistic regression model resulted in the association between homocysteine and SVD no longer being significant. In conclusion, hyperhomocysteinaemia is an independent risk factor for SVD, particularly ischaemic Leukoaraiosis, and this effect may be mediated via endothelial dysfunction. Homocysteine‐lowering therapy may be particularly effective in this subgroup.
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markers of endothelial dysfunction in lacunar infarction and ischaemic Leukoaraiosis
Brain, 2003Co-Authors: Ahamad Hassan, Dennis Briley, Michael Osullivan, Beverley J Hunt, Kiran Parmar, John Bamford, Martin M Brown, Dafydd J Thomas, Hugh S. MarkusAbstract:Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of Leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood samples. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic Leukoaraiosis, defined as a clinical lacunar stroke and Leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of Leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P ≤ 0.006). The ischaemic Leukoaraiosis group had a different endothelial marker profile, with lower levels of TFPI (P = 0.01) and a higher TF/TFPI ratio (P = 0.01) compared with the isolated lacunar infarction group. TM levels were associated with the number of lacunes (P = 0.008) and the Leukoaraiosis score (P = 0.03), but TF levels and the TF/TFPI ratio were associated only with the extent of Leukoaraiosis (P ≤ 0.02). These results suggest that there is evidence of chronic endothelial dysfunction in cerebral SVD, and endothelial prothrombotic changes may be important in mediating the ischaemic Leukoaraiosis phenotype. Therapies which help to stabilize the endothelium may have a role in this group of patients.
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normal appearing white matter in ischemic Leukoaraiosis a diffusion tensor mri study
Neurology, 2001Co-Authors: Michael Osullivan, Jozef Jarosz, Paul Summers, Derek K Jones, Steven Williams, Hugh S. MarkusAbstract:Ischemic Leukoaraiosis is a consistent concomitant of vascular dementia. Conventional MRI provides little information about underlying white matter tract disruption and correlates poorly with cognitive dysfunction. Diffusion tensor MRI may provide better markers of tract integrity. Changes in the normal-appearing white matter were demonstrated in 30 patients with ischemic Leukoaraiosis compared with 17 age-matched control subjects. These changes correlated with executive dysfunction assessed by the Wisconsin Card Sorting Test.
Nils Henninger - One of the best experts on this subject based on the ideXlab platform.
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impact of Leukoaraiosis severity on the association of time to successful reperfusion with 90 day functional outcome after large vessel occlusion stroke
Translational Stroke Research, 2020Co-Authors: Abdul Ghani Mikati, Max Mandelbaum, Shweta Sapnar, Ajit S Puri, Brian Silver, Richard P Goddeau, Diogo C Haussen, Majaz Moonis, Adalia H Junoconnell, Nils HenningerAbstract:The chance for a favorable outcome after mechanical thrombectomy (MT) for large vessel occlusion stroke decreases with the symptom onset-to-reperfusion time (OTR). Patients with severe Leukoaraiosis are at increased risk for a poor outcome after MT. However, whether Leukoaraiosis modulates to the association between OTR and 90-day functional outcome is uncertain. We retrospectively analyzed 144 consecutive patients with successful (TICI ≥ 2b/3) MT for anterior circulation large vessel occlusion within 24 h form OTR between January 2012 to November 2016. Leukoaraiosis was dichotomized to absent-to-mild (van Swieten scale score 0–2) versus moderate-to-severe (3–4) as assessed on admission head CT. Multiple linear, logistic, and ordinal regression analyses were used to determine the association between Leukoaraiosis, OTR, and 90-day modified Rankin Scale (mRS) score, after adjustment for pertinent covariates. Leukoaraiosis was independently associated with the OTR on multivariable linear regression (p = 0.003). The association between OTR and 90-day outcome depended on the degree of pre-existing Leukoaraiosis burden as shown by a significant Leukoaraiosis-by-OTR interaction on multivariable logistic regression (OR 0.76, 95% CI 0.58–0.98, p = 0.037) and multivariable ordinal regression (OR 0.87, 95% CI 0.78–0.97, p = 0.011). Pre-existing Leukoaraiosis is associated with the 90-day functional outcome after successful reperfusion and impacts the association between the OTR and 90-day mRS among patients undergoing MT. Patients with high Leukoaraiosis burden need to present earlier than patients with low Leukoaraiosis burden for a similar favorable outcome. Pending confirmation, these results may have important implications for optimizing patient selection for acute stroke therapies.
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impact of Leukoaraiosis burden on hemispheric lateralization of the national institutes of health stroke scale deficit in acute ischemic stroke
Stroke, 2016Co-Authors: Johanna Helenius, Richard P Goddeau, Majaz Moonis, Nils HenningerAbstract:Background and Purpose— The National Institutes of Health Stroke Scale (NIHSS) awards higher deficit scores for infarcts in the dominant hemisphere when compared with otherwise similar infarcts in the nondominant hemisphere. This has been shown to adversely affect stroke recognition, therapeutic decisions, and outcome. However, factors modifying the association between infarct side and deficit severity are incompletely understood. Thus, we sought to determine whether age and age-related Leukoaraiosis alter the relation between NIHSS deficit score and the side and volume of infarction. Methods— We studied 238 patients with supratentorial, nonlacunar ischemic infarcts prospectively included in our stroke registry between January 2013 and January 2014. NIHSS deficit severity was assessed at the time of presentation. Infarct volumes were assessed by manual planimetry on diffusion-weighted imaging. Leukoaraiosis burden was graded on fluid-attenuated inversion recovery images according to the Fazekas scale and dichotomized to none-to-mild (0–2) versus severe (3–6). Multivariable linear regression with backward elimination was used to identify independent predictors of the admission NIHSS. Results— Left-hemispheric infarction ( P P =0.001), their interaction term ( P =0.005), infarct volume ( P P =0.013) were independently associated with the NIHSS deficit. Analysis of the individual NIHSS components showed that severe Leukoaraiosis was associated with an increase of the lateralizing components of the NIHSS in patients with right-hemispheric infarction ( P Conclusions— Severe Leukoaraiosis substantially attenuates the classic hemispheric lateralization of the NIHSS deficit by relating to greater NIHSS scores of components that are typically assigned to left hemisphere function.
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clinical impact of Leukoaraiosis burden and chronological age on neurological deficit recovery and 90 day outcome after minor ischemic stroke
Journal of the Neurological Sciences, 2015Co-Authors: Sanjeeva Onteddu, Richard P Goddeau, Artin Minaeian, Nils HenningerAbstract:Abstract Background and aims Ischemic stroke remains a leading cause of disability, particularly among the elderly, but this association has not been consistently noted among patients with minor stroke. We sought to determine the association of chronological age and Leukoaraiosis, which is considered a marker of biological age, with the degree of neurological deficit recovery and 90-day disability after minor ischemic stroke. Methods We retrospectively analyzed 185 patients with a minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 5). Leukoaraiosis severity was graded according to the van Swieten scale. NIHSS was assessed at baseline, discharge, and 90-days. Multivariable linear and ordinal logistic regression analyses were constructed to identify independent predictors of the degree of NIHSS-improvement (ΔNIHSS) and 90-day outcome as assessed by the modified Rankin Scale (mRS). Results Patients with severe Leukoaraiosis had attenuated ΔNIHSS at 90 days as compared to patients with none-to-mild Leukoaraiosis (p = 0.028). After adjustment, Leukoaraiosis severity (p Conclusion Leukoaraiosis is a more sensitive predictor for neurological deficit recovery after ischemic stroke than chronological age. Further study is required to establish the specific contribution of Leukoaraiosis to functional outcome after minor ischemic stroke beyond its impact on recovery mechanisms.
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Leukoaraiosis predicts a poor 90 day outcome after endovascular stroke therapy
American Journal of Neuroradiology, 2014Co-Authors: Jingyan Zhang, Ajit S Puri, Richard P Goddeau, Muhammad A Khan, Nils HenningerAbstract:BACKGROUND AND PURPOSE: Leukoaraiosis is a common finding among patients with ischemic stroke and has been associated with poor stroke outcomes. Our aim was to ascertain whether the severity of pre-existing Leukoaraiosis is associated with outcome in patients with acute ischemic stroke who are treated with endovascular stroke therapy. MATERIALS AND METHODS: We retrospectively analyzed data from 129 consecutive, prospectively enrolled patients with stroke undergoing endovascular stroke therapy at a single tertiary care center between January 2006 and August 2013. Leukoaraiosis was assessed as supratentorial white matter hypoattenuation on admission head CT and graded as 0–2 (absent-to-moderate) versus 3–4 (severe) according to the van Swieten scale. We dichotomized the 90-day mRS into good (0–2 or return to baseline) versus poor (3–6) as the primary study outcome. Incremental multivariable logistic regression analyses were performed to identify independent predictors of a poor 90-day outcome. RESULTS: In all multivariable models, severe Leukoaraiosis was independently ( P P = .004). The independent association between Leukoaraiosis and a poor outcome remained when the analysis was restricted to patients who were alive at discharge ( n = 87, P P = .034). CONCLUSIONS: The severity of pre-existing Leukoaraiosis is independently associated with 90-day functional outcome in patients with stroke who underwent endovascular stroke therapy. These results highlight the need to further explore Leukoaraiosis as a promising surrogate marker for poor outcome after endovascular stroke therapy to improve risk assessment, patient selection, and early prognostic accuracy.
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associations of radiographic cerebral small vessel disease with acute intracerebral hemorrhage volume hematoma expansion and intraventricular hemorrhage
Neurocritical Care, 2020Co-Authors: Simone Uniken M Venema, Sandro Marini, Bart H Brouwers, Andrea Morotti, Daniel Woo, Christopher D Anderson, Jonathan RosandAbstract:The aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH). CSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of Leukoaraiosis and cerebral atrophy using visual rating scales. The associations of Leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing. A total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0–25.3) mL. IVH was detected in 971 patients (38%). Neither Leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of Leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend < 0.001). Increasing grades of global atrophy were dose-dependently associated with lower ICH volumes (s (95% Confidence Interval [CI]) − 0.30[− 0.46, − 0.14], − 0.33[− 0.49, − 0.17], − 0.40[− 0.60, − 0.20], and − 0.54[− 0.76, − 0.32], for grades 1, 2, 3 and 4 compared to 0; all P < 0.001). The associations of Leukoaraiosis with ICH volume were consistent with those of atrophy, albeit not meeting statistical significance. Leukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while Leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.
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associations of radiographic cerebral small vessel disease with acute intracerebral hemorrhage volume hematoma expansion and intraventricular hemorrhage
Neurocritical Care, 2020Co-Authors: Simone Uniken M Venema, Sandro Marini, Bart H Brouwers, Andrea Morotti, Christopher D Anderson, Jonathan RosandAbstract:BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH). METHODS: CSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of Leukoaraiosis and cerebral atrophy using visual rating scales. The associations of Leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing. RESULTS: A total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0-25.3) mL. IVH was detected in 971 patients (38%). Neither Leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of Leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend < 0.001). Increasing grades of global atrophy were dose-dependently associated with lower ICH volumes (s (95% Confidence Interval [CI]) - 0.30[- 0.46, - 0.14], - 0.33[- 0.49, - 0.17], - 0.40[- 0.60, - 0.20], and - 0.54[- 0.76, - 0.32], for grades 1, 2, 3 and 4 compared to 0; all P < 0.001). The associations of Leukoaraiosis with ICH volume were consistent with those of atrophy, albeit not meeting statistical significance. CONCLUSIONS: Leukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while Leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.